Andrew M. Kaunitz, MD, NCMP

This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.

Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms

Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
 

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.

A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.

The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.^1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.^3-5

Key study findings

Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,^6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.⁸ Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.^6-9

The published phase 2 trials⁹ and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,^6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.^6,7

Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.¹⁰ Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.⁶ A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.⁶

Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.⁶ Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.⁶

Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.⁶

Continue to: Endometrial and bone safety...

Endometrial and bone safety

Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.⁸

Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).⁸ For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.⁸

In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.⁸

Liver safety

Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.⁸

The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.^11,12

Unmet need for nonhormone treatment of VMS

Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.² Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.^13-15

Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).¹⁶ Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.¹⁷ Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.¹⁵

Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.^18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.^19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.^19,21

Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.^19,21

Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.² In addition, many symptomatic menopausal women without health contraindications choose not to take HT.² Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.

Bottom line

A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.^2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.

One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.

Continue to: When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?...

Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.

The following case represents a common scenario for ObGyns.

CASE Patient with proliferative endometrial changes

A menopausal patient with a body mass index (BMI) > 30 kg/m² presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.

When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.

However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.²²

Endometrial changes and what they suggest

In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.

The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).²³

Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.²⁴

For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.

In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.²⁵ These women had a mean BMI of 34 kg/m². During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.²⁵

Progestin treatment

Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.

We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.²⁶

Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.²⁷ Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.²² In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.²⁸

Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.²²

Role of ultrasonography

Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.²⁹ In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.²⁹

Assessing risk

If proliferative endometrium is found, Abraham suggests assessing risk using²²:

• age
• comorbidities (including obesity)
• endometrial echo thickness on vaginal ultrasonography.

Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.

Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.³⁰ Accordingly, synthetic progestins represent first-line options in this setting^.

In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.²² ●

This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.

Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms

Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
 

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.

A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.

The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.^1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.^3-5

Key study findings

Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,^6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.⁸ Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.^6-9

The published phase 2 trials⁹ and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,^6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.^6,7

Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.¹⁰ Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.⁶ A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.⁶

Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.⁶ Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.⁶

Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.⁶

Continue to: Endometrial and bone safety...

Endometrial and bone safety

Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.⁸

Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).⁸ For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.⁸

In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.⁸

Liver safety

Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.⁸

The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.^11,12

Unmet need for nonhormone treatment of VMS

Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.² Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.^13-15

Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).¹⁶ Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.¹⁷ Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.¹⁵

Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.^18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.^19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.^19,21

Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.^19,21

Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.² In addition, many symptomatic menopausal women without health contraindications choose not to take HT.² Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.

Bottom line

A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.^2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.

One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.

Continue to: When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?...

Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.

The following case represents a common scenario for ObGyns.

CASE Patient with proliferative endometrial changes

A menopausal patient with a body mass index (BMI) > 30 kg/m² presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.

When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.

However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.²²

Endometrial changes and what they suggest

In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.

The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).²³

Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.²⁴

For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.

In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.²⁵ These women had a mean BMI of 34 kg/m². During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.²⁵

Progestin treatment

Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.

We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.²⁶

Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.²⁷ Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.²² In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.²⁸

Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.²²

Role of ultrasonography

Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.²⁹ In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.²⁹

Assessing risk

If proliferative endometrium is found, Abraham suggests assessing risk using²²:

• age
• comorbidities (including obesity)
• endometrial echo thickness on vaginal ultrasonography.

Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.

Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.³⁰ Accordingly, synthetic progestins represent first-line options in this setting^.

In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.²² ●

This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.

Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms

Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
 

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.

A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.

The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.^1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.^3-5

Key study findings

Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,^6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.⁸ Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.^6-9

The published phase 2 trials⁹ and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,^6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.^6,7

Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.¹⁰ Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.⁶ A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.⁶

Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.⁶ Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.⁶

Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.⁶

Continue to: Endometrial and bone safety...

Endometrial and bone safety

Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.⁸

Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).⁸ For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.⁸

In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.⁸

Liver safety

Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.⁸

The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.^11,12

Unmet need for nonhormone treatment of VMS

Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.² Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.^13-15

Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).¹⁶ Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.¹⁷ Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.¹⁵

Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.^18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.^19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.^19,21

Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.^19,21

Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.² In addition, many symptomatic menopausal women without health contraindications choose not to take HT.² Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.

Bottom line

A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.^2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.

One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.

Continue to: When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?...

Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.

The following case represents a common scenario for ObGyns.

CASE Patient with proliferative endometrial changes

A menopausal patient with a body mass index (BMI) > 30 kg/m² presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.

When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.

However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.²²

Endometrial changes and what they suggest

In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.

The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).²³

Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.²⁴

For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.

In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.²⁵ These women had a mean BMI of 34 kg/m². During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.²⁵

Progestin treatment

Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.

We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.²⁶

Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.²⁷ Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.²² In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.²⁸

Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.²²

Role of ultrasonography

Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.²⁹ In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.²⁹

Assessing risk

If proliferative endometrium is found, Abraham suggests assessing risk using²²:

• age
• comorbidities (including obesity)
• endometrial echo thickness on vaginal ultrasonography.

Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.

Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.³⁰ Accordingly, synthetic progestins represent first-line options in this setting^.

In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.²² ●

Illustration: Kimberly Martens for OBG Management

Intrauterine devices (IUDs) are now used by more than 15% of US contraceptors. The majority of these IUDs release the progestin levonorgestrel, and with now longer extended use of the IUDs approved by the US Food and Drug Administration (FDA),^1-3 they become even more attractive for use for contraception,control of menorrhagia or heavy menstrual bleeding (HMB) during reproductive years and perimenopause, and potentially, although not FDA approved for this purpose, postmenopause for endometrial protection in estrogen users. In this roundtable discussion, we will look at some of the benefits of the IUD for contraception effectiveness and control of bleeding, as well as the potential risks if used for postmenopausal women.

Progestin IUDs and contraception

JoAnn V. Pinkerton, MD, NCMP: Dr. Kaunitz, what are the contraceptive benefits of progestin IUDs during perimenopause?
 

Andrew M. Kaunitz, MD, NCMP: We know fertility declines as women approach menopause. However, when pregnancy occurs in older reproductive-age women, the pregnancies are often unintended, as reflected by high rates of induced abortion in this population. In addition, the prevalence of maternal comorbidities (during pregnancy and delivery) is higher in older reproductive-age women, with the maternal mortality rate more than 5 times higher compared with that of younger women.⁴ Two recently published clinical trials assessed the extended use of full-size IUDs containing 52 mg of levonor-gestrel (LNG), with the brand names Mirena and Liletta.^1,2 The data from these trials confirmed that both IUDs remain highly effective for up to 8 years of use, and currently, both devices are approved for up to 8 years of use. One caveat is that, in the unusual occurrence of a pregnancy being diagnosed in a woman using an IUD, we as clinicians, must be alert to the high prevalence of ectopic pregnancies in this setting.

Progestin IUDs and HMB

Dr. Pinkerton: Dr. Goldstein, can you comment on how well progestin IUDs work for HMB?

Steven R. Goldstein, MD, NCMP, CCD: Many women who need contraception will use these devices for suppressing HMB, and they can be quite effective, if the diagnosis truly is HMB, at reducing bleeding.⁵ But that efficacy in bleeding reduction may not be quite as long as the efficacy in pregnancy prevention.⁶ In my experience, among women using IUDs specifically for their HMB, good bleeding control may require changing the IUD at 3 to 5 years.

Barbara S. Levy, MD: When inserting a LNG-IUD for menorrhagia in the perimenopausal time frame, sometimes I will do a progestin withdrawal first, which will thin the endometrium and induce withdrawal bleeding because, in my experience, if you place an IUD in someone with perimenopausal bleeding, you may end up with a lot of breakthrough bleeding.

Perimenopause and hot flashes

Dr. Pinkerton: Dr. Kaunitz, we have learned that hot flashes often occur and become bothersome to women during perimenopause. Many women have IUDs placed during perimenopause for bleeding. Can you comment about IUD use during perimenopause and postmenopause?
 

Dr. Kaunitz: In older reproductive-age women who already have a progestin-releasing IUD placed, as they get closer to menopause when vasomotor symptoms (VMS) might occur, if these symptoms are bothersome, the presence or placement of a progestin-releasing IUD can facilitate treatment of perimenopausal VMS with estrogen therapy.

Progestin IUDs cause profound endometrial suppression, reduce bleeding and often, over time, cause users to become amenorrheic.⁷

The Mirena package insert states, “Amenorrhea develops in about 20% of users by one year.”² By year 3 and continuing through year 8, the prevalence of amenorrhea with the 52-mg LNG-IUD is 35% to 40%.⁸ From a study by Nanette Santoro, MD, and colleagues, we know that, in perimenopausal women with a progestin-releasing IUD in place, who are experiencing bothersome VMS, adding transdermal estrogen is very effective in treating and suppressing those hot flashes. In her small clinical trial, among participants with perimenopausal bothersome VMS with an IUD in place, half were randomized to use of transdermal estradiol and then compared with women who did not get the estradiol patch. There was excellent relief of perimenopausal hot flashes with the combination of the progestin IUD for endometrial suppression and transdermal estrogen to relieve hot flashes.⁹

Dr. Pinkerton: Which women would not be good candidates for the use of this combination?

Dr. Kaunitz: We know that, as women age, the prevalence of conditions that are contraindications to combination contraceptives (estrogen-progestin pills, patches, or rings) starts to increase. Specifically, we see more: hypertension, diabetes, and high body mass index (BMI), or obesity. We also know that migraine headaches in women older than age 35 years is another condition in which ACOG and the Centers for Disease Control and Prevention (CDC) would not recommend use of combination contraceptives.^10,11 These older perimenopausal women may be excellent candidates for a progestin-only releasing IUD combined with use of transdermal menopausal doses of estradiol if needed for VMS.

Dr. Goldstein: I do want to add that, in those patients who don’t have these comorbidities, combination estrogen-progestin contraceptives do a very nice job of ovarian suppression and will prevent the erratic production of estradiol, which, in my experience, often results in not only irregular bleeding but also possible exacerbation of perimenopausal mood symptoms.

Dr. Kaunitz: I agree, Steve. The ideal older reproductive-age candidate for combination pills, patch, or ring would be a slender, healthy, nonsmoking woman with normal blood pressure. Such women would be a fairly small subgroup of my practice, but they can safely continue combination contraceptives right through menopause. Consistent with CDC and ACOG guidance, rather than checking gonadotropins to “determine when menopause has occurred,” (which is, in fact, not an evidence-based approach to diagnosing menopause in this setting), such women can continue the combination contraceptive right up until age 55—the likelihood that women are still going to be ovulating or at risk for pregnancy becomes vanishingly small at that age.^11,12 Women in their mid-50s can either seamlessly transition to use of systemic estrogen-progestin menopausal therapy or go off hormones completely.

Continue to: The IUD and HMB...

The IUD and HMB

Dr. Pinkerton: Dr. Goldstein, there’s been some good literature on the best management options for women with HMB. What is the most current evidence?

Dr. Goldstein: I think that the retiring of the terms menorrhagia and metrorrhagia may have been premature because HMB implies cyclical bleeding, and this population of women with HMB will typically do quite well. Women who have what we used to call metrorrhagia or irregular bleeding, by definition, need endometrial evaluation to be sure they don’t have some sort of organic pathology. It would be a mistake for clinicians to use an LNG-IUD in patients with abnormal uterine bleeding (AUB) that has not been appropriately evaluated.

If we understand that we are discussing HMB, a Cochrane Review from 2022¹³ suggests that an LNG intrauterine system is the best first-line treatment for reducing menstrual blood loss in perimenopausal women with HMB. Antifibrinolytics appeared second best, while long-cycle progestogens came in third place. Evidence on perception of improvement in satisfaction was ranked as low certainty. That same review found that hysterectomy was the best treatment for reducing bleeding, obviously, followed by resectoscopic endometrial ablation or a nonresectoscopic global endometrial ablation.

The evidence rating was low certainty regarding the likelihood that placing an LNG-IUD in women with HMB will result in amenorrhea, and I think that’s a very important point. The expectation of patients should be reduced or a significantly reduced amount of their HMB, not necessarily amenorrhea. Certainly, minimally invasive hysterectomy will result in total amenorrhea and may have a larger increase in satisfaction, but it has its own set of other kinds of possible complications.

Dr. Kaunitz: In an industry-funded, international multicenter trial,¹⁴ women with documented HMB (hemoglobin was eluted from soiled sanitary products), with menstrual blood loss of 80 mL or more per cycle, were randomized to placement of an LNG 52-mg IUD (Mirena) or cyclical medroxyprogesterone acetate (MPA)—oral progestin use.

Although menstrual blood loss declined in both groups, it declined dramatically more in women with an IUD placed, and specifically with the IUD, menstrual blood loss declined by 129 mL on average, whereas the decline in menstrual blood loss with cyclical MPA was 18 mL. This data, along with earlier European data,¹⁵ which showed similar findings in women with HMB led to the approval of the Mirena progestin IUD for a second indication to treat HMB in 2009.

I also want to point out that, in the May 2023 issue of Obstetrics & Gynecology, Creinin and colleagues published a similar trial in women with HMB showing, once again, that progestin IUDs (52-mg LNG-IUD, Liletta) are extremely effective in reducing HMB.¹⁶ There is crystal clear evidence from randomized trials that both 52-mg LNG-IUDs, Mirena and Liletta, are very effective in reducing HMB and, in fact, are contributing to many women who in the past would have proceeded with surgery, such as ablation or hysterectomy, to control their HMB.

Oral contraception

Dr. Pinkerton: What about using low-dose continuous oral contraceptives noncyclically for women with HMB?

Dr. Goldstein: I do that all the time. It is interesting that Dr. Kaunitz mentions his patient population. It’s why we understand that one size does not fit all. You need to see patients one at a time, and if they are good candidates for a combined estrogen-progestin contraception, whether it’s pills, patches, or rings, giving that continuously does a very nice job in reducing HMB and straightening out some of the other symptoms that these perimenopausal women will have.

IUD risks

Dr. Pinkerton: We all know about use of low-dose oral contraceptives for management of AUB, and we use them, although we worry a little bit about breast cancer risk. Dr. Levy, please comment on the risks with IUDs of expulsions and perforations. What are the downsides of IUDs?

Dr. Levy: Beyond the cost, although it is a minimally invasive procedure, IUD insertion can be an invasive procedure for a patient to undergo; expulsions can occur.¹⁷ We know that a substantial percentage of perimenopausal women will have fibroids. Although many fibroids are not located in the uterine cavity, the expulsion rate with HMB for an LNG-IUD can be higher,^13,16,18,19 perhaps because of local prostaglandin release with an increase in uterine contractility. There is a low incidence of perforations, but they do happen, particularly among women with scars in the uterus or who have a severely anteflexed or retroflexed uterus, and women with cervical stenosis, for example, if they have had a LEEP procedure, etc. Even though progestin IUDs are outstanding tools in our toolbox, they are invasive to some extent, and they do have the possibility of complications.

Dr. Kaunitz: As Dr. Levy points out, although placement of an IUD may be considered an invasive procedure, it is also an office-based procedure, so women can drive home or drive back to work afterwards without the disruption in their life and the potential complications associated with surgery and anesthesia.

Continue to: Concerns with malpositioning...

Dr. Pinkerton: After placement of an IUD, during a follow-up visit, sometimes you can’t visualize the string. The ultrasonography report may reveal, “IUD appears to be in the right place within the endometrium.” Dr. Goldstein, can you comment on how we should use ultrasound when we can’t visualize or find the IUD string, or if the patient complains of abdominal pain, lower abdominal discomfort, or irregular bleeding or spotting and we become concerned about IUD malposition?

Dr. Goldstein: Ultrasound is not really required after an uncomplicated placement of an IUD or during routine management of women who have no problems who are using an IUD. In patients who present with pain or some abnormal bleeding, however, sometimes it is the IUD being malpositioned. A very interesting study by the late great Beryl Benacerraf²⁰ showed that there was a statistically significant higher incidence of the IUD being poorly positioned when patients have pain or bleeding (FIGURE 1). It was not always apparent on 2D ultrasonography. Using a standard transvaginal ultrasound of the long access plane, the IUD may appear to be very centrally located. However, if you do a 3D coronal section, not infrequently in these patients with any pain or bleeding, one of the arms has pierced the myometrium (FIGURE 2). This can actually be a source of pain and bleeding.

It’s also very interesting when you talk about perforation. I became aware of a big to-do in the medical/legal world about the possibility of the IUD migrating through the uterine cavity.²¹ This just does not exist, as was already pointed out. If the IUD is really going to go anywhere, if it’s properly placed, it’s going to be expelled through an open cervix. I do believe that, if you have pierced the myometrium through uterine contractility over time, some of these IUDs could work their way through the myometrium and somehow come out of the uterus either totally or partially. I think ultrasound is invaluable in patients with pain and bleeding, but I think you need to have an ultrasound lab capable of doing a 3D coronal section.

Progestin IUDs for HT replacement: Benefits/risks

Dr. Pinkerton: Many clinicians are excited that they can use essentially estrogen alone for women who have a progestin IUD in place. What about the possible off-label use of the progestin IUD to replace oral progestogen for hormone therapy (HT)? Dr. Kaunitz, are there any studies using this for postmenopausal HT (with a reminder that the IUD is not FDA approved for this purpose)?

Dr. Kaunitz: We have data from Europe indicating that, in menopausal women using systemic estrogen, the full-size LNG 52 IUD—Mirena or Liletta—provides excellent endometrial suppression.²² Where we don’t have data is with the smaller IUDs, which would be Kyleena and Skyla, which release smaller amounts of progestin each day into the endometrial cavity.

I have a number of patients, most of them women who started use of a progestin IUD as older reproductive-age women and then started systemic estrogen for treatment of perimenopausal hot flashes and then continued the use of their IUD plus systemic estrogen in treating postmenopausal hot flashes. The IUD is very useful in this setting, but as you pointed out, Dr. Pinkerton, this does represent off-label use.

Dr. Pinkerton: I know this use does not affect plasma lipids or cardiovascular risk markers, although users seem to report that the IUD has improved their quality of life. The question comes up, what are the benefits on cancer risk for using an IUD?

Dr. Levy: It’s such a great question because, as we talk about the balance of risks and benefits for anything that we are offering to our patients, it is really important to focus on some of the benefits. For both the copper and the LNG-IUD, there is a reduction in endometrial cancer,²² as well as pretty good data with the copper IUD about a reduction in cervical cancer.²³ Those data are a little bit less clear for the LNG-IUD.

Interestingly, at least one meta-analysis published in 2020 shows about a 30% reduction in ovarian cancer risk with the LNG-IUD.²⁴ We need to focus our patients on these other benefits. They tend to focus on the risks, and, of course, the media blows up the risks, but the benefits are quite substantial beyond just reducing HMB and providing contraception.

Dr. Pinkerton: As Dr. Kaunitz said, when you use this IUD, with its primarily local uterine progestin effects, it’s more like using estrogen alone without as much systemic progestin. Recently I wrote an editorial on the benefits of estrogen alone on the risk of breast cancer, primarily based on the Women’s Health Initiative (WHI) observational long-term 18-year cumulative follow-up. When estrogen alone was prescribed to women after a hysterectomy, estrogen therapy used at menopause did not increase the risk of invasive breast cancer, and was associated with decreased mortality.²⁵ However, the nurse’s health study has suggested that longer-term use may be increased with estrogen alone.²⁶ For women in the WHI with an intact uterus who used estrogen, oral MPA slightly increased the risk for breast cancer, and this elevated risk persisted even after discontinuation. This leads us to the question, what are the risks of breast cancer with progestin IUD use?

I recently reviewed the literature, and the answer is, it’s mixed. The FDA has put language into the package label that acknowledges a potential breast cancer risk for women who use a progestin IUD,²⁷ and that warning states, “Women who currently have or have had breast cancer or suspect breast cancer should not use hormonal contraception because some breast cancers are hormone sensitive.” The label goes on to say, “Observational studies of the risk of breast cancer with the use of a levonorgestrel-releasing IUS don’t provide conclusive evidence of increased risk.” Thus, there is no conclusive answer as to whether there is a possible link of progestin IUDs to breast cancer.

What I tell my patients is that research is inconclusive. However, it’s unlikely for a 52-mg LNG-IUD to significantly increase a woman’s breast cancer risk, except possibly in those already at high risk from other risk factors. I tell them that breast cancer is listed in the package insert as a potential risk. I could not find any data on whether adding a low-dose estradiol patch would further increase that risk. So I counsel women about potential risk, but tell them that I don’t have any strong evidence of risk.

Continue to: Dr. Goldstein...

Dr. Goldstein: If you look in the package insert for Mirena,² similar to Liletta, certainly the serum levels of LNG are lower than that for combination oral contraceptives. For the IUD progestins, they are not localized only to the uterus, and LNG levels range from about 150 to 200 µg/mL up to 60 months. It’s greater at 12 months, at about 180 µg/mL,at 24 months it was 192 µg/mL, and by 60 months it was 159 µg/mL. It’s important to realize that there is some systemic absorption of progestin with progestin IUDs, and it is not completely a local effect.

JoAnn, you mentioned the WHI data,²⁵ and just to specify, it was not the estrogen-only arm, it was the conjugated equine estrogen-only arm of the WHI. I don’t think that estradiol alone increases breast cancer risk (although there are no good prospective, follow-through, 18-year study data, like the WHI), but I think readers need to understand the difference in the estrogen type.

Endometrial evaluation. My question for the panel is as follows. I agree that the use of the progestin-releasing IUD is very nice for that transition to menopause. I do believe it provides endometrial protection, but we know from other studies that, when we give continuous combined HT, about 21% to 26% of patients will experience some bleeding/staining, responding in the first 4-week cycles, and it can be as high as 9% at 1 year. If I have a patient who bleeds on continuous combined HT, I will evaluate her endometrium, usually just with a simple transvaginal ultrasound. If an IUD is in place, and the patient now begins to have some irregular bleeding, how do you evaluate her with the IUD in place?

Dr. Levy: That is a huge challenge. We know from a recent paper,²⁸ that the endometrial thickness, while an excellent measure for Caucasian and European women, may be a poor marker for endometrial pathology in African-American women. What we thought we knew, which was, if the stripe is 4 mL or less, we can forget about it, I think in our more recent research that is not so true. So you bring up a great point, what do you do? The most reliable evaluation will be with an office hysteroscopy, where you can really look at the entire cavity and for tiny, little polyps and other things. But then we are off label because the use of hysteroscopy with an IUD in place is off label. So we are really in a conundrum.

Dr. Pinkerton: Also, if you do an endometrial biopsy, you might dislodge the IUD. If you think that you are going to take the IUD out, it may not matter if you dislodge it. I will often obtain a transvaginal ultrasound to help me figure out the next step, and maybe look at the dosing of the estrogen and progestin—but you can’t monitor an IUD with blood levels. You are in a vacuum of trying to figure out the best thing to do.

Dr. Kaunitz: One of the hats I wear here in Jacksonville is Director of GYN Ultrasound. I have a fair amount of experience doing endometrial biopsies in women with progestin IUDs in place under abdominal ultrasound guidance and keeping a close eye on the position of the IUD. In the first dozen or so such procedures I did, I was quite concerned about dislodging the IUD. It hasn’t happened yet, and it gives me some reassurance to be able to image the IUD and your endometrial suction curette inside the cavity as you are obtaining endometrial sampling. I have substantial experience now doing that, and so far, no problems. I do counsel all such women in advance that there is some chance I could dislodge their IUD.

Dr. Goldstein: In addition to dislodging the IUD, are you not concerned that, if the pathology is not global, that a blind endometrial sampling may be fraught with some error?

Dr. Kaunitz: The endometrium in women with a progestin-releasing IUD in place tends to be very well suppressed. Although one might occasionally find, for instance, a polyp in that setting, I have not run into, and I don’t expect to encounter going forward, endometrial hyperplasia or cancer in women with current use of a progestin IUD. It’s possible but unlikely.

Dr. Levy: The progestin IUD will counterbalance a type-1 endometrial cancer—an endometrial cancer related to hyperstimulation by estrogen. It will not do anything, to my knowledge, to counterbalance a type 2. I think the art of medicine is, you do the best you can with the first episode of bleeding, and if she persists in her bleeding, we have to persevere and continue to evaluate her.

Dr. Goldstein: I agree 100%.

Dr. Pinkerton: We all agree with you. That’s a really good point.

Continue to: Case examinations...

Case examinations

CASE 1 Woman with intramural fibroids

Dr. Pinkerton: Dr. Goldstein, you have a 48-year-old Black woman who has heavy but regular menstrual bleeding with multiple fibroids (the largest is about 4 to 5 cm, they look intramural, with some distortion of the cavity but not a submucous myoma, and the endometrial depth is 9 cm). Would you insert an IUD, and would you recommend an endometrial biopsy first?

Dr. Goldstein: I am not a huge fan of blind endometrial sampling, and I do think that we use the “biopsy” somewhat inappropriately since sampling is not a directed biopsy. This became obvious in the landmark paper by Guido et al in 1995 and was adopted by ACOG only in 2012.²⁹ Cancers that occupy less than 50% of the endometrial surface area are often missed with such blind sampling. Thus I would not perform an endometrial biopsy first, but would rather rely on properly timed and performed transvaginal ultrasound to rule out any concurrent endometrial disease. I think a lot of patients who have HMB, not only because of their fibroids but also often just due to the surface area of their uterine cavity being increased—so essentially there is more blood volume when they bleed. However, you said that in this case the patient has regular menstrual bleeding, so I am assuming that she is still ovulatory. She may have some adenomyosis. She may have a large uterine cavity. I think she is an excellent candidate for an LNG-releasing IUD to reduce menstrual blood flow significantly. It will not necessarily give her amenorrhea, and it may give her some irregular bleeding. Then at some distant point, say in 5 or 6 months if she does have some irregular staining or bleeding, I would feel much better about the fact that nothing has developed as long as I knew that the endometrium was devoid of pathology when I started.

CASE 2 Woman with family history of breast cancer

Dr. Pinkerton: Dr. Levy, a 44-year-old woman has a family history of breast cancer in her mother at age 72, but she still needs contraceptionbecause of that unintended pregnancy risk in the 40s, and she wants something that is not going to increase her risk of breast cancer. What would you use, and how would you counsel her if you decided to use a progestin IUD?

Dr. Levy: The data are mixed,^30-33 but whatever the risk, it is miniscule, and I would bring up the CDC Medical Eligibility Criteria.¹¹ For a patient with a family history of breast cancer, for use of the progestin IUD, it is a 1—no contraindications. What I tend to tell my patients is, if you are worried about breast cancer, watch how much alcohol you are drinking and maintain regular exercise. There are so many preventive things that we can do to reduce risk of breast cancer when she needs contraception. If there is any increase in risk, it is so miniscule that I would very strongly recommend a progestin IUD for her.

Dr. Pinkerton: In addition, in recognizing the different densities of breast, dense breast density could lead to supplemental screening, which also could give her some reassurance that we are adequately screening for breast cancer.

CASE 3 Woman with IUD and VMS
 

Dr. Pinkerton: Dr. Kaunitz, you have a 52-year-old overweight female. She has been using a progestin IUD for 4 years, is amenorrheic, but now she is having moderate to severe vasomotor symptoms despite the IUD in place. You have talked to her about risks and benefits of HT, and she is interested in starting it. I know we talked about the studies, but I want to know what you are going to tell her. How do you counsel her about off-label use?

Dr. Kaunitz: The most important issue related to treating vasomotor symptoms in this patient is the route of systemic estrogen. Understandably, women’s biggest concern regarding the risks of systemic estrogen-progestin therapy is breast cancer. However, statistically, by far the biggest risk associated with oral estrogen-progestogen therapy, is elevated risk of venous thrombosis and pulmonary embolism. We have seen this, with a number of studies, and the WHI made it crystal clear with risks of oral conjugated equine estrogen at the dose of 0.625 mg daily. Oral estradiol 1 mg daily is also associated with a similar elevated risk of venous thrombosis. We also know that age and BMI are both independent risk factors for thrombosis. So, for a woman in her 50s who has a BMI > 30 mg/kg², I don’t want to further elevate her risk of thrombosis by giving her oral estrogen, whether it is estradiol or conjugated equine estrogen. This is a patient in whom I would be comfortable using transdermal (patch) estradiol, perhaps starting with a standard dose of 0.05 mg weekly or twice weekly patch, keeping in mind that 0.05 mg in the setting of transdermal estrogen refer to the daily or to the 24-hour release rate. The 1.0 mg of oral estradiol and 0.625 mg of conjugated equine estrogen refers to the mg quantity of estrogen in each tablet. This is a source of great confusion for clinicians.

If, during follow-up, the 0.05 mg estradiol patch is not sufficient to substantially reduce symptoms, we could go up, for instance, to a 0.075 mg estradiol patch. We know very clearly from a variety of observational studies, including a very large UK study,³⁴ that in contrast with oral estrogen, transdermal estradiol is safer from the perspective of thrombosis.

Insurance coverage for IUDs

Dr. Pinkerton: Dr. Levy: Can you discuss IUDs and the Affordable Care Act’s requirement to cover contraceptive services?

Dr. Levy: Unfortunately, we do not know whether this benefit will continue based on a very recent finding from a judge in Texas that ruled the preventive benefits of the ACA were illegal.³⁵ We don’t know what will happen going forward. What I will say is that, unfortunately, many insurance companies have not preserved the meaning of “cover all things,” so what we are finding is that, for example, they only have to cover one type in a class. The FDA defined 18 classes of contraceptives, and a hormonal IUD is one class, so they can decide that they are only going to cover one of the four IUDS. And then women don’t have access to the other three, some of which might be more appropriate for them than another.

The other thing very relevant to this conversation is that, if you use an ICD-10 code for menorrhagia, for HMB, it no longer lives within that ACA preventive care requirement of coverage for contraceptives, and now she is going to owe a big deductible or a copay. If you are practicing in an institution that does not allow the use of IUDs for contraception, like a Catholic institution where I used to practice, you will want to use that ICD-10 code for HMB. But if you want it offered with no out-of-pocket cost for the patient, you need to use the preventive medicine codes and the contraception code. These little nuances for us can make a huge difference for our patients.

Dr. Pinkerton: Thank you for that reminder. I want to thank our panelists, Dr. Levy, Dr. Goldstein, and Dr. Kaunitz, for providing us with such a great mix of evidence and expert opinion and also giving a benefit of their vast experience as award-winning gynecologists. Hopefully, today you have learned the benefits of the progestin IUD not only for contraception in reproductive years and perimenopause but also for treatment of HMB, and the potential benefit due to the more prolonged effectiveness of the IUDs for endometrial protection in postmenopause. This allows less progestin risk, essentially estrogen alone for postmenopausal HT. Unsolved questions remain about whether there is a risk of breast cancer with their use, but there is a clear benefit of protecting against pregnancy and endometrial cancer. ●

Illustration: Kimberly Martens for OBG Management

Intrauterine devices (IUDs) are now used by more than 15% of US contraceptors. The majority of these IUDs release the progestin levonorgestrel, and with now longer extended use of the IUDs approved by the US Food and Drug Administration (FDA),^1-3 they become even more attractive for use for contraception,control of menorrhagia or heavy menstrual bleeding (HMB) during reproductive years and perimenopause, and potentially, although not FDA approved for this purpose, postmenopause for endometrial protection in estrogen users. In this roundtable discussion, we will look at some of the benefits of the IUD for contraception effectiveness and control of bleeding, as well as the potential risks if used for postmenopausal women.

Progestin IUDs and contraception

JoAnn V. Pinkerton, MD, NCMP: Dr. Kaunitz, what are the contraceptive benefits of progestin IUDs during perimenopause?
 

Andrew M. Kaunitz, MD, NCMP: We know fertility declines as women approach menopause. However, when pregnancy occurs in older reproductive-age women, the pregnancies are often unintended, as reflected by high rates of induced abortion in this population. In addition, the prevalence of maternal comorbidities (during pregnancy and delivery) is higher in older reproductive-age women, with the maternal mortality rate more than 5 times higher compared with that of younger women.⁴ Two recently published clinical trials assessed the extended use of full-size IUDs containing 52 mg of levonor-gestrel (LNG), with the brand names Mirena and Liletta.^1,2 The data from these trials confirmed that both IUDs remain highly effective for up to 8 years of use, and currently, both devices are approved for up to 8 years of use. One caveat is that, in the unusual occurrence of a pregnancy being diagnosed in a woman using an IUD, we as clinicians, must be alert to the high prevalence of ectopic pregnancies in this setting.

Progestin IUDs and HMB

Dr. Pinkerton: Dr. Goldstein, can you comment on how well progestin IUDs work for HMB?

Steven R. Goldstein, MD, NCMP, CCD: Many women who need contraception will use these devices for suppressing HMB, and they can be quite effective, if the diagnosis truly is HMB, at reducing bleeding.⁵ But that efficacy in bleeding reduction may not be quite as long as the efficacy in pregnancy prevention.⁶ In my experience, among women using IUDs specifically for their HMB, good bleeding control may require changing the IUD at 3 to 5 years.

Barbara S. Levy, MD: When inserting a LNG-IUD for menorrhagia in the perimenopausal time frame, sometimes I will do a progestin withdrawal first, which will thin the endometrium and induce withdrawal bleeding because, in my experience, if you place an IUD in someone with perimenopausal bleeding, you may end up with a lot of breakthrough bleeding.

Perimenopause and hot flashes

Dr. Pinkerton: Dr. Kaunitz, we have learned that hot flashes often occur and become bothersome to women during perimenopause. Many women have IUDs placed during perimenopause for bleeding. Can you comment about IUD use during perimenopause and postmenopause?
 

Dr. Kaunitz: In older reproductive-age women who already have a progestin-releasing IUD placed, as they get closer to menopause when vasomotor symptoms (VMS) might occur, if these symptoms are bothersome, the presence or placement of a progestin-releasing IUD can facilitate treatment of perimenopausal VMS with estrogen therapy.

Progestin IUDs cause profound endometrial suppression, reduce bleeding and often, over time, cause users to become amenorrheic.⁷

The Mirena package insert states, “Amenorrhea develops in about 20% of users by one year.”² By year 3 and continuing through year 8, the prevalence of amenorrhea with the 52-mg LNG-IUD is 35% to 40%.⁸ From a study by Nanette Santoro, MD, and colleagues, we know that, in perimenopausal women with a progestin-releasing IUD in place, who are experiencing bothersome VMS, adding transdermal estrogen is very effective in treating and suppressing those hot flashes. In her small clinical trial, among participants with perimenopausal bothersome VMS with an IUD in place, half were randomized to use of transdermal estradiol and then compared with women who did not get the estradiol patch. There was excellent relief of perimenopausal hot flashes with the combination of the progestin IUD for endometrial suppression and transdermal estrogen to relieve hot flashes.⁹

Dr. Pinkerton: Which women would not be good candidates for the use of this combination?

Dr. Kaunitz: We know that, as women age, the prevalence of conditions that are contraindications to combination contraceptives (estrogen-progestin pills, patches, or rings) starts to increase. Specifically, we see more: hypertension, diabetes, and high body mass index (BMI), or obesity. We also know that migraine headaches in women older than age 35 years is another condition in which ACOG and the Centers for Disease Control and Prevention (CDC) would not recommend use of combination contraceptives.^10,11 These older perimenopausal women may be excellent candidates for a progestin-only releasing IUD combined with use of transdermal menopausal doses of estradiol if needed for VMS.

Dr. Goldstein: I do want to add that, in those patients who don’t have these comorbidities, combination estrogen-progestin contraceptives do a very nice job of ovarian suppression and will prevent the erratic production of estradiol, which, in my experience, often results in not only irregular bleeding but also possible exacerbation of perimenopausal mood symptoms.

Dr. Kaunitz: I agree, Steve. The ideal older reproductive-age candidate for combination pills, patch, or ring would be a slender, healthy, nonsmoking woman with normal blood pressure. Such women would be a fairly small subgroup of my practice, but they can safely continue combination contraceptives right through menopause. Consistent with CDC and ACOG guidance, rather than checking gonadotropins to “determine when menopause has occurred,” (which is, in fact, not an evidence-based approach to diagnosing menopause in this setting), such women can continue the combination contraceptive right up until age 55—the likelihood that women are still going to be ovulating or at risk for pregnancy becomes vanishingly small at that age.^11,12 Women in their mid-50s can either seamlessly transition to use of systemic estrogen-progestin menopausal therapy or go off hormones completely.

Continue to: The IUD and HMB...

The IUD and HMB

Dr. Pinkerton: Dr. Goldstein, there’s been some good literature on the best management options for women with HMB. What is the most current evidence?

Dr. Goldstein: I think that the retiring of the terms menorrhagia and metrorrhagia may have been premature because HMB implies cyclical bleeding, and this population of women with HMB will typically do quite well. Women who have what we used to call metrorrhagia or irregular bleeding, by definition, need endometrial evaluation to be sure they don’t have some sort of organic pathology. It would be a mistake for clinicians to use an LNG-IUD in patients with abnormal uterine bleeding (AUB) that has not been appropriately evaluated.

If we understand that we are discussing HMB, a Cochrane Review from 2022¹³ suggests that an LNG intrauterine system is the best first-line treatment for reducing menstrual blood loss in perimenopausal women with HMB. Antifibrinolytics appeared second best, while long-cycle progestogens came in third place. Evidence on perception of improvement in satisfaction was ranked as low certainty. That same review found that hysterectomy was the best treatment for reducing bleeding, obviously, followed by resectoscopic endometrial ablation or a nonresectoscopic global endometrial ablation.

The evidence rating was low certainty regarding the likelihood that placing an LNG-IUD in women with HMB will result in amenorrhea, and I think that’s a very important point. The expectation of patients should be reduced or a significantly reduced amount of their HMB, not necessarily amenorrhea. Certainly, minimally invasive hysterectomy will result in total amenorrhea and may have a larger increase in satisfaction, but it has its own set of other kinds of possible complications.

Dr. Kaunitz: In an industry-funded, international multicenter trial,¹⁴ women with documented HMB (hemoglobin was eluted from soiled sanitary products), with menstrual blood loss of 80 mL or more per cycle, were randomized to placement of an LNG 52-mg IUD (Mirena) or cyclical medroxyprogesterone acetate (MPA)—oral progestin use.

Although menstrual blood loss declined in both groups, it declined dramatically more in women with an IUD placed, and specifically with the IUD, menstrual blood loss declined by 129 mL on average, whereas the decline in menstrual blood loss with cyclical MPA was 18 mL. This data, along with earlier European data,¹⁵ which showed similar findings in women with HMB led to the approval of the Mirena progestin IUD for a second indication to treat HMB in 2009.

I also want to point out that, in the May 2023 issue of Obstetrics & Gynecology, Creinin and colleagues published a similar trial in women with HMB showing, once again, that progestin IUDs (52-mg LNG-IUD, Liletta) are extremely effective in reducing HMB.¹⁶ There is crystal clear evidence from randomized trials that both 52-mg LNG-IUDs, Mirena and Liletta, are very effective in reducing HMB and, in fact, are contributing to many women who in the past would have proceeded with surgery, such as ablation or hysterectomy, to control their HMB.

Oral contraception

Dr. Pinkerton: What about using low-dose continuous oral contraceptives noncyclically for women with HMB?

Dr. Goldstein: I do that all the time. It is interesting that Dr. Kaunitz mentions his patient population. It’s why we understand that one size does not fit all. You need to see patients one at a time, and if they are good candidates for a combined estrogen-progestin contraception, whether it’s pills, patches, or rings, giving that continuously does a very nice job in reducing HMB and straightening out some of the other symptoms that these perimenopausal women will have.

IUD risks

Dr. Pinkerton: We all know about use of low-dose oral contraceptives for management of AUB, and we use them, although we worry a little bit about breast cancer risk. Dr. Levy, please comment on the risks with IUDs of expulsions and perforations. What are the downsides of IUDs?

Dr. Levy: Beyond the cost, although it is a minimally invasive procedure, IUD insertion can be an invasive procedure for a patient to undergo; expulsions can occur.¹⁷ We know that a substantial percentage of perimenopausal women will have fibroids. Although many fibroids are not located in the uterine cavity, the expulsion rate with HMB for an LNG-IUD can be higher,^13,16,18,19 perhaps because of local prostaglandin release with an increase in uterine contractility. There is a low incidence of perforations, but they do happen, particularly among women with scars in the uterus or who have a severely anteflexed or retroflexed uterus, and women with cervical stenosis, for example, if they have had a LEEP procedure, etc. Even though progestin IUDs are outstanding tools in our toolbox, they are invasive to some extent, and they do have the possibility of complications.

Dr. Kaunitz: As Dr. Levy points out, although placement of an IUD may be considered an invasive procedure, it is also an office-based procedure, so women can drive home or drive back to work afterwards without the disruption in their life and the potential complications associated with surgery and anesthesia.

Continue to: Concerns with malpositioning...

Dr. Pinkerton: After placement of an IUD, during a follow-up visit, sometimes you can’t visualize the string. The ultrasonography report may reveal, “IUD appears to be in the right place within the endometrium.” Dr. Goldstein, can you comment on how we should use ultrasound when we can’t visualize or find the IUD string, or if the patient complains of abdominal pain, lower abdominal discomfort, or irregular bleeding or spotting and we become concerned about IUD malposition?

Dr. Goldstein: Ultrasound is not really required after an uncomplicated placement of an IUD or during routine management of women who have no problems who are using an IUD. In patients who present with pain or some abnormal bleeding, however, sometimes it is the IUD being malpositioned. A very interesting study by the late great Beryl Benacerraf²⁰ showed that there was a statistically significant higher incidence of the IUD being poorly positioned when patients have pain or bleeding (FIGURE 1). It was not always apparent on 2D ultrasonography. Using a standard transvaginal ultrasound of the long access plane, the IUD may appear to be very centrally located. However, if you do a 3D coronal section, not infrequently in these patients with any pain or bleeding, one of the arms has pierced the myometrium (FIGURE 2). This can actually be a source of pain and bleeding.

It’s also very interesting when you talk about perforation. I became aware of a big to-do in the medical/legal world about the possibility of the IUD migrating through the uterine cavity.²¹ This just does not exist, as was already pointed out. If the IUD is really going to go anywhere, if it’s properly placed, it’s going to be expelled through an open cervix. I do believe that, if you have pierced the myometrium through uterine contractility over time, some of these IUDs could work their way through the myometrium and somehow come out of the uterus either totally or partially. I think ultrasound is invaluable in patients with pain and bleeding, but I think you need to have an ultrasound lab capable of doing a 3D coronal section.

Progestin IUDs for HT replacement: Benefits/risks

Dr. Pinkerton: Many clinicians are excited that they can use essentially estrogen alone for women who have a progestin IUD in place. What about the possible off-label use of the progestin IUD to replace oral progestogen for hormone therapy (HT)? Dr. Kaunitz, are there any studies using this for postmenopausal HT (with a reminder that the IUD is not FDA approved for this purpose)?

Dr. Kaunitz: We have data from Europe indicating that, in menopausal women using systemic estrogen, the full-size LNG 52 IUD—Mirena or Liletta—provides excellent endometrial suppression.²² Where we don’t have data is with the smaller IUDs, which would be Kyleena and Skyla, which release smaller amounts of progestin each day into the endometrial cavity.

I have a number of patients, most of them women who started use of a progestin IUD as older reproductive-age women and then started systemic estrogen for treatment of perimenopausal hot flashes and then continued the use of their IUD plus systemic estrogen in treating postmenopausal hot flashes. The IUD is very useful in this setting, but as you pointed out, Dr. Pinkerton, this does represent off-label use.

Dr. Pinkerton: I know this use does not affect plasma lipids or cardiovascular risk markers, although users seem to report that the IUD has improved their quality of life. The question comes up, what are the benefits on cancer risk for using an IUD?

Dr. Levy: It’s such a great question because, as we talk about the balance of risks and benefits for anything that we are offering to our patients, it is really important to focus on some of the benefits. For both the copper and the LNG-IUD, there is a reduction in endometrial cancer,²² as well as pretty good data with the copper IUD about a reduction in cervical cancer.²³ Those data are a little bit less clear for the LNG-IUD.

Interestingly, at least one meta-analysis published in 2020 shows about a 30% reduction in ovarian cancer risk with the LNG-IUD.²⁴ We need to focus our patients on these other benefits. They tend to focus on the risks, and, of course, the media blows up the risks, but the benefits are quite substantial beyond just reducing HMB and providing contraception.

Dr. Pinkerton: As Dr. Kaunitz said, when you use this IUD, with its primarily local uterine progestin effects, it’s more like using estrogen alone without as much systemic progestin. Recently I wrote an editorial on the benefits of estrogen alone on the risk of breast cancer, primarily based on the Women’s Health Initiative (WHI) observational long-term 18-year cumulative follow-up. When estrogen alone was prescribed to women after a hysterectomy, estrogen therapy used at menopause did not increase the risk of invasive breast cancer, and was associated with decreased mortality.²⁵ However, the nurse’s health study has suggested that longer-term use may be increased with estrogen alone.²⁶ For women in the WHI with an intact uterus who used estrogen, oral MPA slightly increased the risk for breast cancer, and this elevated risk persisted even after discontinuation. This leads us to the question, what are the risks of breast cancer with progestin IUD use?

I recently reviewed the literature, and the answer is, it’s mixed. The FDA has put language into the package label that acknowledges a potential breast cancer risk for women who use a progestin IUD,²⁷ and that warning states, “Women who currently have or have had breast cancer or suspect breast cancer should not use hormonal contraception because some breast cancers are hormone sensitive.” The label goes on to say, “Observational studies of the risk of breast cancer with the use of a levonorgestrel-releasing IUS don’t provide conclusive evidence of increased risk.” Thus, there is no conclusive answer as to whether there is a possible link of progestin IUDs to breast cancer.

What I tell my patients is that research is inconclusive. However, it’s unlikely for a 52-mg LNG-IUD to significantly increase a woman’s breast cancer risk, except possibly in those already at high risk from other risk factors. I tell them that breast cancer is listed in the package insert as a potential risk. I could not find any data on whether adding a low-dose estradiol patch would further increase that risk. So I counsel women about potential risk, but tell them that I don’t have any strong evidence of risk.

Continue to: Dr. Goldstein...

Dr. Goldstein: If you look in the package insert for Mirena,² similar to Liletta, certainly the serum levels of LNG are lower than that for combination oral contraceptives. For the IUD progestins, they are not localized only to the uterus, and LNG levels range from about 150 to 200 µg/mL up to 60 months. It’s greater at 12 months, at about 180 µg/mL,at 24 months it was 192 µg/mL, and by 60 months it was 159 µg/mL. It’s important to realize that there is some systemic absorption of progestin with progestin IUDs, and it is not completely a local effect.

JoAnn, you mentioned the WHI data,²⁵ and just to specify, it was not the estrogen-only arm, it was the conjugated equine estrogen-only arm of the WHI. I don’t think that estradiol alone increases breast cancer risk (although there are no good prospective, follow-through, 18-year study data, like the WHI), but I think readers need to understand the difference in the estrogen type.

Endometrial evaluation. My question for the panel is as follows. I agree that the use of the progestin-releasing IUD is very nice for that transition to menopause. I do believe it provides endometrial protection, but we know from other studies that, when we give continuous combined HT, about 21% to 26% of patients will experience some bleeding/staining, responding in the first 4-week cycles, and it can be as high as 9% at 1 year. If I have a patient who bleeds on continuous combined HT, I will evaluate her endometrium, usually just with a simple transvaginal ultrasound. If an IUD is in place, and the patient now begins to have some irregular bleeding, how do you evaluate her with the IUD in place?

Dr. Levy: That is a huge challenge. We know from a recent paper,²⁸ that the endometrial thickness, while an excellent measure for Caucasian and European women, may be a poor marker for endometrial pathology in African-American women. What we thought we knew, which was, if the stripe is 4 mL or less, we can forget about it, I think in our more recent research that is not so true. So you bring up a great point, what do you do? The most reliable evaluation will be with an office hysteroscopy, where you can really look at the entire cavity and for tiny, little polyps and other things. But then we are off label because the use of hysteroscopy with an IUD in place is off label. So we are really in a conundrum.

Dr. Pinkerton: Also, if you do an endometrial biopsy, you might dislodge the IUD. If you think that you are going to take the IUD out, it may not matter if you dislodge it. I will often obtain a transvaginal ultrasound to help me figure out the next step, and maybe look at the dosing of the estrogen and progestin—but you can’t monitor an IUD with blood levels. You are in a vacuum of trying to figure out the best thing to do.

Dr. Kaunitz: One of the hats I wear here in Jacksonville is Director of GYN Ultrasound. I have a fair amount of experience doing endometrial biopsies in women with progestin IUDs in place under abdominal ultrasound guidance and keeping a close eye on the position of the IUD. In the first dozen or so such procedures I did, I was quite concerned about dislodging the IUD. It hasn’t happened yet, and it gives me some reassurance to be able to image the IUD and your endometrial suction curette inside the cavity as you are obtaining endometrial sampling. I have substantial experience now doing that, and so far, no problems. I do counsel all such women in advance that there is some chance I could dislodge their IUD.

Dr. Goldstein: In addition to dislodging the IUD, are you not concerned that, if the pathology is not global, that a blind endometrial sampling may be fraught with some error?

Dr. Kaunitz: The endometrium in women with a progestin-releasing IUD in place tends to be very well suppressed. Although one might occasionally find, for instance, a polyp in that setting, I have not run into, and I don’t expect to encounter going forward, endometrial hyperplasia or cancer in women with current use of a progestin IUD. It’s possible but unlikely.

Dr. Levy: The progestin IUD will counterbalance a type-1 endometrial cancer—an endometrial cancer related to hyperstimulation by estrogen. It will not do anything, to my knowledge, to counterbalance a type 2. I think the art of medicine is, you do the best you can with the first episode of bleeding, and if she persists in her bleeding, we have to persevere and continue to evaluate her.

Dr. Goldstein: I agree 100%.

Dr. Pinkerton: We all agree with you. That’s a really good point.

Continue to: Case examinations...

Case examinations

CASE 1 Woman with intramural fibroids

Dr. Pinkerton: Dr. Goldstein, you have a 48-year-old Black woman who has heavy but regular menstrual bleeding with multiple fibroids (the largest is about 4 to 5 cm, they look intramural, with some distortion of the cavity but not a submucous myoma, and the endometrial depth is 9 cm). Would you insert an IUD, and would you recommend an endometrial biopsy first?

Dr. Goldstein: I am not a huge fan of blind endometrial sampling, and I do think that we use the “biopsy” somewhat inappropriately since sampling is not a directed biopsy. This became obvious in the landmark paper by Guido et al in 1995 and was adopted by ACOG only in 2012.²⁹ Cancers that occupy less than 50% of the endometrial surface area are often missed with such blind sampling. Thus I would not perform an endometrial biopsy first, but would rather rely on properly timed and performed transvaginal ultrasound to rule out any concurrent endometrial disease. I think a lot of patients who have HMB, not only because of their fibroids but also often just due to the surface area of their uterine cavity being increased—so essentially there is more blood volume when they bleed. However, you said that in this case the patient has regular menstrual bleeding, so I am assuming that she is still ovulatory. She may have some adenomyosis. She may have a large uterine cavity. I think she is an excellent candidate for an LNG-releasing IUD to reduce menstrual blood flow significantly. It will not necessarily give her amenorrhea, and it may give her some irregular bleeding. Then at some distant point, say in 5 or 6 months if she does have some irregular staining or bleeding, I would feel much better about the fact that nothing has developed as long as I knew that the endometrium was devoid of pathology when I started.

CASE 2 Woman with family history of breast cancer

Dr. Pinkerton: Dr. Levy, a 44-year-old woman has a family history of breast cancer in her mother at age 72, but she still needs contraceptionbecause of that unintended pregnancy risk in the 40s, and she wants something that is not going to increase her risk of breast cancer. What would you use, and how would you counsel her if you decided to use a progestin IUD?

Dr. Levy: The data are mixed,^30-33 but whatever the risk, it is miniscule, and I would bring up the CDC Medical Eligibility Criteria.¹¹ For a patient with a family history of breast cancer, for use of the progestin IUD, it is a 1—no contraindications. What I tend to tell my patients is, if you are worried about breast cancer, watch how much alcohol you are drinking and maintain regular exercise. There are so many preventive things that we can do to reduce risk of breast cancer when she needs contraception. If there is any increase in risk, it is so miniscule that I would very strongly recommend a progestin IUD for her.

Dr. Pinkerton: In addition, in recognizing the different densities of breast, dense breast density could lead to supplemental screening, which also could give her some reassurance that we are adequately screening for breast cancer.

CASE 3 Woman with IUD and VMS
 

Dr. Pinkerton: Dr. Kaunitz, you have a 52-year-old overweight female. She has been using a progestin IUD for 4 years, is amenorrheic, but now she is having moderate to severe vasomotor symptoms despite the IUD in place. You have talked to her about risks and benefits of HT, and she is interested in starting it. I know we talked about the studies, but I want to know what you are going to tell her. How do you counsel her about off-label use?

Dr. Kaunitz: The most important issue related to treating vasomotor symptoms in this patient is the route of systemic estrogen. Understandably, women’s biggest concern regarding the risks of systemic estrogen-progestin therapy is breast cancer. However, statistically, by far the biggest risk associated with oral estrogen-progestogen therapy, is elevated risk of venous thrombosis and pulmonary embolism. We have seen this, with a number of studies, and the WHI made it crystal clear with risks of oral conjugated equine estrogen at the dose of 0.625 mg daily. Oral estradiol 1 mg daily is also associated with a similar elevated risk of venous thrombosis. We also know that age and BMI are both independent risk factors for thrombosis. So, for a woman in her 50s who has a BMI > 30 mg/kg², I don’t want to further elevate her risk of thrombosis by giving her oral estrogen, whether it is estradiol or conjugated equine estrogen. This is a patient in whom I would be comfortable using transdermal (patch) estradiol, perhaps starting with a standard dose of 0.05 mg weekly or twice weekly patch, keeping in mind that 0.05 mg in the setting of transdermal estrogen refer to the daily or to the 24-hour release rate. The 1.0 mg of oral estradiol and 0.625 mg of conjugated equine estrogen refers to the mg quantity of estrogen in each tablet. This is a source of great confusion for clinicians.

If, during follow-up, the 0.05 mg estradiol patch is not sufficient to substantially reduce symptoms, we could go up, for instance, to a 0.075 mg estradiol patch. We know very clearly from a variety of observational studies, including a very large UK study,³⁴ that in contrast with oral estrogen, transdermal estradiol is safer from the perspective of thrombosis.

Insurance coverage for IUDs

Dr. Pinkerton: Dr. Levy: Can you discuss IUDs and the Affordable Care Act’s requirement to cover contraceptive services?

Dr. Levy: Unfortunately, we do not know whether this benefit will continue based on a very recent finding from a judge in Texas that ruled the preventive benefits of the ACA were illegal.³⁵ We don’t know what will happen going forward. What I will say is that, unfortunately, many insurance companies have not preserved the meaning of “cover all things,” so what we are finding is that, for example, they only have to cover one type in a class. The FDA defined 18 classes of contraceptives, and a hormonal IUD is one class, so they can decide that they are only going to cover one of the four IUDS. And then women don’t have access to the other three, some of which might be more appropriate for them than another.

The other thing very relevant to this conversation is that, if you use an ICD-10 code for menorrhagia, for HMB, it no longer lives within that ACA preventive care requirement of coverage for contraceptives, and now she is going to owe a big deductible or a copay. If you are practicing in an institution that does not allow the use of IUDs for contraception, like a Catholic institution where I used to practice, you will want to use that ICD-10 code for HMB. But if you want it offered with no out-of-pocket cost for the patient, you need to use the preventive medicine codes and the contraception code. These little nuances for us can make a huge difference for our patients.

Dr. Pinkerton: Thank you for that reminder. I want to thank our panelists, Dr. Levy, Dr. Goldstein, and Dr. Kaunitz, for providing us with such a great mix of evidence and expert opinion and also giving a benefit of their vast experience as award-winning gynecologists. Hopefully, today you have learned the benefits of the progestin IUD not only for contraception in reproductive years and perimenopause but also for treatment of HMB, and the potential benefit due to the more prolonged effectiveness of the IUDs for endometrial protection in postmenopause. This allows less progestin risk, essentially estrogen alone for postmenopausal HT. Unsolved questions remain about whether there is a risk of breast cancer with their use, but there is a clear benefit of protecting against pregnancy and endometrial cancer. ●

Illustration: Kimberly Martens for OBG Management

Intrauterine devices (IUDs) are now used by more than 15% of US contraceptors. The majority of these IUDs release the progestin levonorgestrel, and with now longer extended use of the IUDs approved by the US Food and Drug Administration (FDA),^1-3 they become even more attractive for use for contraception,control of menorrhagia or heavy menstrual bleeding (HMB) during reproductive years and perimenopause, and potentially, although not FDA approved for this purpose, postmenopause for endometrial protection in estrogen users. In this roundtable discussion, we will look at some of the benefits of the IUD for contraception effectiveness and control of bleeding, as well as the potential risks if used for postmenopausal women.

Progestin IUDs and contraception

JoAnn V. Pinkerton, MD, NCMP: Dr. Kaunitz, what are the contraceptive benefits of progestin IUDs during perimenopause?
 

Andrew M. Kaunitz, MD, NCMP: We know fertility declines as women approach menopause. However, when pregnancy occurs in older reproductive-age women, the pregnancies are often unintended, as reflected by high rates of induced abortion in this population. In addition, the prevalence of maternal comorbidities (during pregnancy and delivery) is higher in older reproductive-age women, with the maternal mortality rate more than 5 times higher compared with that of younger women.⁴ Two recently published clinical trials assessed the extended use of full-size IUDs containing 52 mg of levonor-gestrel (LNG), with the brand names Mirena and Liletta.^1,2 The data from these trials confirmed that both IUDs remain highly effective for up to 8 years of use, and currently, both devices are approved for up to 8 years of use. One caveat is that, in the unusual occurrence of a pregnancy being diagnosed in a woman using an IUD, we as clinicians, must be alert to the high prevalence of ectopic pregnancies in this setting.

Progestin IUDs and HMB

Dr. Pinkerton: Dr. Goldstein, can you comment on how well progestin IUDs work for HMB?

Steven R. Goldstein, MD, NCMP, CCD: Many women who need contraception will use these devices for suppressing HMB, and they can be quite effective, if the diagnosis truly is HMB, at reducing bleeding.⁵ But that efficacy in bleeding reduction may not be quite as long as the efficacy in pregnancy prevention.⁶ In my experience, among women using IUDs specifically for their HMB, good bleeding control may require changing the IUD at 3 to 5 years.

Barbara S. Levy, MD: When inserting a LNG-IUD for menorrhagia in the perimenopausal time frame, sometimes I will do a progestin withdrawal first, which will thin the endometrium and induce withdrawal bleeding because, in my experience, if you place an IUD in someone with perimenopausal bleeding, you may end up with a lot of breakthrough bleeding.

Perimenopause and hot flashes

Dr. Pinkerton: Dr. Kaunitz, we have learned that hot flashes often occur and become bothersome to women during perimenopause. Many women have IUDs placed during perimenopause for bleeding. Can you comment about IUD use during perimenopause and postmenopause?
 

Dr. Kaunitz: In older reproductive-age women who already have a progestin-releasing IUD placed, as they get closer to menopause when vasomotor symptoms (VMS) might occur, if these symptoms are bothersome, the presence or placement of a progestin-releasing IUD can facilitate treatment of perimenopausal VMS with estrogen therapy.

Progestin IUDs cause profound endometrial suppression, reduce bleeding and often, over time, cause users to become amenorrheic.⁷

The Mirena package insert states, “Amenorrhea develops in about 20% of users by one year.”² By year 3 and continuing through year 8, the prevalence of amenorrhea with the 52-mg LNG-IUD is 35% to 40%.⁸ From a study by Nanette Santoro, MD, and colleagues, we know that, in perimenopausal women with a progestin-releasing IUD in place, who are experiencing bothersome VMS, adding transdermal estrogen is very effective in treating and suppressing those hot flashes. In her small clinical trial, among participants with perimenopausal bothersome VMS with an IUD in place, half were randomized to use of transdermal estradiol and then compared with women who did not get the estradiol patch. There was excellent relief of perimenopausal hot flashes with the combination of the progestin IUD for endometrial suppression and transdermal estrogen to relieve hot flashes.⁹

Dr. Pinkerton: Which women would not be good candidates for the use of this combination?

Dr. Kaunitz: We know that, as women age, the prevalence of conditions that are contraindications to combination contraceptives (estrogen-progestin pills, patches, or rings) starts to increase. Specifically, we see more: hypertension, diabetes, and high body mass index (BMI), or obesity. We also know that migraine headaches in women older than age 35 years is another condition in which ACOG and the Centers for Disease Control and Prevention (CDC) would not recommend use of combination contraceptives.^10,11 These older perimenopausal women may be excellent candidates for a progestin-only releasing IUD combined with use of transdermal menopausal doses of estradiol if needed for VMS.

Dr. Goldstein: I do want to add that, in those patients who don’t have these comorbidities, combination estrogen-progestin contraceptives do a very nice job of ovarian suppression and will prevent the erratic production of estradiol, which, in my experience, often results in not only irregular bleeding but also possible exacerbation of perimenopausal mood symptoms.

Dr. Kaunitz: I agree, Steve. The ideal older reproductive-age candidate for combination pills, patch, or ring would be a slender, healthy, nonsmoking woman with normal blood pressure. Such women would be a fairly small subgroup of my practice, but they can safely continue combination contraceptives right through menopause. Consistent with CDC and ACOG guidance, rather than checking gonadotropins to “determine when menopause has occurred,” (which is, in fact, not an evidence-based approach to diagnosing menopause in this setting), such women can continue the combination contraceptive right up until age 55—the likelihood that women are still going to be ovulating or at risk for pregnancy becomes vanishingly small at that age.^11,12 Women in their mid-50s can either seamlessly transition to use of systemic estrogen-progestin menopausal therapy or go off hormones completely.

Continue to: The IUD and HMB...

The IUD and HMB

Dr. Pinkerton: Dr. Goldstein, there’s been some good literature on the best management options for women with HMB. What is the most current evidence?

Dr. Goldstein: I think that the retiring of the terms menorrhagia and metrorrhagia may have been premature because HMB implies cyclical bleeding, and this population of women with HMB will typically do quite well. Women who have what we used to call metrorrhagia or irregular bleeding, by definition, need endometrial evaluation to be sure they don’t have some sort of organic pathology. It would be a mistake for clinicians to use an LNG-IUD in patients with abnormal uterine bleeding (AUB) that has not been appropriately evaluated.

If we understand that we are discussing HMB, a Cochrane Review from 2022¹³ suggests that an LNG intrauterine system is the best first-line treatment for reducing menstrual blood loss in perimenopausal women with HMB. Antifibrinolytics appeared second best, while long-cycle progestogens came in third place. Evidence on perception of improvement in satisfaction was ranked as low certainty. That same review found that hysterectomy was the best treatment for reducing bleeding, obviously, followed by resectoscopic endometrial ablation or a nonresectoscopic global endometrial ablation.

The evidence rating was low certainty regarding the likelihood that placing an LNG-IUD in women with HMB will result in amenorrhea, and I think that’s a very important point. The expectation of patients should be reduced or a significantly reduced amount of their HMB, not necessarily amenorrhea. Certainly, minimally invasive hysterectomy will result in total amenorrhea and may have a larger increase in satisfaction, but it has its own set of other kinds of possible complications.

Dr. Kaunitz: In an industry-funded, international multicenter trial,¹⁴ women with documented HMB (hemoglobin was eluted from soiled sanitary products), with menstrual blood loss of 80 mL or more per cycle, were randomized to placement of an LNG 52-mg IUD (Mirena) or cyclical medroxyprogesterone acetate (MPA)—oral progestin use.

Although menstrual blood loss declined in both groups, it declined dramatically more in women with an IUD placed, and specifically with the IUD, menstrual blood loss declined by 129 mL on average, whereas the decline in menstrual blood loss with cyclical MPA was 18 mL. This data, along with earlier European data,¹⁵ which showed similar findings in women with HMB led to the approval of the Mirena progestin IUD for a second indication to treat HMB in 2009.

I also want to point out that, in the May 2023 issue of Obstetrics & Gynecology, Creinin and colleagues published a similar trial in women with HMB showing, once again, that progestin IUDs (52-mg LNG-IUD, Liletta) are extremely effective in reducing HMB.¹⁶ There is crystal clear evidence from randomized trials that both 52-mg LNG-IUDs, Mirena and Liletta, are very effective in reducing HMB and, in fact, are contributing to many women who in the past would have proceeded with surgery, such as ablation or hysterectomy, to control their HMB.

Oral contraception

Dr. Pinkerton: What about using low-dose continuous oral contraceptives noncyclically for women with HMB?

Dr. Goldstein: I do that all the time. It is interesting that Dr. Kaunitz mentions his patient population. It’s why we understand that one size does not fit all. You need to see patients one at a time, and if they are good candidates for a combined estrogen-progestin contraception, whether it’s pills, patches, or rings, giving that continuously does a very nice job in reducing HMB and straightening out some of the other symptoms that these perimenopausal women will have.

IUD risks

Dr. Pinkerton: We all know about use of low-dose oral contraceptives for management of AUB, and we use them, although we worry a little bit about breast cancer risk. Dr. Levy, please comment on the risks with IUDs of expulsions and perforations. What are the downsides of IUDs?

Dr. Levy: Beyond the cost, although it is a minimally invasive procedure, IUD insertion can be an invasive procedure for a patient to undergo; expulsions can occur.¹⁷ We know that a substantial percentage of perimenopausal women will have fibroids. Although many fibroids are not located in the uterine cavity, the expulsion rate with HMB for an LNG-IUD can be higher,^13,16,18,19 perhaps because of local prostaglandin release with an increase in uterine contractility. There is a low incidence of perforations, but they do happen, particularly among women with scars in the uterus or who have a severely anteflexed or retroflexed uterus, and women with cervical stenosis, for example, if they have had a LEEP procedure, etc. Even though progestin IUDs are outstanding tools in our toolbox, they are invasive to some extent, and they do have the possibility of complications.

Dr. Kaunitz: As Dr. Levy points out, although placement of an IUD may be considered an invasive procedure, it is also an office-based procedure, so women can drive home or drive back to work afterwards without the disruption in their life and the potential complications associated with surgery and anesthesia.

Continue to: Concerns with malpositioning...

Dr. Pinkerton: After placement of an IUD, during a follow-up visit, sometimes you can’t visualize the string. The ultrasonography report may reveal, “IUD appears to be in the right place within the endometrium.” Dr. Goldstein, can you comment on how we should use ultrasound when we can’t visualize or find the IUD string, or if the patient complains of abdominal pain, lower abdominal discomfort, or irregular bleeding or spotting and we become concerned about IUD malposition?

Dr. Goldstein: Ultrasound is not really required after an uncomplicated placement of an IUD or during routine management of women who have no problems who are using an IUD. In patients who present with pain or some abnormal bleeding, however, sometimes it is the IUD being malpositioned. A very interesting study by the late great Beryl Benacerraf²⁰ showed that there was a statistically significant higher incidence of the IUD being poorly positioned when patients have pain or bleeding (FIGURE 1). It was not always apparent on 2D ultrasonography. Using a standard transvaginal ultrasound of the long access plane, the IUD may appear to be very centrally located. However, if you do a 3D coronal section, not infrequently in these patients with any pain or bleeding, one of the arms has pierced the myometrium (FIGURE 2). This can actually be a source of pain and bleeding.

It’s also very interesting when you talk about perforation. I became aware of a big to-do in the medical/legal world about the possibility of the IUD migrating through the uterine cavity.²¹ This just does not exist, as was already pointed out. If the IUD is really going to go anywhere, if it’s properly placed, it’s going to be expelled through an open cervix. I do believe that, if you have pierced the myometrium through uterine contractility over time, some of these IUDs could work their way through the myometrium and somehow come out of the uterus either totally or partially. I think ultrasound is invaluable in patients with pain and bleeding, but I think you need to have an ultrasound lab capable of doing a 3D coronal section.

Progestin IUDs for HT replacement: Benefits/risks

Dr. Pinkerton: Many clinicians are excited that they can use essentially estrogen alone for women who have a progestin IUD in place. What about the possible off-label use of the progestin IUD to replace oral progestogen for hormone therapy (HT)? Dr. Kaunitz, are there any studies using this for postmenopausal HT (with a reminder that the IUD is not FDA approved for this purpose)?

Dr. Kaunitz: We have data from Europe indicating that, in menopausal women using systemic estrogen, the full-size LNG 52 IUD—Mirena or Liletta—provides excellent endometrial suppression.²² Where we don’t have data is with the smaller IUDs, which would be Kyleena and Skyla, which release smaller amounts of progestin each day into the endometrial cavity.

I have a number of patients, most of them women who started use of a progestin IUD as older reproductive-age women and then started systemic estrogen for treatment of perimenopausal hot flashes and then continued the use of their IUD plus systemic estrogen in treating postmenopausal hot flashes. The IUD is very useful in this setting, but as you pointed out, Dr. Pinkerton, this does represent off-label use.

Dr. Pinkerton: I know this use does not affect plasma lipids or cardiovascular risk markers, although users seem to report that the IUD has improved their quality of life. The question comes up, what are the benefits on cancer risk for using an IUD?

Dr. Levy: It’s such a great question because, as we talk about the balance of risks and benefits for anything that we are offering to our patients, it is really important to focus on some of the benefits. For both the copper and the LNG-IUD, there is a reduction in endometrial cancer,²² as well as pretty good data with the copper IUD about a reduction in cervical cancer.²³ Those data are a little bit less clear for the LNG-IUD.

Interestingly, at least one meta-analysis published in 2020 shows about a 30% reduction in ovarian cancer risk with the LNG-IUD.²⁴ We need to focus our patients on these other benefits. They tend to focus on the risks, and, of course, the media blows up the risks, but the benefits are quite substantial beyond just reducing HMB and providing contraception.

Dr. Pinkerton: As Dr. Kaunitz said, when you use this IUD, with its primarily local uterine progestin effects, it’s more like using estrogen alone without as much systemic progestin. Recently I wrote an editorial on the benefits of estrogen alone on the risk of breast cancer, primarily based on the Women’s Health Initiative (WHI) observational long-term 18-year cumulative follow-up. When estrogen alone was prescribed to women after a hysterectomy, estrogen therapy used at menopause did not increase the risk of invasive breast cancer, and was associated with decreased mortality.²⁵ However, the nurse’s health study has suggested that longer-term use may be increased with estrogen alone.²⁶ For women in the WHI with an intact uterus who used estrogen, oral MPA slightly increased the risk for breast cancer, and this elevated risk persisted even after discontinuation. This leads us to the question, what are the risks of breast cancer with progestin IUD use?

I recently reviewed the literature, and the answer is, it’s mixed. The FDA has put language into the package label that acknowledges a potential breast cancer risk for women who use a progestin IUD,²⁷ and that warning states, “Women who currently have or have had breast cancer or suspect breast cancer should not use hormonal contraception because some breast cancers are hormone sensitive.” The label goes on to say, “Observational studies of the risk of breast cancer with the use of a levonorgestrel-releasing IUS don’t provide conclusive evidence of increased risk.” Thus, there is no conclusive answer as to whether there is a possible link of progestin IUDs to breast cancer.

What I tell my patients is that research is inconclusive. However, it’s unlikely for a 52-mg LNG-IUD to significantly increase a woman’s breast cancer risk, except possibly in those already at high risk from other risk factors. I tell them that breast cancer is listed in the package insert as a potential risk. I could not find any data on whether adding a low-dose estradiol patch would further increase that risk. So I counsel women about potential risk, but tell them that I don’t have any strong evidence of risk.

Continue to: Dr. Goldstein...

Dr. Goldstein: If you look in the package insert for Mirena,² similar to Liletta, certainly the serum levels of LNG are lower than that for combination oral contraceptives. For the IUD progestins, they are not localized only to the uterus, and LNG levels range from about 150 to 200 µg/mL up to 60 months. It’s greater at 12 months, at about 180 µg/mL,at 24 months it was 192 µg/mL, and by 60 months it was 159 µg/mL. It’s important to realize that there is some systemic absorption of progestin with progestin IUDs, and it is not completely a local effect.

JoAnn, you mentioned the WHI data,²⁵ and just to specify, it was not the estrogen-only arm, it was the conjugated equine estrogen-only arm of the WHI. I don’t think that estradiol alone increases breast cancer risk (although there are no good prospective, follow-through, 18-year study data, like the WHI), but I think readers need to understand the difference in the estrogen type.

Endometrial evaluation. My question for the panel is as follows. I agree that the use of the progestin-releasing IUD is very nice for that transition to menopause. I do believe it provides endometrial protection, but we know from other studies that, when we give continuous combined HT, about 21% to 26% of patients will experience some bleeding/staining, responding in the first 4-week cycles, and it can be as high as 9% at 1 year. If I have a patient who bleeds on continuous combined HT, I will evaluate her endometrium, usually just with a simple transvaginal ultrasound. If an IUD is in place, and the patient now begins to have some irregular bleeding, how do you evaluate her with the IUD in place?

Dr. Levy: That is a huge challenge. We know from a recent paper,²⁸ that the endometrial thickness, while an excellent measure for Caucasian and European women, may be a poor marker for endometrial pathology in African-American women. What we thought we knew, which was, if the stripe is 4 mL or less, we can forget about it, I think in our more recent research that is not so true. So you bring up a great point, what do you do? The most reliable evaluation will be with an office hysteroscopy, where you can really look at the entire cavity and for tiny, little polyps and other things. But then we are off label because the use of hysteroscopy with an IUD in place is off label. So we are really in a conundrum.

Dr. Pinkerton: Also, if you do an endometrial biopsy, you might dislodge the IUD. If you think that you are going to take the IUD out, it may not matter if you dislodge it. I will often obtain a transvaginal ultrasound to help me figure out the next step, and maybe look at the dosing of the estrogen and progestin—but you can’t monitor an IUD with blood levels. You are in a vacuum of trying to figure out the best thing to do.

Dr. Kaunitz: One of the hats I wear here in Jacksonville is Director of GYN Ultrasound. I have a fair amount of experience doing endometrial biopsies in women with progestin IUDs in place under abdominal ultrasound guidance and keeping a close eye on the position of the IUD. In the first dozen or so such procedures I did, I was quite concerned about dislodging the IUD. It hasn’t happened yet, and it gives me some reassurance to be able to image the IUD and your endometrial suction curette inside the cavity as you are obtaining endometrial sampling. I have substantial experience now doing that, and so far, no problems. I do counsel all such women in advance that there is some chance I could dislodge their IUD.

Dr. Goldstein: In addition to dislodging the IUD, are you not concerned that, if the pathology is not global, that a blind endometrial sampling may be fraught with some error?

Dr. Kaunitz: The endometrium in women with a progestin-releasing IUD in place tends to be very well suppressed. Although one might occasionally find, for instance, a polyp in that setting, I have not run into, and I don’t expect to encounter going forward, endometrial hyperplasia or cancer in women with current use of a progestin IUD. It’s possible but unlikely.

Dr. Levy: The progestin IUD will counterbalance a type-1 endometrial cancer—an endometrial cancer related to hyperstimulation by estrogen. It will not do anything, to my knowledge, to counterbalance a type 2. I think the art of medicine is, you do the best you can with the first episode of bleeding, and if she persists in her bleeding, we have to persevere and continue to evaluate her.

Dr. Goldstein: I agree 100%.

Dr. Pinkerton: We all agree with you. That’s a really good point.

Continue to: Case examinations...

Case examinations

CASE 1 Woman with intramural fibroids

Dr. Pinkerton: Dr. Goldstein, you have a 48-year-old Black woman who has heavy but regular menstrual bleeding with multiple fibroids (the largest is about 4 to 5 cm, they look intramural, with some distortion of the cavity but not a submucous myoma, and the endometrial depth is 9 cm). Would you insert an IUD, and would you recommend an endometrial biopsy first?

Dr. Goldstein: I am not a huge fan of blind endometrial sampling, and I do think that we use the “biopsy” somewhat inappropriately since sampling is not a directed biopsy. This became obvious in the landmark paper by Guido et al in 1995 and was adopted by ACOG only in 2012.²⁹ Cancers that occupy less than 50% of the endometrial surface area are often missed with such blind sampling. Thus I would not perform an endometrial biopsy first, but would rather rely on properly timed and performed transvaginal ultrasound to rule out any concurrent endometrial disease. I think a lot of patients who have HMB, not only because of their fibroids but also often just due to the surface area of their uterine cavity being increased—so essentially there is more blood volume when they bleed. However, you said that in this case the patient has regular menstrual bleeding, so I am assuming that she is still ovulatory. She may have some adenomyosis. She may have a large uterine cavity. I think she is an excellent candidate for an LNG-releasing IUD to reduce menstrual blood flow significantly. It will not necessarily give her amenorrhea, and it may give her some irregular bleeding. Then at some distant point, say in 5 or 6 months if she does have some irregular staining or bleeding, I would feel much better about the fact that nothing has developed as long as I knew that the endometrium was devoid of pathology when I started.

CASE 2 Woman with family history of breast cancer

Dr. Pinkerton: Dr. Levy, a 44-year-old woman has a family history of breast cancer in her mother at age 72, but she still needs contraceptionbecause of that unintended pregnancy risk in the 40s, and she wants something that is not going to increase her risk of breast cancer. What would you use, and how would you counsel her if you decided to use a progestin IUD?

Dr. Levy: The data are mixed,^30-33 but whatever the risk, it is miniscule, and I would bring up the CDC Medical Eligibility Criteria.¹¹ For a patient with a family history of breast cancer, for use of the progestin IUD, it is a 1—no contraindications. What I tend to tell my patients is, if you are worried about breast cancer, watch how much alcohol you are drinking and maintain regular exercise. There are so many preventive things that we can do to reduce risk of breast cancer when she needs contraception. If there is any increase in risk, it is so miniscule that I would very strongly recommend a progestin IUD for her.

Dr. Pinkerton: In addition, in recognizing the different densities of breast, dense breast density could lead to supplemental screening, which also could give her some reassurance that we are adequately screening for breast cancer.

CASE 3 Woman with IUD and VMS
 

Dr. Pinkerton: Dr. Kaunitz, you have a 52-year-old overweight female. She has been using a progestin IUD for 4 years, is amenorrheic, but now she is having moderate to severe vasomotor symptoms despite the IUD in place. You have talked to her about risks and benefits of HT, and she is interested in starting it. I know we talked about the studies, but I want to know what you are going to tell her. How do you counsel her about off-label use?

Dr. Kaunitz: The most important issue related to treating vasomotor symptoms in this patient is the route of systemic estrogen. Understandably, women’s biggest concern regarding the risks of systemic estrogen-progestin therapy is breast cancer. However, statistically, by far the biggest risk associated with oral estrogen-progestogen therapy, is elevated risk of venous thrombosis and pulmonary embolism. We have seen this, with a number of studies, and the WHI made it crystal clear with risks of oral conjugated equine estrogen at the dose of 0.625 mg daily. Oral estradiol 1 mg daily is also associated with a similar elevated risk of venous thrombosis. We also know that age and BMI are both independent risk factors for thrombosis. So, for a woman in her 50s who has a BMI > 30 mg/kg², I don’t want to further elevate her risk of thrombosis by giving her oral estrogen, whether it is estradiol or conjugated equine estrogen. This is a patient in whom I would be comfortable using transdermal (patch) estradiol, perhaps starting with a standard dose of 0.05 mg weekly or twice weekly patch, keeping in mind that 0.05 mg in the setting of transdermal estrogen refer to the daily or to the 24-hour release rate. The 1.0 mg of oral estradiol and 0.625 mg of conjugated equine estrogen refers to the mg quantity of estrogen in each tablet. This is a source of great confusion for clinicians.

If, during follow-up, the 0.05 mg estradiol patch is not sufficient to substantially reduce symptoms, we could go up, for instance, to a 0.075 mg estradiol patch. We know very clearly from a variety of observational studies, including a very large UK study,³⁴ that in contrast with oral estrogen, transdermal estradiol is safer from the perspective of thrombosis.

Insurance coverage for IUDs

Dr. Pinkerton: Dr. Levy: Can you discuss IUDs and the Affordable Care Act’s requirement to cover contraceptive services?

Dr. Levy: Unfortunately, we do not know whether this benefit will continue based on a very recent finding from a judge in Texas that ruled the preventive benefits of the ACA were illegal.³⁵ We don’t know what will happen going forward. What I will say is that, unfortunately, many insurance companies have not preserved the meaning of “cover all things,” so what we are finding is that, for example, they only have to cover one type in a class. The FDA defined 18 classes of contraceptives, and a hormonal IUD is one class, so they can decide that they are only going to cover one of the four IUDS. And then women don’t have access to the other three, some of which might be more appropriate for them than another.

The other thing very relevant to this conversation is that, if you use an ICD-10 code for menorrhagia, for HMB, it no longer lives within that ACA preventive care requirement of coverage for contraceptives, and now she is going to owe a big deductible or a copay. If you are practicing in an institution that does not allow the use of IUDs for contraception, like a Catholic institution where I used to practice, you will want to use that ICD-10 code for HMB. But if you want it offered with no out-of-pocket cost for the patient, you need to use the preventive medicine codes and the contraception code. These little nuances for us can make a huge difference for our patients.

Dr. Pinkerton: Thank you for that reminder. I want to thank our panelists, Dr. Levy, Dr. Goldstein, and Dr. Kaunitz, for providing us with such a great mix of evidence and expert opinion and also giving a benefit of their vast experience as award-winning gynecologists. Hopefully, today you have learned the benefits of the progestin IUD not only for contraception in reproductive years and perimenopause but also for treatment of HMB, and the potential benefit due to the more prolonged effectiveness of the IUDs for endometrial protection in postmenopause. This allows less progestin risk, essentially estrogen alone for postmenopausal HT. Unsolved questions remain about whether there is a risk of breast cancer with their use, but there is a clear benefit of protecting against pregnancy and endometrial cancer. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021;374:n2182. doi: 10.1136/bmj.n2182.

Much interest has surrounded whether the use of menopausal HT impacts future risk of cognitive decline. Recently, Vinogradova and colleagues conducted an observational study using data from 2 large primary care databases, QResearch and the Clinical Practice Research Datalink (CPRD), in the United Kingdom.¹ The investigators conducted case-control studies that included women aged 55 and older diagnosed with dementia and up to 5 controls without dementia. Only cases and controls with at least 10 years of medical records prior to the index date (that is, the time of dementia diagnosis in cases) were included. Since early symptoms of dementia prior to diagnosis may cause sleep problems and dysphoria (which also may be symptoms of menopause), HT prescriptions during the 3 years prior to the index date were excluded.

Details of the study

Among 16,291 cases and 68,726 controls, the women’s mean age was approximately 83 years. Cases were identified by using codes for dementia from patients’ clinical records or records of prescriptions for drugs used to treat dementia.

More than half the women were being treated for hypertension, and 14% of women in both groups had used HT. Women were considered users of estrogen-only therapy if they had no prescriptions containing a progestogen after their first prescription for systemic estrogen as the start of exposure to HT. Those with any subsequent prescription containing a progestogen were classified as combined HT users.

Results. In an analysis adjusted for all available potential confounders—including lifestyle factors, ethnicity, family history of dementia, early menopause, oophorectomy/ hysterectomy, comorbidities, and use of other relevant drugs—the use of HT was not associated with risk of dementia.

A reduced risk of dementia was noted among women who had been taking estrogen-only HT for 10 years or more (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.94). An elevated risk of Alzheimer disease was noted among women who had used estrogen-progestin HT for 5 to 9 years (OR, 1.19; CI, 1.06–1.33).¹

Study strengths and limitations

The authors pointed out that this study’s main strengths were that it had a very large sample size representative of the general population and that its design permitted capture of all known cases as well as precision recording for prescribed drugs. On the other hand, the study is limited by the possible lack of data for some older women before the index date; that is, menopause in this latter group started before their registration or before these data were gathered electronically by their practice. ●

Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021;374:n2182. doi: 10.1136/bmj.n2182.

Much interest has surrounded whether the use of menopausal HT impacts future risk of cognitive decline. Recently, Vinogradova and colleagues conducted an observational study using data from 2 large primary care databases, QResearch and the Clinical Practice Research Datalink (CPRD), in the United Kingdom.¹ The investigators conducted case-control studies that included women aged 55 and older diagnosed with dementia and up to 5 controls without dementia. Only cases and controls with at least 10 years of medical records prior to the index date (that is, the time of dementia diagnosis in cases) were included. Since early symptoms of dementia prior to diagnosis may cause sleep problems and dysphoria (which also may be symptoms of menopause), HT prescriptions during the 3 years prior to the index date were excluded.

Details of the study

Among 16,291 cases and 68,726 controls, the women’s mean age was approximately 83 years. Cases were identified by using codes for dementia from patients’ clinical records or records of prescriptions for drugs used to treat dementia.

More than half the women were being treated for hypertension, and 14% of women in both groups had used HT. Women were considered users of estrogen-only therapy if they had no prescriptions containing a progestogen after their first prescription for systemic estrogen as the start of exposure to HT. Those with any subsequent prescription containing a progestogen were classified as combined HT users.

Results. In an analysis adjusted for all available potential confounders—including lifestyle factors, ethnicity, family history of dementia, early menopause, oophorectomy/ hysterectomy, comorbidities, and use of other relevant drugs—the use of HT was not associated with risk of dementia.

A reduced risk of dementia was noted among women who had been taking estrogen-only HT for 10 years or more (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.94). An elevated risk of Alzheimer disease was noted among women who had used estrogen-progestin HT for 5 to 9 years (OR, 1.19; CI, 1.06–1.33).¹

Study strengths and limitations

The authors pointed out that this study’s main strengths were that it had a very large sample size representative of the general population and that its design permitted capture of all known cases as well as precision recording for prescribed drugs. On the other hand, the study is limited by the possible lack of data for some older women before the index date; that is, menopause in this latter group started before their registration or before these data were gathered electronically by their practice. ●

Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021;374:n2182. doi: 10.1136/bmj.n2182.

Much interest has surrounded whether the use of menopausal HT impacts future risk of cognitive decline. Recently, Vinogradova and colleagues conducted an observational study using data from 2 large primary care databases, QResearch and the Clinical Practice Research Datalink (CPRD), in the United Kingdom.¹ The investigators conducted case-control studies that included women aged 55 and older diagnosed with dementia and up to 5 controls without dementia. Only cases and controls with at least 10 years of medical records prior to the index date (that is, the time of dementia diagnosis in cases) were included. Since early symptoms of dementia prior to diagnosis may cause sleep problems and dysphoria (which also may be symptoms of menopause), HT prescriptions during the 3 years prior to the index date were excluded.

Details of the study

Among 16,291 cases and 68,726 controls, the women’s mean age was approximately 83 years. Cases were identified by using codes for dementia from patients’ clinical records or records of prescriptions for drugs used to treat dementia.

More than half the women were being treated for hypertension, and 14% of women in both groups had used HT. Women were considered users of estrogen-only therapy if they had no prescriptions containing a progestogen after their first prescription for systemic estrogen as the start of exposure to HT. Those with any subsequent prescription containing a progestogen were classified as combined HT users.

Results. In an analysis adjusted for all available potential confounders—including lifestyle factors, ethnicity, family history of dementia, early menopause, oophorectomy/ hysterectomy, comorbidities, and use of other relevant drugs—the use of HT was not associated with risk of dementia.

A reduced risk of dementia was noted among women who had been taking estrogen-only HT for 10 years or more (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.94). An elevated risk of Alzheimer disease was noted among women who had used estrogen-progestin HT for 5 to 9 years (OR, 1.19; CI, 1.06–1.33).¹

Study strengths and limitations

The authors pointed out that this study’s main strengths were that it had a very large sample size representative of the general population and that its design permitted capture of all known cases as well as precision recording for prescribed drugs. On the other hand, the study is limited by the possible lack of data for some older women before the index date; that is, menopause in this latter group started before their registration or before these data were gathered electronically by their practice. ●

Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326:1381-1389. doi: 10.1001/jama.2021.14892.

EXPERT COMMENTARY

Symptomatic vaginal atrophy, also referred to as genitourinary syndrome of menopause (GSM), is common and tends to progress without treatment. When use of over-the-counter lubricants and/or moisturizers are not sufficient to address symptoms, vaginal estrogen has represented the mainstay of treatment for this condition and effectively addresses GSM symptoms.¹ In recent years, some physicians have been offering vaginal carbon dioxide (CO2) laser therapy as an alternative to vaginal estrogen in the treatment of GSM; however, the efficacy of laser therapy in this setting has been uncertain.

Li and colleagues conducted a double-blind randomized trial in postmenopausal women with bothersome vaginal symptoms to compare the efficacy of the fractional CO2 vaginal laser with that of sham treatment.

Details of the study

Investigators (who received no funding from any relevant commercial entity) at a teaching hospital in Sydney, Australia, randomly assigned 85 women with menopausal symptoms suggestive of GSM to laser (n = 43) or sham (n = 42) treatment. Participants underwent 3 treatments at monthly intervals. Laser treatments were performed with standard settings (40-watt power), while sham treatments were conducted with low settings that have no tissue effect. Local anesthesia cream was employed for all procedures, and a plume evacuator was used to remove visual and olfactory effects from laser smoke.

To maintain blinding, different clinicians performed assessments and treatments. Symptom severity assessments were based on a visual analog scale (VAS) and the Vulvovaginal Symptom Questionnaire (VSQ), with a minimal clinically important difference specified as a 50% decrease in severity scores of both assessment tools. Change in severity of symptoms, including dyspareunia, dysuria, vaginal dryness, and burning and itching, was assessed at 12 months. Quality of life, the Vaginal Health Index (VHI) score, and vaginal histology were among the secondary outcomes. In addition, vaginal biopsies were performed at baseline and 6 months after study treatment.

Among the 78 women (91.7%) who completed the 12-month evaluations, the mean age was approximately 57, more than 95% were White, and approximately half were sexually active.

Results. For the laser and sham treatment groups, at 12 months no significant differences were noted for change in overall symptoms or in the most severe symptom. Many participants who received laser or sham treatment reported an improvement in vaginal symptoms 12 months following treatment.

The VAS score for a change in symptom severity in the laser-treated group compared with the sham-treated group was -17.2 versus -26.6, a difference of 9.4 (95% confidence interval [CI], -28.6 to 47.5), while the VAS score for the most severe symptom was -24.5 versus -20.4, a difference of -4.1 (95% CI, -32.5 to 24.3). The VSQ score was, respectively, -3.1 versus -1.6 (difference, -1.5 [95% CI, -5.9 to 3.0]). The mean quality of life score showed no significant differences between the laser and the sham group (6.3 vs 1.4, a difference of 4.8 [95% CI, -3.9 to 13.5]). The VHI score was 0.9 in the laser group versus 1.3 in the sham group, for a difference of -0.4 (95% CI, -4.3 to 3.6). Likewise, the proportion of participants who noted a reduction of more than 50% in bother from their most severe symptoms was similar in the 2 groups. Similarly, changes in vaginal histology were similar in the laser and sham groups.

The proportion of participants who reported adverse events, including transient vaginal discomfort, discharge, or urinary tract symptoms, was similar in the 2 groups.

Study strengths and limitations

Although other randomized studies of fractionated laser therapy for GSM have been reported, this Australian trial is the largest and longest to date and also is the first to have used sham-treated controls.

Breast cancer survivors represent a group of patients for whom treatment of GSM can be a major conundrum—induced menopause that often results when combination chemotherapy is employed in premenopausal survivors can result in severe GSM; use of aromatase inhibitors likewise can cause bothersome GSM symptoms. Since the US Food and Drug Administration lists a personal history of breast cancer as a contraindication to use of any estrogen formulation, breast cancer survivors represent a population targeted by physicians offering vaginal laser treatment. Accordingly, that approximately 50% of trial participants were breast cancer survivors means the investigators were assessing the impact of laser therapy in a population of particular clinical relevance. Of note, as with participants overall, laser therapy when employed in breast cancer survivors did not result in outcomes distinct from sham treatments.² ●

Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326:1381-1389. doi: 10.1001/jama.2021.14892.

EXPERT COMMENTARY

Symptomatic vaginal atrophy, also referred to as genitourinary syndrome of menopause (GSM), is common and tends to progress without treatment. When use of over-the-counter lubricants and/or moisturizers are not sufficient to address symptoms, vaginal estrogen has represented the mainstay of treatment for this condition and effectively addresses GSM symptoms.¹ In recent years, some physicians have been offering vaginal carbon dioxide (CO2) laser therapy as an alternative to vaginal estrogen in the treatment of GSM; however, the efficacy of laser therapy in this setting has been uncertain.

Li and colleagues conducted a double-blind randomized trial in postmenopausal women with bothersome vaginal symptoms to compare the efficacy of the fractional CO2 vaginal laser with that of sham treatment.

Details of the study

Investigators (who received no funding from any relevant commercial entity) at a teaching hospital in Sydney, Australia, randomly assigned 85 women with menopausal symptoms suggestive of GSM to laser (n = 43) or sham (n = 42) treatment. Participants underwent 3 treatments at monthly intervals. Laser treatments were performed with standard settings (40-watt power), while sham treatments were conducted with low settings that have no tissue effect. Local anesthesia cream was employed for all procedures, and a plume evacuator was used to remove visual and olfactory effects from laser smoke.

To maintain blinding, different clinicians performed assessments and treatments. Symptom severity assessments were based on a visual analog scale (VAS) and the Vulvovaginal Symptom Questionnaire (VSQ), with a minimal clinically important difference specified as a 50% decrease in severity scores of both assessment tools. Change in severity of symptoms, including dyspareunia, dysuria, vaginal dryness, and burning and itching, was assessed at 12 months. Quality of life, the Vaginal Health Index (VHI) score, and vaginal histology were among the secondary outcomes. In addition, vaginal biopsies were performed at baseline and 6 months after study treatment.

Among the 78 women (91.7%) who completed the 12-month evaluations, the mean age was approximately 57, more than 95% were White, and approximately half were sexually active.

Results. For the laser and sham treatment groups, at 12 months no significant differences were noted for change in overall symptoms or in the most severe symptom. Many participants who received laser or sham treatment reported an improvement in vaginal symptoms 12 months following treatment.

The VAS score for a change in symptom severity in the laser-treated group compared with the sham-treated group was -17.2 versus -26.6, a difference of 9.4 (95% confidence interval [CI], -28.6 to 47.5), while the VAS score for the most severe symptom was -24.5 versus -20.4, a difference of -4.1 (95% CI, -32.5 to 24.3). The VSQ score was, respectively, -3.1 versus -1.6 (difference, -1.5 [95% CI, -5.9 to 3.0]). The mean quality of life score showed no significant differences between the laser and the sham group (6.3 vs 1.4, a difference of 4.8 [95% CI, -3.9 to 13.5]). The VHI score was 0.9 in the laser group versus 1.3 in the sham group, for a difference of -0.4 (95% CI, -4.3 to 3.6). Likewise, the proportion of participants who noted a reduction of more than 50% in bother from their most severe symptoms was similar in the 2 groups. Similarly, changes in vaginal histology were similar in the laser and sham groups.

The proportion of participants who reported adverse events, including transient vaginal discomfort, discharge, or urinary tract symptoms, was similar in the 2 groups.

Study strengths and limitations

Although other randomized studies of fractionated laser therapy for GSM have been reported, this Australian trial is the largest and longest to date and also is the first to have used sham-treated controls.

Breast cancer survivors represent a group of patients for whom treatment of GSM can be a major conundrum—induced menopause that often results when combination chemotherapy is employed in premenopausal survivors can result in severe GSM; use of aromatase inhibitors likewise can cause bothersome GSM symptoms. Since the US Food and Drug Administration lists a personal history of breast cancer as a contraindication to use of any estrogen formulation, breast cancer survivors represent a population targeted by physicians offering vaginal laser treatment. Accordingly, that approximately 50% of trial participants were breast cancer survivors means the investigators were assessing the impact of laser therapy in a population of particular clinical relevance. Of note, as with participants overall, laser therapy when employed in breast cancer survivors did not result in outcomes distinct from sham treatments.² ●

Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326:1381-1389. doi: 10.1001/jama.2021.14892.

EXPERT COMMENTARY

Symptomatic vaginal atrophy, also referred to as genitourinary syndrome of menopause (GSM), is common and tends to progress without treatment. When use of over-the-counter lubricants and/or moisturizers are not sufficient to address symptoms, vaginal estrogen has represented the mainstay of treatment for this condition and effectively addresses GSM symptoms.¹ In recent years, some physicians have been offering vaginal carbon dioxide (CO2) laser therapy as an alternative to vaginal estrogen in the treatment of GSM; however, the efficacy of laser therapy in this setting has been uncertain.

Li and colleagues conducted a double-blind randomized trial in postmenopausal women with bothersome vaginal symptoms to compare the efficacy of the fractional CO2 vaginal laser with that of sham treatment.

Details of the study

Investigators (who received no funding from any relevant commercial entity) at a teaching hospital in Sydney, Australia, randomly assigned 85 women with menopausal symptoms suggestive of GSM to laser (n = 43) or sham (n = 42) treatment. Participants underwent 3 treatments at monthly intervals. Laser treatments were performed with standard settings (40-watt power), while sham treatments were conducted with low settings that have no tissue effect. Local anesthesia cream was employed for all procedures, and a plume evacuator was used to remove visual and olfactory effects from laser smoke.

To maintain blinding, different clinicians performed assessments and treatments. Symptom severity assessments were based on a visual analog scale (VAS) and the Vulvovaginal Symptom Questionnaire (VSQ), with a minimal clinically important difference specified as a 50% decrease in severity scores of both assessment tools. Change in severity of symptoms, including dyspareunia, dysuria, vaginal dryness, and burning and itching, was assessed at 12 months. Quality of life, the Vaginal Health Index (VHI) score, and vaginal histology were among the secondary outcomes. In addition, vaginal biopsies were performed at baseline and 6 months after study treatment.

Among the 78 women (91.7%) who completed the 12-month evaluations, the mean age was approximately 57, more than 95% were White, and approximately half were sexually active.

Results. For the laser and sham treatment groups, at 12 months no significant differences were noted for change in overall symptoms or in the most severe symptom. Many participants who received laser or sham treatment reported an improvement in vaginal symptoms 12 months following treatment.

The VAS score for a change in symptom severity in the laser-treated group compared with the sham-treated group was -17.2 versus -26.6, a difference of 9.4 (95% confidence interval [CI], -28.6 to 47.5), while the VAS score for the most severe symptom was -24.5 versus -20.4, a difference of -4.1 (95% CI, -32.5 to 24.3). The VSQ score was, respectively, -3.1 versus -1.6 (difference, -1.5 [95% CI, -5.9 to 3.0]). The mean quality of life score showed no significant differences between the laser and the sham group (6.3 vs 1.4, a difference of 4.8 [95% CI, -3.9 to 13.5]). The VHI score was 0.9 in the laser group versus 1.3 in the sham group, for a difference of -0.4 (95% CI, -4.3 to 3.6). Likewise, the proportion of participants who noted a reduction of more than 50% in bother from their most severe symptoms was similar in the 2 groups. Similarly, changes in vaginal histology were similar in the laser and sham groups.

The proportion of participants who reported adverse events, including transient vaginal discomfort, discharge, or urinary tract symptoms, was similar in the 2 groups.

Study strengths and limitations

Although other randomized studies of fractionated laser therapy for GSM have been reported, this Australian trial is the largest and longest to date and also is the first to have used sham-treated controls.

Breast cancer survivors represent a group of patients for whom treatment of GSM can be a major conundrum—induced menopause that often results when combination chemotherapy is employed in premenopausal survivors can result in severe GSM; use of aromatase inhibitors likewise can cause bothersome GSM symptoms. Since the US Food and Drug Administration lists a personal history of breast cancer as a contraindication to use of any estrogen formulation, breast cancer survivors represent a population targeted by physicians offering vaginal laser treatment. Accordingly, that approximately 50% of trial participants were breast cancer survivors means the investigators were assessing the impact of laser therapy in a population of particular clinical relevance. Of note, as with participants overall, laser therapy when employed in breast cancer survivors did not result in outcomes distinct from sham treatments.² ●

Short-term hormonal contraceptives remain the most popular class of reversible contraceptives in the United States, despite the availability of longer-acting methods. Oral contraceptives (OCs), contraceptive patches, and contraceptive vaginal rings are extensively used not only because these methods are easy to initiate but also because their ongoing use remains under the control of the woman herself and also provides her with a wide range of important noncontraceptive benefits.

Despite the more than 60 years of innovation that have made hormonal contraceptives safer, more tolerable, and more convenient, there has been room for improvement. Over the last few years, 4 new hormonal methods have been introduced, and each addresses different limitations and problems associated with the existing, often generic, products.

Compared with the traditional norethindrone pill (Micronor and generics), a new drospirenone progestin-only pill (POP) increases ovulation suppression, offers an improved cyclical bleeding profile, and relaxes the tight missed-pill rules that are usually associated with POPs.

In contrast with the older norelgestromin patch (Evra, Xulane), a new contraceptive transdermal patch significantly decreases total estrogen exposure and pairs its estrogen with levonorgestrel, the progestin associated with the lowest venous thromboembolism (VTE) risk in combined hormonal pills.

While existing combination OCs are formulated with the potent estrogen ethinyl estradiol (EE), a new combination pill, formulated with estetrol (E4) and drospirenone, introduces the first new estrogen (estetrol) used in a contraceptive in more than 50 years. Estetrol, a native estrogen, has selective tissue activity with minimal hepatic and breast impacts. Combined with drospirenone, this formulation offers women good contraceptive efficacy and bleeding patterns.

A new contraceptive vaginal ring introduces a new long-acting, specific progestin (segesterone acetate) and pairs it with low-dose EE. These hormones are packaged in a soft vaginal ring that provides up to 13 cycles of contraceptive protection (3 weeks in/1 week out) with one ring, greatly increasing convenience for women.

Each of these new products represents important incremental improvement over existing options.

Continue to: 1. The drospirenone-only OC...

The new POP with drospirenone 4 mg (Slynd), which received US Food and Drug Administration (FDA) approval in 2019, is packaged in a 24/4 formulation (24 hormonally active tablets followed by 4 inactive tablets). This formulation results in more predictable bleeding than does the 0.35-mg norethindrone POP, which contains 28 hormonally active tablets in each pack. In the US clinical trials of drospirenone 4 mg, scheduled bleeding decreased from 81% in cycle 1 to 20% in cycle 13. Unscheduled spotting and bleeding decreased from 61% to 40% in the same timeframe. Notably, this bleeding pattern was well tolerated; only 0.4% of trial participants discontinued this drospirenone POP due to problems with irregular bleeding or amenorrhea.

In contrast to the continuous norethindrone POP, which is not sufficiently dosed to consistently suppress ovulation, the 4-mg daily dose of drospirenone in this new POP is higher than the 3 mg used in commonly prescribed combination OCs that contain EE and drospirenone. This results in a POP that has more consistent ovulation suppression. Because this drospirenone POP is appropriately dosed and based on a longer-acting progestin, it is more forgiving of inconsistent pill taking. Accordingly, the missed-pill rules for this pill are the same as with combination estrogen-progestin OCs.¹ The package labeling cites a first-year failure rate of 4%, but this includes unconfirmed pregnancies. The Pearl Index from the North American trials, based on confirmed pregnancies in nonbreastfeeding women, was 2.9.²

The package labeling for this drospirenone POP includes few contraindications. Conditions that preclude use include the US Medical Eligibility Criteria for contraception Category 4 condition (breast cancer in the last 5 years), renal impairment, and adrenal insufficiency. Other standard contraindications are listed in the prescribing information. Serum potassium levels should be checked (one time only) in the first cycle only for women who chronically use medications that could cause hyperkalemia, such as nonsteroidal anti-inflammatory drugs.

Given the ovulation suppression associated with this drospirenone POP, the safety of a progestin-only method, and the persistent popularity of OC pills, this pill should greatly increase the use of POPs beyond their traditional niche of postpartum and breastfeeding women. The advent of the drospirenone POP means that clinicians now have better options for women who have contraindications to estrogen and desire to control their own contraceptive use. It would be a logical consideration for over-the-counter accessibility.

2. Transdermal patch with ethinyl estradiol/levonorgestrel

The new EE/levonorgestrel transdermal contraceptive patch (Twirla) is soft and flexible, about the same size as other contraceptive patches, and contains EE 2.3 mg/levonorgestrel 2.6 mg. It provides total estrogen exposure that is similar to that of OCs with EE 30 µg and distinctly lower than estrogen levels seen with the original norelgestromin-containing patch or its 2 subsequent generic versions.³ This EE/levonorgestrel patch uses a new 5-layer drug delivery system that focuses the steroids for absorption beneath the patch; there is no peripheral spread of drug around the patch (FIGURE 1).

Transdermal patches offer the convenience of once-a-week dosing. One patch is used each week for 3 consecutive weeks followed by a patch-free week. Patches can be worn on the abdomen, buttock, or trunk (except breasts). Patches should not be placed consecutively on the same site; after a week’s rest, however, the first site can be reused. All transdermal contraceptive products are indicated for use only by women with a body mass index (BMI) <30 kg/m².⁴

While no head-to-head trials have compared this new lower-dose patch with older patches, each patch was compared against a standardized pill, so meaningful comparisons can be made.

In each case, the circulating estrogen levels associated with use of the EE/levonorgestrel patch were considerably lower than those of the comparator pill, while the older norelgestromin patch consistently delivered higher total estrogen levels than its 35-µg comparator pill (TABLE).³ Along these lines, no VTE events occurred in women in the clinical trial of the new patch among women with a BMI <30 kg/m².⁴

Women with a BMI <25 kg/m² experienced lower Pearl Index (PI) pregnancy rates (3.5%) compared with women with a BMI between 25 and 30 kg/m² (5.7%), according to clinical trial data cited in the package labeling. All the modern PI criteria were used to calculate these failure rates. Cycles in which no coitus occurred were excluded. Similarly, cycles in which another contraceptive method (for example, condoms) was added (even once) were excluded. Frequent pregnancy testing was done in the study centers and by the women at home. Bleeding patterns were well accepted; only 2.2% of study participants exited the study early due to menstrual disorders of any kind. Similarly, 3.1% of women discontinued use because of application site disorders. Women should be advised to press down on the patch edges after emerging from water exposure. Replacement patches are rapidly available from the manufacturer should permanent complete patch detachment occur.

Larger-scale phase 4 trials will be conducted to study the impact of this lower-dose patch on VTE rates.

Continue to: 3. A 1-year contraceptive vaginal ring...

The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).⁵ A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.

The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.⁶

Continue to: 4. An OC with a novel estrogen...

4. An OC with a novel estrogen

Even as use of intrauterine devices and contraceptive implants continues to grow, OCs remain the reversible contraceptive most used by US women. While OCs have been widely studied and represent a safe method of contraception for most reproductive-age women, combination estrogen-progestin OCs are well recognized to increase the risk of VTE. Although the primary role of the progestin component of combination OCs is to suppress ovulation, estrogen is included in combination OCs to stimulate endometrial proliferation, thereby causing predictable bleeding. EE, the potent synthetic estrogen used in the great majority of current OC formulations, induces hepatic production of prothrombotic proteins while inhibiting synthesis of antithrombotic proteins. While the lower EE doses (10–35 µg) in today’s OC formulations are associated with a lower VTE risk than older OCs that contained higher doses of estrogen, VTE continues to represent the principal health risk associated with use of combination OCs. Accordingly, development of a combination OC that has less impact on risk of VTE would be appealing.

In April 2021, the FDA approved an OC formulation that combines 15 mg of the novel estrogen estetrol with 3 mg of drospirenone (Nextstellis). This dose of drospirenone is the same as that used in commonly prescribed EE/drospirenone OC formulations. Also known as E4, estetrol is a natural estrogen synthesized by the fetal liver. Plant-derived E4 is used in this new OC.

Depending on the tissue, E4 acts differently than other estrogens. Similar to other estrogens, E4 acts as an agonist on the nuclear receptor to produce beneficial effects in bone, vaginal mucosa, and heart.⁸ Unlike other estrogens, E4 inhibits proliferation of mammary gland cells and has a neutral impact on the liver.⁹

In contrast with EE, E4 is not inhibited by the liver’s P450 enzymes; accordingly, the risk of drug-drug interactions is reduced. Because E4 is primarily excreted through the urine and not through the biliary tract, the risk of gallstone formation may be lower than with an EE OC. Likewise, E4 has substantially less impact on triglycerides, which are increased with EE. Finally, because of E4’s reduced effect on the liver, the impact on clotting parameters is less than that observed with an OC formulated with EE.¹⁰ This latter observation raises the possibility that VTE risk is lower with the E4/drospirenone OC than an OC formulated with EE.

A 13-cycle phase 3 trial of the E4/drospirenone OC conducted in the United States and Canada enrolled 1,864 women aged 16 to 50 years, including 1,674 who were aged 16 to 35 years.¹¹ Among women in this latter age group, the PI was 2.65 per 100 woman-years. Bleeding/cycle control patterns were similar to those observed in recent trials of other combination contraceptives. Likewise, the proportion of trial participants who discontinued the study due to adverse effects was similar to or lower than that noted in recent trials of other combination contraceptives. Of particular note, no cases of VTE were noted among trial participants of any BMI, a finding which contrasts with recent phase 3 trials of other combination contraceptives. The result of this pivotal trial suggests that the theoretic advantages of E4 when used in a combination OC formulation may translate into a safer, effective, and well-tolerated contraceptive.

Refinements in hormonal contraceptives continue

The 4 new short-acting hormonal contraceptives we reviewed represent enhancements on existing pills, patches, and rings. We hope that, financially, women will have access to these innovative methods and, in particular, that third-party payers will facilitate women’s access to these enhanced short-acting hormonal contraceptives. ●

Short-term hormonal contraceptives remain the most popular class of reversible contraceptives in the United States, despite the availability of longer-acting methods. Oral contraceptives (OCs), contraceptive patches, and contraceptive vaginal rings are extensively used not only because these methods are easy to initiate but also because their ongoing use remains under the control of the woman herself and also provides her with a wide range of important noncontraceptive benefits.

Despite the more than 60 years of innovation that have made hormonal contraceptives safer, more tolerable, and more convenient, there has been room for improvement. Over the last few years, 4 new hormonal methods have been introduced, and each addresses different limitations and problems associated with the existing, often generic, products.

Compared with the traditional norethindrone pill (Micronor and generics), a new drospirenone progestin-only pill (POP) increases ovulation suppression, offers an improved cyclical bleeding profile, and relaxes the tight missed-pill rules that are usually associated with POPs.

In contrast with the older norelgestromin patch (Evra, Xulane), a new contraceptive transdermal patch significantly decreases total estrogen exposure and pairs its estrogen with levonorgestrel, the progestin associated with the lowest venous thromboembolism (VTE) risk in combined hormonal pills.

While existing combination OCs are formulated with the potent estrogen ethinyl estradiol (EE), a new combination pill, formulated with estetrol (E4) and drospirenone, introduces the first new estrogen (estetrol) used in a contraceptive in more than 50 years. Estetrol, a native estrogen, has selective tissue activity with minimal hepatic and breast impacts. Combined with drospirenone, this formulation offers women good contraceptive efficacy and bleeding patterns.

A new contraceptive vaginal ring introduces a new long-acting, specific progestin (segesterone acetate) and pairs it with low-dose EE. These hormones are packaged in a soft vaginal ring that provides up to 13 cycles of contraceptive protection (3 weeks in/1 week out) with one ring, greatly increasing convenience for women.

Each of these new products represents important incremental improvement over existing options.

Continue to: 1. The drospirenone-only OC...

The new POP with drospirenone 4 mg (Slynd), which received US Food and Drug Administration (FDA) approval in 2019, is packaged in a 24/4 formulation (24 hormonally active tablets followed by 4 inactive tablets). This formulation results in more predictable bleeding than does the 0.35-mg norethindrone POP, which contains 28 hormonally active tablets in each pack. In the US clinical trials of drospirenone 4 mg, scheduled bleeding decreased from 81% in cycle 1 to 20% in cycle 13. Unscheduled spotting and bleeding decreased from 61% to 40% in the same timeframe. Notably, this bleeding pattern was well tolerated; only 0.4% of trial participants discontinued this drospirenone POP due to problems with irregular bleeding or amenorrhea.

In contrast to the continuous norethindrone POP, which is not sufficiently dosed to consistently suppress ovulation, the 4-mg daily dose of drospirenone in this new POP is higher than the 3 mg used in commonly prescribed combination OCs that contain EE and drospirenone. This results in a POP that has more consistent ovulation suppression. Because this drospirenone POP is appropriately dosed and based on a longer-acting progestin, it is more forgiving of inconsistent pill taking. Accordingly, the missed-pill rules for this pill are the same as with combination estrogen-progestin OCs.¹ The package labeling cites a first-year failure rate of 4%, but this includes unconfirmed pregnancies. The Pearl Index from the North American trials, based on confirmed pregnancies in nonbreastfeeding women, was 2.9.²

The package labeling for this drospirenone POP includes few contraindications. Conditions that preclude use include the US Medical Eligibility Criteria for contraception Category 4 condition (breast cancer in the last 5 years), renal impairment, and adrenal insufficiency. Other standard contraindications are listed in the prescribing information. Serum potassium levels should be checked (one time only) in the first cycle only for women who chronically use medications that could cause hyperkalemia, such as nonsteroidal anti-inflammatory drugs.

Given the ovulation suppression associated with this drospirenone POP, the safety of a progestin-only method, and the persistent popularity of OC pills, this pill should greatly increase the use of POPs beyond their traditional niche of postpartum and breastfeeding women. The advent of the drospirenone POP means that clinicians now have better options for women who have contraindications to estrogen and desire to control their own contraceptive use. It would be a logical consideration for over-the-counter accessibility.

2. Transdermal patch with ethinyl estradiol/levonorgestrel

The new EE/levonorgestrel transdermal contraceptive patch (Twirla) is soft and flexible, about the same size as other contraceptive patches, and contains EE 2.3 mg/levonorgestrel 2.6 mg. It provides total estrogen exposure that is similar to that of OCs with EE 30 µg and distinctly lower than estrogen levels seen with the original norelgestromin-containing patch or its 2 subsequent generic versions.³ This EE/levonorgestrel patch uses a new 5-layer drug delivery system that focuses the steroids for absorption beneath the patch; there is no peripheral spread of drug around the patch (FIGURE 1).

Transdermal patches offer the convenience of once-a-week dosing. One patch is used each week for 3 consecutive weeks followed by a patch-free week. Patches can be worn on the abdomen, buttock, or trunk (except breasts). Patches should not be placed consecutively on the same site; after a week’s rest, however, the first site can be reused. All transdermal contraceptive products are indicated for use only by women with a body mass index (BMI) <30 kg/m².⁴

While no head-to-head trials have compared this new lower-dose patch with older patches, each patch was compared against a standardized pill, so meaningful comparisons can be made.

In each case, the circulating estrogen levels associated with use of the EE/levonorgestrel patch were considerably lower than those of the comparator pill, while the older norelgestromin patch consistently delivered higher total estrogen levels than its 35-µg comparator pill (TABLE).³ Along these lines, no VTE events occurred in women in the clinical trial of the new patch among women with a BMI <30 kg/m².⁴

Women with a BMI <25 kg/m² experienced lower Pearl Index (PI) pregnancy rates (3.5%) compared with women with a BMI between 25 and 30 kg/m² (5.7%), according to clinical trial data cited in the package labeling. All the modern PI criteria were used to calculate these failure rates. Cycles in which no coitus occurred were excluded. Similarly, cycles in which another contraceptive method (for example, condoms) was added (even once) were excluded. Frequent pregnancy testing was done in the study centers and by the women at home. Bleeding patterns were well accepted; only 2.2% of study participants exited the study early due to menstrual disorders of any kind. Similarly, 3.1% of women discontinued use because of application site disorders. Women should be advised to press down on the patch edges after emerging from water exposure. Replacement patches are rapidly available from the manufacturer should permanent complete patch detachment occur.

Larger-scale phase 4 trials will be conducted to study the impact of this lower-dose patch on VTE rates.

Continue to: 3. A 1-year contraceptive vaginal ring...

The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).⁵ A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.

The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.⁶

Continue to: 4. An OC with a novel estrogen...

4. An OC with a novel estrogen

Even as use of intrauterine devices and contraceptive implants continues to grow, OCs remain the reversible contraceptive most used by US women. While OCs have been widely studied and represent a safe method of contraception for most reproductive-age women, combination estrogen-progestin OCs are well recognized to increase the risk of VTE. Although the primary role of the progestin component of combination OCs is to suppress ovulation, estrogen is included in combination OCs to stimulate endometrial proliferation, thereby causing predictable bleeding. EE, the potent synthetic estrogen used in the great majority of current OC formulations, induces hepatic production of prothrombotic proteins while inhibiting synthesis of antithrombotic proteins. While the lower EE doses (10–35 µg) in today’s OC formulations are associated with a lower VTE risk than older OCs that contained higher doses of estrogen, VTE continues to represent the principal health risk associated with use of combination OCs. Accordingly, development of a combination OC that has less impact on risk of VTE would be appealing.

In April 2021, the FDA approved an OC formulation that combines 15 mg of the novel estrogen estetrol with 3 mg of drospirenone (Nextstellis). This dose of drospirenone is the same as that used in commonly prescribed EE/drospirenone OC formulations. Also known as E4, estetrol is a natural estrogen synthesized by the fetal liver. Plant-derived E4 is used in this new OC.

Depending on the tissue, E4 acts differently than other estrogens. Similar to other estrogens, E4 acts as an agonist on the nuclear receptor to produce beneficial effects in bone, vaginal mucosa, and heart.⁸ Unlike other estrogens, E4 inhibits proliferation of mammary gland cells and has a neutral impact on the liver.⁹

In contrast with EE, E4 is not inhibited by the liver’s P450 enzymes; accordingly, the risk of drug-drug interactions is reduced. Because E4 is primarily excreted through the urine and not through the biliary tract, the risk of gallstone formation may be lower than with an EE OC. Likewise, E4 has substantially less impact on triglycerides, which are increased with EE. Finally, because of E4’s reduced effect on the liver, the impact on clotting parameters is less than that observed with an OC formulated with EE.¹⁰ This latter observation raises the possibility that VTE risk is lower with the E4/drospirenone OC than an OC formulated with EE.

A 13-cycle phase 3 trial of the E4/drospirenone OC conducted in the United States and Canada enrolled 1,864 women aged 16 to 50 years, including 1,674 who were aged 16 to 35 years.¹¹ Among women in this latter age group, the PI was 2.65 per 100 woman-years. Bleeding/cycle control patterns were similar to those observed in recent trials of other combination contraceptives. Likewise, the proportion of trial participants who discontinued the study due to adverse effects was similar to or lower than that noted in recent trials of other combination contraceptives. Of particular note, no cases of VTE were noted among trial participants of any BMI, a finding which contrasts with recent phase 3 trials of other combination contraceptives. The result of this pivotal trial suggests that the theoretic advantages of E4 when used in a combination OC formulation may translate into a safer, effective, and well-tolerated contraceptive.

Refinements in hormonal contraceptives continue

The 4 new short-acting hormonal contraceptives we reviewed represent enhancements on existing pills, patches, and rings. We hope that, financially, women will have access to these innovative methods and, in particular, that third-party payers will facilitate women’s access to these enhanced short-acting hormonal contraceptives. ●

Short-term hormonal contraceptives remain the most popular class of reversible contraceptives in the United States, despite the availability of longer-acting methods. Oral contraceptives (OCs), contraceptive patches, and contraceptive vaginal rings are extensively used not only because these methods are easy to initiate but also because their ongoing use remains under the control of the woman herself and also provides her with a wide range of important noncontraceptive benefits.

Despite the more than 60 years of innovation that have made hormonal contraceptives safer, more tolerable, and more convenient, there has been room for improvement. Over the last few years, 4 new hormonal methods have been introduced, and each addresses different limitations and problems associated with the existing, often generic, products.

Compared with the traditional norethindrone pill (Micronor and generics), a new drospirenone progestin-only pill (POP) increases ovulation suppression, offers an improved cyclical bleeding profile, and relaxes the tight missed-pill rules that are usually associated with POPs.

In contrast with the older norelgestromin patch (Evra, Xulane), a new contraceptive transdermal patch significantly decreases total estrogen exposure and pairs its estrogen with levonorgestrel, the progestin associated with the lowest venous thromboembolism (VTE) risk in combined hormonal pills.

While existing combination OCs are formulated with the potent estrogen ethinyl estradiol (EE), a new combination pill, formulated with estetrol (E4) and drospirenone, introduces the first new estrogen (estetrol) used in a contraceptive in more than 50 years. Estetrol, a native estrogen, has selective tissue activity with minimal hepatic and breast impacts. Combined with drospirenone, this formulation offers women good contraceptive efficacy and bleeding patterns.

A new contraceptive vaginal ring introduces a new long-acting, specific progestin (segesterone acetate) and pairs it with low-dose EE. These hormones are packaged in a soft vaginal ring that provides up to 13 cycles of contraceptive protection (3 weeks in/1 week out) with one ring, greatly increasing convenience for women.

Each of these new products represents important incremental improvement over existing options.

Continue to: 1. The drospirenone-only OC...

The new POP with drospirenone 4 mg (Slynd), which received US Food and Drug Administration (FDA) approval in 2019, is packaged in a 24/4 formulation (24 hormonally active tablets followed by 4 inactive tablets). This formulation results in more predictable bleeding than does the 0.35-mg norethindrone POP, which contains 28 hormonally active tablets in each pack. In the US clinical trials of drospirenone 4 mg, scheduled bleeding decreased from 81% in cycle 1 to 20% in cycle 13. Unscheduled spotting and bleeding decreased from 61% to 40% in the same timeframe. Notably, this bleeding pattern was well tolerated; only 0.4% of trial participants discontinued this drospirenone POP due to problems with irregular bleeding or amenorrhea.

In contrast to the continuous norethindrone POP, which is not sufficiently dosed to consistently suppress ovulation, the 4-mg daily dose of drospirenone in this new POP is higher than the 3 mg used in commonly prescribed combination OCs that contain EE and drospirenone. This results in a POP that has more consistent ovulation suppression. Because this drospirenone POP is appropriately dosed and based on a longer-acting progestin, it is more forgiving of inconsistent pill taking. Accordingly, the missed-pill rules for this pill are the same as with combination estrogen-progestin OCs.¹ The package labeling cites a first-year failure rate of 4%, but this includes unconfirmed pregnancies. The Pearl Index from the North American trials, based on confirmed pregnancies in nonbreastfeeding women, was 2.9.²

The package labeling for this drospirenone POP includes few contraindications. Conditions that preclude use include the US Medical Eligibility Criteria for contraception Category 4 condition (breast cancer in the last 5 years), renal impairment, and adrenal insufficiency. Other standard contraindications are listed in the prescribing information. Serum potassium levels should be checked (one time only) in the first cycle only for women who chronically use medications that could cause hyperkalemia, such as nonsteroidal anti-inflammatory drugs.

Given the ovulation suppression associated with this drospirenone POP, the safety of a progestin-only method, and the persistent popularity of OC pills, this pill should greatly increase the use of POPs beyond their traditional niche of postpartum and breastfeeding women. The advent of the drospirenone POP means that clinicians now have better options for women who have contraindications to estrogen and desire to control their own contraceptive use. It would be a logical consideration for over-the-counter accessibility.

2. Transdermal patch with ethinyl estradiol/levonorgestrel

The new EE/levonorgestrel transdermal contraceptive patch (Twirla) is soft and flexible, about the same size as other contraceptive patches, and contains EE 2.3 mg/levonorgestrel 2.6 mg. It provides total estrogen exposure that is similar to that of OCs with EE 30 µg and distinctly lower than estrogen levels seen with the original norelgestromin-containing patch or its 2 subsequent generic versions.³ This EE/levonorgestrel patch uses a new 5-layer drug delivery system that focuses the steroids for absorption beneath the patch; there is no peripheral spread of drug around the patch (FIGURE 1).

Transdermal patches offer the convenience of once-a-week dosing. One patch is used each week for 3 consecutive weeks followed by a patch-free week. Patches can be worn on the abdomen, buttock, or trunk (except breasts). Patches should not be placed consecutively on the same site; after a week’s rest, however, the first site can be reused. All transdermal contraceptive products are indicated for use only by women with a body mass index (BMI) <30 kg/m².⁴

While no head-to-head trials have compared this new lower-dose patch with older patches, each patch was compared against a standardized pill, so meaningful comparisons can be made.

In each case, the circulating estrogen levels associated with use of the EE/levonorgestrel patch were considerably lower than those of the comparator pill, while the older norelgestromin patch consistently delivered higher total estrogen levels than its 35-µg comparator pill (TABLE).³ Along these lines, no VTE events occurred in women in the clinical trial of the new patch among women with a BMI <30 kg/m².⁴

Women with a BMI <25 kg/m² experienced lower Pearl Index (PI) pregnancy rates (3.5%) compared with women with a BMI between 25 and 30 kg/m² (5.7%), according to clinical trial data cited in the package labeling. All the modern PI criteria were used to calculate these failure rates. Cycles in which no coitus occurred were excluded. Similarly, cycles in which another contraceptive method (for example, condoms) was added (even once) were excluded. Frequent pregnancy testing was done in the study centers and by the women at home. Bleeding patterns were well accepted; only 2.2% of study participants exited the study early due to menstrual disorders of any kind. Similarly, 3.1% of women discontinued use because of application site disorders. Women should be advised to press down on the patch edges after emerging from water exposure. Replacement patches are rapidly available from the manufacturer should permanent complete patch detachment occur.

Larger-scale phase 4 trials will be conducted to study the impact of this lower-dose patch on VTE rates.

Continue to: 3. A 1-year contraceptive vaginal ring...

The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).⁵ A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.

The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.⁶

Continue to: 4. An OC with a novel estrogen...

4. An OC with a novel estrogen

Even as use of intrauterine devices and contraceptive implants continues to grow, OCs remain the reversible contraceptive most used by US women. While OCs have been widely studied and represent a safe method of contraception for most reproductive-age women, combination estrogen-progestin OCs are well recognized to increase the risk of VTE. Although the primary role of the progestin component of combination OCs is to suppress ovulation, estrogen is included in combination OCs to stimulate endometrial proliferation, thereby causing predictable bleeding. EE, the potent synthetic estrogen used in the great majority of current OC formulations, induces hepatic production of prothrombotic proteins while inhibiting synthesis of antithrombotic proteins. While the lower EE doses (10–35 µg) in today’s OC formulations are associated with a lower VTE risk than older OCs that contained higher doses of estrogen, VTE continues to represent the principal health risk associated with use of combination OCs. Accordingly, development of a combination OC that has less impact on risk of VTE would be appealing.

In April 2021, the FDA approved an OC formulation that combines 15 mg of the novel estrogen estetrol with 3 mg of drospirenone (Nextstellis). This dose of drospirenone is the same as that used in commonly prescribed EE/drospirenone OC formulations. Also known as E4, estetrol is a natural estrogen synthesized by the fetal liver. Plant-derived E4 is used in this new OC.

Depending on the tissue, E4 acts differently than other estrogens. Similar to other estrogens, E4 acts as an agonist on the nuclear receptor to produce beneficial effects in bone, vaginal mucosa, and heart.⁸ Unlike other estrogens, E4 inhibits proliferation of mammary gland cells and has a neutral impact on the liver.⁹

In contrast with EE, E4 is not inhibited by the liver’s P450 enzymes; accordingly, the risk of drug-drug interactions is reduced. Because E4 is primarily excreted through the urine and not through the biliary tract, the risk of gallstone formation may be lower than with an EE OC. Likewise, E4 has substantially less impact on triglycerides, which are increased with EE. Finally, because of E4’s reduced effect on the liver, the impact on clotting parameters is less than that observed with an OC formulated with EE.¹⁰ This latter observation raises the possibility that VTE risk is lower with the E4/drospirenone OC than an OC formulated with EE.

A 13-cycle phase 3 trial of the E4/drospirenone OC conducted in the United States and Canada enrolled 1,864 women aged 16 to 50 years, including 1,674 who were aged 16 to 35 years.¹¹ Among women in this latter age group, the PI was 2.65 per 100 woman-years. Bleeding/cycle control patterns were similar to those observed in recent trials of other combination contraceptives. Likewise, the proportion of trial participants who discontinued the study due to adverse effects was similar to or lower than that noted in recent trials of other combination contraceptives. Of particular note, no cases of VTE were noted among trial participants of any BMI, a finding which contrasts with recent phase 3 trials of other combination contraceptives. The result of this pivotal trial suggests that the theoretic advantages of E4 when used in a combination OC formulation may translate into a safer, effective, and well-tolerated contraceptive.

Refinements in hormonal contraceptives continue

The 4 new short-acting hormonal contraceptives we reviewed represent enhancements on existing pills, patches, and rings. We hope that, financially, women will have access to these innovative methods and, in particular, that third-party payers will facilitate women’s access to these enhanced short-acting hormonal contraceptives. ●

Among the studies we review in this Update are a follow-up of the US Women’s Health Initiative clinical trials and a large observational study from the United Kingdom, which exlore the impact of different hormone therapies (HTs) on breast cancer risk. We look at the interesting patterns found by authors of a study in Canada that analyzed predictors of unnecessary bilateral salpingo-oophorectomy. In addition, we review a study that investigates whether hormone therapy can be effective, alone or adjunctively, in peri- and postmenopausal women with depression. Finally, Dr. Chrisandra Shufelt and Dr. JoAnn Manson summarize highlights from the recent American Heart Association’s scientific statement on the menopause transition and increasing risk factors for cardiovascular disease, and how this period can be viewed as an opportunity to encourage healthy, cardiovascular risk–reducing behaviors.

Studies clarify menopausal HT’s impact on breast cancer risk

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324:369-380. doi: 10.1001/jama.2020.9482.

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020;371:m3873. doi: 10.1136/bmj.m3873.

For many menopausal women, the most worrisome concern related to the use of HT is that it might increase breast cancer risk. In the summer and fall of 2020, 2 important articles were published that addressed how the use of menopausal HT impacts the risk of breast cancer.

The Women’s Health Initiative (WHI) represents the largest and longest-term randomized trial assessing the health impacts of systemic HT. A 2013 WHI report found that with a median of 13 years’ cumulative follow-up, estrogen-only HT (ET) reduced the risk for breast cancer while estrogen-progestin therapy (EPT) increased the risk.¹ In a July 2020 issue of JAMA, WHI investigators analyzed longer-term data (cumulative median follow-up >20 years), which allowed assessment of whether these trends (breast cancer incidence) persisted and if they led to changes in mortality from breast cancer.²

WHI data on breast cancer risk trends in ET vs EPT users

In the ET trial, in which Chlebowski and colleagues studied 10,739 women with prior hysterectomy, 238 versus 296 new cases of breast cancer were diagnosed in women in the ET versus placebo groups, respectively (annualized incidence, 0.30% [ET] vs 0.37% [placebo]; hazard ratio [HR], 0.78; P = .005). ET also was associated with significantly lower mortality from breast cancer: 30 versus 46 deaths (annualized mortality, 0.031% [ET] vs 0.046% [placebo]; HR, 0.60; P = 0.04).

In the EPT trial, which included 16,608 participants with an intact uterus, EPT compared with placebo was associated with significantly elevated risk for incident breast cancer: 584 versus 447 new cases, respectively (annualized incidence, 0.45% [EPT] vs 0.36% [placebo]; HR, 1.28; P<.001). However, mortality from breast cancer was similar in the EPT and placebo groups: 71 and 53 deaths (annualized mortality, 0.045% [EPT] and 0.035% [placebo]; HR, 1.35; P = .11).²

For women with previous hysterectomy who are considering initiating or continuing ET for treatment of bothersome menopausal symptoms, the breast cancer mortality benefit documented in this long-term WHI analysis could, as editorialists point out, “tip the scales” in favor of ET.³ Furthermore, the mortality benefit raises the possibility that ET could be evaluated as a risk-reduction strategy for selected high-risk menopausal women who have undergone hysterectomy. Although tamoxifen and aromatase inhibitors are approved for breast cancer chemoprophylaxis in high-risk menopausal women, these agents have not been found to lower breast cancer mortality.²

UK data analysis and risk for breast cancer in HT users

In an October 2020 issue of BMJ, Vinogradova and colleagues described their analysis of 2 primary care databases in the United Kingdom that in aggregate included roughly 99,000 women with breast cancer diagnosed between 1998 and 2018 (age range, 50–79; mean age at diagnosis, 63; >95% White); these were matched with more than 450,000 women without breast cancer (controls).⁴ Analyses were adjusted for smoking, body mass index (BMI), ethnicity, and mammography.

In this study, ever-use of EPT was associated with an adjusted odds ratio (OR) for breast cancer of 1.26 (95% confidence interval [CI], 1.24–1.29), while ET had an OR of 1.06 (95% CI, 1.03–1.10). In women aged 50 to 59 who used EPT for 5 years or more, 15 additional breast cancers were diagnosed per 10,000 woman-years; for ET users, the attributable risk was 3. Although risk rose with longer HT duration, this trend was less evident with ET than EPT.

In addition, the increased risk associated with ET use was less pronounced in women with a BMI greater than 30 kg/m². Among EPT users, risks were similar with the progestins medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). Likewise, risks were similar regardless of estrogen dose and route of administration (that is, oral vs transdermal). Vaginal estrogen was not associated with a higher or lower risk for breast cancer. Among past users of ET or EPT (with MPA), no increased risk was noted 5 years or more after stopping HT. For users of EPT (with NET or LNG), risks diminished 5 years or more after stopping HT but remained modestly elevated compared with risk in never-users.⁴

In this large observational UK study, ET was associated with minimally elevated risk for breast cancer, while in the WHI study, ET reduced the risk for breast cancer. For EPT, the excess risk in both studies was identical. As the authors note, mean BMI in the UK study participants was slightly lower than that in the WHI participants, a distinction that might explain the differing findings with ET use.

Continue to: Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women...

Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women

Wong J, Murji A, Sunderji Z, et al. Unnecessary bilateral salpingo-oophorectomy at the time of hysterectomy and potential for ovarian preservation. Menopause. 2020;28:8-11. doi: 10.1097/GME.0000000000001652.

While prevention of ovarian cancer is an important benefit of bilateral salpingo-oophorectomy (BSO), performing a BSO at the time of hysterectomy in pre- or perimenopausal patients not only will induce surgical menopause but also is associated with significantly increased overall mortality and an increased risk of mortality due to cardiovascular disease in patients younger than age 45.^5,6 Earlier BSO also has been associated with diabetes, accelerated bone density loss, sexual dysfunction, mood disorders, and decreased cognitive function.⁷

BSO at hysterectomy: How many procedures are not indicated?

To evaluate the prevalence and predictors of unnecessary BSO at the time of hysterectomy, Wong and colleagues conducted a multicenter retrospective review of hysterectomy procedures completed at 6 Canadian hospitals.⁸ Criteria for unnecessary BSO included age younger than 51 years; benign preoperative diagnosis (other than endometriosis, premenstrual dysphoric disorder, and gender dysphoria); and absence of endometriosis and pelvic adhesions.

A total of 2,656 hysterectomies were performed by 75 surgeons (28 fellowship trained and 47 generalists) across 3 community and 3 tertiary care hospitals between 2016 and 2018. At the time of hysterectomy, 749 patients (28%) underwent BSO. Of these, 509 women (68%) had at least 1 indication for concurrent BSO based on preoperative diagnosis.

Key study findings. Concurrent BSO procedures performed at academic hospitals were more likely to have a preoperative indication compared with BSO performed at community sites (70% vs 63%; OR, 1.42; 95% CI, 1.02–1.97; P = .04). BSO was more likely to be indicated when performed by fellowship-trained surgeons compared with surgeries performed by generalist surgeons (75% vs 63%; OR, 1.76; 95% CI, 1.26–2.44, P = .001). BSO procedures performed with vaginal hysterectomy were less likely to be indicated (3 of 20, 15%) when compared with open hysterectomy (74 of 154, 48%) and laparoscopic hysterectomy (432 of 575, 75%).

Of the patients who lacked a preoperative indication for concomitant BSO, 105 of 239 (43.9%) were younger than age 51. Overall, 8% (59 of 749) of patients in the study cohort had an unnecessary BSO based on a combination of preoperative diagnosis, age younger than age 51, and intraoperative factors including absence of endometriosis and adhesions.

Continue to: HT for menopausal depression: Which patients may benefit?

HT for menopausal depression: Which patients may benefit?

Dwyer JB, Aftab A, Radhakrishnan R, et al; APA Council of Research Task Force on Novel Biomarkers and Treatments. Hormonal treatments for major depressive disorder: state of the art. Am J Psychiatry. 2020;177:686- 705. doi:10.1176/appi.ajp.2020.19080848.

The cumulative lifetime prevalence of major depression in US women is 21%.9 An increased risk of mood symptoms and major depressive disorder occurs with the cessation of ovarian hormone production during menopause. In a review of both physiology and clinical studies, an American Psychiatric Association task force found support for several hormone-related strategies for treating depression and highlighted the rapidly advancing, but mixed, findings in this field.¹⁰

Clinical trials that examined mood in peri- and postmenopausal women treated with HT have produced mixed results for a variety of reasons, including differences in psychiatric symptomatology across studies and differences in treatment timing in relation to menopause onset.

HT effectiveness for depression depends on menopausal status

Five studies included in a meta-analysis by Rubinow and colleagues examined the use of ET and EPT as antidepressant monotherapy in peri- or postmenopausal women with major depression.¹¹ Of the 3 higher-quality studies, 2 conducted in perimenopausal women demonstrated the antidepressant efficacy of transdermal estrogen patches compared with placebo. The third study included a mixed population of both peri- and postmenopausal women, and it found that increased estradiol levels (spontaneously occurring or due to ET) were associated with improvement in depression in perimenopausal women but not in postmenopausal women.¹¹

ET also has been investigated as a potential adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs). In a retrospective analysis of a multicenter randomized controlled trial of fluoxetine in patients with depression, women who received ET and fluoxetine demonstrated a greater improvement than those who received fluoxetine monotherapy.¹² One small study that prospectively assessed ET in combination with an antidepressant in postmenopausal women demonstrated no benefit of ET in treating depression.¹³ Another small trial found that while combining transdermal ET with an SSRI accelerated symptom improvement, by the end of the 10-week study, treatment efficacy in the HT plus SSRI group was no greater than that observed in the SSRI-only group.¹⁴

Nineteen studies included in the metaanalysis by Rubinow and colleagues, which examined mood after ET or EPT treatment in nondepressed women, found little evidence of benefit, particularly in women without other physical symptoms of menopause.¹¹

The Kronos Early Estrogen Prevention Study (KEEPS) followed 661 women who received either oral estrogen plus progesterone, transdermal estrogen plus progesterone, or placebo over 4 years.¹⁵ Women with clinical depression were excluded from the study; however, women with mild to moderate mood symptoms who were being treated with an antidepressant were included. Improvements in depressive symptoms and anxiety were observed only in the oral estrogen plus progesterone group compared with the placebo group.¹⁵

In a study of 172 euthymic peri- and postmenopausal women treated for 12 months with transdermal estrogen plus oral progesterone, investigators found that, unlike postmenopausal women and those in the late perimenopausal transition, only women in the early perimenopausal transition had a lower risk of developing depressive symptoms.¹⁶

Bottom line

This complex literature suggests that ET/HT interventions are most likely to be successful when implemented early in the menopausal transition. The clearest indication for the use of HT is for perimenopausal women experiencing depression who are also experiencing menopausal symptoms (for example, bothersome hot flashes). There is little evidence that the use of ET/HT in late perimenopausal or postmenopausal women effectively treats depression; accordingly, HT is not recommended for the treatment of mood disorders in this population. The more ambiguous cases are those of perimenopausal women who are depressed but do not have classic vasomotor symptoms; some evidence supports the antidepressant efficacy of HT in this setting.¹¹ Although some studies suggest that HT can be effective in preventing depression in perimenopausal women, more evidence is needed.¹⁶

 

The menopause transition: A key period for strategizing CVD risk factor reduction

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Chrisandra L. Shufelt, MD, MS, NCMP

Dr. Shufelt is Associate Director of the Barbra
Streisand Women’s Heart Center, Smidt
Heart Institute, Cedars-Sinai Medical Center,
Los Angeles, California.

JoAnn E. Manson, MD, DrPH, NCMP

Dr. Manson is Professor of Medicine and the
Michael and Lee Bell Professor of Women’s
Health at Harvard Medical School; Professor
in the Department of Epidemiology, Harvard
T.H. Chan School of Public Health; and Chief
of the Division of Preventive Medicine
at Brigham and Women’s Hospital, Boston,
Massachusetts.

The authors report no financial relationships relevant to this article. Dr. Manson is a coauthor of the AHA Scientific Statement discussed in this article.

In the United States, nearly one-half of a woman’s life, on average, will be lived after menopause. For women with natural menopause, the menopause transition (MT) can begin 2 to 7 years before and may extend 1 year past the final menstrual period, which occurs at an average age of 51 years. For women with surgical menopause, the MT occurs abruptly with the sudden loss of endogenous ovarian hormones. Both types of transitions mark a critical time period when reproduction and endogenous sex hormone levels diminish and when cardiovascular disease (CVD) risk factors begin to rise.

The 2020 American Heart Association (AHA) scientific statement, “Menopause transition and cardiovascular disease risk: Implications for timing of early prevention,” highlights the MT as a window of opportunity for CVD prevention.¹

CVD risk factors associated with ovarian aging

In the AHA scientific statement, data from several longitudinal women’s health studies were used to identify which CVD risk factor changes during the MT are related to ovarian aging as opposed to chronologic aging. Independent of aging, those associated with reproductive or ovarian aging included an increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B. Changes in high-density lipoprotein cholesterol (HDL-C) particles and function also occur during the MT, which may explain why higher HDL-C levels during the MT and the postmenopausal years are not as cardioprotective as during the premenopausal period.

Changes in body composition and adipose tissue distribution also are associated with ovarian aging, with reduction in muscle mass and lean body mass and an increase in abdominal/visceral fat and subcutaneous adipose tissue. Although these body composition changes reflect ovarian aging, midlife weight gain is more closely related to chronologic aging.

The risk of the metabolic syndrome constellation of risk factors was found to be more closely associated with ovarian aging, whereas changes in blood pressure, insulin, and glucose individually tracked more closely with chronologic aging. Additionally, the AHA statement notes the research that identified several symptoms during the MT—including vasomotor symptoms, sleep disturbance, and depression—as being associated with more adverse CVD risk factor status and with subclinical measures of atherosclerosis. Additional research on the mechanistic basis for these associations is needed.

Chronologic age and type of menopause

Notably, a woman’s age and type of menopause matter with respect to CVD risk. Higher CVD risk is seen in women with premature onset (age < 40 years) or early onset (age < 45 years) of menopause and in women undergoing surgical menopause (bilateral oophorectomy) before age 45. In general, menopausal hormone therapy (HT) is recommended for women with premature or early menopause, whether natural or surgical, with continuation through at least the average age of natural menopause. In other women, although not recommended for the express purpose of CVD prevention, menopausal HT is appropriate for the treatment of bothersome vasomotor or other menopausal symptoms, especially when therapy is started before age 60 or within 10 years of menopause among women who are not at elevated risk of CVD.

While the AHA statement suggests that some women who begin estrogen early in menopause may experience reduced coronary heart disease risk, major research gaps remain with regard to HT dose, formulation, route of delivery, and recommended duration of treatment.

An opportunity to promote healthy lifestyle behaviors

Translating the AHA’s first-of-its-kind scientific statement into clinical practice requires recognition and awareness of the MT as a unique phase in a woman’s life associated with myriad changes in CVD risk factors. The statement underscores that the MT is an important time to target behavioral changes to promote CVD risk reduction, including lifestyle modifications in the AHA’s Life’s Simple 7 components (increased physical activity, smoking cessation, healthy diet, avoidance of weight gain) as well as vigilant control of blood pressure, cholesterol, and glucose levels. The MT is truly a window of opportunity for reinvigorated efforts to lower women’s CVD risk. ●

Reference

1. El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532. doi: 10.1161/CIR.000000000000912.