OBG Management

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

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. ●

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Contraception and family planning have improved the health of all people by reducing maternal mortality, improving maternal and child health through birth spacing, supporting full education attainment, and advancing workforce participation.¹ Contraception is cost-effective and should be supported by all health insurers. One economic study reported that depending on the contraceptive method utilized, up to $7 of health care costs were saved for each dollar spent on contraceptive services and supplies.²

Progestin-only pills (POPs) are an important contraceptive option for people in the following situations who³:

• have a contraindication to estrogen-containing contraceptives
• are actively breastfeeding
• are less than 21 days since birth
• have a preference to avoid estrogen.

POPs are contraindicated for women who have breast cancer, abnormal uterine bleeding, or active liver disease and for women who are pregnant. A history of bariatric surgery with a malabsorption procedure (Roux-en-Y and biliopancreatic diversion) and the use of antiepileptic medications that are strong enzyme inducers are additional situations where the risk of POP may outweigh the benefit.³ Alternative progestin-only options include the subdermal etonogestrel implant, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine devices. These 3 options provide superior contraceptive efficacy to POP.

As a contraceptive, norethindrone at a dose of 0.35 mg daily has two major flaws:

• it does not reliably inhibit ovulation
• it has a short half-life.

In clinical studies, norethindrone inhibits ovulation in approximately 50% of cycles.^4,5 Because norethindrone at a dose of 0.35 mg does not reliably inhibit ovulation it relies on additional mechanisms for contraceptive efficacy, including thickening of the cervical mucus to block sperm entry into the upper reproductive tract, reduced fallopian tube motility, and thinning of the endometrium.⁶

Norethindrone POP is formulated in packs of 28 pills containing 0.35 mg intended for daily continuous administration and no medication-free intervals. One rationale for the low dose of 0.35 mg in norethindrone POP is that it approximates the lowest dose with contraceptive efficacy for breastfeeding women, which has the benefit of minimizing exposure of the baby to the medication. Estrogen-progestin birth control pills containing norethindrone as the progestin reliably inhibit ovulation and have a minimum of 1 mg of norethindrone in each hormone pill. A POP with 1 mg of norethindrone per pill would likely have greater contraceptive efficacy. When taken daily, norethindrone acetate 5 mg (Aygestin) suppresses ovarian estrogen production, ovulation, and often causes cessation of uterine bleeding.⁷ The short half-life of norethindrone (7.7 hours) further exacerbates the problem of an insufficient daily dose.⁶ The standard guidance is that norethindrone must be taken at the same time every day, a goal that is nearly impossible to achieve. If a dose of norethindrone is taken >3 hours late, backup contraception is recommended for 48 hours.⁶

Drospirenone is a chemical analogue of spironolactone. Drospirenone is a progestin that suppresses LH and FSH and has anti-androgenic and partial anti-mineralocorticoid effects.⁸ Drospirenone POP contains 4 mg of a nonmicronized formulation that is believed to provide a pharmacologically similar area under the curve in drug metabolism studies to the 3 mg of micronized drospirenone, present in drospirenone-containing estrogen-progestin contraceptives.⁸ It is provided in a pack of 28 pills with 24 drospirenone pills and 4 pills without hormone. Drospirenone has a long half-life of 30 to 34 hours.⁸ If ≥2 drospirenone pills are missed, backup contraception is recommended for 7 days.⁹ The contraceptive effectiveness of drospirenone POP is thought to be similar to estrogen-progestin pills.⁸ Theoretically, drospirenone, acting as an anti-mineralocorticoid, can cause hyperkalemia. People with renal and adrenal insufficiency are most vulnerable to this adverse effect and should not be prescribed drospirenone. Women taking drospirenone and a medication that strongly inhibits CYP3A4, an enzyme involved in drospirenone degradation—including ketoconazole, indinavir, boceprevir, and clarithromycin—may have increased circulating levels of drospirenone and be at an increased risk of hyperkalemia. The US Food and Drug Administration (FDA) suggests that clinicians consider monitoring potassium concentration in women taking drospirenone who are also prescribed a strong CYP3A4 inhibitor.⁹ In people with normal renal and adrenal function, drospirenone-induced hyperkalemia is not commonly observed.⁹

Drospirenone 4 mg has been reported to not affect the natural balance of pro- and anti-coagulation factors in women.¹⁰ Drospirenone 4 mg daily has been reported to cause a modest decrease in systolic (-8 mm Hg) and diastolic (-5 mm Hg) blood pressure for women with a baseline blood pressure ≥130 mm Hg. Drospirenone 4 mg daily did not change blood pressure measurement in women with a baseline systolic blood pressure <130 mm Hg.¹¹ For women using drospirenone POP, circulating estradiol concentration is usually >30 pg/mL, with a mean concentration of 51 pg/mL.^12,13 Drospirenone POP does not result in a significant change in body weight.¹⁴ Preliminary studies suggest that drospirenone is an effective contraceptive in women with a BMI >30 kg/m².^14,15 Drospirenone enters breast milk and the relative infant dose is reported to be 1.5%.⁹ In general, breastfeeding is considered reasonably safe when the relative infant dose of a medication is <10%.¹⁶

The most common adverse effect reported with both norethindrone and drospirenone POP is unscheduled uterine bleeding. With norethindrone POP about 50% of users have a relatively preserved monthly bleeding pattern and approximately 50% have bleeding between periods, spotting and/or prolonged bleeding.^17,18 A similar frequency of unscheduled uterine bleeding has been reported with drospirenone POP.^14,19 Unscheduled and bothersome uterine bleeding is a common reason people discontinue POP. For drospirenone POP, the FDA reports a Pearl Index of 4.⁹ Other studies report a Pearl Index of 0.73 (95% confidence interval [CI], 0.31 to 1.43) for drospirenone POP.¹⁴ For norethindrone POP, the FDA reports that in typical use about 5% of people using the contraceptive method would become pregnant.⁶ The TABLE provides a comparison of the key features of the two available POP contraceptives. My assessment is that drospirenone has superior contraceptive properties over norethindrone POP. However, a head-to-head clinical trial would be necessary to determine the relative contraceptive effectiveness of drospirenone versus norethindrone POP.

Maintaining contraception access

Access to contraception without a copayment is an important component of a comprehensive and equitable insurance program.²⁰ The American College of Obstetricians and Gynecologists (ACOG) advocates that all people “should have unhindered and affordable access to all U.S. Food and Drug Administration-approved contraceptives.”²¹ ACOG also calls for the “full implementation of the Affordable Care Act requirement that new and revised private health insurance plans cover all U.S. Food and Drug Administration approved contraceptives without cost sharing, including nonequivalent options within one method category.” The National Women’s Law Center²² provides helpful resources to ensure access to legislated contraceptive benefits, including a phone script for speaking with an insurance benefits agent²³ and a toolkit for advocating for your contraceptive choice.²⁴ We need to ensure that people have unfettered access to all FDA-approved contraceptives because access to contraception is an important component of public health. Although drospirenone is more costly than norethindrone POP, drospirenone contraception should be available to all patients seeking POP contraception. ●

Contraception and family planning have improved the health of all people by reducing maternal mortality, improving maternal and child health through birth spacing, supporting full education attainment, and advancing workforce participation.¹ Contraception is cost-effective and should be supported by all health insurers. One economic study reported that depending on the contraceptive method utilized, up to $7 of health care costs were saved for each dollar spent on contraceptive services and supplies.²

Progestin-only pills (POPs) are an important contraceptive option for people in the following situations who³:

• have a contraindication to estrogen-containing contraceptives
• are actively breastfeeding
• are less than 21 days since birth
• have a preference to avoid estrogen.

POPs are contraindicated for women who have breast cancer, abnormal uterine bleeding, or active liver disease and for women who are pregnant. A history of bariatric surgery with a malabsorption procedure (Roux-en-Y and biliopancreatic diversion) and the use of antiepileptic medications that are strong enzyme inducers are additional situations where the risk of POP may outweigh the benefit.³ Alternative progestin-only options include the subdermal etonogestrel implant, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine devices. These 3 options provide superior contraceptive efficacy to POP.

As a contraceptive, norethindrone at a dose of 0.35 mg daily has two major flaws:

• it does not reliably inhibit ovulation
• it has a short half-life.

In clinical studies, norethindrone inhibits ovulation in approximately 50% of cycles.^4,5 Because norethindrone at a dose of 0.35 mg does not reliably inhibit ovulation it relies on additional mechanisms for contraceptive efficacy, including thickening of the cervical mucus to block sperm entry into the upper reproductive tract, reduced fallopian tube motility, and thinning of the endometrium.⁶

Norethindrone POP is formulated in packs of 28 pills containing 0.35 mg intended for daily continuous administration and no medication-free intervals. One rationale for the low dose of 0.35 mg in norethindrone POP is that it approximates the lowest dose with contraceptive efficacy for breastfeeding women, which has the benefit of minimizing exposure of the baby to the medication. Estrogen-progestin birth control pills containing norethindrone as the progestin reliably inhibit ovulation and have a minimum of 1 mg of norethindrone in each hormone pill. A POP with 1 mg of norethindrone per pill would likely have greater contraceptive efficacy. When taken daily, norethindrone acetate 5 mg (Aygestin) suppresses ovarian estrogen production, ovulation, and often causes cessation of uterine bleeding.⁷ The short half-life of norethindrone (7.7 hours) further exacerbates the problem of an insufficient daily dose.⁶ The standard guidance is that norethindrone must be taken at the same time every day, a goal that is nearly impossible to achieve. If a dose of norethindrone is taken >3 hours late, backup contraception is recommended for 48 hours.⁶

Drospirenone is a chemical analogue of spironolactone. Drospirenone is a progestin that suppresses LH and FSH and has anti-androgenic and partial anti-mineralocorticoid effects.⁸ Drospirenone POP contains 4 mg of a nonmicronized formulation that is believed to provide a pharmacologically similar area under the curve in drug metabolism studies to the 3 mg of micronized drospirenone, present in drospirenone-containing estrogen-progestin contraceptives.⁸ It is provided in a pack of 28 pills with 24 drospirenone pills and 4 pills without hormone. Drospirenone has a long half-life of 30 to 34 hours.⁸ If ≥2 drospirenone pills are missed, backup contraception is recommended for 7 days.⁹ The contraceptive effectiveness of drospirenone POP is thought to be similar to estrogen-progestin pills.⁸ Theoretically, drospirenone, acting as an anti-mineralocorticoid, can cause hyperkalemia. People with renal and adrenal insufficiency are most vulnerable to this adverse effect and should not be prescribed drospirenone. Women taking drospirenone and a medication that strongly inhibits CYP3A4, an enzyme involved in drospirenone degradation—including ketoconazole, indinavir, boceprevir, and clarithromycin—may have increased circulating levels of drospirenone and be at an increased risk of hyperkalemia. The US Food and Drug Administration (FDA) suggests that clinicians consider monitoring potassium concentration in women taking drospirenone who are also prescribed a strong CYP3A4 inhibitor.⁹ In people with normal renal and adrenal function, drospirenone-induced hyperkalemia is not commonly observed.⁹

Drospirenone 4 mg has been reported to not affect the natural balance of pro- and anti-coagulation factors in women.¹⁰ Drospirenone 4 mg daily has been reported to cause a modest decrease in systolic (-8 mm Hg) and diastolic (-5 mm Hg) blood pressure for women with a baseline blood pressure ≥130 mm Hg. Drospirenone 4 mg daily did not change blood pressure measurement in women with a baseline systolic blood pressure <130 mm Hg.¹¹ For women using drospirenone POP, circulating estradiol concentration is usually >30 pg/mL, with a mean concentration of 51 pg/mL.^12,13 Drospirenone POP does not result in a significant change in body weight.¹⁴ Preliminary studies suggest that drospirenone is an effective contraceptive in women with a BMI >30 kg/m².^14,15 Drospirenone enters breast milk and the relative infant dose is reported to be 1.5%.⁹ In general, breastfeeding is considered reasonably safe when the relative infant dose of a medication is <10%.¹⁶

The most common adverse effect reported with both norethindrone and drospirenone POP is unscheduled uterine bleeding. With norethindrone POP about 50% of users have a relatively preserved monthly bleeding pattern and approximately 50% have bleeding between periods, spotting and/or prolonged bleeding.^17,18 A similar frequency of unscheduled uterine bleeding has been reported with drospirenone POP.^14,19 Unscheduled and bothersome uterine bleeding is a common reason people discontinue POP. For drospirenone POP, the FDA reports a Pearl Index of 4.⁹ Other studies report a Pearl Index of 0.73 (95% confidence interval [CI], 0.31 to 1.43) for drospirenone POP.¹⁴ For norethindrone POP, the FDA reports that in typical use about 5% of people using the contraceptive method would become pregnant.⁶ The TABLE provides a comparison of the key features of the two available POP contraceptives. My assessment is that drospirenone has superior contraceptive properties over norethindrone POP. However, a head-to-head clinical trial would be necessary to determine the relative contraceptive effectiveness of drospirenone versus norethindrone POP.

Maintaining contraception access

Access to contraception without a copayment is an important component of a comprehensive and equitable insurance program.²⁰ The American College of Obstetricians and Gynecologists (ACOG) advocates that all people “should have unhindered and affordable access to all U.S. Food and Drug Administration-approved contraceptives.”²¹ ACOG also calls for the “full implementation of the Affordable Care Act requirement that new and revised private health insurance plans cover all U.S. Food and Drug Administration approved contraceptives without cost sharing, including nonequivalent options within one method category.” The National Women’s Law Center²² provides helpful resources to ensure access to legislated contraceptive benefits, including a phone script for speaking with an insurance benefits agent²³ and a toolkit for advocating for your contraceptive choice.²⁴ We need to ensure that people have unfettered access to all FDA-approved contraceptives because access to contraception is an important component of public health. Although drospirenone is more costly than norethindrone POP, drospirenone contraception should be available to all patients seeking POP contraception. ●

Contraception and family planning have improved the health of all people by reducing maternal mortality, improving maternal and child health through birth spacing, supporting full education attainment, and advancing workforce participation.¹ Contraception is cost-effective and should be supported by all health insurers. One economic study reported that depending on the contraceptive method utilized, up to $7 of health care costs were saved for each dollar spent on contraceptive services and supplies.²

Progestin-only pills (POPs) are an important contraceptive option for people in the following situations who³:

• have a contraindication to estrogen-containing contraceptives
• are actively breastfeeding
• are less than 21 days since birth
• have a preference to avoid estrogen.

POPs are contraindicated for women who have breast cancer, abnormal uterine bleeding, or active liver disease and for women who are pregnant. A history of bariatric surgery with a malabsorption procedure (Roux-en-Y and biliopancreatic diversion) and the use of antiepileptic medications that are strong enzyme inducers are additional situations where the risk of POP may outweigh the benefit.³ Alternative progestin-only options include the subdermal etonogestrel implant, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine devices. These 3 options provide superior contraceptive efficacy to POP.

As a contraceptive, norethindrone at a dose of 0.35 mg daily has two major flaws:

• it does not reliably inhibit ovulation
• it has a short half-life.

In clinical studies, norethindrone inhibits ovulation in approximately 50% of cycles.^4,5 Because norethindrone at a dose of 0.35 mg does not reliably inhibit ovulation it relies on additional mechanisms for contraceptive efficacy, including thickening of the cervical mucus to block sperm entry into the upper reproductive tract, reduced fallopian tube motility, and thinning of the endometrium.⁶

Norethindrone POP is formulated in packs of 28 pills containing 0.35 mg intended for daily continuous administration and no medication-free intervals. One rationale for the low dose of 0.35 mg in norethindrone POP is that it approximates the lowest dose with contraceptive efficacy for breastfeeding women, which has the benefit of minimizing exposure of the baby to the medication. Estrogen-progestin birth control pills containing norethindrone as the progestin reliably inhibit ovulation and have a minimum of 1 mg of norethindrone in each hormone pill. A POP with 1 mg of norethindrone per pill would likely have greater contraceptive efficacy. When taken daily, norethindrone acetate 5 mg (Aygestin) suppresses ovarian estrogen production, ovulation, and often causes cessation of uterine bleeding.⁷ The short half-life of norethindrone (7.7 hours) further exacerbates the problem of an insufficient daily dose.⁶ The standard guidance is that norethindrone must be taken at the same time every day, a goal that is nearly impossible to achieve. If a dose of norethindrone is taken >3 hours late, backup contraception is recommended for 48 hours.⁶

Drospirenone is a chemical analogue of spironolactone. Drospirenone is a progestin that suppresses LH and FSH and has anti-androgenic and partial anti-mineralocorticoid effects.⁸ Drospirenone POP contains 4 mg of a nonmicronized formulation that is believed to provide a pharmacologically similar area under the curve in drug metabolism studies to the 3 mg of micronized drospirenone, present in drospirenone-containing estrogen-progestin contraceptives.⁸ It is provided in a pack of 28 pills with 24 drospirenone pills and 4 pills without hormone. Drospirenone has a long half-life of 30 to 34 hours.⁸ If ≥2 drospirenone pills are missed, backup contraception is recommended for 7 days.⁹ The contraceptive effectiveness of drospirenone POP is thought to be similar to estrogen-progestin pills.⁸ Theoretically, drospirenone, acting as an anti-mineralocorticoid, can cause hyperkalemia. People with renal and adrenal insufficiency are most vulnerable to this adverse effect and should not be prescribed drospirenone. Women taking drospirenone and a medication that strongly inhibits CYP3A4, an enzyme involved in drospirenone degradation—including ketoconazole, indinavir, boceprevir, and clarithromycin—may have increased circulating levels of drospirenone and be at an increased risk of hyperkalemia. The US Food and Drug Administration (FDA) suggests that clinicians consider monitoring potassium concentration in women taking drospirenone who are also prescribed a strong CYP3A4 inhibitor.⁹ In people with normal renal and adrenal function, drospirenone-induced hyperkalemia is not commonly observed.⁹

Drospirenone 4 mg has been reported to not affect the natural balance of pro- and anti-coagulation factors in women.¹⁰ Drospirenone 4 mg daily has been reported to cause a modest decrease in systolic (-8 mm Hg) and diastolic (-5 mm Hg) blood pressure for women with a baseline blood pressure ≥130 mm Hg. Drospirenone 4 mg daily did not change blood pressure measurement in women with a baseline systolic blood pressure <130 mm Hg.¹¹ For women using drospirenone POP, circulating estradiol concentration is usually >30 pg/mL, with a mean concentration of 51 pg/mL.^12,13 Drospirenone POP does not result in a significant change in body weight.¹⁴ Preliminary studies suggest that drospirenone is an effective contraceptive in women with a BMI >30 kg/m².^14,15 Drospirenone enters breast milk and the relative infant dose is reported to be 1.5%.⁹ In general, breastfeeding is considered reasonably safe when the relative infant dose of a medication is <10%.¹⁶

The most common adverse effect reported with both norethindrone and drospirenone POP is unscheduled uterine bleeding. With norethindrone POP about 50% of users have a relatively preserved monthly bleeding pattern and approximately 50% have bleeding between periods, spotting and/or prolonged bleeding.^17,18 A similar frequency of unscheduled uterine bleeding has been reported with drospirenone POP.^14,19 Unscheduled and bothersome uterine bleeding is a common reason people discontinue POP. For drospirenone POP, the FDA reports a Pearl Index of 4.⁹ Other studies report a Pearl Index of 0.73 (95% confidence interval [CI], 0.31 to 1.43) for drospirenone POP.¹⁴ For norethindrone POP, the FDA reports that in typical use about 5% of people using the contraceptive method would become pregnant.⁶ The TABLE provides a comparison of the key features of the two available POP contraceptives. My assessment is that drospirenone has superior contraceptive properties over norethindrone POP. However, a head-to-head clinical trial would be necessary to determine the relative contraceptive effectiveness of drospirenone versus norethindrone POP.

Maintaining contraception access

Access to contraception without a copayment is an important component of a comprehensive and equitable insurance program.²⁰ The American College of Obstetricians and Gynecologists (ACOG) advocates that all people “should have unhindered and affordable access to all U.S. Food and Drug Administration-approved contraceptives.”²¹ ACOG also calls for the “full implementation of the Affordable Care Act requirement that new and revised private health insurance plans cover all U.S. Food and Drug Administration approved contraceptives without cost sharing, including nonequivalent options within one method category.” The National Women’s Law Center²² provides helpful resources to ensure access to legislated contraceptive benefits, including a phone script for speaking with an insurance benefits agent²³ and a toolkit for advocating for your contraceptive choice.²⁴ We need to ensure that people have unfettered access to all FDA-approved contraceptives because access to contraception is an important component of public health. Although drospirenone is more costly than norethindrone POP, drospirenone contraception should be available to all patients seeking POP contraception. ●

For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?

Continue to the answer...
 

This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)

For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?

Continue to the answer...
 

This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)

For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?

Continue to the answer...
 

This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)

What are the best office-based tests for the diagnosis of bacterial vaginosis?

Continue to the answer...

In patients with bacterial vaginosis, the vaginal pH typically is elevated in the range of 4.5. When a drop of potassium hydroxide solution is added to the vaginal secretions, a characteristic fishlike (amine) odor is liberated (positive “whiff test”). With saline microscopy, the key findings are a relative absence of lactobacilli in the background, an abundance of small cocci and bacilli, and the presence of clue cells, which are epithelial cells studded with bacteria along their outer margin.

What are the best office-based tests for the diagnosis of bacterial vaginosis?

Continue to the answer...

In patients with bacterial vaginosis, the vaginal pH typically is elevated in the range of 4.5. When a drop of potassium hydroxide solution is added to the vaginal secretions, a characteristic fishlike (amine) odor is liberated (positive “whiff test”). With saline microscopy, the key findings are a relative absence of lactobacilli in the background, an abundance of small cocci and bacilli, and the presence of clue cells, which are epithelial cells studded with bacteria along their outer margin.

What are the best office-based tests for the diagnosis of bacterial vaginosis?

Continue to the answer...

In patients with bacterial vaginosis, the vaginal pH typically is elevated in the range of 4.5. When a drop of potassium hydroxide solution is added to the vaginal secretions, a characteristic fishlike (amine) odor is liberated (positive “whiff test”). With saline microscopy, the key findings are a relative absence of lactobacilli in the background, an abundance of small cocci and bacilli, and the presence of clue cells, which are epithelial cells studded with bacteria along their outer margin.