JoAnn V. Pinkerton, MD

In this special installment of Cases in Menopause, I interview series contributor and menopause expert JoAnn V. Pinkerton, MD. We discuss a fairly new therapy: the combination conjugated estrogen and bazedoxifene (CE/BZA; Duavee) for the treatment of moderate to severe hot flashes due to menopause and the prevention of menopausal osteoporosis.

Much of my practice has focused on the treatment of menopausal women, but which of my patients can benefit from this particular combination of CE 0.45 mg plus BZA 20 mg? I asked Dr. Pinkerton this question, and more.

Which patients can benefit most?
Dr. Pinkerton CE/BZA was tested in healthy postmenopausal women with a uterus at risk for bone loss who were reporting 50 or more moderate to severe hot flashes per week. The combination of CE and BZA is a good choice for women who have bothersome menopausal symptoms: hot flashes, night sweats, and sleep disruption or symptomatic vulvovaginal atrophy (VVA)—although it’s not approved for VVA.

Efficacy and safety data show that compared with placebo:

• CE/BZA decreases the frequency and severity of hot flashes at 12 weeks, and those decreases are maintained at 12 months.^1,2
• Women taking CE/BZA have greater improvements in sleep, with both decreased sleep disturbance and time to fall asleep.³
• CE/BZA maintained or prevented lumbar spine and hip bone loss in postmenopausal women at risk for osteoporosis. ^1,4,5

Although fracture data were not captured and the drug was not tested in osteoporotic women, study results showed bone loss prevention at 12 months, which was sustained at 24 months. The improvement in bone mineral density from baseline was about 1% to 1.5%. This was compared with a bone loss of 1.8% in women taking placebo (P<.01).

In clinical studies, women taking CE/BZA versus placebo also have reported a lower incidence of painful intercourse,⁶ and some improvement in health-related quality of life and treatment satisfaction.^7,8

In short, CE/BZA is a good option for symptomatic menopausal women with a uterus who have bothersome hot flashes, night sweats, and sleep disruptions and want to prevent bone loss.

What about adverse effects?
Dr. Pinkerton In general, CE/BZA has a favorable safety and tolerability profile, with an overall incidence of adverse events similar to placebo. The rates of cardiovascular and cerebrovascular events, cancers (breast, endometrial, and ovarian), and mortality are comparable to placebo in 2-year trials. These data are limited; studies have been conducted in healthy postmenopausal women. Future studies need to define the full risk profile, particularly among overweight or obese women and different ethnic groups and for longer-term use.

Is there a role among women with breast cancer?
Dr. Pinkerton CE/BZA has not been tested in women at risk for or with prior breast cancer. In preclinical trials of up to 2 years, involving healthy postmenopausal women, the rates for breast cancer with CE/BZA were similar to placebo. There are no long-term data, however, and there are no data in women at risk for breast cancer. I recommend that women who have or are at high risk for breast cancer consider nonhormonal treatment options.^9–11

Has there been an associated increase in breast density with CE/BZA?
Dr. Pinkerton No. Data from two randomized clinical trials showed that the breast density changes with 12-month CE/BZA treatment was similar to placebo—which is markedly different from comparisons of placebo and combination estrogen-progestin therapy (EPT), where EPT increased breast density. If indeed this lack of an association translates into fewer breast cancers, it would be wonderful, but we do not have long-term data. We can tell our patients that using CE/BZA has not been shown to increase the risk of breast cancer, at least up to 2 years.

What makes CE/BZA different from traditional EPT?
Dr. Pinkerton There are two exciting differences:

In addition, high rates of amenorrhea have been found—comparable to placebo.¹³

CE/BZA is similar to traditional EPT in several ways. For instance, compared with placebo, at 2 years, CE/BZA was not found to increase the incidence of endometrial hyperplasia, endometrial thickness (increase from baseline was <1 mm and comparable to placebo), or endometrial cancers.¹⁴ Lastly, similar to EPT, there is probably a twofold risk of venous thromboembolism (VTE) with BZA 20 mg alone.¹⁵ Importantly, there has been no additive effect on VTE risk when combining CE with BZA; however, we will need longer studies, in older women, to fully evaluate this risk.¹

Overall, in symptomatic postmenopausal women with a uterus, randomized controlled data show the same improvement with CE/BZA as that seen with traditional oral EPTs, with improvements in hot flashes; night sweats, with fewer sleep disruptions; and prevention of bone loss. In addition, the changes in cholesterol (an increase in triglyceride levels) and effect on the vagina are the same. Yet, CE/BZA appears to have a neutral effect on the breast and protects against endometrial hyperplasia and endometrial cancer without causing bleeding.^9,10 CE/BZA’s VTE and stroke risks are expected to be similar to traditional oral EPT.

Therefore, the major benefit of CE/BZA for women who have a uterus is the lack of significant breast tenderness, lack of changes in breast density, and lack of vaginal bleeding that is often seen with traditional EPT.¹²

Then, is progestogen the harmful agent in traditional HT options?
Dr. Pinkerton There is evidence that estrogen plus progestogen therapy has more risk for breast cancer than estrogen alone. But in women who have a uterus, you need to protect against uterine cancer so, up until now, the only option was to add progestogen. Some studies suggest the risk of breast cancer may differ depending on the type of progestogen. So it’s a laudable goal to try to protect the endometrium without using a progestogen.

Given its safety profile, do you see CE/BZA being indicated for women without a uterus?
Dr. Pinkerton CE/BZA has been tested only in women with a uterus; there is no indication for using it in hysterectomized women. In the future, unless trial data show a benefit to hysterectomized women—by a reduction in breast cancer compared with estrogen alone—there would be no reason to add BZA to the CE for these women. You would just use CE or another type of estrogen alone.

Do you anticipate BZA being used alone?
Dr. Pinkerton For treating osteoporosis in postmenopausal women at increased fracture risk, BZA alone has greater benefits than risks. It is approved in other countries to prevent or treat osteoporosis. In 2008, Wyeth received an approval letter from the US Food and Drug Administration for BZA alone but, for whatever reason, the drug was not brought to market. BZA reduces the number of new lumbar spine fractures by 4% (vs 2% for placebo), with efficacy better in those with a higher risk of fractures. Like raloxifene, it has not been shown effective at reducing nonvertebral fractures, although it maintains spinal bone density.¹⁶

BZA available as monotherapy could tempt clinicians to pair it with other estrogens. We must recognize that the combination of the specific estrogen and BZA dose and type need to be balanced to provide endometrial hyperplasia protection. It would not be safe or effective to take BZA as a selective estrogen-receptor modulator and pair it with any other untested systemic estrogen. I do not anticipate, in this country, that BZA will become available as monotherapy.

New options are welcome
Dr. Moore Novel strategies for clinicians to optimally treat menopausal symptoms are always welcome. I look forward to more data from the SMART trials on CE/BZA and to moving forward as we gain experience with using this new treatment option.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this special installment of Cases in Menopause, I interview series contributor and menopause expert JoAnn V. Pinkerton, MD. We discuss a fairly new therapy: the combination conjugated estrogen and bazedoxifene (CE/BZA; Duavee) for the treatment of moderate to severe hot flashes due to menopause and the prevention of menopausal osteoporosis.

Much of my practice has focused on the treatment of menopausal women, but which of my patients can benefit from this particular combination of CE 0.45 mg plus BZA 20 mg? I asked Dr. Pinkerton this question, and more.

Which patients can benefit most?
Dr. Pinkerton CE/BZA was tested in healthy postmenopausal women with a uterus at risk for bone loss who were reporting 50 or more moderate to severe hot flashes per week. The combination of CE and BZA is a good choice for women who have bothersome menopausal symptoms: hot flashes, night sweats, and sleep disruption or symptomatic vulvovaginal atrophy (VVA)—although it’s not approved for VVA.

Efficacy and safety data show that compared with placebo:

• CE/BZA decreases the frequency and severity of hot flashes at 12 weeks, and those decreases are maintained at 12 months.^1,2
• Women taking CE/BZA have greater improvements in sleep, with both decreased sleep disturbance and time to fall asleep.³
• CE/BZA maintained or prevented lumbar spine and hip bone loss in postmenopausal women at risk for osteoporosis. ^1,4,5

Although fracture data were not captured and the drug was not tested in osteoporotic women, study results showed bone loss prevention at 12 months, which was sustained at 24 months. The improvement in bone mineral density from baseline was about 1% to 1.5%. This was compared with a bone loss of 1.8% in women taking placebo (P<.01).

In clinical studies, women taking CE/BZA versus placebo also have reported a lower incidence of painful intercourse,⁶ and some improvement in health-related quality of life and treatment satisfaction.^7,8

In short, CE/BZA is a good option for symptomatic menopausal women with a uterus who have bothersome hot flashes, night sweats, and sleep disruptions and want to prevent bone loss.

What about adverse effects?
Dr. Pinkerton In general, CE/BZA has a favorable safety and tolerability profile, with an overall incidence of adverse events similar to placebo. The rates of cardiovascular and cerebrovascular events, cancers (breast, endometrial, and ovarian), and mortality are comparable to placebo in 2-year trials. These data are limited; studies have been conducted in healthy postmenopausal women. Future studies need to define the full risk profile, particularly among overweight or obese women and different ethnic groups and for longer-term use.

Is there a role among women with breast cancer?
Dr. Pinkerton CE/BZA has not been tested in women at risk for or with prior breast cancer. In preclinical trials of up to 2 years, involving healthy postmenopausal women, the rates for breast cancer with CE/BZA were similar to placebo. There are no long-term data, however, and there are no data in women at risk for breast cancer. I recommend that women who have or are at high risk for breast cancer consider nonhormonal treatment options.^9–11

Has there been an associated increase in breast density with CE/BZA?
Dr. Pinkerton No. Data from two randomized clinical trials showed that the breast density changes with 12-month CE/BZA treatment was similar to placebo—which is markedly different from comparisons of placebo and combination estrogen-progestin therapy (EPT), where EPT increased breast density. If indeed this lack of an association translates into fewer breast cancers, it would be wonderful, but we do not have long-term data. We can tell our patients that using CE/BZA has not been shown to increase the risk of breast cancer, at least up to 2 years.

What makes CE/BZA different from traditional EPT?
Dr. Pinkerton There are two exciting differences:

In addition, high rates of amenorrhea have been found—comparable to placebo.¹³

CE/BZA is similar to traditional EPT in several ways. For instance, compared with placebo, at 2 years, CE/BZA was not found to increase the incidence of endometrial hyperplasia, endometrial thickness (increase from baseline was <1 mm and comparable to placebo), or endometrial cancers.¹⁴ Lastly, similar to EPT, there is probably a twofold risk of venous thromboembolism (VTE) with BZA 20 mg alone.¹⁵ Importantly, there has been no additive effect on VTE risk when combining CE with BZA; however, we will need longer studies, in older women, to fully evaluate this risk.¹

Overall, in symptomatic postmenopausal women with a uterus, randomized controlled data show the same improvement with CE/BZA as that seen with traditional oral EPTs, with improvements in hot flashes; night sweats, with fewer sleep disruptions; and prevention of bone loss. In addition, the changes in cholesterol (an increase in triglyceride levels) and effect on the vagina are the same. Yet, CE/BZA appears to have a neutral effect on the breast and protects against endometrial hyperplasia and endometrial cancer without causing bleeding.^9,10 CE/BZA’s VTE and stroke risks are expected to be similar to traditional oral EPT.

Therefore, the major benefit of CE/BZA for women who have a uterus is the lack of significant breast tenderness, lack of changes in breast density, and lack of vaginal bleeding that is often seen with traditional EPT.¹²

Then, is progestogen the harmful agent in traditional HT options?
Dr. Pinkerton There is evidence that estrogen plus progestogen therapy has more risk for breast cancer than estrogen alone. But in women who have a uterus, you need to protect against uterine cancer so, up until now, the only option was to add progestogen. Some studies suggest the risk of breast cancer may differ depending on the type of progestogen. So it’s a laudable goal to try to protect the endometrium without using a progestogen.

Given its safety profile, do you see CE/BZA being indicated for women without a uterus?
Dr. Pinkerton CE/BZA has been tested only in women with a uterus; there is no indication for using it in hysterectomized women. In the future, unless trial data show a benefit to hysterectomized women—by a reduction in breast cancer compared with estrogen alone—there would be no reason to add BZA to the CE for these women. You would just use CE or another type of estrogen alone.

Do you anticipate BZA being used alone?
Dr. Pinkerton For treating osteoporosis in postmenopausal women at increased fracture risk, BZA alone has greater benefits than risks. It is approved in other countries to prevent or treat osteoporosis. In 2008, Wyeth received an approval letter from the US Food and Drug Administration for BZA alone but, for whatever reason, the drug was not brought to market. BZA reduces the number of new lumbar spine fractures by 4% (vs 2% for placebo), with efficacy better in those with a higher risk of fractures. Like raloxifene, it has not been shown effective at reducing nonvertebral fractures, although it maintains spinal bone density.¹⁶

BZA available as monotherapy could tempt clinicians to pair it with other estrogens. We must recognize that the combination of the specific estrogen and BZA dose and type need to be balanced to provide endometrial hyperplasia protection. It would not be safe or effective to take BZA as a selective estrogen-receptor modulator and pair it with any other untested systemic estrogen. I do not anticipate, in this country, that BZA will become available as monotherapy.

New options are welcome
Dr. Moore Novel strategies for clinicians to optimally treat menopausal symptoms are always welcome. I look forward to more data from the SMART trials on CE/BZA and to moving forward as we gain experience with using this new treatment option.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

In this special installment of Cases in Menopause, I interview series contributor and menopause expert JoAnn V. Pinkerton, MD. We discuss a fairly new therapy: the combination conjugated estrogen and bazedoxifene (CE/BZA; Duavee) for the treatment of moderate to severe hot flashes due to menopause and the prevention of menopausal osteoporosis.

Much of my practice has focused on the treatment of menopausal women, but which of my patients can benefit from this particular combination of CE 0.45 mg plus BZA 20 mg? I asked Dr. Pinkerton this question, and more.

Which patients can benefit most?
Dr. Pinkerton CE/BZA was tested in healthy postmenopausal women with a uterus at risk for bone loss who were reporting 50 or more moderate to severe hot flashes per week. The combination of CE and BZA is a good choice for women who have bothersome menopausal symptoms: hot flashes, night sweats, and sleep disruption or symptomatic vulvovaginal atrophy (VVA)—although it’s not approved for VVA.

Efficacy and safety data show that compared with placebo:

• CE/BZA decreases the frequency and severity of hot flashes at 12 weeks, and those decreases are maintained at 12 months.^1,2
• Women taking CE/BZA have greater improvements in sleep, with both decreased sleep disturbance and time to fall asleep.³
• CE/BZA maintained or prevented lumbar spine and hip bone loss in postmenopausal women at risk for osteoporosis. ^1,4,5

Although fracture data were not captured and the drug was not tested in osteoporotic women, study results showed bone loss prevention at 12 months, which was sustained at 24 months. The improvement in bone mineral density from baseline was about 1% to 1.5%. This was compared with a bone loss of 1.8% in women taking placebo (P<.01).

In clinical studies, women taking CE/BZA versus placebo also have reported a lower incidence of painful intercourse,⁶ and some improvement in health-related quality of life and treatment satisfaction.^7,8

In short, CE/BZA is a good option for symptomatic menopausal women with a uterus who have bothersome hot flashes, night sweats, and sleep disruptions and want to prevent bone loss.

What about adverse effects?
Dr. Pinkerton In general, CE/BZA has a favorable safety and tolerability profile, with an overall incidence of adverse events similar to placebo. The rates of cardiovascular and cerebrovascular events, cancers (breast, endometrial, and ovarian), and mortality are comparable to placebo in 2-year trials. These data are limited; studies have been conducted in healthy postmenopausal women. Future studies need to define the full risk profile, particularly among overweight or obese women and different ethnic groups and for longer-term use.

Is there a role among women with breast cancer?
Dr. Pinkerton CE/BZA has not been tested in women at risk for or with prior breast cancer. In preclinical trials of up to 2 years, involving healthy postmenopausal women, the rates for breast cancer with CE/BZA were similar to placebo. There are no long-term data, however, and there are no data in women at risk for breast cancer. I recommend that women who have or are at high risk for breast cancer consider nonhormonal treatment options.^9–11

Has there been an associated increase in breast density with CE/BZA?
Dr. Pinkerton No. Data from two randomized clinical trials showed that the breast density changes with 12-month CE/BZA treatment was similar to placebo—which is markedly different from comparisons of placebo and combination estrogen-progestin therapy (EPT), where EPT increased breast density. If indeed this lack of an association translates into fewer breast cancers, it would be wonderful, but we do not have long-term data. We can tell our patients that using CE/BZA has not been shown to increase the risk of breast cancer, at least up to 2 years.

What makes CE/BZA different from traditional EPT?
Dr. Pinkerton There are two exciting differences:

In addition, high rates of amenorrhea have been found—comparable to placebo.¹³

CE/BZA is similar to traditional EPT in several ways. For instance, compared with placebo, at 2 years, CE/BZA was not found to increase the incidence of endometrial hyperplasia, endometrial thickness (increase from baseline was <1 mm and comparable to placebo), or endometrial cancers.¹⁴ Lastly, similar to EPT, there is probably a twofold risk of venous thromboembolism (VTE) with BZA 20 mg alone.¹⁵ Importantly, there has been no additive effect on VTE risk when combining CE with BZA; however, we will need longer studies, in older women, to fully evaluate this risk.¹

Overall, in symptomatic postmenopausal women with a uterus, randomized controlled data show the same improvement with CE/BZA as that seen with traditional oral EPTs, with improvements in hot flashes; night sweats, with fewer sleep disruptions; and prevention of bone loss. In addition, the changes in cholesterol (an increase in triglyceride levels) and effect on the vagina are the same. Yet, CE/BZA appears to have a neutral effect on the breast and protects against endometrial hyperplasia and endometrial cancer without causing bleeding.^9,10 CE/BZA’s VTE and stroke risks are expected to be similar to traditional oral EPT.

Therefore, the major benefit of CE/BZA for women who have a uterus is the lack of significant breast tenderness, lack of changes in breast density, and lack of vaginal bleeding that is often seen with traditional EPT.¹²

Then, is progestogen the harmful agent in traditional HT options?
Dr. Pinkerton There is evidence that estrogen plus progestogen therapy has more risk for breast cancer than estrogen alone. But in women who have a uterus, you need to protect against uterine cancer so, up until now, the only option was to add progestogen. Some studies suggest the risk of breast cancer may differ depending on the type of progestogen. So it’s a laudable goal to try to protect the endometrium without using a progestogen.

Given its safety profile, do you see CE/BZA being indicated for women without a uterus?
Dr. Pinkerton CE/BZA has been tested only in women with a uterus; there is no indication for using it in hysterectomized women. In the future, unless trial data show a benefit to hysterectomized women—by a reduction in breast cancer compared with estrogen alone—there would be no reason to add BZA to the CE for these women. You would just use CE or another type of estrogen alone.

Do you anticipate BZA being used alone?
Dr. Pinkerton For treating osteoporosis in postmenopausal women at increased fracture risk, BZA alone has greater benefits than risks. It is approved in other countries to prevent or treat osteoporosis. In 2008, Wyeth received an approval letter from the US Food and Drug Administration for BZA alone but, for whatever reason, the drug was not brought to market. BZA reduces the number of new lumbar spine fractures by 4% (vs 2% for placebo), with efficacy better in those with a higher risk of fractures. Like raloxifene, it has not been shown effective at reducing nonvertebral fractures, although it maintains spinal bone density.¹⁶

BZA available as monotherapy could tempt clinicians to pair it with other estrogens. We must recognize that the combination of the specific estrogen and BZA dose and type need to be balanced to provide endometrial hyperplasia protection. It would not be safe or effective to take BZA as a selective estrogen-receptor modulator and pair it with any other untested systemic estrogen. I do not anticipate, in this country, that BZA will become available as monotherapy.

New options are welcome
Dr. Moore Novel strategies for clinicians to optimally treat menopausal symptoms are always welcome. I look forward to more data from the SMART trials on CE/BZA and to moving forward as we gain experience with using this new treatment option.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Related article:  Your menopausal patient’s breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD; Andrew M. Kaunitz, MD, James A. Simon, MD (Cases in Menopause, May 2013)

Related article:  Your menopausal patient’s breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD; Andrew M. Kaunitz, MD, James A. Simon, MD (Cases in Menopause, May 2013)

Related article:  Your menopausal patient’s breast biopsy reveals atypical hyperplasia JoAnn V. Pinkerton, MD; Andrew M. Kaunitz, MD, James A. Simon, MD (Cases in Menopause, May 2013)

CASES IN MENOPAUSE

A new series brought to you by the menopause experts

	Andrew M. Kaunitz, MD Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.
	JoAnn V. Pinkerton, MD Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.
	James A. Simon, MD Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

Disclosures
Dr. Kaunitz reports that his institution receives grant or research support from Agile, Bayer, Endoceutics, Teva, Medical Diagnostic Laboratories, and Noven, and that he is a consultant to Bayer, Merck, and Teva.

Dr. Pinkerton reports that her institution receives consulting fees from Pfizer, DepoMed, Shionogi, and Noven and multicenter research fees from DepoMed, Endoceutics, and Bionova.

Dr. Simon reports being a consultant to or on the advisory boards of Abbott Laboratories, Agile Therapeutics, Amgen, Ascend Therapeutics, BioSante, Depomed, Lelo, MD Therapeutics, Meda Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, Shionogi, Shippan Point Advisors LLC, Slate Pharmaceuticals, Sprout Pharmaceuticals, Teva, Warner Chilcott, and Watson. He also reports receiving (currently or in the past year) grant/research support from BioSante, EndoCeutics, Novo Nordisk, Novogyne, Palatin Technologies, Teva, and Warner Chilcott. He reports serving on the speakers bureaus of Amgen, Merck, Novartis, Noven, Novo Nordisk, Novogyne, Teva, and Warner Chilcott. Dr. Simon is currently the Chief Medical Officer for Sprout Pharmaceuticals.

CASE: Atypical ductal hyperplasia

Your 56-year-old, married, white patient has been on hormone therapy (HT) since age 52 for the treatment of vasomotor symptoms. She is taking a low-dose oral estrogen and micronized progesterone combination as she has an intact uterus. Her family history is positive for breast cancer, as her mother was diagnosed at age 68.

Her most recent annual screening mammogram shows linear calcifications. Because fine, linear, branching or casting calcifications are worrisome for atypical ductal hyperplasia (ADH) or ductal carcinoma in situ, a biopsy is recommended.

She elects to wean off and discontinue HT during the evaluation of her abnormal mammogram. The mammographic-guided stereotactic biopsy reveals ADH. She undergoes an open excisional biopsy, the results of which reveal extensive ADH with negative margins.

Six weeks after a lumpectomy she returns to your office reporting moderate to severe hot flashes that occur seven to 10 times per day and impair her sleep, leading to fatigue and “brain fog.” In addition, she is noticing vaginal dryness and dyspareunia despite use of lubricants. She requests treatment for her symptoms and wonders if she can restart HT systemically or vaginally.

How do you manage her hot flashes?

What are the alternatives to HT for hot flashes?

Certain lifestyle changes have been reported to provide relief for hot flushes.¹ These include:

• use of layered clothing
• maintenance of cool ambient temperature (particularly during sleep)
• consumption of cool foods or beverages
• relaxation techniques (such as deep breathing, or paced respirations, for 20 min three times per day).

Despite sparse data, avoiding triggers such as spicy or hot foods or alcohol may be helpful.

Therapies such as evening primrose oil, dong quai, ginseng, wild yam, magnet therapy, reflexology, and homeopathy have not been found more effective in treating hot flashes than placebo.²

Andrew M. Kaunitz, MD:
I would add soy isoflavones, red clover, and black cohosh to this list of therapies that have not been shown to be more effective than placebo.³

Phytoestrogens (such as equol), acupuncture, yoga, and hypnosis continue to be tested in randomized trials with mixed results.

Off-label drug options offer modest help. There are currently no FDA-approved nonhormonal pharmaceutical options for relief of hot flashes; the gold standard for treatment remains estrogen therapy. For moderate to severe bothersome hot flashes, potentially effective drug therapies used off label include clonidine, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and gabapentin (TABLE 1).^2,4 In large, randomized, controlled trials, the following agents were modestly more effective than placebo: desvenlafaxine,⁵ low-dose paroxetine salt,⁶ escitalopram,⁷ and gastroretentive gabapentin.⁸ Participants in these trials included women with both spontaneous and surgically induced menopause.

Although sponsors have applied for approval for three of these agents, the FDA so far has declined to approve these agents for vasomotor treatment due to concerns about risks versus benefits. Benefits of these nonhormonal prescription therapies need to be weighed carefully against side effects, because the reduction in absolute hot flushes is modest.

Many small trials have assessed other medications and complementary and alternative therapies regarding management of menopausal symptoms. Most, however, are limited by small numbers of enrolled participants and shorter study duration (≤12 weeks). In addition, enrolled participants have variable numbers of hot flashes, often less than 14 per week.^2,4

TABLE 1

Nonhormonal treatment of vasomotor symptoms

Can your patient restart HT? If so, should HT be offered vaginally or systemically?

Non-HT may be enough for vaginal dryness. Benefit has been shown with the use of vaginal moisturizers twice weekly and lubricants as needed for sexual activity.⁹ Therefore, the local application of daily lubricants, such as olive oil, along with the use of moisturizers with regular sexual intercourse may be enough to maintain vaginal health and function.

In randomized trials, phytoestrogens lack benefit data for vaginal atrophy. Small pilot studies of the effect of oral/ vaginal phytoestrogens on vaginal atrophy do not show any benefit on vaginal pH or vaginal maturation index and mixed improvement in vaginal dryness. In addition, no clear effect of these agents has been seen compared with placebo, except that there may be less progression of vaginal atrophy over time with phytoestrogens.¹⁰ It is possible that the benefits of phytoestrogens may take longer to take effect than the 12 weeks required to see an effect with HT.

Vaginal estrogen: limited safety data. No published clinical trials have assessed the impact of topical vaginal estrogen on risk of recurrence in breast cancer survivors, and concern exists because detectable estradiol levels have been reported in women who take aromatase inhibitors and have very atrophic vaginal mucosa.¹¹ NAMS recommends that the discussion about vaginal estrogen be individualized between the patient, her provider, and her oncologist.¹²

Vaginal estrogen creams and tablets (Vagifem 10 μg per tablet) are often started daily for 2 weeks for a “priming dose” then dosed twice per week. To minimize systemic absorption, creams may be used externally or with smaller doses vaginally. The higher the dose or more frequent the use, the greater the risk of significant systemic absorption, particularly when the vagina is atrophic.¹³

Another option is the vaginal estradiol ring, which delivers a low dose (7.5 μg per day) for 90 days.^14,15

James A. Simon, MD:
When you want the lowest dose of vaginal estradiol, consider Vagifem; the total dose of estrogen is lower over 90 days than with the vaginal ring.¹⁶

Progestogen therapy is generally not needed when low-dose estrogen is administered locally to treat vaginal atrophy.¹²

A new oral option. In February 2013, ospemifene, a selective estrogen receptor modulator (SERM), was approved for pain with intercourse and vaginal dryness.

Related article: “New treatment option for vulvar and vaginal atrophy,” by Andrew M. Kaunitz, MD (May 2013)

There is concern with systemic estrogen use

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered. However, data from the Breast Cancer Surveillance Consortium⁹ showed that as postmenopausal HT use decreased (from 35% to 11% between 1999 and 2005), rates of ADH decreased from a peak of 5.5 per 10,000 mammograms in 1999 to 2.4 per 10,000 mammograms in 2005. Similarly, rates of invasive cancer with ADH decreased from a peak of 4.3 per 10,000 mammograms in 2003 to 3.3 per 10,000 mammograms in 2005. This finding—that rates of ADH and invasive breast cancer were significantly linked to postmenopausal use of HT—raises concern about using HT in women with prior ADH. Of note, the cancers linked with ADH were of lower grade and stage and more estrogen receptor–positive than cancers not linked with ADH.¹⁷

How do you manage your patient’s increased risk of breast cancer?

In examining the answer to this management point, we need to first ask and answer, “How does ADH develop?” and “What is her risk of developing breast cancer?”

The development of invasive breast cancer is believed to involve a complex, multistep process. Initially, there is disruption of normal cell development and growth, with overproduction of normal-looking cells (hyperplasia). These excess cells stack up and/or become abnormal. Then, there is continued change in appearance and multiplication, becoming ductal carcinoma in situ (noninvasive). If left untreated, the cells may develop into invasive cancer.¹⁸ See TABLE 2 for the relative risk of a patient with ADH developing breast cancer.¹⁰

Now, we can address, “How do you manage this patient’s increased risk of breast cancer?”

TABLE 2. Relative risk of developing breast cancer

More frequent breast screening!

• Clinical breast exams twice per year
• Screening mammograms annually
• Screening tomosynthesis (These are additional digital screening views which provide almost a 3D view.)
• Screening breast ultrasound
• Screening breast MRI — if she has a 20% lifetime risk of breast cancer (family history or genetic predisposition) (TABLE 3).

TABLE 3. ACS guidelines for screening breast MRI

Careful consideration of medications

Since it is possible that estrogen may fuel the growth of some breast cancers, avoiding systemic menopausal HT may be safest.

Counsel her about strategies to reduce breast cancer risk

These include:

• Lifestyle changes, including weight loss, exercise, and avoiding excess alcohol intake.
• Preventive medications. Tamoxifen or raloxifene (Evista) can be used for 5 years. These medications block estrogen from binding to the breast estrogen receptors. Another option is an aromatase inhibitor, which decreases estrogen production.
• Risk-reducing (prophylactic) mastectomy.

Andrew M. Kaunitz, MD:
It is important to note that both of the SERMs just mentioned (tamoxifen and raloxifene), as well as aromatase inhibitors, may cause women to experience vasomotor symptoms. SERMS also increase the risk of venous thromboembolism.

Management approach for this patient

This patient has had her ADH surgically excised. She will remain at higher risk for breast cancer and should consider strategies to decrease her risk, including lifestyle changes and the possible initiation of medications such as tamoxifen or raloxifene. New screening modalities, such as tomosynthesis or breast ultrasound, may be used to screen for breast cancer, and she may be a candidate for alternating mammograms and MRIs at 6-month intervals.

For her vaginal dryness, over-the-counter lubricants and moisturizers may be helpful. If not, topical or vaginal estrogen is available (as creams, tablets, or a ring) and provides primarily local benefit with limited systemic absorption.

For her bothersome hot flashes, if lifestyle changes don’t work, nonhormonal therapies can be offered off label, such as effexor, desvenlafaxine, gabapentin, or any of the SSRIs—including those tested in large, randomized, controlled trials, such as escitalopram and low-dose paroxetine salt, at low doses.

Andrew M. Kaunitz, MD:
Sertraline seems to be more likely to cause sweating than other SSRIs.³ For this reason, I don’t prescribe sertraline off label to treat vasomotor symptoms.

If she is taking tamoxifen, however, SSRIs such as paroxetine should be avoided due to P450 interaction.

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered, with education about the potential risks, as she is already at higher risk for breast cancer.

Acknowledgment

The author would like to thank Andrew M. Kaunitz, MD, for his forward thinking in helping to establish this new series on menopause.

CASES IN MENOPAUSE

A new series brought to you by the menopause experts

	Andrew M. Kaunitz, MD Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.
	JoAnn V. Pinkerton, MD Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.
	James A. Simon, MD Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

Disclosures
Dr. Kaunitz reports that his institution receives grant or research support from Agile, Bayer, Endoceutics, Teva, Medical Diagnostic Laboratories, and Noven, and that he is a consultant to Bayer, Merck, and Teva.

Dr. Pinkerton reports that her institution receives consulting fees from Pfizer, DepoMed, Shionogi, and Noven and multicenter research fees from DepoMed, Endoceutics, and Bionova.

Dr. Simon reports being a consultant to or on the advisory boards of Abbott Laboratories, Agile Therapeutics, Amgen, Ascend Therapeutics, BioSante, Depomed, Lelo, MD Therapeutics, Meda Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, Shionogi, Shippan Point Advisors LLC, Slate Pharmaceuticals, Sprout Pharmaceuticals, Teva, Warner Chilcott, and Watson. He also reports receiving (currently or in the past year) grant/research support from BioSante, EndoCeutics, Novo Nordisk, Novogyne, Palatin Technologies, Teva, and Warner Chilcott. He reports serving on the speakers bureaus of Amgen, Merck, Novartis, Noven, Novo Nordisk, Novogyne, Teva, and Warner Chilcott. Dr. Simon is currently the Chief Medical Officer for Sprout Pharmaceuticals.

CASE: Atypical ductal hyperplasia

Your 56-year-old, married, white patient has been on hormone therapy (HT) since age 52 for the treatment of vasomotor symptoms. She is taking a low-dose oral estrogen and micronized progesterone combination as she has an intact uterus. Her family history is positive for breast cancer, as her mother was diagnosed at age 68.

Her most recent annual screening mammogram shows linear calcifications. Because fine, linear, branching or casting calcifications are worrisome for atypical ductal hyperplasia (ADH) or ductal carcinoma in situ, a biopsy is recommended.

She elects to wean off and discontinue HT during the evaluation of her abnormal mammogram. The mammographic-guided stereotactic biopsy reveals ADH. She undergoes an open excisional biopsy, the results of which reveal extensive ADH with negative margins.

Six weeks after a lumpectomy she returns to your office reporting moderate to severe hot flashes that occur seven to 10 times per day and impair her sleep, leading to fatigue and “brain fog.” In addition, she is noticing vaginal dryness and dyspareunia despite use of lubricants. She requests treatment for her symptoms and wonders if she can restart HT systemically or vaginally.

How do you manage her hot flashes?

What are the alternatives to HT for hot flashes?

Certain lifestyle changes have been reported to provide relief for hot flushes.¹ These include:

• use of layered clothing
• maintenance of cool ambient temperature (particularly during sleep)
• consumption of cool foods or beverages
• relaxation techniques (such as deep breathing, or paced respirations, for 20 min three times per day).

Despite sparse data, avoiding triggers such as spicy or hot foods or alcohol may be helpful.

Therapies such as evening primrose oil, dong quai, ginseng, wild yam, magnet therapy, reflexology, and homeopathy have not been found more effective in treating hot flashes than placebo.²

Andrew M. Kaunitz, MD:
I would add soy isoflavones, red clover, and black cohosh to this list of therapies that have not been shown to be more effective than placebo.³

Phytoestrogens (such as equol), acupuncture, yoga, and hypnosis continue to be tested in randomized trials with mixed results.

Off-label drug options offer modest help. There are currently no FDA-approved nonhormonal pharmaceutical options for relief of hot flashes; the gold standard for treatment remains estrogen therapy. For moderate to severe bothersome hot flashes, potentially effective drug therapies used off label include clonidine, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and gabapentin (TABLE 1).^2,4 In large, randomized, controlled trials, the following agents were modestly more effective than placebo: desvenlafaxine,⁵ low-dose paroxetine salt,⁶ escitalopram,⁷ and gastroretentive gabapentin.⁸ Participants in these trials included women with both spontaneous and surgically induced menopause.

Although sponsors have applied for approval for three of these agents, the FDA so far has declined to approve these agents for vasomotor treatment due to concerns about risks versus benefits. Benefits of these nonhormonal prescription therapies need to be weighed carefully against side effects, because the reduction in absolute hot flushes is modest.

Many small trials have assessed other medications and complementary and alternative therapies regarding management of menopausal symptoms. Most, however, are limited by small numbers of enrolled participants and shorter study duration (≤12 weeks). In addition, enrolled participants have variable numbers of hot flashes, often less than 14 per week.^2,4

TABLE 1

Nonhormonal treatment of vasomotor symptoms

Can your patient restart HT? If so, should HT be offered vaginally or systemically?

Non-HT may be enough for vaginal dryness. Benefit has been shown with the use of vaginal moisturizers twice weekly and lubricants as needed for sexual activity.⁹ Therefore, the local application of daily lubricants, such as olive oil, along with the use of moisturizers with regular sexual intercourse may be enough to maintain vaginal health and function.

In randomized trials, phytoestrogens lack benefit data for vaginal atrophy. Small pilot studies of the effect of oral/ vaginal phytoestrogens on vaginal atrophy do not show any benefit on vaginal pH or vaginal maturation index and mixed improvement in vaginal dryness. In addition, no clear effect of these agents has been seen compared with placebo, except that there may be less progression of vaginal atrophy over time with phytoestrogens.¹⁰ It is possible that the benefits of phytoestrogens may take longer to take effect than the 12 weeks required to see an effect with HT.

Vaginal estrogen: limited safety data. No published clinical trials have assessed the impact of topical vaginal estrogen on risk of recurrence in breast cancer survivors, and concern exists because detectable estradiol levels have been reported in women who take aromatase inhibitors and have very atrophic vaginal mucosa.¹¹ NAMS recommends that the discussion about vaginal estrogen be individualized between the patient, her provider, and her oncologist.¹²

Vaginal estrogen creams and tablets (Vagifem 10 μg per tablet) are often started daily for 2 weeks for a “priming dose” then dosed twice per week. To minimize systemic absorption, creams may be used externally or with smaller doses vaginally. The higher the dose or more frequent the use, the greater the risk of significant systemic absorption, particularly when the vagina is atrophic.¹³

Another option is the vaginal estradiol ring, which delivers a low dose (7.5 μg per day) for 90 days.^14,15

James A. Simon, MD:
When you want the lowest dose of vaginal estradiol, consider Vagifem; the total dose of estrogen is lower over 90 days than with the vaginal ring.¹⁶

Progestogen therapy is generally not needed when low-dose estrogen is administered locally to treat vaginal atrophy.¹²

A new oral option. In February 2013, ospemifene, a selective estrogen receptor modulator (SERM), was approved for pain with intercourse and vaginal dryness.

Related article: “New treatment option for vulvar and vaginal atrophy,” by Andrew M. Kaunitz, MD (May 2013)

There is concern with systemic estrogen use

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered. However, data from the Breast Cancer Surveillance Consortium⁹ showed that as postmenopausal HT use decreased (from 35% to 11% between 1999 and 2005), rates of ADH decreased from a peak of 5.5 per 10,000 mammograms in 1999 to 2.4 per 10,000 mammograms in 2005. Similarly, rates of invasive cancer with ADH decreased from a peak of 4.3 per 10,000 mammograms in 2003 to 3.3 per 10,000 mammograms in 2005. This finding—that rates of ADH and invasive breast cancer were significantly linked to postmenopausal use of HT—raises concern about using HT in women with prior ADH. Of note, the cancers linked with ADH were of lower grade and stage and more estrogen receptor–positive than cancers not linked with ADH.¹⁷

How do you manage your patient’s increased risk of breast cancer?

In examining the answer to this management point, we need to first ask and answer, “How does ADH develop?” and “What is her risk of developing breast cancer?”

The development of invasive breast cancer is believed to involve a complex, multistep process. Initially, there is disruption of normal cell development and growth, with overproduction of normal-looking cells (hyperplasia). These excess cells stack up and/or become abnormal. Then, there is continued change in appearance and multiplication, becoming ductal carcinoma in situ (noninvasive). If left untreated, the cells may develop into invasive cancer.¹⁸ See TABLE 2 for the relative risk of a patient with ADH developing breast cancer.¹⁰

Now, we can address, “How do you manage this patient’s increased risk of breast cancer?”

TABLE 2. Relative risk of developing breast cancer

More frequent breast screening!

• Clinical breast exams twice per year
• Screening mammograms annually
• Screening tomosynthesis (These are additional digital screening views which provide almost a 3D view.)
• Screening breast ultrasound
• Screening breast MRI — if she has a 20% lifetime risk of breast cancer (family history or genetic predisposition) (TABLE 3).

TABLE 3. ACS guidelines for screening breast MRI

Careful consideration of medications

Since it is possible that estrogen may fuel the growth of some breast cancers, avoiding systemic menopausal HT may be safest.

Counsel her about strategies to reduce breast cancer risk

These include:

• Lifestyle changes, including weight loss, exercise, and avoiding excess alcohol intake.
• Preventive medications. Tamoxifen or raloxifene (Evista) can be used for 5 years. These medications block estrogen from binding to the breast estrogen receptors. Another option is an aromatase inhibitor, which decreases estrogen production.
• Risk-reducing (prophylactic) mastectomy.

Andrew M. Kaunitz, MD:
It is important to note that both of the SERMs just mentioned (tamoxifen and raloxifene), as well as aromatase inhibitors, may cause women to experience vasomotor symptoms. SERMS also increase the risk of venous thromboembolism.

Management approach for this patient

This patient has had her ADH surgically excised. She will remain at higher risk for breast cancer and should consider strategies to decrease her risk, including lifestyle changes and the possible initiation of medications such as tamoxifen or raloxifene. New screening modalities, such as tomosynthesis or breast ultrasound, may be used to screen for breast cancer, and she may be a candidate for alternating mammograms and MRIs at 6-month intervals.

For her vaginal dryness, over-the-counter lubricants and moisturizers may be helpful. If not, topical or vaginal estrogen is available (as creams, tablets, or a ring) and provides primarily local benefit with limited systemic absorption.

For her bothersome hot flashes, if lifestyle changes don’t work, nonhormonal therapies can be offered off label, such as effexor, desvenlafaxine, gabapentin, or any of the SSRIs—including those tested in large, randomized, controlled trials, such as escitalopram and low-dose paroxetine salt, at low doses.

Andrew M. Kaunitz, MD:
Sertraline seems to be more likely to cause sweating than other SSRIs.³ For this reason, I don’t prescribe sertraline off label to treat vasomotor symptoms.

If she is taking tamoxifen, however, SSRIs such as paroxetine should be avoided due to P450 interaction.

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered, with education about the potential risks, as she is already at higher risk for breast cancer.

Acknowledgment

The author would like to thank Andrew M. Kaunitz, MD, for his forward thinking in helping to establish this new series on menopause.

CASES IN MENOPAUSE

A new series brought to you by the menopause experts

	Andrew M. Kaunitz, MD Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.
	JoAnn V. Pinkerton, MD Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.
	James A. Simon, MD Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

Disclosures
Dr. Kaunitz reports that his institution receives grant or research support from Agile, Bayer, Endoceutics, Teva, Medical Diagnostic Laboratories, and Noven, and that he is a consultant to Bayer, Merck, and Teva.

Dr. Pinkerton reports that her institution receives consulting fees from Pfizer, DepoMed, Shionogi, and Noven and multicenter research fees from DepoMed, Endoceutics, and Bionova.

Dr. Simon reports being a consultant to or on the advisory boards of Abbott Laboratories, Agile Therapeutics, Amgen, Ascend Therapeutics, BioSante, Depomed, Lelo, MD Therapeutics, Meda Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, Shionogi, Shippan Point Advisors LLC, Slate Pharmaceuticals, Sprout Pharmaceuticals, Teva, Warner Chilcott, and Watson. He also reports receiving (currently or in the past year) grant/research support from BioSante, EndoCeutics, Novo Nordisk, Novogyne, Palatin Technologies, Teva, and Warner Chilcott. He reports serving on the speakers bureaus of Amgen, Merck, Novartis, Noven, Novo Nordisk, Novogyne, Teva, and Warner Chilcott. Dr. Simon is currently the Chief Medical Officer for Sprout Pharmaceuticals.

CASE: Atypical ductal hyperplasia

Your 56-year-old, married, white patient has been on hormone therapy (HT) since age 52 for the treatment of vasomotor symptoms. She is taking a low-dose oral estrogen and micronized progesterone combination as she has an intact uterus. Her family history is positive for breast cancer, as her mother was diagnosed at age 68.

Her most recent annual screening mammogram shows linear calcifications. Because fine, linear, branching or casting calcifications are worrisome for atypical ductal hyperplasia (ADH) or ductal carcinoma in situ, a biopsy is recommended.

She elects to wean off and discontinue HT during the evaluation of her abnormal mammogram. The mammographic-guided stereotactic biopsy reveals ADH. She undergoes an open excisional biopsy, the results of which reveal extensive ADH with negative margins.

Six weeks after a lumpectomy she returns to your office reporting moderate to severe hot flashes that occur seven to 10 times per day and impair her sleep, leading to fatigue and “brain fog.” In addition, she is noticing vaginal dryness and dyspareunia despite use of lubricants. She requests treatment for her symptoms and wonders if she can restart HT systemically or vaginally.

How do you manage her hot flashes?

What are the alternatives to HT for hot flashes?

Certain lifestyle changes have been reported to provide relief for hot flushes.¹ These include:

• use of layered clothing
• maintenance of cool ambient temperature (particularly during sleep)
• consumption of cool foods or beverages
• relaxation techniques (such as deep breathing, or paced respirations, for 20 min three times per day).

Despite sparse data, avoiding triggers such as spicy or hot foods or alcohol may be helpful.

Therapies such as evening primrose oil, dong quai, ginseng, wild yam, magnet therapy, reflexology, and homeopathy have not been found more effective in treating hot flashes than placebo.²

Andrew M. Kaunitz, MD:
I would add soy isoflavones, red clover, and black cohosh to this list of therapies that have not been shown to be more effective than placebo.³

Phytoestrogens (such as equol), acupuncture, yoga, and hypnosis continue to be tested in randomized trials with mixed results.

Off-label drug options offer modest help. There are currently no FDA-approved nonhormonal pharmaceutical options for relief of hot flashes; the gold standard for treatment remains estrogen therapy. For moderate to severe bothersome hot flashes, potentially effective drug therapies used off label include clonidine, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and gabapentin (TABLE 1).^2,4 In large, randomized, controlled trials, the following agents were modestly more effective than placebo: desvenlafaxine,⁵ low-dose paroxetine salt,⁶ escitalopram,⁷ and gastroretentive gabapentin.⁸ Participants in these trials included women with both spontaneous and surgically induced menopause.

Although sponsors have applied for approval for three of these agents, the FDA so far has declined to approve these agents for vasomotor treatment due to concerns about risks versus benefits. Benefits of these nonhormonal prescription therapies need to be weighed carefully against side effects, because the reduction in absolute hot flushes is modest.

Many small trials have assessed other medications and complementary and alternative therapies regarding management of menopausal symptoms. Most, however, are limited by small numbers of enrolled participants and shorter study duration (≤12 weeks). In addition, enrolled participants have variable numbers of hot flashes, often less than 14 per week.^2,4

TABLE 1

Nonhormonal treatment of vasomotor symptoms

Can your patient restart HT? If so, should HT be offered vaginally or systemically?

Non-HT may be enough for vaginal dryness. Benefit has been shown with the use of vaginal moisturizers twice weekly and lubricants as needed for sexual activity.⁹ Therefore, the local application of daily lubricants, such as olive oil, along with the use of moisturizers with regular sexual intercourse may be enough to maintain vaginal health and function.

In randomized trials, phytoestrogens lack benefit data for vaginal atrophy. Small pilot studies of the effect of oral/ vaginal phytoestrogens on vaginal atrophy do not show any benefit on vaginal pH or vaginal maturation index and mixed improvement in vaginal dryness. In addition, no clear effect of these agents has been seen compared with placebo, except that there may be less progression of vaginal atrophy over time with phytoestrogens.¹⁰ It is possible that the benefits of phytoestrogens may take longer to take effect than the 12 weeks required to see an effect with HT.

Vaginal estrogen: limited safety data. No published clinical trials have assessed the impact of topical vaginal estrogen on risk of recurrence in breast cancer survivors, and concern exists because detectable estradiol levels have been reported in women who take aromatase inhibitors and have very atrophic vaginal mucosa.¹¹ NAMS recommends that the discussion about vaginal estrogen be individualized between the patient, her provider, and her oncologist.¹²

Vaginal estrogen creams and tablets (Vagifem 10 μg per tablet) are often started daily for 2 weeks for a “priming dose” then dosed twice per week. To minimize systemic absorption, creams may be used externally or with smaller doses vaginally. The higher the dose or more frequent the use, the greater the risk of significant systemic absorption, particularly when the vagina is atrophic.¹³

Another option is the vaginal estradiol ring, which delivers a low dose (7.5 μg per day) for 90 days.^14,15

James A. Simon, MD:
When you want the lowest dose of vaginal estradiol, consider Vagifem; the total dose of estrogen is lower over 90 days than with the vaginal ring.¹⁶

Progestogen therapy is generally not needed when low-dose estrogen is administered locally to treat vaginal atrophy.¹²

A new oral option. In February 2013, ospemifene, a selective estrogen receptor modulator (SERM), was approved for pain with intercourse and vaginal dryness.

Related article: “New treatment option for vulvar and vaginal atrophy,” by Andrew M. Kaunitz, MD (May 2013)

There is concern with systemic estrogen use

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered. However, data from the Breast Cancer Surveillance Consortium⁹ showed that as postmenopausal HT use decreased (from 35% to 11% between 1999 and 2005), rates of ADH decreased from a peak of 5.5 per 10,000 mammograms in 1999 to 2.4 per 10,000 mammograms in 2005. Similarly, rates of invasive cancer with ADH decreased from a peak of 4.3 per 10,000 mammograms in 2003 to 3.3 per 10,000 mammograms in 2005. This finding—that rates of ADH and invasive breast cancer were significantly linked to postmenopausal use of HT—raises concern about using HT in women with prior ADH. Of note, the cancers linked with ADH were of lower grade and stage and more estrogen receptor–positive than cancers not linked with ADH.¹⁷

How do you manage your patient’s increased risk of breast cancer?

In examining the answer to this management point, we need to first ask and answer, “How does ADH develop?” and “What is her risk of developing breast cancer?”

The development of invasive breast cancer is believed to involve a complex, multistep process. Initially, there is disruption of normal cell development and growth, with overproduction of normal-looking cells (hyperplasia). These excess cells stack up and/or become abnormal. Then, there is continued change in appearance and multiplication, becoming ductal carcinoma in situ (noninvasive). If left untreated, the cells may develop into invasive cancer.¹⁸ See TABLE 2 for the relative risk of a patient with ADH developing breast cancer.¹⁰

Now, we can address, “How do you manage this patient’s increased risk of breast cancer?”

TABLE 2. Relative risk of developing breast cancer

More frequent breast screening!

• Clinical breast exams twice per year
• Screening mammograms annually
• Screening tomosynthesis (These are additional digital screening views which provide almost a 3D view.)
• Screening breast ultrasound
• Screening breast MRI — if she has a 20% lifetime risk of breast cancer (family history or genetic predisposition) (TABLE 3).

TABLE 3. ACS guidelines for screening breast MRI

Careful consideration of medications

Since it is possible that estrogen may fuel the growth of some breast cancers, avoiding systemic menopausal HT may be safest.

Counsel her about strategies to reduce breast cancer risk

These include:

• Lifestyle changes, including weight loss, exercise, and avoiding excess alcohol intake.
• Preventive medications. Tamoxifen or raloxifene (Evista) can be used for 5 years. These medications block estrogen from binding to the breast estrogen receptors. Another option is an aromatase inhibitor, which decreases estrogen production.
• Risk-reducing (prophylactic) mastectomy.

Andrew M. Kaunitz, MD:
It is important to note that both of the SERMs just mentioned (tamoxifen and raloxifene), as well as aromatase inhibitors, may cause women to experience vasomotor symptoms. SERMS also increase the risk of venous thromboembolism.

Management approach for this patient

This patient has had her ADH surgically excised. She will remain at higher risk for breast cancer and should consider strategies to decrease her risk, including lifestyle changes and the possible initiation of medications such as tamoxifen or raloxifene. New screening modalities, such as tomosynthesis or breast ultrasound, may be used to screen for breast cancer, and she may be a candidate for alternating mammograms and MRIs at 6-month intervals.

For her vaginal dryness, over-the-counter lubricants and moisturizers may be helpful. If not, topical or vaginal estrogen is available (as creams, tablets, or a ring) and provides primarily local benefit with limited systemic absorption.

For her bothersome hot flashes, if lifestyle changes don’t work, nonhormonal therapies can be offered off label, such as effexor, desvenlafaxine, gabapentin, or any of the SSRIs—including those tested in large, randomized, controlled trials, such as escitalopram and low-dose paroxetine salt, at low doses.

Andrew M. Kaunitz, MD:
Sertraline seems to be more likely to cause sweating than other SSRIs.³ For this reason, I don’t prescribe sertraline off label to treat vasomotor symptoms.

If she is taking tamoxifen, however, SSRIs such as paroxetine should be avoided due to P450 interaction.

If her hot flashes remain persistent and bothersome, low-dose estrogen could be considered, with education about the potential risks, as she is already at higher risk for breast cancer.

Acknowledgment

The author would like to thank Andrew M. Kaunitz, MD, for his forward thinking in helping to establish this new series on menopause.

A frequent challenge facing clinicians who manage breast cancer survivors is identifying treatment options to attenuate hot flushes and night sweats without resorting to estrogen, which is contraindicated because it can induce cancer growth.

Variables associated with a high prevalence of hot flushes in this population:

• age at diagnosis (>50 years)
• abrupt discontinuation of estrogen therapy at diagnosis
• induction of premature menopause by therapy (i.e., chemotherapy and surgical or medical ovarian ablation)
• induction of estrogen deficiency symptoms by chemotherapy (e.g., tamoxifen or an aromatase inhibitor).

There are no FDA-approved nonhormonal pharmaceutical options to alleviate bothersome hot flushes that accompany breast cancer treatment and the menopausal transition, whether spontaneous or induced. Moreover, meaningful guidance from published trials is limited by the small number of enrolled subjects and short duration of study (i.e., ≤12 weeks).

How hot flushes happen

According to Freedman, body temperature is regulated over a range called the thermo-neutral zone.^1,2 Reduced or fluctuating ovarian hormones are believed to narrow the thermoregulatory zone such that variations in core body temperature trigger heat loss mechanisms. A narrowed thermoregulatory zone has been associated with increased norepinephrine.

Clonidine, an α-2 adrenergic agonist, decreases norepinephrine and has been found to reduce hot flushes. Other nonhormonal agents that have been found to be at least partially effective in reducing hot flushes include SSRI and SNRI antidepressants, which enhance central serotonin and norepinephrine activity. Gabapentin has also proved to be effective.

Potential adverse events or negative side effects, such as insomnia, weight gain, drowsiness, and sedation, need to be taken into account when evaluating the benefits of pharmaceutical options.

We want to hear from you! Tell us what you think.

A frequent challenge facing clinicians who manage breast cancer survivors is identifying treatment options to attenuate hot flushes and night sweats without resorting to estrogen, which is contraindicated because it can induce cancer growth.

Variables associated with a high prevalence of hot flushes in this population:

• age at diagnosis (>50 years)
• abrupt discontinuation of estrogen therapy at diagnosis
• induction of premature menopause by therapy (i.e., chemotherapy and surgical or medical ovarian ablation)
• induction of estrogen deficiency symptoms by chemotherapy (e.g., tamoxifen or an aromatase inhibitor).

There are no FDA-approved nonhormonal pharmaceutical options to alleviate bothersome hot flushes that accompany breast cancer treatment and the menopausal transition, whether spontaneous or induced. Moreover, meaningful guidance from published trials is limited by the small number of enrolled subjects and short duration of study (i.e., ≤12 weeks).

How hot flushes happen

According to Freedman, body temperature is regulated over a range called the thermo-neutral zone.^1,2 Reduced or fluctuating ovarian hormones are believed to narrow the thermoregulatory zone such that variations in core body temperature trigger heat loss mechanisms. A narrowed thermoregulatory zone has been associated with increased norepinephrine.

Clonidine, an α-2 adrenergic agonist, decreases norepinephrine and has been found to reduce hot flushes. Other nonhormonal agents that have been found to be at least partially effective in reducing hot flushes include SSRI and SNRI antidepressants, which enhance central serotonin and norepinephrine activity. Gabapentin has also proved to be effective.

Potential adverse events or negative side effects, such as insomnia, weight gain, drowsiness, and sedation, need to be taken into account when evaluating the benefits of pharmaceutical options.

We want to hear from you! Tell us what you think.

A frequent challenge facing clinicians who manage breast cancer survivors is identifying treatment options to attenuate hot flushes and night sweats without resorting to estrogen, which is contraindicated because it can induce cancer growth.

Variables associated with a high prevalence of hot flushes in this population:

• age at diagnosis (>50 years)
• abrupt discontinuation of estrogen therapy at diagnosis
• induction of premature menopause by therapy (i.e., chemotherapy and surgical or medical ovarian ablation)
• induction of estrogen deficiency symptoms by chemotherapy (e.g., tamoxifen or an aromatase inhibitor).

There are no FDA-approved nonhormonal pharmaceutical options to alleviate bothersome hot flushes that accompany breast cancer treatment and the menopausal transition, whether spontaneous or induced. Moreover, meaningful guidance from published trials is limited by the small number of enrolled subjects and short duration of study (i.e., ≤12 weeks).

How hot flushes happen

According to Freedman, body temperature is regulated over a range called the thermo-neutral zone.^1,2 Reduced or fluctuating ovarian hormones are believed to narrow the thermoregulatory zone such that variations in core body temperature trigger heat loss mechanisms. A narrowed thermoregulatory zone has been associated with increased norepinephrine.

Clonidine, an α-2 adrenergic agonist, decreases norepinephrine and has been found to reduce hot flushes. Other nonhormonal agents that have been found to be at least partially effective in reducing hot flushes include SSRI and SNRI antidepressants, which enhance central serotonin and norepinephrine activity. Gabapentin has also proved to be effective.

Potential adverse events or negative side effects, such as insomnia, weight gain, drowsiness, and sedation, need to be taken into account when evaluating the benefits of pharmaceutical options.

We want to hear from you! Tell us what you think.

OBG Management Senior Editor Janelle Yates contributed to this article.

Hear Dr. Pinkerton discuss this article

The Women’s Health Initiative (WHI) caused a sea change in women’s attitudes toward menopausal hormone therapy and aroused many fears—not always rational—that remain almost palpable today. One study of the aftermath of the WHI found that 70% of women who were taking hormone therapy discontinued it, and 26% of women lost confidence in medical recommendations in general.¹

Into the chaos stepped Suzanne Somers, Michael Platt, and other celebrities, touting the benefits of a new kind of hormone: bioidentical. You don’t have to read Somers’ bestseller, The Sexy Years, to encounter the claims it makes on behalf of bioidenticals; the cover itself makes them clear: Discover the Hormone Connection—The Secret to Fabulous Sex, Great Health and Vitality, for Women and Men. Since publication of the book, the demand for bioidentical hormones has only increased, as women remain fearful about conventional hormone therapy.

Many ObGyns regularly field requests from patients for specially compounded bioidentical regimens. In most cases, the women who ask for these drugs are poorly informed about their risks and willing to pay out of pocket to acquire them. JoAnn V. Pinkerton, MD, sees many of these patients at The Women’s Place Midlife Health Center in Charlottesville, Virginia. OBG Management recently sat down with Dr. Pinkerton to discuss her concerns about the growing ubiquity of compounded bioidentical hormones. In the Q&A that follows, we talk about what “bioidentical” actually means, whether these hormones are ever justified, common misconceptions about them, and other issues.

In a special accompanying commentary, former Food and Drug Administration (FDA) Senior Medical Officer Bruce Patsner, MD, JD, also weighs in on the issue.

What is “bioidentical”?

OBG MANAGEMENT: Let’s start with the basics. What does the word “bioidentical” mean? Is it a legitimate medical term?

DR. PINKERTON: Bioidentical hormones are exogenous hormones that are biochemically similar to those produced endogenously by the body or ovaries. These include estrone, estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA has approved many prescription products that contain bioidentical hormones. However, the term “bioidentical” is often used to refer to custom-compounded hormones. The major difference between the FDA-approved prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety.

Bioidenticals are not “natural” hormones, although many consumers think they are. In reality, compounded bioidentical hormones and FDA-approved bioidentical hormones all come from the same precursors. They begin as soy products or wild yam and then get converted to the different hormones in a laboratory in Germany before finding their way to the various world markets.

The claim that all bioidentical hormones are bioengineered to contain the same chemical structure as natural female sex hormones is false. As one expert noted, “the term ‘bioidentical’ has become inappropriately synonymous with ‘natural’ or ‘not synthetic’ and should be redefined to correct patient misconceptions.”²

Common misconceptions

OBG MANAGEMENT: What are some of the other false impressions you encounter among patients who ask for bioidenticals?

DR. PINKERTON: That the hormones are safer or more effective than hormone therapy, that they carry no risks, and that they are as well-monitored as FDA-approved products, to name a few. (For more, see “10 erroneous beliefs patients have about compounded hormones”).

OBG MANAGEMENT: Where do these ideas originate?

DR. PINKERTON: They are propagated by self-proclaimed experts and celebrities or by laypersons and physicians who devote the bulk of their time to promoting these hormones, usually at considerable cost to the patient.

OBG MANAGEMENT: What are the risks of compounded bioidentical hormones?

DR. PINKERTON: According to FDA guidance for industry, in the absence of data about these hormones, the risks and benefits should be assumed to be identical to those of FDA-approved hormone therapies, with the caveat that we don’t know from batch to batch what a woman is receiving. However, they are not regulated or monitored by the FDA, so we are lacking testing for purity, potency, efficacy, and safety. When the FDA did analyze compounded bioidentical hormones, a significant percentage (34%) failed one or more standard quality tests.³ In comparison, FDA-approved drugs fail analytical testing at a rate of less than 2%.³

The problems with compounded hormones

BRUCE PATSNER, MD, JD
Dr. Patsner is Research Professor of Law at the University of Houston Law Center in Houston, Tex. He served as Senior Medical Officer at the US Food and Drug Administration (FDA), where he was one of the agency’s experts on pharmacy compounding of prescription hormone drug therapy for the treatment of menopausal conditions.

The FDA has nothing against compounding pharmacies per se. Individualized preparation of a customized medication for a patient, based on a valid prescription, is an essential part of the practice of pharmacy. However, some actors in the pharmacy compounding business have taken the practice to a different level, not just in terms of the volume of business they do, but in the way compounded hormones are advertised and promoted. The courts aren’t necessarily interested in intervening in cases involving high volume alone. And when it comes to unsubstantiated claims of benefit, the FDA has found it difficult to assert jurisdiction over pharmacy compounding in general, making it hard to assert control over the advertising claims these pharmacies make on behalf of compounded drugs.

The result? The FDA has been unable to rein in claims that compounded prescription drugs are safer or better than commercially prepared medications. These drugs are probably as safe and effective as their manufactured counterparts, but there are no data to confirm this assumption.

What’s in a name?

“Bioidentical” isn’t a bona fide term. There is no definition of it in any medical dictionary; it’s just a name the industry cooked up, a catchy one at that. And when bioidenticals are advertised and promoted, the term “natural” is usually in close proximity. Most patients equate the word natural with plant-derived substances that have not been chemically altered. The fact is, many compounded prescription drugs are derived from plants—but they are also chemically altered.

Some applications are legitimate

A number of women use compounded medications because they make it possible to obtain hormone combinations that are not readily available in cream form. For example, if a patient wants testosterone as part of a cream of estrogen and progesterone, a compounded product is the only option.

Show me the data

No studies have compared compounded drugs with commercial drugs—and such studies are exceedingly unlikely. Compounding pharmacies have no incentive to conduct or participate in such studies. The pharmaceutical compounding industry is a multibillion-dollar enterprise in this country, and compounded prescription drugs for menopausal conditions are probably the biggest product outside of the oncology arena. Proponents of compounded hormones have a captive audience, so to speak, made up of women who don’t like commercial drug manufacturers or who prefer products that appear to be natural, or both.

The problem is that these women receive no package insert or prescription drug label with their hormones. Warning labels are not required because compounded drugs are not regulated by the FDA. Consumers are basically at the mercy of whatever claims they read on the Internet or in the lay literature, which tends to be written by people who have a financial interest in affiliating with the compounding industry. It’s a very frustrating situation for a lot of people.

Unintended consequences of the WHI

The Women’s Health Initiative (WHI) stirred demand for bioidentical hormones by casting the safety claims for some commercial hormone therapy products in a less than favorable light. That wasn’t the investigators’ intent, of course, and some of the findings of the WHI have since been questioned.

The goal of the WHI was to critically evaluate some of the touted health benefits of commercial hormone therapy prescription drugs, but, by questioning some of these claims, it inadvertently pushed a significant percentage of patients toward compounded prescription drugs—and we have no safety data on them.

No one knows exactly how many women were swayed, but the consensus is that they were, and no one’s been happy about that.

The main problem with the compounded hormones, as I see it, is that women who use them do not receive any written information from the compounding pharmacist about risks and benefits. Nor do they receive the black box warnings on FDA-approved estrogen therapy. I believe women need to be adequately educated about the potential risks and benefits, as well as the lack of efficacy data and quality control, if compounded products are requested. That means it’s up to the prescriber to educate the patient about the potential risks and benefits.

Rosenthal states that symptomatic menopausal women or those who fear breast cancer or heart disease can be considered a vulnerable population: “Patients do not have the background to decipher credible sources from noncredible sources.” False claims present convincing arguments for laypersons. A woman may be vulnerable to unsubstantiated claims by virtue of her symptoms and the anxiety and even depression that they can produce. Without comprehensive education, these women cannot be assumed to be adequately informed.

Let me put it in perspective. If a patient with a history of breast cancer complains about severe vaginal dryness that interferes with her sex life, I might decide to give her the smallest amount of topical estrogen that I can—for example, a dime-sized amount of estrogen to apply to her vulvar area twice a week. This amount of estrogen can’t be detected in her system with current assays. I know that some of it will be systemically absorbed, but it cannot be detected. When the patient buys that commercially prepared cream from the pharmacist, she will receive the same black box warning that comes with all systemic hormones since the WHI. However, if she goes to a compounding pharmacist with a prescription for bioidentical hormone therapy, she will not get the warning, regardless of the ingredients or dosage.

Are compounded bioidenticals ever justified?

OBG MANAGEMENT: According to the FDA, compounding of drug products is justified only when a practitioner finds that an FDA-approved drug does not meet the patient’s needs. Do you think this is ever really the case, given the availability of FDA-approved bioidentical hormone preparations?

DR. PINKERTON: In rare cases, compounding of bioidentical hormones is justified, such as when a patient cannot tolerate an FDA-approved product. The problem is that women have been especially concerned about the safety of hormone therapy since the WHI, and bioidentical hormones have been promoted as being safer than FDA-regulated preparations, despite the lack of evidence of their safety or efficacy in peer-reviewed literature. So many women request them.

In a recent commentary, Boothby and Doering call bioidentical hormone therapy “a panacea that lacks supportive evidence.” They say, “It’s our belief that pharmacists are compounding these with the best intentions, but they are ill informed regarding the lack of scientific underpinning associated with efficacy and safety.”³

OBG MANAGEMENT: Do you ever prescribe bioidentical hormones?

DR. PINKERTON: Yes, but rarely, and primarily for women who can’t tolerate FDA-approved hormones or who, after adequate information and education, refuse FDA-approved hormone therapy.

Is salivary hormone testing informative?

OBG MANAGEMENT: Many clinicians who prescribe bioidentical hormones base the dosage on salivary hormone testing. They claim that this allows them to offer individualized formulations. Is this a reliable claim?

DR. PINKERTON: No, it isn’t. Although compounded bioidentical hormone therapy is often prescribed on the basis of salivary hormone testing, there is no scientific evidence that a correlation exists between a patient’s symptoms and salivary hormones, or that salivary hormone testing reflects what is happening at the tissue level. As Fugh-Berman and Bythrow have observed, this type of testing is often used to convince asymptomatic consumers to use hormones—or symptomatic women to take higher dosages. That practice is likely to lead to adverse events.⁵ The practice also directly contradicts evidence-based guidelines, which recommend that hormone therapy be individualized on the basis of symptoms, not hormone levels.⁶

There are no published studies in the peer-reviewed literature that show that salivary testing is a reliable measure on which to safely and effectively base dosing decisions. Indeed, The Endocrine Society issued a position statement that notes, among other issues, that salivary hormone tests are “inaccurate and should not be considered reliable measures of hormones in the body.”⁷ The American College of Obstetricians and Gynecologists also advises against salivary testing, observing that:

• 1) there is no biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone concentrations
• 2) there is large within-patient variability in salivary hormone concentrations. Salivary hormone levels vary depending on diet, time of day of testing, the specific hormone being tested, and other variables.³

Do bioidenticals protect against cancer?

OBG MANAGEMENT: Some reports mention the fact that many women believe that bioidentical hormones—specifically, estriol—can reduce their risk of breast and endometrial cancer. Is there any truth behind this belief?

DR. PINKERTON: Estriol is a weak estrogen. There is no evidence that, if it is given at a dosage high enough to relieve symptoms, it is any safer than estradiol.

In regard to endometrial cancer, if the exogenous estrogen—bioidentical or otherwise—is unopposed or inadequately opposed, the risk of endometrial cancer is elevated. The problem is that it is hard to determine whether estrogen is being adequately opposed, particularly when transdermal compounded progesterone is given, because the progesterone molecule is too large to be well-absorbed systemically.⁹

In regard to breast cancer, estriol is a less potent estrogen than estradiol, but it is believed to carry the same risks if it is dosed at effective levels. There is nothing about estriol per se in the peer-reviewed literature that shows that it protects against breast cancer.

The data on risk of breast cancer with estrogen therapy is confusing, with potentially higher risks if estrogen is combined with progestogen. Most of the data we have on estriol come from animals, but a study from 1980 in humans showed that, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases.⁸

How do you monitor use of bioidentical hormones?

OBG MANAGEMENT: When you do prescribe a compounded bioidentical hormone, how do you monitor the patient?

DR. PINKERTON: First, I want to reiterate that I prescribe these hormones after considerable patient education about FDA-approved options and their potential risks. Second, when a patient needs or requests hormone therapy, I recommend conventional therapy. Only when she cannot tolerate or refuses FDA-approved drugs do I consider prescribing compounded bioidentical hormones—which, as I said earlier, are assumed to carry risks identical to those of FDA-approved hormones.

In some cases, I provide gynecologic care for patients who obtain compounded bioidentical hormones from other sources. What I will sometimes do, just to give myself some idea of how much estrogen they are getting, is to measure the peak and trough estradiol and estrone levels. That is, I measure the hormone level within 4 hours of the patient taking the drug to see how high it goes, and again about 12 hours later to see how low it goes. I measure both because estradiol may be peripherally converted to estrone.

Regrettably, we don’t know what to do about the various hormone levels. It isn’t like treating thyroid disorders; we normally dose estrogen therapy based on symptoms.

Who pays?

OBG MANAGEMENT: Who pays for salivary testing and compounded bioidentical hormones? Does health insurance cover them?

DR. PINKERTON: Like other “natural” products, compounded bioidenticals may cost more than their commercially prepared counterparts and often are not covered by insurance. In addition, prescribers may charge more for a “consultation” than do practitioners who accept insurance; they also may recommend salivary testing, which is expensive. Patients can end up paying large sums out of pocket.

As Rosenthal noted, many women do not appear to be concerned about the added costs.² That may be because compounded bioidentical hormone therapy is usually offered to economically advantaged patients.²

Ethical considerations

OBG MANAGEMENT: That raises an important question: What ethical considerations are inherent in the prescribing of compounded bioidenticals?

DR. PINKERTON: The fact that women who are able to pay out of pocket are the primary users of these drugs is one important point. In her analysis of the ethics surrounding bioidentical hormones, Rosenthal noted that the drugs remain “an unequal alternative, and any data collected would not be representative of the overall menopausal community.”²

A critical issue pointed out by Rosenthal is that perimenopausal and menopausal women may be particularly vulnerable to the unsubstantiated claims of purveyors of bio identical hormones. “A substantial number of women seek out bioidentical hormone replacement therapy to restore sexual well-being and functioning, in particular, who may be psychologically more vulnerable,” she writes.²

Another concern arises when the practitioner who prescribes bioidentical hormones also happens to sell them. This poses a potential conflict of interest and “violates professional ethical conduct.”²

OBG MANAGEMENT: Do physicians aggravate the problem when they accede to a patient’s request for compounded hormones?

DR. PINKERTON: Physicians and health-care providers need to stop and educate the patient about the lack of safety and efficacy data, the risks and benefits, and recognize the possibility that she has been influenced by unsubstantiated claims.

OBG Management Senior Editor Janelle Yates contributed to this article.

Hear Dr. Pinkerton discuss this article

The Women’s Health Initiative (WHI) caused a sea change in women’s attitudes toward menopausal hormone therapy and aroused many fears—not always rational—that remain almost palpable today. One study of the aftermath of the WHI found that 70% of women who were taking hormone therapy discontinued it, and 26% of women lost confidence in medical recommendations in general.¹

Into the chaos stepped Suzanne Somers, Michael Platt, and other celebrities, touting the benefits of a new kind of hormone: bioidentical. You don’t have to read Somers’ bestseller, The Sexy Years, to encounter the claims it makes on behalf of bioidenticals; the cover itself makes them clear: Discover the Hormone Connection—The Secret to Fabulous Sex, Great Health and Vitality, for Women and Men. Since publication of the book, the demand for bioidentical hormones has only increased, as women remain fearful about conventional hormone therapy.

Many ObGyns regularly field requests from patients for specially compounded bioidentical regimens. In most cases, the women who ask for these drugs are poorly informed about their risks and willing to pay out of pocket to acquire them. JoAnn V. Pinkerton, MD, sees many of these patients at The Women’s Place Midlife Health Center in Charlottesville, Virginia. OBG Management recently sat down with Dr. Pinkerton to discuss her concerns about the growing ubiquity of compounded bioidentical hormones. In the Q&A that follows, we talk about what “bioidentical” actually means, whether these hormones are ever justified, common misconceptions about them, and other issues.

In a special accompanying commentary, former Food and Drug Administration (FDA) Senior Medical Officer Bruce Patsner, MD, JD, also weighs in on the issue.

What is “bioidentical”?

OBG MANAGEMENT: Let’s start with the basics. What does the word “bioidentical” mean? Is it a legitimate medical term?

DR. PINKERTON: Bioidentical hormones are exogenous hormones that are biochemically similar to those produced endogenously by the body or ovaries. These include estrone, estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA has approved many prescription products that contain bioidentical hormones. However, the term “bioidentical” is often used to refer to custom-compounded hormones. The major difference between the FDA-approved prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety.

Bioidenticals are not “natural” hormones, although many consumers think they are. In reality, compounded bioidentical hormones and FDA-approved bioidentical hormones all come from the same precursors. They begin as soy products or wild yam and then get converted to the different hormones in a laboratory in Germany before finding their way to the various world markets.

The claim that all bioidentical hormones are bioengineered to contain the same chemical structure as natural female sex hormones is false. As one expert noted, “the term ‘bioidentical’ has become inappropriately synonymous with ‘natural’ or ‘not synthetic’ and should be redefined to correct patient misconceptions.”²

Common misconceptions

OBG MANAGEMENT: What are some of the other false impressions you encounter among patients who ask for bioidenticals?

DR. PINKERTON: That the hormones are safer or more effective than hormone therapy, that they carry no risks, and that they are as well-monitored as FDA-approved products, to name a few. (For more, see “10 erroneous beliefs patients have about compounded hormones”).

OBG MANAGEMENT: Where do these ideas originate?

DR. PINKERTON: They are propagated by self-proclaimed experts and celebrities or by laypersons and physicians who devote the bulk of their time to promoting these hormones, usually at considerable cost to the patient.

OBG MANAGEMENT: What are the risks of compounded bioidentical hormones?

DR. PINKERTON: According to FDA guidance for industry, in the absence of data about these hormones, the risks and benefits should be assumed to be identical to those of FDA-approved hormone therapies, with the caveat that we don’t know from batch to batch what a woman is receiving. However, they are not regulated or monitored by the FDA, so we are lacking testing for purity, potency, efficacy, and safety. When the FDA did analyze compounded bioidentical hormones, a significant percentage (34%) failed one or more standard quality tests.³ In comparison, FDA-approved drugs fail analytical testing at a rate of less than 2%.³

The problems with compounded hormones

BRUCE PATSNER, MD, JD
Dr. Patsner is Research Professor of Law at the University of Houston Law Center in Houston, Tex. He served as Senior Medical Officer at the US Food and Drug Administration (FDA), where he was one of the agency’s experts on pharmacy compounding of prescription hormone drug therapy for the treatment of menopausal conditions.

The FDA has nothing against compounding pharmacies per se. Individualized preparation of a customized medication for a patient, based on a valid prescription, is an essential part of the practice of pharmacy. However, some actors in the pharmacy compounding business have taken the practice to a different level, not just in terms of the volume of business they do, but in the way compounded hormones are advertised and promoted. The courts aren’t necessarily interested in intervening in cases involving high volume alone. And when it comes to unsubstantiated claims of benefit, the FDA has found it difficult to assert jurisdiction over pharmacy compounding in general, making it hard to assert control over the advertising claims these pharmacies make on behalf of compounded drugs.

The result? The FDA has been unable to rein in claims that compounded prescription drugs are safer or better than commercially prepared medications. These drugs are probably as safe and effective as their manufactured counterparts, but there are no data to confirm this assumption.

What’s in a name?

“Bioidentical” isn’t a bona fide term. There is no definition of it in any medical dictionary; it’s just a name the industry cooked up, a catchy one at that. And when bioidenticals are advertised and promoted, the term “natural” is usually in close proximity. Most patients equate the word natural with plant-derived substances that have not been chemically altered. The fact is, many compounded prescription drugs are derived from plants—but they are also chemically altered.

Some applications are legitimate

A number of women use compounded medications because they make it possible to obtain hormone combinations that are not readily available in cream form. For example, if a patient wants testosterone as part of a cream of estrogen and progesterone, a compounded product is the only option.

Show me the data

No studies have compared compounded drugs with commercial drugs—and such studies are exceedingly unlikely. Compounding pharmacies have no incentive to conduct or participate in such studies. The pharmaceutical compounding industry is a multibillion-dollar enterprise in this country, and compounded prescription drugs for menopausal conditions are probably the biggest product outside of the oncology arena. Proponents of compounded hormones have a captive audience, so to speak, made up of women who don’t like commercial drug manufacturers or who prefer products that appear to be natural, or both.

The problem is that these women receive no package insert or prescription drug label with their hormones. Warning labels are not required because compounded drugs are not regulated by the FDA. Consumers are basically at the mercy of whatever claims they read on the Internet or in the lay literature, which tends to be written by people who have a financial interest in affiliating with the compounding industry. It’s a very frustrating situation for a lot of people.

Unintended consequences of the WHI

The Women’s Health Initiative (WHI) stirred demand for bioidentical hormones by casting the safety claims for some commercial hormone therapy products in a less than favorable light. That wasn’t the investigators’ intent, of course, and some of the findings of the WHI have since been questioned.

The goal of the WHI was to critically evaluate some of the touted health benefits of commercial hormone therapy prescription drugs, but, by questioning some of these claims, it inadvertently pushed a significant percentage of patients toward compounded prescription drugs—and we have no safety data on them.

No one knows exactly how many women were swayed, but the consensus is that they were, and no one’s been happy about that.

The main problem with the compounded hormones, as I see it, is that women who use them do not receive any written information from the compounding pharmacist about risks and benefits. Nor do they receive the black box warnings on FDA-approved estrogen therapy. I believe women need to be adequately educated about the potential risks and benefits, as well as the lack of efficacy data and quality control, if compounded products are requested. That means it’s up to the prescriber to educate the patient about the potential risks and benefits.

Rosenthal states that symptomatic menopausal women or those who fear breast cancer or heart disease can be considered a vulnerable population: “Patients do not have the background to decipher credible sources from noncredible sources.” False claims present convincing arguments for laypersons. A woman may be vulnerable to unsubstantiated claims by virtue of her symptoms and the anxiety and even depression that they can produce. Without comprehensive education, these women cannot be assumed to be adequately informed.

Let me put it in perspective. If a patient with a history of breast cancer complains about severe vaginal dryness that interferes with her sex life, I might decide to give her the smallest amount of topical estrogen that I can—for example, a dime-sized amount of estrogen to apply to her vulvar area twice a week. This amount of estrogen can’t be detected in her system with current assays. I know that some of it will be systemically absorbed, but it cannot be detected. When the patient buys that commercially prepared cream from the pharmacist, she will receive the same black box warning that comes with all systemic hormones since the WHI. However, if she goes to a compounding pharmacist with a prescription for bioidentical hormone therapy, she will not get the warning, regardless of the ingredients or dosage.

Are compounded bioidenticals ever justified?

OBG MANAGEMENT: According to the FDA, compounding of drug products is justified only when a practitioner finds that an FDA-approved drug does not meet the patient’s needs. Do you think this is ever really the case, given the availability of FDA-approved bioidentical hormone preparations?

DR. PINKERTON: In rare cases, compounding of bioidentical hormones is justified, such as when a patient cannot tolerate an FDA-approved product. The problem is that women have been especially concerned about the safety of hormone therapy since the WHI, and bioidentical hormones have been promoted as being safer than FDA-regulated preparations, despite the lack of evidence of their safety or efficacy in peer-reviewed literature. So many women request them.

In a recent commentary, Boothby and Doering call bioidentical hormone therapy “a panacea that lacks supportive evidence.” They say, “It’s our belief that pharmacists are compounding these with the best intentions, but they are ill informed regarding the lack of scientific underpinning associated with efficacy and safety.”³

OBG MANAGEMENT: Do you ever prescribe bioidentical hormones?

DR. PINKERTON: Yes, but rarely, and primarily for women who can’t tolerate FDA-approved hormones or who, after adequate information and education, refuse FDA-approved hormone therapy.

Is salivary hormone testing informative?

OBG MANAGEMENT: Many clinicians who prescribe bioidentical hormones base the dosage on salivary hormone testing. They claim that this allows them to offer individualized formulations. Is this a reliable claim?

DR. PINKERTON: No, it isn’t. Although compounded bioidentical hormone therapy is often prescribed on the basis of salivary hormone testing, there is no scientific evidence that a correlation exists between a patient’s symptoms and salivary hormones, or that salivary hormone testing reflects what is happening at the tissue level. As Fugh-Berman and Bythrow have observed, this type of testing is often used to convince asymptomatic consumers to use hormones—or symptomatic women to take higher dosages. That practice is likely to lead to adverse events.⁵ The practice also directly contradicts evidence-based guidelines, which recommend that hormone therapy be individualized on the basis of symptoms, not hormone levels.⁶

There are no published studies in the peer-reviewed literature that show that salivary testing is a reliable measure on which to safely and effectively base dosing decisions. Indeed, The Endocrine Society issued a position statement that notes, among other issues, that salivary hormone tests are “inaccurate and should not be considered reliable measures of hormones in the body.”⁷ The American College of Obstetricians and Gynecologists also advises against salivary testing, observing that:

• 1) there is no biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone concentrations
• 2) there is large within-patient variability in salivary hormone concentrations. Salivary hormone levels vary depending on diet, time of day of testing, the specific hormone being tested, and other variables.³

Do bioidenticals protect against cancer?

OBG MANAGEMENT: Some reports mention the fact that many women believe that bioidentical hormones—specifically, estriol—can reduce their risk of breast and endometrial cancer. Is there any truth behind this belief?

DR. PINKERTON: Estriol is a weak estrogen. There is no evidence that, if it is given at a dosage high enough to relieve symptoms, it is any safer than estradiol.

In regard to endometrial cancer, if the exogenous estrogen—bioidentical or otherwise—is unopposed or inadequately opposed, the risk of endometrial cancer is elevated. The problem is that it is hard to determine whether estrogen is being adequately opposed, particularly when transdermal compounded progesterone is given, because the progesterone molecule is too large to be well-absorbed systemically.⁹

In regard to breast cancer, estriol is a less potent estrogen than estradiol, but it is believed to carry the same risks if it is dosed at effective levels. There is nothing about estriol per se in the peer-reviewed literature that shows that it protects against breast cancer.

The data on risk of breast cancer with estrogen therapy is confusing, with potentially higher risks if estrogen is combined with progestogen. Most of the data we have on estriol come from animals, but a study from 1980 in humans showed that, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases.⁸

How do you monitor use of bioidentical hormones?

OBG MANAGEMENT: When you do prescribe a compounded bioidentical hormone, how do you monitor the patient?

DR. PINKERTON: First, I want to reiterate that I prescribe these hormones after considerable patient education about FDA-approved options and their potential risks. Second, when a patient needs or requests hormone therapy, I recommend conventional therapy. Only when she cannot tolerate or refuses FDA-approved drugs do I consider prescribing compounded bioidentical hormones—which, as I said earlier, are assumed to carry risks identical to those of FDA-approved hormones.

In some cases, I provide gynecologic care for patients who obtain compounded bioidentical hormones from other sources. What I will sometimes do, just to give myself some idea of how much estrogen they are getting, is to measure the peak and trough estradiol and estrone levels. That is, I measure the hormone level within 4 hours of the patient taking the drug to see how high it goes, and again about 12 hours later to see how low it goes. I measure both because estradiol may be peripherally converted to estrone.

Regrettably, we don’t know what to do about the various hormone levels. It isn’t like treating thyroid disorders; we normally dose estrogen therapy based on symptoms.

Who pays?

OBG MANAGEMENT: Who pays for salivary testing and compounded bioidentical hormones? Does health insurance cover them?

DR. PINKERTON: Like other “natural” products, compounded bioidenticals may cost more than their commercially prepared counterparts and often are not covered by insurance. In addition, prescribers may charge more for a “consultation” than do practitioners who accept insurance; they also may recommend salivary testing, which is expensive. Patients can end up paying large sums out of pocket.

As Rosenthal noted, many women do not appear to be concerned about the added costs.² That may be because compounded bioidentical hormone therapy is usually offered to economically advantaged patients.²

Ethical considerations

OBG MANAGEMENT: That raises an important question: What ethical considerations are inherent in the prescribing of compounded bioidenticals?

DR. PINKERTON: The fact that women who are able to pay out of pocket are the primary users of these drugs is one important point. In her analysis of the ethics surrounding bioidentical hormones, Rosenthal noted that the drugs remain “an unequal alternative, and any data collected would not be representative of the overall menopausal community.”²

A critical issue pointed out by Rosenthal is that perimenopausal and menopausal women may be particularly vulnerable to the unsubstantiated claims of purveyors of bio identical hormones. “A substantial number of women seek out bioidentical hormone replacement therapy to restore sexual well-being and functioning, in particular, who may be psychologically more vulnerable,” she writes.²

Another concern arises when the practitioner who prescribes bioidentical hormones also happens to sell them. This poses a potential conflict of interest and “violates professional ethical conduct.”²

OBG MANAGEMENT: Do physicians aggravate the problem when they accede to a patient’s request for compounded hormones?

DR. PINKERTON: Physicians and health-care providers need to stop and educate the patient about the lack of safety and efficacy data, the risks and benefits, and recognize the possibility that she has been influenced by unsubstantiated claims.

OBG Management Senior Editor Janelle Yates contributed to this article.

Hear Dr. Pinkerton discuss this article

The Women’s Health Initiative (WHI) caused a sea change in women’s attitudes toward menopausal hormone therapy and aroused many fears—not always rational—that remain almost palpable today. One study of the aftermath of the WHI found that 70% of women who were taking hormone therapy discontinued it, and 26% of women lost confidence in medical recommendations in general.¹

Into the chaos stepped Suzanne Somers, Michael Platt, and other celebrities, touting the benefits of a new kind of hormone: bioidentical. You don’t have to read Somers’ bestseller, The Sexy Years, to encounter the claims it makes on behalf of bioidenticals; the cover itself makes them clear: Discover the Hormone Connection—The Secret to Fabulous Sex, Great Health and Vitality, for Women and Men. Since publication of the book, the demand for bioidentical hormones has only increased, as women remain fearful about conventional hormone therapy.

Many ObGyns regularly field requests from patients for specially compounded bioidentical regimens. In most cases, the women who ask for these drugs are poorly informed about their risks and willing to pay out of pocket to acquire them. JoAnn V. Pinkerton, MD, sees many of these patients at The Women’s Place Midlife Health Center in Charlottesville, Virginia. OBG Management recently sat down with Dr. Pinkerton to discuss her concerns about the growing ubiquity of compounded bioidentical hormones. In the Q&A that follows, we talk about what “bioidentical” actually means, whether these hormones are ever justified, common misconceptions about them, and other issues.

In a special accompanying commentary, former Food and Drug Administration (FDA) Senior Medical Officer Bruce Patsner, MD, JD, also weighs in on the issue.

What is “bioidentical”?

OBG MANAGEMENT: Let’s start with the basics. What does the word “bioidentical” mean? Is it a legitimate medical term?

DR. PINKERTON: Bioidentical hormones are exogenous hormones that are biochemically similar to those produced endogenously by the body or ovaries. These include estrone, estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA has approved many prescription products that contain bioidentical hormones. However, the term “bioidentical” is often used to refer to custom-compounded hormones. The major difference between the FDA-approved prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety.

Bioidenticals are not “natural” hormones, although many consumers think they are. In reality, compounded bioidentical hormones and FDA-approved bioidentical hormones all come from the same precursors. They begin as soy products or wild yam and then get converted to the different hormones in a laboratory in Germany before finding their way to the various world markets.

The claim that all bioidentical hormones are bioengineered to contain the same chemical structure as natural female sex hormones is false. As one expert noted, “the term ‘bioidentical’ has become inappropriately synonymous with ‘natural’ or ‘not synthetic’ and should be redefined to correct patient misconceptions.”²

Common misconceptions

OBG MANAGEMENT: What are some of the other false impressions you encounter among patients who ask for bioidenticals?

DR. PINKERTON: That the hormones are safer or more effective than hormone therapy, that they carry no risks, and that they are as well-monitored as FDA-approved products, to name a few. (For more, see “10 erroneous beliefs patients have about compounded hormones”).

OBG MANAGEMENT: Where do these ideas originate?

DR. PINKERTON: They are propagated by self-proclaimed experts and celebrities or by laypersons and physicians who devote the bulk of their time to promoting these hormones, usually at considerable cost to the patient.

OBG MANAGEMENT: What are the risks of compounded bioidentical hormones?

DR. PINKERTON: According to FDA guidance for industry, in the absence of data about these hormones, the risks and benefits should be assumed to be identical to those of FDA-approved hormone therapies, with the caveat that we don’t know from batch to batch what a woman is receiving. However, they are not regulated or monitored by the FDA, so we are lacking testing for purity, potency, efficacy, and safety. When the FDA did analyze compounded bioidentical hormones, a significant percentage (34%) failed one or more standard quality tests.³ In comparison, FDA-approved drugs fail analytical testing at a rate of less than 2%.³

The problems with compounded hormones

BRUCE PATSNER, MD, JD
Dr. Patsner is Research Professor of Law at the University of Houston Law Center in Houston, Tex. He served as Senior Medical Officer at the US Food and Drug Administration (FDA), where he was one of the agency’s experts on pharmacy compounding of prescription hormone drug therapy for the treatment of menopausal conditions.

The FDA has nothing against compounding pharmacies per se. Individualized preparation of a customized medication for a patient, based on a valid prescription, is an essential part of the practice of pharmacy. However, some actors in the pharmacy compounding business have taken the practice to a different level, not just in terms of the volume of business they do, but in the way compounded hormones are advertised and promoted. The courts aren’t necessarily interested in intervening in cases involving high volume alone. And when it comes to unsubstantiated claims of benefit, the FDA has found it difficult to assert jurisdiction over pharmacy compounding in general, making it hard to assert control over the advertising claims these pharmacies make on behalf of compounded drugs.

The result? The FDA has been unable to rein in claims that compounded prescription drugs are safer or better than commercially prepared medications. These drugs are probably as safe and effective as their manufactured counterparts, but there are no data to confirm this assumption.

What’s in a name?

“Bioidentical” isn’t a bona fide term. There is no definition of it in any medical dictionary; it’s just a name the industry cooked up, a catchy one at that. And when bioidenticals are advertised and promoted, the term “natural” is usually in close proximity. Most patients equate the word natural with plant-derived substances that have not been chemically altered. The fact is, many compounded prescription drugs are derived from plants—but they are also chemically altered.

Some applications are legitimate

A number of women use compounded medications because they make it possible to obtain hormone combinations that are not readily available in cream form. For example, if a patient wants testosterone as part of a cream of estrogen and progesterone, a compounded product is the only option.

Show me the data

No studies have compared compounded drugs with commercial drugs—and such studies are exceedingly unlikely. Compounding pharmacies have no incentive to conduct or participate in such studies. The pharmaceutical compounding industry is a multibillion-dollar enterprise in this country, and compounded prescription drugs for menopausal conditions are probably the biggest product outside of the oncology arena. Proponents of compounded hormones have a captive audience, so to speak, made up of women who don’t like commercial drug manufacturers or who prefer products that appear to be natural, or both.

The problem is that these women receive no package insert or prescription drug label with their hormones. Warning labels are not required because compounded drugs are not regulated by the FDA. Consumers are basically at the mercy of whatever claims they read on the Internet or in the lay literature, which tends to be written by people who have a financial interest in affiliating with the compounding industry. It’s a very frustrating situation for a lot of people.

Unintended consequences of the WHI

The Women’s Health Initiative (WHI) stirred demand for bioidentical hormones by casting the safety claims for some commercial hormone therapy products in a less than favorable light. That wasn’t the investigators’ intent, of course, and some of the findings of the WHI have since been questioned.

The goal of the WHI was to critically evaluate some of the touted health benefits of commercial hormone therapy prescription drugs, but, by questioning some of these claims, it inadvertently pushed a significant percentage of patients toward compounded prescription drugs—and we have no safety data on them.

No one knows exactly how many women were swayed, but the consensus is that they were, and no one’s been happy about that.

The main problem with the compounded hormones, as I see it, is that women who use them do not receive any written information from the compounding pharmacist about risks and benefits. Nor do they receive the black box warnings on FDA-approved estrogen therapy. I believe women need to be adequately educated about the potential risks and benefits, as well as the lack of efficacy data and quality control, if compounded products are requested. That means it’s up to the prescriber to educate the patient about the potential risks and benefits.

Rosenthal states that symptomatic menopausal women or those who fear breast cancer or heart disease can be considered a vulnerable population: “Patients do not have the background to decipher credible sources from noncredible sources.” False claims present convincing arguments for laypersons. A woman may be vulnerable to unsubstantiated claims by virtue of her symptoms and the anxiety and even depression that they can produce. Without comprehensive education, these women cannot be assumed to be adequately informed.

Let me put it in perspective. If a patient with a history of breast cancer complains about severe vaginal dryness that interferes with her sex life, I might decide to give her the smallest amount of topical estrogen that I can—for example, a dime-sized amount of estrogen to apply to her vulvar area twice a week. This amount of estrogen can’t be detected in her system with current assays. I know that some of it will be systemically absorbed, but it cannot be detected. When the patient buys that commercially prepared cream from the pharmacist, she will receive the same black box warning that comes with all systemic hormones since the WHI. However, if she goes to a compounding pharmacist with a prescription for bioidentical hormone therapy, she will not get the warning, regardless of the ingredients or dosage.

Are compounded bioidenticals ever justified?

OBG MANAGEMENT: According to the FDA, compounding of drug products is justified only when a practitioner finds that an FDA-approved drug does not meet the patient’s needs. Do you think this is ever really the case, given the availability of FDA-approved bioidentical hormone preparations?

DR. PINKERTON: In rare cases, compounding of bioidentical hormones is justified, such as when a patient cannot tolerate an FDA-approved product. The problem is that women have been especially concerned about the safety of hormone therapy since the WHI, and bioidentical hormones have been promoted as being safer than FDA-regulated preparations, despite the lack of evidence of their safety or efficacy in peer-reviewed literature. So many women request them.

In a recent commentary, Boothby and Doering call bioidentical hormone therapy “a panacea that lacks supportive evidence.” They say, “It’s our belief that pharmacists are compounding these with the best intentions, but they are ill informed regarding the lack of scientific underpinning associated with efficacy and safety.”³

OBG MANAGEMENT: Do you ever prescribe bioidentical hormones?

DR. PINKERTON: Yes, but rarely, and primarily for women who can’t tolerate FDA-approved hormones or who, after adequate information and education, refuse FDA-approved hormone therapy.

Is salivary hormone testing informative?

OBG MANAGEMENT: Many clinicians who prescribe bioidentical hormones base the dosage on salivary hormone testing. They claim that this allows them to offer individualized formulations. Is this a reliable claim?

DR. PINKERTON: No, it isn’t. Although compounded bioidentical hormone therapy is often prescribed on the basis of salivary hormone testing, there is no scientific evidence that a correlation exists between a patient’s symptoms and salivary hormones, or that salivary hormone testing reflects what is happening at the tissue level. As Fugh-Berman and Bythrow have observed, this type of testing is often used to convince asymptomatic consumers to use hormones—or symptomatic women to take higher dosages. That practice is likely to lead to adverse events.⁵ The practice also directly contradicts evidence-based guidelines, which recommend that hormone therapy be individualized on the basis of symptoms, not hormone levels.⁶

There are no published studies in the peer-reviewed literature that show that salivary testing is a reliable measure on which to safely and effectively base dosing decisions. Indeed, The Endocrine Society issued a position statement that notes, among other issues, that salivary hormone tests are “inaccurate and should not be considered reliable measures of hormones in the body.”⁷ The American College of Obstetricians and Gynecologists also advises against salivary testing, observing that:

• 1) there is no biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone concentrations
• 2) there is large within-patient variability in salivary hormone concentrations. Salivary hormone levels vary depending on diet, time of day of testing, the specific hormone being tested, and other variables.³

Do bioidenticals protect against cancer?

OBG MANAGEMENT: Some reports mention the fact that many women believe that bioidentical hormones—specifically, estriol—can reduce their risk of breast and endometrial cancer. Is there any truth behind this belief?

DR. PINKERTON: Estriol is a weak estrogen. There is no evidence that, if it is given at a dosage high enough to relieve symptoms, it is any safer than estradiol.

In regard to endometrial cancer, if the exogenous estrogen—bioidentical or otherwise—is unopposed or inadequately opposed, the risk of endometrial cancer is elevated. The problem is that it is hard to determine whether estrogen is being adequately opposed, particularly when transdermal compounded progesterone is given, because the progesterone molecule is too large to be well-absorbed systemically.⁹

In regard to breast cancer, estriol is a less potent estrogen than estradiol, but it is believed to carry the same risks if it is dosed at effective levels. There is nothing about estriol per se in the peer-reviewed literature that shows that it protects against breast cancer.

The data on risk of breast cancer with estrogen therapy is confusing, with potentially higher risks if estrogen is combined with progestogen. Most of the data we have on estriol come from animals, but a study from 1980 in humans showed that, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases.⁸

How do you monitor use of bioidentical hormones?

OBG MANAGEMENT: When you do prescribe a compounded bioidentical hormone, how do you monitor the patient?

DR. PINKERTON: First, I want to reiterate that I prescribe these hormones after considerable patient education about FDA-approved options and their potential risks. Second, when a patient needs or requests hormone therapy, I recommend conventional therapy. Only when she cannot tolerate or refuses FDA-approved drugs do I consider prescribing compounded bioidentical hormones—which, as I said earlier, are assumed to carry risks identical to those of FDA-approved hormones.

In some cases, I provide gynecologic care for patients who obtain compounded bioidentical hormones from other sources. What I will sometimes do, just to give myself some idea of how much estrogen they are getting, is to measure the peak and trough estradiol and estrone levels. That is, I measure the hormone level within 4 hours of the patient taking the drug to see how high it goes, and again about 12 hours later to see how low it goes. I measure both because estradiol may be peripherally converted to estrone.

Regrettably, we don’t know what to do about the various hormone levels. It isn’t like treating thyroid disorders; we normally dose estrogen therapy based on symptoms.

Who pays?

OBG MANAGEMENT: Who pays for salivary testing and compounded bioidentical hormones? Does health insurance cover them?

DR. PINKERTON: Like other “natural” products, compounded bioidenticals may cost more than their commercially prepared counterparts and often are not covered by insurance. In addition, prescribers may charge more for a “consultation” than do practitioners who accept insurance; they also may recommend salivary testing, which is expensive. Patients can end up paying large sums out of pocket.

As Rosenthal noted, many women do not appear to be concerned about the added costs.² That may be because compounded bioidentical hormone therapy is usually offered to economically advantaged patients.²

Ethical considerations

OBG MANAGEMENT: That raises an important question: What ethical considerations are inherent in the prescribing of compounded bioidenticals?

DR. PINKERTON: The fact that women who are able to pay out of pocket are the primary users of these drugs is one important point. In her analysis of the ethics surrounding bioidentical hormones, Rosenthal noted that the drugs remain “an unequal alternative, and any data collected would not be representative of the overall menopausal community.”²

A critical issue pointed out by Rosenthal is that perimenopausal and menopausal women may be particularly vulnerable to the unsubstantiated claims of purveyors of bio identical hormones. “A substantial number of women seek out bioidentical hormone replacement therapy to restore sexual well-being and functioning, in particular, who may be psychologically more vulnerable,” she writes.²

Another concern arises when the practitioner who prescribes bioidentical hormones also happens to sell them. This poses a potential conflict of interest and “violates professional ethical conduct.”²

OBG MANAGEMENT: Do physicians aggravate the problem when they accede to a patient’s request for compounded hormones?

DR. PINKERTON: Physicians and health-care providers need to stop and educate the patient about the lack of safety and efficacy data, the risks and benefits, and recognize the possibility that she has been influenced by unsubstantiated claims.

Using data from their large population-based, frequency-matched control study from Germany (3,464 breast cancer cases, 6,657 matched controls), they found a higher risk of lobular cancer with use of norethisterone- and levonorgestrel-derived progestogens than with progestogens derived from progesterone.

Other studies have also suggested that women who use estrogen–progestogen therapy (EPT) are more likely to be given a diagnosis of lobular, rather than ductal, cancer, and that various dosages, routes of administration, frequency of use, and type of estrogen or progestogen differentially affect the type of breast cancer—although the reason for this intriguing observation is unknown.

Fournier and associates, for example, found that EPT regimens containing progesterone or dydrogesterone were associated with a lower risk of breast cancer than other types of progestogen.¹ The Women’s Health Initiative (WHI) evaluated only one type of oral EPT and found too few lobular cancers to answer the question of whether breast cancers found in women in the EPT group differed by histologic type.²

Li and colleagues³ and Flesch-Janys and associates found no statistically significant risk of breast cancer 5 years after EPT was discontinued. Heiss and colleagues reported that, 2.4 years after cessation of EPT, the risk of breast cancer remained stable for prior users in the WHI, compared with women taking placebo (5-year data are not yet available).⁴

Estrogen-only therapy in the WHI was not associated with an increased risk after 6.7 years of use.⁵

In the study by Flesch-Janys and associates, 67.9% of cases and 59.5% of controls had ever used HRT. Cases had a higher age at menopause and lower parity, and were less likely to have breastfed, more likely to have a family history of breast cancer, and more likely to have had benign breast disease.

Study design may invite bias

Case-control methodology is appropriate to study rare cases, examine conditions that develop over time, and generate preliminary hypotheses. Bias can occur, however, depending on the quality of existing records or self-recall and whether it is possible to collect information from all eligible controls.

Recall bias can occur because cases tend to provide more accurate information than controls. In the study by Flesch-Janys and colleagues, trained interviewers conducted face-to-face interviews to limit recall bias, but the low response rate, particularly among controls, is of concern, as is the variety of HRT preparations used by participants. The lack of verification of histologic subtype or re-review of histology by blinded pathologists limits the generalizability of the findings.

Using data from their large population-based, frequency-matched control study from Germany (3,464 breast cancer cases, 6,657 matched controls), they found a higher risk of lobular cancer with use of norethisterone- and levonorgestrel-derived progestogens than with progestogens derived from progesterone.

Other studies have also suggested that women who use estrogen–progestogen therapy (EPT) are more likely to be given a diagnosis of lobular, rather than ductal, cancer, and that various dosages, routes of administration, frequency of use, and type of estrogen or progestogen differentially affect the type of breast cancer—although the reason for this intriguing observation is unknown.

Fournier and associates, for example, found that EPT regimens containing progesterone or dydrogesterone were associated with a lower risk of breast cancer than other types of progestogen.¹ The Women’s Health Initiative (WHI) evaluated only one type of oral EPT and found too few lobular cancers to answer the question of whether breast cancers found in women in the EPT group differed by histologic type.²

Li and colleagues³ and Flesch-Janys and associates found no statistically significant risk of breast cancer 5 years after EPT was discontinued. Heiss and colleagues reported that, 2.4 years after cessation of EPT, the risk of breast cancer remained stable for prior users in the WHI, compared with women taking placebo (5-year data are not yet available).⁴

Estrogen-only therapy in the WHI was not associated with an increased risk after 6.7 years of use.⁵

In the study by Flesch-Janys and associates, 67.9% of cases and 59.5% of controls had ever used HRT. Cases had a higher age at menopause and lower parity, and were less likely to have breastfed, more likely to have a family history of breast cancer, and more likely to have had benign breast disease.

Study design may invite bias

Case-control methodology is appropriate to study rare cases, examine conditions that develop over time, and generate preliminary hypotheses. Bias can occur, however, depending on the quality of existing records or self-recall and whether it is possible to collect information from all eligible controls.

Recall bias can occur because cases tend to provide more accurate information than controls. In the study by Flesch-Janys and colleagues, trained interviewers conducted face-to-face interviews to limit recall bias, but the low response rate, particularly among controls, is of concern, as is the variety of HRT preparations used by participants. The lack of verification of histologic subtype or re-review of histology by blinded pathologists limits the generalizability of the findings.

Using data from their large population-based, frequency-matched control study from Germany (3,464 breast cancer cases, 6,657 matched controls), they found a higher risk of lobular cancer with use of norethisterone- and levonorgestrel-derived progestogens than with progestogens derived from progesterone.

Other studies have also suggested that women who use estrogen–progestogen therapy (EPT) are more likely to be given a diagnosis of lobular, rather than ductal, cancer, and that various dosages, routes of administration, frequency of use, and type of estrogen or progestogen differentially affect the type of breast cancer—although the reason for this intriguing observation is unknown.

Fournier and associates, for example, found that EPT regimens containing progesterone or dydrogesterone were associated with a lower risk of breast cancer than other types of progestogen.¹ The Women’s Health Initiative (WHI) evaluated only one type of oral EPT and found too few lobular cancers to answer the question of whether breast cancers found in women in the EPT group differed by histologic type.²

Li and colleagues³ and Flesch-Janys and associates found no statistically significant risk of breast cancer 5 years after EPT was discontinued. Heiss and colleagues reported that, 2.4 years after cessation of EPT, the risk of breast cancer remained stable for prior users in the WHI, compared with women taking placebo (5-year data are not yet available).⁴

Estrogen-only therapy in the WHI was not associated with an increased risk after 6.7 years of use.⁵

In the study by Flesch-Janys and associates, 67.9% of cases and 59.5% of controls had ever used HRT. Cases had a higher age at menopause and lower parity, and were less likely to have breastfed, more likely to have a family history of breast cancer, and more likely to have had benign breast disease.

Study design may invite bias

Case-control methodology is appropriate to study rare cases, examine conditions that develop over time, and generate preliminary hypotheses. Bias can occur, however, depending on the quality of existing records or self-recall and whether it is possible to collect information from all eligible controls.

Recall bias can occur because cases tend to provide more accurate information than controls. In the study by Flesch-Janys and colleagues, trained interviewers conducted face-to-face interviews to limit recall bias, but the low response rate, particularly among controls, is of concern, as is the variety of HRT preparations used by participants. The lack of verification of histologic subtype or re-review of histology by blinded pathologists limits the generalizability of the findings.