Menopause

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

[email protected]

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.

Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.

Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.

When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.

These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.

In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”

“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.

Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.

The investigators disclosed no external funding or conflicts of interest.
 

[email protected]

SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.

Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.

Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.

Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.

When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.

These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.

In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”

“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.

Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.

The investigators disclosed no external funding or conflicts of interest.
 

[email protected]

SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.

Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.

Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.

Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.

When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.

These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.

In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”

“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.

Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.

The investigators disclosed no external funding or conflicts of interest.
 

[email protected]

SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.

A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).

Bruce Jancin/MDedge News

“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.

To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.

In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”

Mitchel L. Zoler/Frontline Medical News

“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.

“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
 

Contraception

In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.

For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
 

Assisted reproductive technology

In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.

For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
 

Fertility preservation

In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.

Hormone therapy

In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.

Pregnancy assessment and management

Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.

For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”

Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily

For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.

For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.

Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.

Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.

The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.

The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.

The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.

SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.

A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).

Bruce Jancin/MDedge News

“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.

To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.

In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”

Mitchel L. Zoler/Frontline Medical News

“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.

“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
 

Contraception

In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.

For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
 

Assisted reproductive technology

In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.

For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
 

Fertility preservation

In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.

Hormone therapy

In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.

Pregnancy assessment and management

Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.

For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”

Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily

For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.

For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.

Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.

Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.

The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.

The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.

The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.

SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.

A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).

Bruce Jancin/MDedge News

“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.

To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.

In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”

Mitchel L. Zoler/Frontline Medical News

“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.

“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
 

Contraception

In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.

For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
 

Assisted reproductive technology

In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.

For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
 

Fertility preservation

In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.

Hormone therapy

In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.

Pregnancy assessment and management

Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.

For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”

Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily

For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.

For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.

Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.

Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.

The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.

The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.

The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.

SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.

The field of menopause medicine is dominated by studies documenting the effectiveness of systemic estrogen or estrogen-progestin hormone therapy for the treatment of hot flashes caused by hypoestrogenism. The effectiveness of progestin-only systemic hormone therapy for the treatment of hot flashes is much less studied and seldom is utilized in clinical practice. A small number of studies have reported that progestins, including micronized progesterone, medroxyprogesterone acetate, and norethindrone acetate, are effective treatment for hot flashes. Progestin-only systemic hormone therapy might be especially helpful for postmenopausal women with moderate to severe hot flashes who have a contraindication to estrogen treatment.

Micronized progesterone

Micronized progesterone (Prometrium) 300 mg daily taken at bedtime has been reported to effectively treat hot flashes in postmenopausal women. In one study, 133 postmenopausal women with an average age of 55 years and approximately 3 years from their last menstrual period were randomly assigned to 12 weeks of treatment with placebo or micronized progesterone 300 mg daily taken at bedtime.¹ Mean serum progesterone levels were 0.28 ng/mL (0.89 nM) and 27 ng/mL (86 nM) in the women taking placebo and micronized progesterone, respectively. Compared with placebo, micronized progesterone reduced daytime and nighttime hot flash frequency and severity. In addition, compared with placebo, micronized progesterone improved the quality of sleep.¹

Most reviews conclude that micronized progesterone has minimal cardiovascular risk.² Micronized progesterone therapy might be especially helpful for postmenopausal women with moderate to severe hot flashes who have a contraindication to estrogen treatment such as those at increased risk for cardiovascular disease or women with a thrombophilia. Many experts believe that systemic estrogen therapy is contraindicated in postmenopausal women with an American Heart Association risk score greater than 10% over 10 years.³ Additional contraindications to systemic estrogen include women with cardiac disease who have a thrombophilia, such as the Factor V Leiden mutation.⁴

For women who are at high risk for estrogen-induced cardiovascular events, micronized progesterone may be a better option than systemic estrogen for treating hot flashes. Alternatively, in these women at risk of cardiovascular disease a selective serotonin reuptake inhibitor, such as escitalopram, 10 mg to 20 mg daily, may be a good option for treating postmenopausal hot flashes.⁵

Medroxyprogesterone acetate

Medroxyprogesterone acetate, at a dosage of 20 mg daily, is an effective treatment for hot flashes. In a randomized clinical trial 27 postmenopausal women with hot flashes were randomly assigned to treatment with placebo or medroxyprogesterone acetate 20 mg daily for 4 weeks. Vasomotor flushes were decreased by 26% and 74% in the placebo and medroxyprogesterone groups, respectively.⁶

Depot medroxyprogesterone acetate injections at dosages from 150 mg to 400 mg also have been reported to effectively treat hot flashes.^7,8 In a trial comparing the effectiveness of estrogen monotherapy (conjugated equine estrogen 0.6 mg daily) with progestin monotherapy (medroxyprogesterone acetate 10 mg daily), both treatments were equally effective in reducing hot flashes.⁹

Continue to: Micronized progesterone vs medroxyprogesterone acetate...

Micronized progesterone vs medroxyprogesterone acetate

Experts in menopause medicine have suggested that in postmeno­pausal women micronized progesterone has a better pattern of benefits and fewer risks than medroxyprogesterone acetate.^10,11 For example, in the E3N observational study of hormones and breast cancer risk, among 80,377 French postmenopausal women followed for a mean of 8 years, the combination of transdermal estradiol plus oral micronized progesterone was associated with no significantly increased risk of breast cancer (relative risk [RR], 1.08, 95% confidence interval [CI], 0.89–1.31) compared with never users of postmenopausal hormone therapy.¹² By contrast, the combination of oral estrogen plus medroxyprogesterone acetate was associated with an increased risk of breast cancer (RR, 1.48; 95% CI, 1.02–2.16) compared with never users of postmenopausal hormone therapy. The E3N study indicates that micronized progesterone may have a more favorable breast health profile than medroxyprogesterone acetate.¹²

Norethindrone acetate

Norethindrone acetate monotherapy is not commonly prescribed for the treatment of menopausal hot flashes. However, a large clinical trial has demonstrated that norethindrone acetate effectively suppresses hot flashes in women with endometriosis treated with depot leuprolide acetate (LA). In one trial 201 women with endometriosis were randomly assigned to 12 months of treatment with¹³:

• LA plus placebo pills
• LA plus norethindrone acetate (NEA) 5 mg daily
• LA plus NEA 5 mg daily plus conjugated equine estrogen (CEE) 0.625 mg daily, or
• LA plus NEA 5 mg daily plus CEE 1.25 mg daily.

The median number of hot flashes in 24 hours was 6 in the LA plus placebo group and 0 in both the LA plus NEA 5 mg daily group and the LA plus NEA 5 mg plus CEE 1.25 mg daily group. This study demonstrates that NEA 5 mg daily is an effective treatment for hot flashes.

In the same study, LA plus placebo was associated with a significant decrease in lumbar spine bone mineral density. No significant decrease in bone mineral density was observed in the women who received LA plus NEA 5 mg daily. This finding indicates that NEA 5 mg reduces bone absorption caused by hypoestrogenism. In humans, norethindrone is a substrate for the aromatase enzyme system.¹⁴ Small quantities of ethinyl estradiol may be formed by aromatization of norethindrone in vivo,^15,16 contributing to the effectiveness of NEA in suppressing hot flashes and preserving bone density.

Progestin: The estrogen alternative to hot flashes

For postmenopausal women with moderate to severe hot flashes, estrogen treatment reliably suppresses hot flashes and often improves sleep quality and mood. For postmenopausal women with a contraindication to estrogen treatment, progestin-only treatment with micronized progesterone or norethindrone acetate may be an effective option.
 

The field of menopause medicine is dominated by studies documenting the effectiveness of systemic estrogen or estrogen-progestin hormone therapy for the treatment of hot flashes caused by hypoestrogenism. The effectiveness of progestin-only systemic hormone therapy for the treatment of hot flashes is much less studied and seldom is utilized in clinical practice. A small number of studies have reported that progestins, including micronized progesterone, medroxyprogesterone acetate, and norethindrone acetate, are effective treatment for hot flashes. Progestin-only systemic hormone therapy might be especially helpful for postmenopausal women with moderate to severe hot flashes who have a contraindication to estrogen treatment.

Micronized progesterone

Micronized progesterone (Prometrium) 300 mg daily taken at bedtime has been reported to effectively treat hot flashes in postmenopausal women. In one study, 133 postmenopausal women with an average age of 55 years and approximately 3 years from their last menstrual period were randomly assigned to 12 weeks of treatment with placebo or micronized progesterone 300 mg daily taken at bedtime.¹ Mean serum progesterone levels were 0.28 ng/mL (0.89 nM) and 27 ng/mL (86 nM) in the women taking placebo and micronized progesterone, respectively. Compared with placebo, micronized progesterone reduced daytime and nighttime hot flash frequency and severity. In addition, compared with placebo, micronized progesterone improved the quality of sleep.¹

Most reviews conclude that micronized progesterone has minimal cardiovascular risk.² Micronized progesterone therapy might be especially helpful for postmenopausal women with moderate to severe hot flashes who have a contraindication to estrogen treatment such as those at increased risk for cardiovascular disease or women with a thrombophilia. Many experts believe that systemic estrogen therapy is contraindicated in postmenopausal women with an American Heart Association risk score greater than 10% over 10 years.³ Additional contraindications to systemic estrogen include women with cardiac disease who have a thrombophilia, such as the Factor V Leiden mutation.⁴

For women who are at high risk for estrogen-induced cardiovascular events, micronized progesterone may be a better option than systemic estrogen for treating hot flashes. Alternatively, in these women at risk of cardiovascular disease a selective serotonin reuptake inhibitor, such as escitalopram, 10 mg to 20 mg daily, may be a good option for treating postmenopausal hot flashes.⁵

Medroxyprogesterone acetate

Medroxyprogesterone acetate, at a dosage of 20 mg daily, is an effective treatment for hot flashes. In a randomized clinical trial 27 postmenopausal women with hot flashes were randomly assigned to treatment with placebo or medroxyprogesterone acetate 20 mg daily for 4 weeks. Vasomotor flushes were decreased by 26% and 74% in the placebo and medroxyprogesterone groups, respectively.⁶

Depot medroxyprogesterone acetate injections at dosages from 150 mg to 400 mg also have been reported to effectively treat hot flashes.^7,8 In a trial comparing the effectiveness of estrogen monotherapy (conjugated equine estrogen 0.6 mg daily) with progestin monotherapy (medroxyprogesterone acetate 10 mg daily), both treatments were equally effective in reducing hot flashes.⁹

Continue to: Micronized progesterone vs medroxyprogesterone acetate...

Micronized progesterone vs medroxyprogesterone acetate

Experts in menopause medicine have suggested that in postmeno­pausal women micronized progesterone has a better pattern of benefits and fewer risks than medroxyprogesterone acetate.^10,11 For example, in the E3N observational study of hormones and breast cancer risk, among 80,377 French postmenopausal women followed for a mean of 8 years, the combination of transdermal estradiol plus oral micronized progesterone was associated with no significantly increased risk of breast cancer (relative risk [RR], 1.08, 95% confidence interval [CI], 0.89–1.31) compared with never users of postmenopausal hormone therapy.¹² By contrast, the combination of oral estrogen plus medroxyprogesterone acetate was associated with an increased risk of breast cancer (RR, 1.48; 95% CI, 1.02–2.16) compared with never users of postmenopausal hormone therapy. The E3N study indicates that micronized progesterone may have a more favorable breast health profile than medroxyprogesterone acetate.¹²

Norethindrone acetate

Norethindrone acetate monotherapy is not commonly prescribed for the treatment of menopausal hot flashes. However, a large clinical trial has demonstrated that norethindrone acetate effectively suppresses hot flashes in women with endometriosis treated with depot leuprolide acetate (LA). In one trial 201 women with endometriosis were randomly assigned to 12 months of treatment with¹³:

• LA plus placebo pills
• LA plus norethindrone acetate (NEA) 5 mg daily
• LA plus NEA 5 mg daily plus conjugated equine estrogen (CEE) 0.625 mg daily, or
• LA plus NEA 5 mg daily plus CEE 1.25 mg daily.

The median number of hot flashes in 24 hours was 6 in the LA plus placebo group and 0 in both the LA plus NEA 5 mg daily group and the LA plus NEA 5 mg plus CEE 1.25 mg daily group. This study demonstrates that NEA 5 mg daily is an effective treatment for hot flashes.

In the same study, LA plus placebo was associated with a significant decrease in lumbar spine bone mineral density. No significant decrease in bone mineral density was observed in the women who received LA plus NEA 5 mg daily. This finding indicates that NEA 5 mg reduces bone absorption caused by hypoestrogenism. In humans, norethindrone is a substrate for the aromatase enzyme system.¹⁴ Small quantities of ethinyl estradiol may be formed by aromatization of norethindrone in vivo,^15,16 contributing to the effectiveness of NEA in suppressing hot flashes and preserving bone density.

Progestin: The estrogen alternative to hot flashes

For postmenopausal women with moderate to severe hot flashes, estrogen treatment reliably suppresses hot flashes and often improves sleep quality and mood. For postmenopausal women with a contraindication to estrogen treatment, progestin-only treatment with micronized progesterone or norethindrone acetate may be an effective option.
 

The field of menopause medicine is dominated by studies documenting the effectiveness of systemic estrogen or estrogen-progestin hormone therapy for the treatment of hot flashes caused by hypoestrogenism. The effectiveness of progestin-only systemic hormone therapy for the treatment of hot flashes is much less studied and seldom is utilized in clinical practice. A small number of studies have reported that progestins, including micronized progesterone, medroxyprogesterone acetate, and norethindrone acetate, are effective treatment for hot flashes. Progestin-only systemic hormone therapy might be especially helpful for postmenopausal women with moderate to severe hot flashes who have a contraindication to estrogen treatment.

Micronized progesterone

Micronized progesterone (Prometrium) 300 mg daily taken at bedtime has been reported to effectively treat hot flashes in postmenopausal women. In one study, 133 postmenopausal women with an average age of 55 years and approximately 3 years from their last menstrual period were randomly assigned to 12 weeks of treatment with placebo or micronized progesterone 300 mg daily taken at bedtime.¹ Mean serum progesterone levels were 0.28 ng/mL (0.89 nM) and 27 ng/mL (86 nM) in the women taking placebo and micronized progesterone, respectively. Compared with placebo, micronized progesterone reduced daytime and nighttime hot flash frequency and severity. In addition, compared with placebo, micronized progesterone improved the quality of sleep.¹

Most reviews conclude that micronized progesterone has minimal cardiovascular risk.² Micronized progesterone therapy might be especially helpful for postmenopausal women with moderate to severe hot flashes who have a contraindication to estrogen treatment such as those at increased risk for cardiovascular disease or women with a thrombophilia. Many experts believe that systemic estrogen therapy is contraindicated in postmenopausal women with an American Heart Association risk score greater than 10% over 10 years.³ Additional contraindications to systemic estrogen include women with cardiac disease who have a thrombophilia, such as the Factor V Leiden mutation.⁴

For women who are at high risk for estrogen-induced cardiovascular events, micronized progesterone may be a better option than systemic estrogen for treating hot flashes. Alternatively, in these women at risk of cardiovascular disease a selective serotonin reuptake inhibitor, such as escitalopram, 10 mg to 20 mg daily, may be a good option for treating postmenopausal hot flashes.⁵

Medroxyprogesterone acetate

Medroxyprogesterone acetate, at a dosage of 20 mg daily, is an effective treatment for hot flashes. In a randomized clinical trial 27 postmenopausal women with hot flashes were randomly assigned to treatment with placebo or medroxyprogesterone acetate 20 mg daily for 4 weeks. Vasomotor flushes were decreased by 26% and 74% in the placebo and medroxyprogesterone groups, respectively.⁶

Depot medroxyprogesterone acetate injections at dosages from 150 mg to 400 mg also have been reported to effectively treat hot flashes.^7,8 In a trial comparing the effectiveness of estrogen monotherapy (conjugated equine estrogen 0.6 mg daily) with progestin monotherapy (medroxyprogesterone acetate 10 mg daily), both treatments were equally effective in reducing hot flashes.⁹

Continue to: Micronized progesterone vs medroxyprogesterone acetate...

Micronized progesterone vs medroxyprogesterone acetate

Experts in menopause medicine have suggested that in postmeno­pausal women micronized progesterone has a better pattern of benefits and fewer risks than medroxyprogesterone acetate.^10,11 For example, in the E3N observational study of hormones and breast cancer risk, among 80,377 French postmenopausal women followed for a mean of 8 years, the combination of transdermal estradiol plus oral micronized progesterone was associated with no significantly increased risk of breast cancer (relative risk [RR], 1.08, 95% confidence interval [CI], 0.89–1.31) compared with never users of postmenopausal hormone therapy.¹² By contrast, the combination of oral estrogen plus medroxyprogesterone acetate was associated with an increased risk of breast cancer (RR, 1.48; 95% CI, 1.02–2.16) compared with never users of postmenopausal hormone therapy. The E3N study indicates that micronized progesterone may have a more favorable breast health profile than medroxyprogesterone acetate.¹²

Norethindrone acetate

Norethindrone acetate monotherapy is not commonly prescribed for the treatment of menopausal hot flashes. However, a large clinical trial has demonstrated that norethindrone acetate effectively suppresses hot flashes in women with endometriosis treated with depot leuprolide acetate (LA). In one trial 201 women with endometriosis were randomly assigned to 12 months of treatment with¹³:

• LA plus placebo pills
• LA plus norethindrone acetate (NEA) 5 mg daily
• LA plus NEA 5 mg daily plus conjugated equine estrogen (CEE) 0.625 mg daily, or
• LA plus NEA 5 mg daily plus CEE 1.25 mg daily.

The median number of hot flashes in 24 hours was 6 in the LA plus placebo group and 0 in both the LA plus NEA 5 mg daily group and the LA plus NEA 5 mg plus CEE 1.25 mg daily group. This study demonstrates that NEA 5 mg daily is an effective treatment for hot flashes.

In the same study, LA plus placebo was associated with a significant decrease in lumbar spine bone mineral density. No significant decrease in bone mineral density was observed in the women who received LA plus NEA 5 mg daily. This finding indicates that NEA 5 mg reduces bone absorption caused by hypoestrogenism. In humans, norethindrone is a substrate for the aromatase enzyme system.¹⁴ Small quantities of ethinyl estradiol may be formed by aromatization of norethindrone in vivo,^15,16 contributing to the effectiveness of NEA in suppressing hot flashes and preserving bone density.

Progestin: The estrogen alternative to hot flashes

For postmenopausal women with moderate to severe hot flashes, estrogen treatment reliably suppresses hot flashes and often improves sleep quality and mood. For postmenopausal women with a contraindication to estrogen treatment, progestin-only treatment with micronized progesterone or norethindrone acetate may be an effective option.
 

LOS ANGELES – Although menopausal hormone therapy is not approved for the prevention of type 2 diabetes because of its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms, according to Franck Mauvais-Jarvis, MD.

Doug Brunk/MDedge News

“During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension,” Dr. Mauvais-Jarvis, director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, said at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”

The best evidence of this synergy comes from older trials. Nearly 30 years ago, researchers examined the association between postmenopausal hormone use and the subsequent incidence of non–insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal U.S. women aged 30-55 years, who were enrolled in the Nurse’s Health Study and followed for 12 years (Ann Epidemiol. 1992;2[5]:665-73). They found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. In a more recent trial, researchers examined the association between use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women who were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). It found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes.

In the Heart and Estrogen/Progestin Replacement Study, researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes in 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). At 20 U.S. centers, the study participants received 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone, or placebo, and were followed for 4 years. The researchers found that the use of hormone therapy reduced the incidence of diabetes by 35%.

According to Dr. Mauvais-Jarvis, the strongest data come from the Women’s Health Initiative (WHI), a randomized, double-blind trial that compared the effect of daily 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up (Diabetologia. 2004; 47[7]:1175-87). It showed a 20% decrease in the incidence of diabetes at 5 years. More recently, researchers found that, whether WHI participants took estrogen plus medroxyprogesterone or estrogen alone, the protection from diabetes was present (N Engl J Med. 2016;374:803-6).

In 2006, researchers published results from a meta-analysis of 107 trials in an effort to quantify the effects of hormone therapy on components of metabolic syndrome in postmenopausal women (Diabetes Obes Metab. 2006;8[5]:538-54). In women without diabetes, hormone therapy reduced the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. In women with diabetes, hormone therapy reduced fasting glucose by 11% and HOMA-IR by 36%.

The mechanisms by which estrogens improve glucose homeostasis are yet to be fully understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation,” Dr. Mauvais-Jarvis said. “However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.”

Route of estrogen administration also comes into play. For example, oral estrogens increase liver exposure to estrogen, increase triglycerides, and increase clotting factors. “That is why oral estrogens are not indicated in women with risk of deep venous thrombosis,” Dr. Mauvais-Jarvis said. “They also increase inflammatory factors like C-reactive protein. Advantages are that they decrease LDL cholesterol levels and increase HDL cholesterol levels more than transdermal estrogen does.”

The main advantage with transdermal delivery of estrogen, he continued, is that it does not raise triglycerides, clotting factors, or inflammatory factors, and it confers less exposure to the liver. “That’s why it’s the preferred way of administration in women who are obese, who have a risk of DVT, or who have cardiovascular risk factors,” he said. “It has a lower suppression of hepatic glucose production, it increases circulating estradiol, and the delivery to nonhepatic tissue is increased. The oral form of estrogen is cheaper, compared with the transdermal form, though. This is a factor that is always taken into account.”

Dr. Mauvais-Jarvis and colleagues were first to evaluate the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). “The idea was that by combining estrogen and bazedoxifene, you have the beneficial effect of estrogen in the tissues but you block estrogen in the breast and in the uterus, and therefore, you prevent the risk of cancer,” he said. “We found that tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. It increased energy expenditure and decreased fatty liver.”

In a subsequent pilot study, he and his colleagues assessed the effect of 12 weeks’ treatment with bazedoxifene/conjugated estrogens, compared with placebo, on glucose homeostasis and body composition in 12 postmenopausal women (NCT02237079). “We did not find any significant alterations in the IVGTT [Intravenous Glucose Tolerance Test] but we observed improved fasting beta-cell function and serum glucose in menopausal women with obesity,” Dr. Mauvais-Jarvis said (J Endocr Soc. 2019;3[8]:1583-94).

In a separate, randomized, double-blind, placebo-controlled, crossover trial that he and his colleagues performed in eight postmenopausal women with obesity, the primary endpoint was insulin action as measured by a two-step hyperinsulinemic-euglycemic clamp. Secondary endpoints were body composition, basal metabolic rate, ectopic fat, and metabolome. “We did not find any difference in systemic insulin action, ectopic fat, or energy expenditure,” he said. “But we found something very interesting. We did a metabolic analysis and found that oral estrogens increase hepatic de novo lipogenesis and liver triacylglycerol production. In other words, the oral estrogens were increasing [triacylglycerol] synthesis from glucose, but it does not accumulate in the liver.”

Dr. Mauvais-Jarvis disclosed that he has received research support from the National Institutes of Health, the American Diabetes Association, the Department of Veterans Affairs, and Pfizer.
 

[email protected]

LOS ANGELES – Although menopausal hormone therapy is not approved for the prevention of type 2 diabetes because of its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms, according to Franck Mauvais-Jarvis, MD.

Doug Brunk/MDedge News

“During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension,” Dr. Mauvais-Jarvis, director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, said at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”

The best evidence of this synergy comes from older trials. Nearly 30 years ago, researchers examined the association between postmenopausal hormone use and the subsequent incidence of non–insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal U.S. women aged 30-55 years, who were enrolled in the Nurse’s Health Study and followed for 12 years (Ann Epidemiol. 1992;2[5]:665-73). They found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. In a more recent trial, researchers examined the association between use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women who were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). It found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes.

In the Heart and Estrogen/Progestin Replacement Study, researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes in 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). At 20 U.S. centers, the study participants received 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone, or placebo, and were followed for 4 years. The researchers found that the use of hormone therapy reduced the incidence of diabetes by 35%.

According to Dr. Mauvais-Jarvis, the strongest data come from the Women’s Health Initiative (WHI), a randomized, double-blind trial that compared the effect of daily 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up (Diabetologia. 2004; 47[7]:1175-87). It showed a 20% decrease in the incidence of diabetes at 5 years. More recently, researchers found that, whether WHI participants took estrogen plus medroxyprogesterone or estrogen alone, the protection from diabetes was present (N Engl J Med. 2016;374:803-6).

In 2006, researchers published results from a meta-analysis of 107 trials in an effort to quantify the effects of hormone therapy on components of metabolic syndrome in postmenopausal women (Diabetes Obes Metab. 2006;8[5]:538-54). In women without diabetes, hormone therapy reduced the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. In women with diabetes, hormone therapy reduced fasting glucose by 11% and HOMA-IR by 36%.

The mechanisms by which estrogens improve glucose homeostasis are yet to be fully understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation,” Dr. Mauvais-Jarvis said. “However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.”

Route of estrogen administration also comes into play. For example, oral estrogens increase liver exposure to estrogen, increase triglycerides, and increase clotting factors. “That is why oral estrogens are not indicated in women with risk of deep venous thrombosis,” Dr. Mauvais-Jarvis said. “They also increase inflammatory factors like C-reactive protein. Advantages are that they decrease LDL cholesterol levels and increase HDL cholesterol levels more than transdermal estrogen does.”

The main advantage with transdermal delivery of estrogen, he continued, is that it does not raise triglycerides, clotting factors, or inflammatory factors, and it confers less exposure to the liver. “That’s why it’s the preferred way of administration in women who are obese, who have a risk of DVT, or who have cardiovascular risk factors,” he said. “It has a lower suppression of hepatic glucose production, it increases circulating estradiol, and the delivery to nonhepatic tissue is increased. The oral form of estrogen is cheaper, compared with the transdermal form, though. This is a factor that is always taken into account.”

Dr. Mauvais-Jarvis and colleagues were first to evaluate the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). “The idea was that by combining estrogen and bazedoxifene, you have the beneficial effect of estrogen in the tissues but you block estrogen in the breast and in the uterus, and therefore, you prevent the risk of cancer,” he said. “We found that tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. It increased energy expenditure and decreased fatty liver.”

In a subsequent pilot study, he and his colleagues assessed the effect of 12 weeks’ treatment with bazedoxifene/conjugated estrogens, compared with placebo, on glucose homeostasis and body composition in 12 postmenopausal women (NCT02237079). “We did not find any significant alterations in the IVGTT [Intravenous Glucose Tolerance Test] but we observed improved fasting beta-cell function and serum glucose in menopausal women with obesity,” Dr. Mauvais-Jarvis said (J Endocr Soc. 2019;3[8]:1583-94).

In a separate, randomized, double-blind, placebo-controlled, crossover trial that he and his colleagues performed in eight postmenopausal women with obesity, the primary endpoint was insulin action as measured by a two-step hyperinsulinemic-euglycemic clamp. Secondary endpoints were body composition, basal metabolic rate, ectopic fat, and metabolome. “We did not find any difference in systemic insulin action, ectopic fat, or energy expenditure,” he said. “But we found something very interesting. We did a metabolic analysis and found that oral estrogens increase hepatic de novo lipogenesis and liver triacylglycerol production. In other words, the oral estrogens were increasing [triacylglycerol] synthesis from glucose, but it does not accumulate in the liver.”

Dr. Mauvais-Jarvis disclosed that he has received research support from the National Institutes of Health, the American Diabetes Association, the Department of Veterans Affairs, and Pfizer.
 

[email protected]

LOS ANGELES – Although menopausal hormone therapy is not approved for the prevention of type 2 diabetes because of its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms, according to Franck Mauvais-Jarvis, MD.

Doug Brunk/MDedge News

“During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension,” Dr. Mauvais-Jarvis, director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, said at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”

The best evidence of this synergy comes from older trials. Nearly 30 years ago, researchers examined the association between postmenopausal hormone use and the subsequent incidence of non–insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal U.S. women aged 30-55 years, who were enrolled in the Nurse’s Health Study and followed for 12 years (Ann Epidemiol. 1992;2[5]:665-73). They found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. In a more recent trial, researchers examined the association between use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women who were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). It found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes.

In the Heart and Estrogen/Progestin Replacement Study, researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes in 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). At 20 U.S. centers, the study participants received 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone, or placebo, and were followed for 4 years. The researchers found that the use of hormone therapy reduced the incidence of diabetes by 35%.

According to Dr. Mauvais-Jarvis, the strongest data come from the Women’s Health Initiative (WHI), a randomized, double-blind trial that compared the effect of daily 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up (Diabetologia. 2004; 47[7]:1175-87). It showed a 20% decrease in the incidence of diabetes at 5 years. More recently, researchers found that, whether WHI participants took estrogen plus medroxyprogesterone or estrogen alone, the protection from diabetes was present (N Engl J Med. 2016;374:803-6).

In 2006, researchers published results from a meta-analysis of 107 trials in an effort to quantify the effects of hormone therapy on components of metabolic syndrome in postmenopausal women (Diabetes Obes Metab. 2006;8[5]:538-54). In women without diabetes, hormone therapy reduced the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. In women with diabetes, hormone therapy reduced fasting glucose by 11% and HOMA-IR by 36%.

The mechanisms by which estrogens improve glucose homeostasis are yet to be fully understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation,” Dr. Mauvais-Jarvis said. “However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.”

Route of estrogen administration also comes into play. For example, oral estrogens increase liver exposure to estrogen, increase triglycerides, and increase clotting factors. “That is why oral estrogens are not indicated in women with risk of deep venous thrombosis,” Dr. Mauvais-Jarvis said. “They also increase inflammatory factors like C-reactive protein. Advantages are that they decrease LDL cholesterol levels and increase HDL cholesterol levels more than transdermal estrogen does.”

The main advantage with transdermal delivery of estrogen, he continued, is that it does not raise triglycerides, clotting factors, or inflammatory factors, and it confers less exposure to the liver. “That’s why it’s the preferred way of administration in women who are obese, who have a risk of DVT, or who have cardiovascular risk factors,” he said. “It has a lower suppression of hepatic glucose production, it increases circulating estradiol, and the delivery to nonhepatic tissue is increased. The oral form of estrogen is cheaper, compared with the transdermal form, though. This is a factor that is always taken into account.”

Dr. Mauvais-Jarvis and colleagues were first to evaluate the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). “The idea was that by combining estrogen and bazedoxifene, you have the beneficial effect of estrogen in the tissues but you block estrogen in the breast and in the uterus, and therefore, you prevent the risk of cancer,” he said. “We found that tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. It increased energy expenditure and decreased fatty liver.”

In a subsequent pilot study, he and his colleagues assessed the effect of 12 weeks’ treatment with bazedoxifene/conjugated estrogens, compared with placebo, on glucose homeostasis and body composition in 12 postmenopausal women (NCT02237079). “We did not find any significant alterations in the IVGTT [Intravenous Glucose Tolerance Test] but we observed improved fasting beta-cell function and serum glucose in menopausal women with obesity,” Dr. Mauvais-Jarvis said (J Endocr Soc. 2019;3[8]:1583-94).

In a separate, randomized, double-blind, placebo-controlled, crossover trial that he and his colleagues performed in eight postmenopausal women with obesity, the primary endpoint was insulin action as measured by a two-step hyperinsulinemic-euglycemic clamp. Secondary endpoints were body composition, basal metabolic rate, ectopic fat, and metabolome. “We did not find any difference in systemic insulin action, ectopic fat, or energy expenditure,” he said. “But we found something very interesting. We did a metabolic analysis and found that oral estrogens increase hepatic de novo lipogenesis and liver triacylglycerol production. In other words, the oral estrogens were increasing [triacylglycerol] synthesis from glucose, but it does not accumulate in the liver.”

Dr. Mauvais-Jarvis disclosed that he has received research support from the National Institutes of Health, the American Diabetes Association, the Department of Veterans Affairs, and Pfizer.
 

[email protected]

PHILADELPHIA – Postmenopausal women are at risk of numerous medical conditions after the onset of menopause, but many ob.gyns feel uncomfortable treating those patients, according to a keynote speaker at the annual meeting of the American Society for Reproductive Medicine.

Jeff Craven/MDedge News

The population of women entering menopause continues to rise, and they are at risk for developing chronic diseases about a decade after the onset of menopause, said Rogerio A. Lobo, MD, professor of obstetrics and gynecology at Columbia University, New York.

“For me, from a primary care perspective, there’s a major opportunity for all of us providers at the onset of menopause to identify risks and initiate preventive strategies,” he said.

These newly menopausal women are at risk for diseases across multiple specialty areas, which include obesity, metabolic syndrome, diabetes, cardiovascular disease, osteoporosis, chronic arthritis, dementia, cognitive decline, depression, and cancer. “My focus along these lines is really longevity, reduction in mortality as well as quality of life,” said Dr. Lobo.

Understanding of the benefits of estrogen therapy for postmenopausal women began with work in two studies in the 1990s. One paper by Meir J. Stampfer, MD, and associates on 15 studies examining the effects of hormone therapy on coronary heart disease (CHD) found that the relative risk of estrogen therapy on the disease was 0.50 (95% confidence interval, 0.43-0.56) after adjusting for only prospective and angiographic studies (Prev Med. 1991;20[1]:47-63).

A second paper by Deborah Grady, MD, MPH, and associates found that hormone therapy with estrogen plus progestin decreased the risk of CHD and hip fracture in women but increased the risk of endometrial and breast cancer, and carried a recommendation for using estrogen plus progestin for women who have received a hysterectomy or who are at high risk for CHD (Ann Intern Med. 1992 Dec 15;117[12]:1016-37).

In the early 2000s, data from the Women’s Health Initiative (WHI) began to show a different story: Therapy with estrogen plus progestin was shown to carry risks of early harm in postmenopausal women, and one study by JoAnn E. Manson, MD, DrPH, and associates had a hazard ratio of 1.24 (nominal 95% confidence interval, 1.00-1.54) for CHD in postmenopausal women aged 50-79 years receiving the combined therapy (N Engl J Med. 2003;349:523-34).

The confidence intervals were later adjusted so the association was not significant, but the results led to conclusions that hormone therapy was harmful to women and increased risk of breast cancer, declining cognition, and dementia, as well as cardiovascular diseases such as coronary disease, stroke and thrombosis.

“That was the dogma for many people to this day, but it was clearly a rush to judgment,” said Dr. Lobo. “More harm than good was done for the field.”

The contradictory findings from the WHI and other studies may be explained by the timing of hormone therapy, Dr. Lobo explained. In the ELITE trial, 643 postmenopausal women, stratified into early-postmenopausal (less than 6 years) and late-postmenopausal (equal to or greater than 10 years) groups, received 1 mg of daily oral 17-beta-estradiol with 45 mg of progesterone vaginal gel or placebo. Researchers found that it was beneficial for preventing the progression of subclinical atherosclerosis when therapy was initiated in early but not in late menopause (N Eng J Med. 2016; 374:1221-31).

Estrogen also has benefits for the brain, and might help improve rates of cognitive decline and Alzheimer’s disease in postmenopausal women, Dr. Lobo said. Of the 1,768 women in the Cache County Study who described their use of hormone therapy after menopause, 176 women developed Alzheimer’s; however, use of hormone therapy within 5 years of menopause was associated with a 30% reduced risk of Alzheimer’s (95% confidence interval, 0.49-0.99) and had better benefits for long-term use up to 10 years. But this effect was not present in women who started hormone therapy 5 years or more after onset of menopause (Neurology. 2012 Oct 30. doi: 10.1212/WNL.0b013e318271f823).

Clinicians also should look at the risk of hormone therapy in terms of absolute real risk rather than relative risk. “In WHI, even though many of these events were not statistically significant, even if they assumed they were, the absolute numbers were 7-8 events per 10,000 women per year,” he said. “Those, according to WHI, are rare events if they’re even true.”

“For breast cancer, which is a big concern a lot of women have, endogenous risk factors are much higher than what hormones do,” he added.

Yet clinicians continue to act on data from the WHI, Dr. Lobo noted. In fact, many ob.gyns. report that they are uncomfortable treating women with symptoms associated with menopause.

“Post WHI, we have lost at least a generation of providers who do not deal with menopause,” he added. “Three out of four women who seek help for symptoms don’t receive it. The practice of menopause has largely disappeared from for many, many practices.”

The American Society for Reproductive Medicine used to have a “menopause day,” but the society no longer offers a track for menopause, Dr. Lobo said. One solution aimed at addressing the absence of training might be a menopause curriculum for ob.gyn. residents to help them initiate prevention strategies for postmenopausal women and have the confidence to manage this patient population. Dr. Lobo cited one study from Johns Hopkins where ob.gyn. residents underwent a 2-year menopause medicine curriculum and scored significantly higher on posttest scores after completing the program (78.7% vs. 57.3%; P less than .05). After the curriculum, 85.7% also reported they were more comfortable treating patients with menopause (Menopause. 2016 Mar. 23[3]:275-9).

Work also needs to be done on the front of understanding which hormone therapies are most effective for postmenopausal women. While there is currently no one hormone therapy to specifically recommend, in the future, pharmacogenetics and genetic or molecular risk analyses will play a role in knowing which products to prescribe. “It can be done, to be able to have a clear path for longevity and improved quality of life,” Dr. Lobo said.

Dr. Lobo reported serving as a consultant to Amgen, Mithra, Sojournix, and TherapeuticsMD. In addition, his institution is receiving support from Bayer and the National Institutes of Health for a clinical trial.

PHILADELPHIA – Postmenopausal women are at risk of numerous medical conditions after the onset of menopause, but many ob.gyns feel uncomfortable treating those patients, according to a keynote speaker at the annual meeting of the American Society for Reproductive Medicine.

Jeff Craven/MDedge News

The population of women entering menopause continues to rise, and they are at risk for developing chronic diseases about a decade after the onset of menopause, said Rogerio A. Lobo, MD, professor of obstetrics and gynecology at Columbia University, New York.

“For me, from a primary care perspective, there’s a major opportunity for all of us providers at the onset of menopause to identify risks and initiate preventive strategies,” he said.

These newly menopausal women are at risk for diseases across multiple specialty areas, which include obesity, metabolic syndrome, diabetes, cardiovascular disease, osteoporosis, chronic arthritis, dementia, cognitive decline, depression, and cancer. “My focus along these lines is really longevity, reduction in mortality as well as quality of life,” said Dr. Lobo.

Understanding of the benefits of estrogen therapy for postmenopausal women began with work in two studies in the 1990s. One paper by Meir J. Stampfer, MD, and associates on 15 studies examining the effects of hormone therapy on coronary heart disease (CHD) found that the relative risk of estrogen therapy on the disease was 0.50 (95% confidence interval, 0.43-0.56) after adjusting for only prospective and angiographic studies (Prev Med. 1991;20[1]:47-63).

A second paper by Deborah Grady, MD, MPH, and associates found that hormone therapy with estrogen plus progestin decreased the risk of CHD and hip fracture in women but increased the risk of endometrial and breast cancer, and carried a recommendation for using estrogen plus progestin for women who have received a hysterectomy or who are at high risk for CHD (Ann Intern Med. 1992 Dec 15;117[12]:1016-37).

In the early 2000s, data from the Women’s Health Initiative (WHI) began to show a different story: Therapy with estrogen plus progestin was shown to carry risks of early harm in postmenopausal women, and one study by JoAnn E. Manson, MD, DrPH, and associates had a hazard ratio of 1.24 (nominal 95% confidence interval, 1.00-1.54) for CHD in postmenopausal women aged 50-79 years receiving the combined therapy (N Engl J Med. 2003;349:523-34).

The confidence intervals were later adjusted so the association was not significant, but the results led to conclusions that hormone therapy was harmful to women and increased risk of breast cancer, declining cognition, and dementia, as well as cardiovascular diseases such as coronary disease, stroke and thrombosis.

“That was the dogma for many people to this day, but it was clearly a rush to judgment,” said Dr. Lobo. “More harm than good was done for the field.”

The contradictory findings from the WHI and other studies may be explained by the timing of hormone therapy, Dr. Lobo explained. In the ELITE trial, 643 postmenopausal women, stratified into early-postmenopausal (less than 6 years) and late-postmenopausal (equal to or greater than 10 years) groups, received 1 mg of daily oral 17-beta-estradiol with 45 mg of progesterone vaginal gel or placebo. Researchers found that it was beneficial for preventing the progression of subclinical atherosclerosis when therapy was initiated in early but not in late menopause (N Eng J Med. 2016; 374:1221-31).

Estrogen also has benefits for the brain, and might help improve rates of cognitive decline and Alzheimer’s disease in postmenopausal women, Dr. Lobo said. Of the 1,768 women in the Cache County Study who described their use of hormone therapy after menopause, 176 women developed Alzheimer’s; however, use of hormone therapy within 5 years of menopause was associated with a 30% reduced risk of Alzheimer’s (95% confidence interval, 0.49-0.99) and had better benefits for long-term use up to 10 years. But this effect was not present in women who started hormone therapy 5 years or more after onset of menopause (Neurology. 2012 Oct 30. doi: 10.1212/WNL.0b013e318271f823).

Clinicians also should look at the risk of hormone therapy in terms of absolute real risk rather than relative risk. “In WHI, even though many of these events were not statistically significant, even if they assumed they were, the absolute numbers were 7-8 events per 10,000 women per year,” he said. “Those, according to WHI, are rare events if they’re even true.”

“For breast cancer, which is a big concern a lot of women have, endogenous risk factors are much higher than what hormones do,” he added.

Yet clinicians continue to act on data from the WHI, Dr. Lobo noted. In fact, many ob.gyns. report that they are uncomfortable treating women with symptoms associated with menopause.

“Post WHI, we have lost at least a generation of providers who do not deal with menopause,” he added. “Three out of four women who seek help for symptoms don’t receive it. The practice of menopause has largely disappeared from for many, many practices.”

The American Society for Reproductive Medicine used to have a “menopause day,” but the society no longer offers a track for menopause, Dr. Lobo said. One solution aimed at addressing the absence of training might be a menopause curriculum for ob.gyn. residents to help them initiate prevention strategies for postmenopausal women and have the confidence to manage this patient population. Dr. Lobo cited one study from Johns Hopkins where ob.gyn. residents underwent a 2-year menopause medicine curriculum and scored significantly higher on posttest scores after completing the program (78.7% vs. 57.3%; P less than .05). After the curriculum, 85.7% also reported they were more comfortable treating patients with menopause (Menopause. 2016 Mar. 23[3]:275-9).

Work also needs to be done on the front of understanding which hormone therapies are most effective for postmenopausal women. While there is currently no one hormone therapy to specifically recommend, in the future, pharmacogenetics and genetic or molecular risk analyses will play a role in knowing which products to prescribe. “It can be done, to be able to have a clear path for longevity and improved quality of life,” Dr. Lobo said.

Dr. Lobo reported serving as a consultant to Amgen, Mithra, Sojournix, and TherapeuticsMD. In addition, his institution is receiving support from Bayer and the National Institutes of Health for a clinical trial.

PHILADELPHIA – Postmenopausal women are at risk of numerous medical conditions after the onset of menopause, but many ob.gyns feel uncomfortable treating those patients, according to a keynote speaker at the annual meeting of the American Society for Reproductive Medicine.

Jeff Craven/MDedge News

The population of women entering menopause continues to rise, and they are at risk for developing chronic diseases about a decade after the onset of menopause, said Rogerio A. Lobo, MD, professor of obstetrics and gynecology at Columbia University, New York.

“For me, from a primary care perspective, there’s a major opportunity for all of us providers at the onset of menopause to identify risks and initiate preventive strategies,” he said.

These newly menopausal women are at risk for diseases across multiple specialty areas, which include obesity, metabolic syndrome, diabetes, cardiovascular disease, osteoporosis, chronic arthritis, dementia, cognitive decline, depression, and cancer. “My focus along these lines is really longevity, reduction in mortality as well as quality of life,” said Dr. Lobo.

Understanding of the benefits of estrogen therapy for postmenopausal women began with work in two studies in the 1990s. One paper by Meir J. Stampfer, MD, and associates on 15 studies examining the effects of hormone therapy on coronary heart disease (CHD) found that the relative risk of estrogen therapy on the disease was 0.50 (95% confidence interval, 0.43-0.56) after adjusting for only prospective and angiographic studies (Prev Med. 1991;20[1]:47-63).

A second paper by Deborah Grady, MD, MPH, and associates found that hormone therapy with estrogen plus progestin decreased the risk of CHD and hip fracture in women but increased the risk of endometrial and breast cancer, and carried a recommendation for using estrogen plus progestin for women who have received a hysterectomy or who are at high risk for CHD (Ann Intern Med. 1992 Dec 15;117[12]:1016-37).

In the early 2000s, data from the Women’s Health Initiative (WHI) began to show a different story: Therapy with estrogen plus progestin was shown to carry risks of early harm in postmenopausal women, and one study by JoAnn E. Manson, MD, DrPH, and associates had a hazard ratio of 1.24 (nominal 95% confidence interval, 1.00-1.54) for CHD in postmenopausal women aged 50-79 years receiving the combined therapy (N Engl J Med. 2003;349:523-34).

The confidence intervals were later adjusted so the association was not significant, but the results led to conclusions that hormone therapy was harmful to women and increased risk of breast cancer, declining cognition, and dementia, as well as cardiovascular diseases such as coronary disease, stroke and thrombosis.

“That was the dogma for many people to this day, but it was clearly a rush to judgment,” said Dr. Lobo. “More harm than good was done for the field.”

The contradictory findings from the WHI and other studies may be explained by the timing of hormone therapy, Dr. Lobo explained. In the ELITE trial, 643 postmenopausal women, stratified into early-postmenopausal (less than 6 years) and late-postmenopausal (equal to or greater than 10 years) groups, received 1 mg of daily oral 17-beta-estradiol with 45 mg of progesterone vaginal gel or placebo. Researchers found that it was beneficial for preventing the progression of subclinical atherosclerosis when therapy was initiated in early but not in late menopause (N Eng J Med. 2016; 374:1221-31).

Estrogen also has benefits for the brain, and might help improve rates of cognitive decline and Alzheimer’s disease in postmenopausal women, Dr. Lobo said. Of the 1,768 women in the Cache County Study who described their use of hormone therapy after menopause, 176 women developed Alzheimer’s; however, use of hormone therapy within 5 years of menopause was associated with a 30% reduced risk of Alzheimer’s (95% confidence interval, 0.49-0.99) and had better benefits for long-term use up to 10 years. But this effect was not present in women who started hormone therapy 5 years or more after onset of menopause (Neurology. 2012 Oct 30. doi: 10.1212/WNL.0b013e318271f823).

Clinicians also should look at the risk of hormone therapy in terms of absolute real risk rather than relative risk. “In WHI, even though many of these events were not statistically significant, even if they assumed they were, the absolute numbers were 7-8 events per 10,000 women per year,” he said. “Those, according to WHI, are rare events if they’re even true.”

“For breast cancer, which is a big concern a lot of women have, endogenous risk factors are much higher than what hormones do,” he added.

Yet clinicians continue to act on data from the WHI, Dr. Lobo noted. In fact, many ob.gyns. report that they are uncomfortable treating women with symptoms associated with menopause.

“Post WHI, we have lost at least a generation of providers who do not deal with menopause,” he added. “Three out of four women who seek help for symptoms don’t receive it. The practice of menopause has largely disappeared from for many, many practices.”

The American Society for Reproductive Medicine used to have a “menopause day,” but the society no longer offers a track for menopause, Dr. Lobo said. One solution aimed at addressing the absence of training might be a menopause curriculum for ob.gyn. residents to help them initiate prevention strategies for postmenopausal women and have the confidence to manage this patient population. Dr. Lobo cited one study from Johns Hopkins where ob.gyn. residents underwent a 2-year menopause medicine curriculum and scored significantly higher on posttest scores after completing the program (78.7% vs. 57.3%; P less than .05). After the curriculum, 85.7% also reported they were more comfortable treating patients with menopause (Menopause. 2016 Mar. 23[3]:275-9).

Work also needs to be done on the front of understanding which hormone therapies are most effective for postmenopausal women. While there is currently no one hormone therapy to specifically recommend, in the future, pharmacogenetics and genetic or molecular risk analyses will play a role in knowing which products to prescribe. “It can be done, to be able to have a clear path for longevity and improved quality of life,” Dr. Lobo said.

Dr. Lobo reported serving as a consultant to Amgen, Mithra, Sojournix, and TherapeuticsMD. In addition, his institution is receiving support from Bayer and the National Institutes of Health for a clinical trial.

ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.

“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
 

Mixed findings in early studies

Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).

However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.

In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).

In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”

For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
 

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.

ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.

“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
 

Mixed findings in early studies

Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).

However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.

In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).

In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”

For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
 

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.

ORLANDO – Cumulative evidence over the years has shown that bisphosphonates reduce distant metastases in postmenopausal women with early-stage breast cancer but that effect does not seem to extend to younger, premenopausal women who may experience adverse effects with bisphosphonates, nor has it been replicated in other types of cancer, such as lung or prostate, Robert Coleman MBBS, MD, said in a presentation marking the 50th anniversary of the publication of the first papers describing the then-new class of drugs.

“We have some science – at least in postmenopausal breast cancer – [showing] that we’re really making a difference, but we don’t understand why it’s not working in the other patients or in the other diseases,” said Dr. Coleman of the University of Sheffield (England) at the annual meeting of the American Society for Bone and Mineral Research.
 

Mixed findings in early studies

Early studies showing the metastases-prevention effects of bisphosphonates were with clodronate. In one study, Dr. Coleman said, researchers found that oral clodronate at a dose of 1,600 mg/day as a supplementary treatment to standard treatment for primary, operable breast cancer reduced the risk of bone metastases in a cohort of 1,069 patients with stage 1-3 breast cancer (hazard ratio, 0.692; P = .043) over 5 years (Breast Cancer Res. 2006 Mar 15. doi: 10.1186/bcr1384). Another trial, of 302 patients with breast cancer who received oral clodronate at 1,600 mg/day for 2 years, found that 20.4% of patients who received oral clodronate had died by 8.5 years of follow-up, compared with 40.7% of those who did not receive the intervention (Ann Oncol. 2008;19[12]:2007-11).

However, those results were in conflict with findings from an earlier study in which researchers followed patients with breast cancer who received 1,600 mg/day of oral clodronate or placebo for 3 years. They found a similar number of bone metastases in the clodronate and placebo groups (32% and 29%, respectively), as well as a lower overall disease-free survival rate at 10 years for the clodronate group, compared with the placebo group (45% vs. 58%; Acta Oncol. 2004;43[7]:650-6).“For various other reasons, clodronate did not gain traction as a therapeutic strategy in early-stage breast cancer,” said Dr. Coleman, although emerging evidence showed that other bisphosphonate agents were effective in some patients with breast cancer.

In a 2009 article, Gnant et al. reported that premenopausal patients, who underwent primary surgery for stage 1 or stage 2 breast cancer and received standard goserelin therapy for induced menopause and endocrine therapy (either tamoxifen or anastrozole) in addition to treatment with zoledronic acid, had a disease-free survival rate of 94.0% at a median 47.8 months of follow-up (N Eng J Med. 2009;360:679-91). After a median 94.4 months of follow-up, the investigators reported a lower risk of disease progression (HR, 0.77; 95% confidence interval, 0.60-0.99; P = .042) and death (HR, 0.66; 95% CI, 0.43-1.02; P = .064; Ann Oncol. 2015;26[2]:313-20).

In his own group, Dr. Coleman and colleagues recruited patients with early-stage breast cancer in the AZURE trial, a phase 3 study of 3,360 patients who received standard therapy with or without zoledronic acid 4 mg every 3-4 weeks for 6 doses, followed by 8 doses every 3 months then 5 doses every 6 months (N Eng J Med. 2011;365:1396-405). “We saw no effect,” said Dr. Coleman. “[That was] very different from what was shown by [Dr.] Gnant.”

For a subgroup of postmenopausal patients, Dr. Coleman and colleagues found that the adjusted HR for disease-free survival was 0.82 for women who were more than 5 years postmenopausal (95% CI, 0.67-1.00) at the time of breast cancer and bisphosphonate treatment, but women younger than 40 years had worse survival outcomes at 10 years (HR, 1.56; 95% CI, 1.09-2.22) and had a significantly higher risk of death from breast cancer (HR, 1.67; 95% CI, 1.16-2.40; J Bone Oncol. 2018 Sep 27. doi: 10.1016/j.jbo.2018.09.008).
 

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.

Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,¹ which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.

OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
 

OBG Management: How many women undergo BSO with their hysterectomy?

Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,^2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.^4,5
 

OBG Management: Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?

Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).⁵
 

OBG Management: What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?

Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.

However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.

Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
 

Continue to: OBG Management: Do your data give support to the timing hypothesis?

OBG Management: Do your data give support to the timing hypothesis?

Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.

By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
 

OBG Management: Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?

Dr. Manson: Current guidelines^6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.

Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)

So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.

By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).

Continue to: OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.

Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,¹ which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.

OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
 

OBG Management: How many women undergo BSO with their hysterectomy?

Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,^2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.^4,5
 

OBG Management: Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?

Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).⁵
 

OBG Management: What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?

Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.

However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.

Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
 

Continue to: OBG Management: Do your data give support to the timing hypothesis?

OBG Management: Do your data give support to the timing hypothesis?

Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.

By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
 

OBG Management: Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?

Dr. Manson: Current guidelines^6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.

Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)

So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.

By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).

Continue to: OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.

Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,¹ which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.

OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
 

OBG Management: How many women undergo BSO with their hysterectomy?

Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,^2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.^4,5
 

OBG Management: Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?

Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).⁵
 

OBG Management: What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?

Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.

However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.

Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
 

Continue to: OBG Management: Do your data give support to the timing hypothesis?

OBG Management: Do your data give support to the timing hypothesis?

Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.

By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
 

OBG Management: Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?

Dr. Manson: Current guidelines^6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.

Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)

So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.

By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).

Continue to: OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.

FDA REMOVES ALCOHOL BAN WITH ADDYI

Sprout Pharmaceuticals announced that the US Food and Drug Administration (FDA) has removed their contraindication on alcohol use with Addyi® (flibanserin). Addyi was approved in 2015 and is an oral nonhormonal pill for acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Patients are advised to discontinue drinking alcohol at least 2 hours before taking Addyi at bedtime or skip the Addyi dose that evening.

The FDA also removed the requirement, under its Risk Evaluation and Mitigation Strategy (REMS) program, for health care practitioners or pharmacies to be certified to prescribe or dispense Addyi. Sprout says that to make all labeling elements consistent with the FDA’s findings the boxed warning will change and the medication guide will be updated and included under the REMS. 

The most commonly reported adverse events among patients taking Addyi are dizziness, sleepiness, nausea, fatigue, insomnia, and dry mouth. Addyi is contraindicated in patients taking moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors and in those with hepatic impairment.

FOR MORE INFORMATION AND THE FULL PRESCRIBING INFORMATION AND MEDICATION GUIDE, VISIT: www.addyi.com

FEZOLINETANT FOR VMS

FOR MORE INFORMATION, VISIT: http://www.clinicaltrials.gov, TRIAL IDENTIFIERS NCT04003155, NCT04003142, AND NCT04003389

SOLUTIONS FOR OUTCOME TRACKING

DrChrono and OutcomeMD announce a partnership to track and analyze patient outcome data and confounding factors. DrChrono is an electronic health record (EHR) system, and OutcomeMD is a software solution that uses literature-validated patient-reported outcome instruments to score and track a patient’s symptom severity and inform treatment decisions for users.

Via a HIPAA compliant process, patients answer a list of questions that are accessed through a web link on their mobile or desktop devices. OutcomeMD summarizes the symptoms into a score that displays to both the physician and patient. Patients’ answers and scores are pushed to the clinician’s DrChrono EHR medical note. As care progresses in the OutcomeMD platform, patients remotely track how their symptoms change, and notifications alert clinicians of patients who may need attention. The integration with DrChrono also allows patient data on confounding factors to be automatically pushed from the patient’s device into the clinician’s medical note. The partnership will enable physicians to visualize patients’ status, and all the factors involved in their care, on one screen, says DrChrono and OutcomeMD, strengthening documentation and saving time for both patients and clinicians. An integration demo video is available at https://youtu.be/jnh7YPII080.

FOR MORE INFORMATION, VISIT: www.outcomemd.com

Continue to: NEW MATERNITY GOWN...

ImageFIRST launched a new maternity gown for expecting mothers. The Comfort Care^® Maternity Gown is a lightweight, premium polyester/nylon fabric that front snaps to allow for skin-to-skin access and optional breastfeeding. The gown also includes shoulder snaps and a full cut for extra coverage and to accommodate a variety of body types, says ImageFIRST.

ImageFIRST is a national linen rental provider. It developed the Comfort Care^® Maternity Gown with input from labor and delivery departments to best meet the needs of expecting mothers. It also says that a portion of the proceeds from each gown rental will be donated to the National Pediatric Cancer Foundation. 

FOR MORE INFORMATION, VISIT: www.imagefirst.com

FDA REMOVES ALCOHOL BAN WITH ADDYI

Sprout Pharmaceuticals announced that the US Food and Drug Administration (FDA) has removed their contraindication on alcohol use with Addyi® (flibanserin). Addyi was approved in 2015 and is an oral nonhormonal pill for acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Patients are advised to discontinue drinking alcohol at least 2 hours before taking Addyi at bedtime or skip the Addyi dose that evening.

The FDA also removed the requirement, under its Risk Evaluation and Mitigation Strategy (REMS) program, for health care practitioners or pharmacies to be certified to prescribe or dispense Addyi. Sprout says that to make all labeling elements consistent with the FDA’s findings the boxed warning will change and the medication guide will be updated and included under the REMS. 

The most commonly reported adverse events among patients taking Addyi are dizziness, sleepiness, nausea, fatigue, insomnia, and dry mouth. Addyi is contraindicated in patients taking moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors and in those with hepatic impairment.

FOR MORE INFORMATION AND THE FULL PRESCRIBING INFORMATION AND MEDICATION GUIDE, VISIT: www.addyi.com

FEZOLINETANT FOR VMS

FOR MORE INFORMATION, VISIT: http://www.clinicaltrials.gov, TRIAL IDENTIFIERS NCT04003155, NCT04003142, AND NCT04003389

SOLUTIONS FOR OUTCOME TRACKING

DrChrono and OutcomeMD announce a partnership to track and analyze patient outcome data and confounding factors. DrChrono is an electronic health record (EHR) system, and OutcomeMD is a software solution that uses literature-validated patient-reported outcome instruments to score and track a patient’s symptom severity and inform treatment decisions for users.

Via a HIPAA compliant process, patients answer a list of questions that are accessed through a web link on their mobile or desktop devices. OutcomeMD summarizes the symptoms into a score that displays to both the physician and patient. Patients’ answers and scores are pushed to the clinician’s DrChrono EHR medical note. As care progresses in the OutcomeMD platform, patients remotely track how their symptoms change, and notifications alert clinicians of patients who may need attention. The integration with DrChrono also allows patient data on confounding factors to be automatically pushed from the patient’s device into the clinician’s medical note. The partnership will enable physicians to visualize patients’ status, and all the factors involved in their care, on one screen, says DrChrono and OutcomeMD, strengthening documentation and saving time for both patients and clinicians. An integration demo video is available at https://youtu.be/jnh7YPII080.

FOR MORE INFORMATION, VISIT: www.outcomemd.com

Continue to: NEW MATERNITY GOWN...

ImageFIRST launched a new maternity gown for expecting mothers. The Comfort Care^® Maternity Gown is a lightweight, premium polyester/nylon fabric that front snaps to allow for skin-to-skin access and optional breastfeeding. The gown also includes shoulder snaps and a full cut for extra coverage and to accommodate a variety of body types, says ImageFIRST.

ImageFIRST is a national linen rental provider. It developed the Comfort Care^® Maternity Gown with input from labor and delivery departments to best meet the needs of expecting mothers. It also says that a portion of the proceeds from each gown rental will be donated to the National Pediatric Cancer Foundation. 

FOR MORE INFORMATION, VISIT: www.imagefirst.com

FDA REMOVES ALCOHOL BAN WITH ADDYI

Sprout Pharmaceuticals announced that the US Food and Drug Administration (FDA) has removed their contraindication on alcohol use with Addyi® (flibanserin). Addyi was approved in 2015 and is an oral nonhormonal pill for acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Patients are advised to discontinue drinking alcohol at least 2 hours before taking Addyi at bedtime or skip the Addyi dose that evening.

The FDA also removed the requirement, under its Risk Evaluation and Mitigation Strategy (REMS) program, for health care practitioners or pharmacies to be certified to prescribe or dispense Addyi. Sprout says that to make all labeling elements consistent with the FDA’s findings the boxed warning will change and the medication guide will be updated and included under the REMS. 

The most commonly reported adverse events among patients taking Addyi are dizziness, sleepiness, nausea, fatigue, insomnia, and dry mouth. Addyi is contraindicated in patients taking moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors and in those with hepatic impairment.

FOR MORE INFORMATION AND THE FULL PRESCRIBING INFORMATION AND MEDICATION GUIDE, VISIT: www.addyi.com

FEZOLINETANT FOR VMS

FOR MORE INFORMATION, VISIT: http://www.clinicaltrials.gov, TRIAL IDENTIFIERS NCT04003155, NCT04003142, AND NCT04003389

SOLUTIONS FOR OUTCOME TRACKING

DrChrono and OutcomeMD announce a partnership to track and analyze patient outcome data and confounding factors. DrChrono is an electronic health record (EHR) system, and OutcomeMD is a software solution that uses literature-validated patient-reported outcome instruments to score and track a patient’s symptom severity and inform treatment decisions for users.

Via a HIPAA compliant process, patients answer a list of questions that are accessed through a web link on their mobile or desktop devices. OutcomeMD summarizes the symptoms into a score that displays to both the physician and patient. Patients’ answers and scores are pushed to the clinician’s DrChrono EHR medical note. As care progresses in the OutcomeMD platform, patients remotely track how their symptoms change, and notifications alert clinicians of patients who may need attention. The integration with DrChrono also allows patient data on confounding factors to be automatically pushed from the patient’s device into the clinician’s medical note. The partnership will enable physicians to visualize patients’ status, and all the factors involved in their care, on one screen, says DrChrono and OutcomeMD, strengthening documentation and saving time for both patients and clinicians. An integration demo video is available at https://youtu.be/jnh7YPII080.

FOR MORE INFORMATION, VISIT: www.outcomemd.com

Continue to: NEW MATERNITY GOWN...

ImageFIRST launched a new maternity gown for expecting mothers. The Comfort Care^® Maternity Gown is a lightweight, premium polyester/nylon fabric that front snaps to allow for skin-to-skin access and optional breastfeeding. The gown also includes shoulder snaps and a full cut for extra coverage and to accommodate a variety of body types, says ImageFIRST.

ImageFIRST is a national linen rental provider. It developed the Comfort Care^® Maternity Gown with input from labor and delivery departments to best meet the needs of expecting mothers. It also says that a portion of the proceeds from each gown rental will be donated to the National Pediatric Cancer Foundation. 

FOR MORE INFORMATION, VISIT: www.imagefirst.com

PHILADELPHIA – Ovarian tissue cryopreservation should no longer be considered experimental, Sherman J. Silber, MD, said at the annual meeting of the American Society for Reproductive Medicine.

That claim is based on more than 20 years of experience at his center performing the procedure and results he presented from patients for whom frozen ovarian tissue has been reimplanted resulting in a spontaneous pregnancy.

“For prepubertal girls with cancer and for patients who have already had a preliminary round of chemotherapy, ovarian tissue freezing is the only method available to preserve their fertility,” said Dr. Silber, of the Infertility Center of St. Louis in Chesterfield, Missouri. “It is also the only method available to preserve their fertility.”

“I have very strong feelings about this,” he added. “It has huge societal implications for insurance payments.”

Dr. Silber presented results of ovarian tissue freezing and reimplantation at his center beginning in 1997, where 115 patients between the ages of 2 and 35 years underwent the procedure using the same technique. Of these patients, 14 women came back years later to have their frozen ovary cortex reimplanted. Dr. Silber and his group followed these patients monthly for more than 2 years after reimplantation for signs of return of menses, hormonal changes, pregnancy, and live birth.

Most of the patients who chose ovarian tissue freezing had cancer. Eight patients underwent the procedure after being diagnosed with solid tissue cancer and three had leukemia, while two patients underwent ovarian tissue freezing due to premature ovarian failure, and one because of multiple sclerosis. Patients who underwent reimplantation were menopausal for at least 3 years, said Dr. Silber.

Dr. Silber also described the technique used for reimplantation. After the cortical tissue was thawed, the tissue was quilted into one piece from three to five slices using 9-0 nylon interrupted sutures. The quilted tissue was then sutured to the medulla after the surgeon completely removed the dead cortex from the other ovary. “Hemostasis was achieved with micro bipolar forceps,” said Dr. Silber. “Constant irrigation was employed with pulsed heparinized media because we wanted to avoid adhesions, and we wanted to try for spontaneous pregnancy rather than IVF.”

“Then, we put [the quilted ovarian slices] on to the medulla on the other side in such a way that the fallopian tube would be able to reach and catch any egg that’s ovulated during that time,” he added.

Dr. Silber and his group found that, over time, follicle-stimulating hormone (FSH) levels sharply decreased to normal or near-normal levels between 69 days and 133 days after the procedure while Anti-Müllerian hormone (AMH) levels dramatically rose to higher levels between 133 days and 227 days post-procedure before dropping to very low levels, “and the AMH remained at low levels despite the fact that [transplants] would last 8 to 10 years,” said Dr. Silber.

Of the 14 cases where frozen ovarian tissue was reimplanted, 11 patients (78%) achieved pregnancy, 10 patients (71%) delivered healthy babies, and 1 patient (9%) experienced a miscarriage. All patients had spontaneous pregnancies, and none used in vitro fertilization (IVF), noted Dr. Silber. There were 2 patients who had four children from transplanted ovarian tissue, and 2 of 3 patients with leukemia had a total of five children.

Additionally, Dr. Silber’s group examined the literature for other examples of ovarian tissue reimplantation after cryopreservation to determine how many live births resulted from the procedure. They found an additional 170 live births in addition to the 15 live births at their center, with a pregnancy rate ranging from 31% to 71% in different studies. Cancer was not transmitted from mother to child in any case, said Dr. Silber.

Compared with egg freezing, there is a benefit to performing ovarian tissue freezing, even after chemotherapy has begun, noted Dr. Silber. The cost of ovarian tissue freezing is also roughly one-tenth that of egg freezing, and the procedure is less burdensome than multiple cycles with the potential for ovarian hyperstimulation, and it restores the hormone function and the fertility of eggs after reimplantation.

“Because the greater primordial follicle recruitment decreases as the ovarian reserve decreases, you can put a piece of ovary tissue back every 8 years, and a woman can have endocrine function until she’s 100 years old,” said Dr. Silber.

Dr. Silber reported no relevant conflicts of interest.

[email protected]

SOURCE: Silber SJ. ASRM 2019. Abstract O-203.

PHILADELPHIA – Ovarian tissue cryopreservation should no longer be considered experimental, Sherman J. Silber, MD, said at the annual meeting of the American Society for Reproductive Medicine.

That claim is based on more than 20 years of experience at his center performing the procedure and results he presented from patients for whom frozen ovarian tissue has been reimplanted resulting in a spontaneous pregnancy.

“For prepubertal girls with cancer and for patients who have already had a preliminary round of chemotherapy, ovarian tissue freezing is the only method available to preserve their fertility,” said Dr. Silber, of the Infertility Center of St. Louis in Chesterfield, Missouri. “It is also the only method available to preserve their fertility.”

“I have very strong feelings about this,” he added. “It has huge societal implications for insurance payments.”

Dr. Silber presented results of ovarian tissue freezing and reimplantation at his center beginning in 1997, where 115 patients between the ages of 2 and 35 years underwent the procedure using the same technique. Of these patients, 14 women came back years later to have their frozen ovary cortex reimplanted. Dr. Silber and his group followed these patients monthly for more than 2 years after reimplantation for signs of return of menses, hormonal changes, pregnancy, and live birth.

Most of the patients who chose ovarian tissue freezing had cancer. Eight patients underwent the procedure after being diagnosed with solid tissue cancer and three had leukemia, while two patients underwent ovarian tissue freezing due to premature ovarian failure, and one because of multiple sclerosis. Patients who underwent reimplantation were menopausal for at least 3 years, said Dr. Silber.

Dr. Silber also described the technique used for reimplantation. After the cortical tissue was thawed, the tissue was quilted into one piece from three to five slices using 9-0 nylon interrupted sutures. The quilted tissue was then sutured to the medulla after the surgeon completely removed the dead cortex from the other ovary. “Hemostasis was achieved with micro bipolar forceps,” said Dr. Silber. “Constant irrigation was employed with pulsed heparinized media because we wanted to avoid adhesions, and we wanted to try for spontaneous pregnancy rather than IVF.”

“Then, we put [the quilted ovarian slices] on to the medulla on the other side in such a way that the fallopian tube would be able to reach and catch any egg that’s ovulated during that time,” he added.

Dr. Silber and his group found that, over time, follicle-stimulating hormone (FSH) levels sharply decreased to normal or near-normal levels between 69 days and 133 days after the procedure while Anti-Müllerian hormone (AMH) levels dramatically rose to higher levels between 133 days and 227 days post-procedure before dropping to very low levels, “and the AMH remained at low levels despite the fact that [transplants] would last 8 to 10 years,” said Dr. Silber.

Of the 14 cases where frozen ovarian tissue was reimplanted, 11 patients (78%) achieved pregnancy, 10 patients (71%) delivered healthy babies, and 1 patient (9%) experienced a miscarriage. All patients had spontaneous pregnancies, and none used in vitro fertilization (IVF), noted Dr. Silber. There were 2 patients who had four children from transplanted ovarian tissue, and 2 of 3 patients with leukemia had a total of five children.

Additionally, Dr. Silber’s group examined the literature for other examples of ovarian tissue reimplantation after cryopreservation to determine how many live births resulted from the procedure. They found an additional 170 live births in addition to the 15 live births at their center, with a pregnancy rate ranging from 31% to 71% in different studies. Cancer was not transmitted from mother to child in any case, said Dr. Silber.

Compared with egg freezing, there is a benefit to performing ovarian tissue freezing, even after chemotherapy has begun, noted Dr. Silber. The cost of ovarian tissue freezing is also roughly one-tenth that of egg freezing, and the procedure is less burdensome than multiple cycles with the potential for ovarian hyperstimulation, and it restores the hormone function and the fertility of eggs after reimplantation.

“Because the greater primordial follicle recruitment decreases as the ovarian reserve decreases, you can put a piece of ovary tissue back every 8 years, and a woman can have endocrine function until she’s 100 years old,” said Dr. Silber.

Dr. Silber reported no relevant conflicts of interest.

[email protected]

SOURCE: Silber SJ. ASRM 2019. Abstract O-203.

PHILADELPHIA – Ovarian tissue cryopreservation should no longer be considered experimental, Sherman J. Silber, MD, said at the annual meeting of the American Society for Reproductive Medicine.

That claim is based on more than 20 years of experience at his center performing the procedure and results he presented from patients for whom frozen ovarian tissue has been reimplanted resulting in a spontaneous pregnancy.

“For prepubertal girls with cancer and for patients who have already had a preliminary round of chemotherapy, ovarian tissue freezing is the only method available to preserve their fertility,” said Dr. Silber, of the Infertility Center of St. Louis in Chesterfield, Missouri. “It is also the only method available to preserve their fertility.”

“I have very strong feelings about this,” he added. “It has huge societal implications for insurance payments.”

Dr. Silber presented results of ovarian tissue freezing and reimplantation at his center beginning in 1997, where 115 patients between the ages of 2 and 35 years underwent the procedure using the same technique. Of these patients, 14 women came back years later to have their frozen ovary cortex reimplanted. Dr. Silber and his group followed these patients monthly for more than 2 years after reimplantation for signs of return of menses, hormonal changes, pregnancy, and live birth.

Most of the patients who chose ovarian tissue freezing had cancer. Eight patients underwent the procedure after being diagnosed with solid tissue cancer and three had leukemia, while two patients underwent ovarian tissue freezing due to premature ovarian failure, and one because of multiple sclerosis. Patients who underwent reimplantation were menopausal for at least 3 years, said Dr. Silber.

Dr. Silber also described the technique used for reimplantation. After the cortical tissue was thawed, the tissue was quilted into one piece from three to five slices using 9-0 nylon interrupted sutures. The quilted tissue was then sutured to the medulla after the surgeon completely removed the dead cortex from the other ovary. “Hemostasis was achieved with micro bipolar forceps,” said Dr. Silber. “Constant irrigation was employed with pulsed heparinized media because we wanted to avoid adhesions, and we wanted to try for spontaneous pregnancy rather than IVF.”

“Then, we put [the quilted ovarian slices] on to the medulla on the other side in such a way that the fallopian tube would be able to reach and catch any egg that’s ovulated during that time,” he added.

Dr. Silber and his group found that, over time, follicle-stimulating hormone (FSH) levels sharply decreased to normal or near-normal levels between 69 days and 133 days after the procedure while Anti-Müllerian hormone (AMH) levels dramatically rose to higher levels between 133 days and 227 days post-procedure before dropping to very low levels, “and the AMH remained at low levels despite the fact that [transplants] would last 8 to 10 years,” said Dr. Silber.

Of the 14 cases where frozen ovarian tissue was reimplanted, 11 patients (78%) achieved pregnancy, 10 patients (71%) delivered healthy babies, and 1 patient (9%) experienced a miscarriage. All patients had spontaneous pregnancies, and none used in vitro fertilization (IVF), noted Dr. Silber. There were 2 patients who had four children from transplanted ovarian tissue, and 2 of 3 patients with leukemia had a total of five children.

Additionally, Dr. Silber’s group examined the literature for other examples of ovarian tissue reimplantation after cryopreservation to determine how many live births resulted from the procedure. They found an additional 170 live births in addition to the 15 live births at their center, with a pregnancy rate ranging from 31% to 71% in different studies. Cancer was not transmitted from mother to child in any case, said Dr. Silber.

Compared with egg freezing, there is a benefit to performing ovarian tissue freezing, even after chemotherapy has begun, noted Dr. Silber. The cost of ovarian tissue freezing is also roughly one-tenth that of egg freezing, and the procedure is less burdensome than multiple cycles with the potential for ovarian hyperstimulation, and it restores the hormone function and the fertility of eggs after reimplantation.

“Because the greater primordial follicle recruitment decreases as the ovarian reserve decreases, you can put a piece of ovary tissue back every 8 years, and a woman can have endocrine function until she’s 100 years old,” said Dr. Silber.

Dr. Silber reported no relevant conflicts of interest.

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SOURCE: Silber SJ. ASRM 2019. Abstract O-203.