Menopause

It is projected that by 2050, 1.6 billion women in the world will have reached menopause or the postmenopausal period, a significant increase, compared with a billion women in 2020. Of all menopausal women, around 75% are affected by troublesome menopause symptoms, such as hot flashes and night sweats.

Around 84% of postmenopausal women experience genitourinary symptoms, such as vulvovaginal atrophy and incontinence.

Menopausal hormone therapy (MHT) is the most effective treatment for managing these symptoms; however, its effects on numerous aspects of female health remain uncertain, in particular with regard to breast cancer. The influence of MHT on breast cancer remains unsettled, with discordant findings from observational studies and randomized clinical trials, a factor that affects the decisions made by doctors concerning hormone therapy in menopausal women.
 

Background

Conjugated equine estrogens (CEEs) were introduced into clinical practice in the 1940s. For decades, MHT was the main treatment in conventional medicine for the symptoms of menopause. MHT was used in Western countries for about 600 million women starting from 1970, and it progressively increased during the 1990s. Professional organizations recommended MHT for the prevention of osteoporosis and chronic heart disease (CHD), and a third of prescriptions were for women older than 60 years.

Against this background, the National Institutes of Health launched randomized trials of MHT through the Women’s Health Initiative (WHI) to test whether the association with reduced risk for CHD found in observational studies was real and to obtain reliable information on the overall risks and benefits regarding the prevention of chronic disease for postmenopausal women aged 50-79 years.

The WHI trials tested standard-dose oral CEEs with and without standard-dose continuous medroxyprogesterone acetate (EPT). In 2002, the results of the WHI studies raised a series of concerns about the long-term safety of MHT, in particular the finding of an increased risk of breast cancer for women undergoing therapy. That risk exceeded the benefits from reductions in hip fractures and colorectal cancer.

The WHI findings received wide attention. Prescriptions for MHT dropped precipitously after 2002 and continued to decline in subsequent years. Declines were most marked for standard-dose EPT and in older women. The results of the CEE study were less negative, compared with those for EPT, as they showed no effect on CHD, a nonsignificant reduction in the risk of breast cancer, and a more favorable risk-benefit ratio for younger women, compared with older women. A decade later, it had become widely accepted that MHT should not be used for the prevention of chronic disease in older women; however, short-term use for treatment of vasomotor symptoms remains an accepted indication.
 

Risks and outcomes

Emerging from a series of WHI reports are complex models on the effect of hormonal therapy on the risk and outcome of breast cancer. In one study, women with an intact uterus received CEEs plus medroxyprogesterone acetate (MPA). An increase in the risk of breast cancer was observed over a median of 5.6 years of treatment, followed by a moderate reduction, with the risk increasing after 13 years of cumulative follow-up. For women treated with CEE alone, the reduction in risk observed over an average of 7.2 years of treatment was maintained for 13 years of follow-up.

Results from observational studies contrast with those from randomized controlled trials, particularly those concerning the use of estrogens only. A meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer showed that both EPT and CEE were associated with a higher risk of breast neoplasia. Results of the Million Women Study showed a higher death rate.
 

Treatment methods and duration

Information from prospective studies on the effects of commencing MHT at various ages between 40 and 59 years show that for women who commenced treatment at any time within this age range, the relative risk was similar and was highly significant for all ages. Few women had started MHT treatment well after menopause at ages 60-69 years, and their excess risks during years 5-14 of current use were significant for estrogen-progestogen but not for estrogen-only MHT.

If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50-69 years by about 1 in every 50 users of estrogen plus daily progestogen preparations; 1 in every 70 users of estrogen plus intermittent progestogen preparations; and 1 in every 200 users of estrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

During 5-14 years of MHT use, the RRs were similarly increased if MHT use had started at ages 40-44 years, 45-49 years, 50-54 years, and 55-59 years; RRs appeared to be attenuated if MHT use had started after age 60 years. They were also attenuated by adiposity, particularly for estrogen-only MHT (which had little effect in obese women). After MHT use ceased, some excess risk of breast cancer persisted for more than a decade; this is directly correlated with the duration of treatment.

Therefore, it can be expected that the effects of MHT may vary between participants on the basis of age or time since menopause, as well as treatments (MHT type, dose, formulation, duration of use, and route of administration). Regarding formulation effects on the risk of breast cancer, new evidence shows an increased risk of 28%. Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: odds ratio, 0.99; 95% confidence interval 0.55-1.79; synthetic progestin: OR, 1.28; 95% CI, 1.22-1.35). When prescribing MHT, micronized progesterone may be the safer progestogen to use.

In conclusion, MHT has a complex balance of benefits and risk on various health outcomes. Some effects differ qualitatively between ET and EPT. Regarding use of MHT, consideration should be given to the full range of effects, along with patients’ values and preferences. The overall quality of existing systematic reviews is moderate to poor. Clinicians should evaluate their scientific strength before considering applying their results in clinical practice. Regarding use of any hormone therapy regimen, consideration should be given to the full range of risk and benefits and should involve shared decisionmaking with the patient. It should be recognized that risk-benefit balance is altered by factors such as age, time from menopause, oophorectomy status, and prior hysterectomy and that some outcomes persist and there is some attenuation after stopping use.

This article was translated from Univadis Italy.

A version of the article appeared on Medscape.com.

It is projected that by 2050, 1.6 billion women in the world will have reached menopause or the postmenopausal period, a significant increase, compared with a billion women in 2020. Of all menopausal women, around 75% are affected by troublesome menopause symptoms, such as hot flashes and night sweats.

Around 84% of postmenopausal women experience genitourinary symptoms, such as vulvovaginal atrophy and incontinence.

Menopausal hormone therapy (MHT) is the most effective treatment for managing these symptoms; however, its effects on numerous aspects of female health remain uncertain, in particular with regard to breast cancer. The influence of MHT on breast cancer remains unsettled, with discordant findings from observational studies and randomized clinical trials, a factor that affects the decisions made by doctors concerning hormone therapy in menopausal women.
 

Background

Conjugated equine estrogens (CEEs) were introduced into clinical practice in the 1940s. For decades, MHT was the main treatment in conventional medicine for the symptoms of menopause. MHT was used in Western countries for about 600 million women starting from 1970, and it progressively increased during the 1990s. Professional organizations recommended MHT for the prevention of osteoporosis and chronic heart disease (CHD), and a third of prescriptions were for women older than 60 years.

Against this background, the National Institutes of Health launched randomized trials of MHT through the Women’s Health Initiative (WHI) to test whether the association with reduced risk for CHD found in observational studies was real and to obtain reliable information on the overall risks and benefits regarding the prevention of chronic disease for postmenopausal women aged 50-79 years.

The WHI trials tested standard-dose oral CEEs with and without standard-dose continuous medroxyprogesterone acetate (EPT). In 2002, the results of the WHI studies raised a series of concerns about the long-term safety of MHT, in particular the finding of an increased risk of breast cancer for women undergoing therapy. That risk exceeded the benefits from reductions in hip fractures and colorectal cancer.

The WHI findings received wide attention. Prescriptions for MHT dropped precipitously after 2002 and continued to decline in subsequent years. Declines were most marked for standard-dose EPT and in older women. The results of the CEE study were less negative, compared with those for EPT, as they showed no effect on CHD, a nonsignificant reduction in the risk of breast cancer, and a more favorable risk-benefit ratio for younger women, compared with older women. A decade later, it had become widely accepted that MHT should not be used for the prevention of chronic disease in older women; however, short-term use for treatment of vasomotor symptoms remains an accepted indication.
 

Risks and outcomes

Emerging from a series of WHI reports are complex models on the effect of hormonal therapy on the risk and outcome of breast cancer. In one study, women with an intact uterus received CEEs plus medroxyprogesterone acetate (MPA). An increase in the risk of breast cancer was observed over a median of 5.6 years of treatment, followed by a moderate reduction, with the risk increasing after 13 years of cumulative follow-up. For women treated with CEE alone, the reduction in risk observed over an average of 7.2 years of treatment was maintained for 13 years of follow-up.

Results from observational studies contrast with those from randomized controlled trials, particularly those concerning the use of estrogens only. A meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer showed that both EPT and CEE were associated with a higher risk of breast neoplasia. Results of the Million Women Study showed a higher death rate.
 

Treatment methods and duration

Information from prospective studies on the effects of commencing MHT at various ages between 40 and 59 years show that for women who commenced treatment at any time within this age range, the relative risk was similar and was highly significant for all ages. Few women had started MHT treatment well after menopause at ages 60-69 years, and their excess risks during years 5-14 of current use were significant for estrogen-progestogen but not for estrogen-only MHT.

If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50-69 years by about 1 in every 50 users of estrogen plus daily progestogen preparations; 1 in every 70 users of estrogen plus intermittent progestogen preparations; and 1 in every 200 users of estrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

During 5-14 years of MHT use, the RRs were similarly increased if MHT use had started at ages 40-44 years, 45-49 years, 50-54 years, and 55-59 years; RRs appeared to be attenuated if MHT use had started after age 60 years. They were also attenuated by adiposity, particularly for estrogen-only MHT (which had little effect in obese women). After MHT use ceased, some excess risk of breast cancer persisted for more than a decade; this is directly correlated with the duration of treatment.

Therefore, it can be expected that the effects of MHT may vary between participants on the basis of age or time since menopause, as well as treatments (MHT type, dose, formulation, duration of use, and route of administration). Regarding formulation effects on the risk of breast cancer, new evidence shows an increased risk of 28%. Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: odds ratio, 0.99; 95% confidence interval 0.55-1.79; synthetic progestin: OR, 1.28; 95% CI, 1.22-1.35). When prescribing MHT, micronized progesterone may be the safer progestogen to use.

In conclusion, MHT has a complex balance of benefits and risk on various health outcomes. Some effects differ qualitatively between ET and EPT. Regarding use of MHT, consideration should be given to the full range of effects, along with patients’ values and preferences. The overall quality of existing systematic reviews is moderate to poor. Clinicians should evaluate their scientific strength before considering applying their results in clinical practice. Regarding use of any hormone therapy regimen, consideration should be given to the full range of risk and benefits and should involve shared decisionmaking with the patient. It should be recognized that risk-benefit balance is altered by factors such as age, time from menopause, oophorectomy status, and prior hysterectomy and that some outcomes persist and there is some attenuation after stopping use.

This article was translated from Univadis Italy.

A version of the article appeared on Medscape.com.

It is projected that by 2050, 1.6 billion women in the world will have reached menopause or the postmenopausal period, a significant increase, compared with a billion women in 2020. Of all menopausal women, around 75% are affected by troublesome menopause symptoms, such as hot flashes and night sweats.

Around 84% of postmenopausal women experience genitourinary symptoms, such as vulvovaginal atrophy and incontinence.

Menopausal hormone therapy (MHT) is the most effective treatment for managing these symptoms; however, its effects on numerous aspects of female health remain uncertain, in particular with regard to breast cancer. The influence of MHT on breast cancer remains unsettled, with discordant findings from observational studies and randomized clinical trials, a factor that affects the decisions made by doctors concerning hormone therapy in menopausal women.
 

Background

Conjugated equine estrogens (CEEs) were introduced into clinical practice in the 1940s. For decades, MHT was the main treatment in conventional medicine for the symptoms of menopause. MHT was used in Western countries for about 600 million women starting from 1970, and it progressively increased during the 1990s. Professional organizations recommended MHT for the prevention of osteoporosis and chronic heart disease (CHD), and a third of prescriptions were for women older than 60 years.

Against this background, the National Institutes of Health launched randomized trials of MHT through the Women’s Health Initiative (WHI) to test whether the association with reduced risk for CHD found in observational studies was real and to obtain reliable information on the overall risks and benefits regarding the prevention of chronic disease for postmenopausal women aged 50-79 years.

The WHI trials tested standard-dose oral CEEs with and without standard-dose continuous medroxyprogesterone acetate (EPT). In 2002, the results of the WHI studies raised a series of concerns about the long-term safety of MHT, in particular the finding of an increased risk of breast cancer for women undergoing therapy. That risk exceeded the benefits from reductions in hip fractures and colorectal cancer.

The WHI findings received wide attention. Prescriptions for MHT dropped precipitously after 2002 and continued to decline in subsequent years. Declines were most marked for standard-dose EPT and in older women. The results of the CEE study were less negative, compared with those for EPT, as they showed no effect on CHD, a nonsignificant reduction in the risk of breast cancer, and a more favorable risk-benefit ratio for younger women, compared with older women. A decade later, it had become widely accepted that MHT should not be used for the prevention of chronic disease in older women; however, short-term use for treatment of vasomotor symptoms remains an accepted indication.
 

Risks and outcomes

Emerging from a series of WHI reports are complex models on the effect of hormonal therapy on the risk and outcome of breast cancer. In one study, women with an intact uterus received CEEs plus medroxyprogesterone acetate (MPA). An increase in the risk of breast cancer was observed over a median of 5.6 years of treatment, followed by a moderate reduction, with the risk increasing after 13 years of cumulative follow-up. For women treated with CEE alone, the reduction in risk observed over an average of 7.2 years of treatment was maintained for 13 years of follow-up.

Results from observational studies contrast with those from randomized controlled trials, particularly those concerning the use of estrogens only. A meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer showed that both EPT and CEE were associated with a higher risk of breast neoplasia. Results of the Million Women Study showed a higher death rate.
 

Treatment methods and duration

Information from prospective studies on the effects of commencing MHT at various ages between 40 and 59 years show that for women who commenced treatment at any time within this age range, the relative risk was similar and was highly significant for all ages. Few women had started MHT treatment well after menopause at ages 60-69 years, and their excess risks during years 5-14 of current use were significant for estrogen-progestogen but not for estrogen-only MHT.

If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50-69 years by about 1 in every 50 users of estrogen plus daily progestogen preparations; 1 in every 70 users of estrogen plus intermittent progestogen preparations; and 1 in every 200 users of estrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

During 5-14 years of MHT use, the RRs were similarly increased if MHT use had started at ages 40-44 years, 45-49 years, 50-54 years, and 55-59 years; RRs appeared to be attenuated if MHT use had started after age 60 years. They were also attenuated by adiposity, particularly for estrogen-only MHT (which had little effect in obese women). After MHT use ceased, some excess risk of breast cancer persisted for more than a decade; this is directly correlated with the duration of treatment.

Therefore, it can be expected that the effects of MHT may vary between participants on the basis of age or time since menopause, as well as treatments (MHT type, dose, formulation, duration of use, and route of administration). Regarding formulation effects on the risk of breast cancer, new evidence shows an increased risk of 28%. Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: odds ratio, 0.99; 95% confidence interval 0.55-1.79; synthetic progestin: OR, 1.28; 95% CI, 1.22-1.35). When prescribing MHT, micronized progesterone may be the safer progestogen to use.

In conclusion, MHT has a complex balance of benefits and risk on various health outcomes. Some effects differ qualitatively between ET and EPT. Regarding use of MHT, consideration should be given to the full range of effects, along with patients’ values and preferences. The overall quality of existing systematic reviews is moderate to poor. Clinicians should evaluate their scientific strength before considering applying their results in clinical practice. Regarding use of any hormone therapy regimen, consideration should be given to the full range of risk and benefits and should involve shared decisionmaking with the patient. It should be recognized that risk-benefit balance is altered by factors such as age, time from menopause, oophorectomy status, and prior hysterectomy and that some outcomes persist and there is some attenuation after stopping use.

This article was translated from Univadis Italy.

A version of the article appeared on Medscape.com.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.

Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.

It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.

“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.

Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.

“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
 

The ‘untold misery of oestrogen-starved women’

These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken

homes caused by these unstable, oestrogen-starved women.’ ”

Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.

“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”

The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
 

Promoting exercise, stopping smoking among positive messages

An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.

The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).

The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.

While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
 

Menopause blamed in a difficult time of life

Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.

It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.

People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.

The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”

Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.

Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.

Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”

She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.

The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.

Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.

Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.

It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.

“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.

Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.

“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
 

The ‘untold misery of oestrogen-starved women’

These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken

homes caused by these unstable, oestrogen-starved women.’ ”

Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.

“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”

The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
 

Promoting exercise, stopping smoking among positive messages

An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.

The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).

The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.

While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
 

Menopause blamed in a difficult time of life

Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.

It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.

People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.

The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”

Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.

Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.

Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”

She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.

The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.

Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.

Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.

It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.

“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.

Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.

“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
 

The ‘untold misery of oestrogen-starved women’

These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken

homes caused by these unstable, oestrogen-starved women.’ ”

Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.

“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”

The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
 

Promoting exercise, stopping smoking among positive messages

An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.

The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).

The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.

While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
 

Menopause blamed in a difficult time of life

Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.

It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.

People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.

The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”

Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.

Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.

Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”

She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.

The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

Surgeons may significantly underestimate how long it will take women to return to normal activities following sling surgery to correct stress urinary incontinence, a new study has found.

The researchers found that just over 40% of women reported returning to work and other normal activities within 2 weeks of having undergone midurethral sling procedures – a much less optimistic forecast than what surgeons typically provide in these cases.

“This is in contrast to a published survey of physicians that showed the majority of surgeons suggested patients return to work within 2 weeks,” Rui Wang, MD, a fellow in female pelvic medicine and reconstructive surgery at Hartford Hospital, Conn., said in an interview.

Dr. Wang referred to a published survey of 135 physicians that was conducted at a 2018 meeting of the Society of Gynecologic Surgeons. In that survey, 88% of respondents indicated that patients could return to sedentary work within 2 weeks after undergoing sling surgery. Most recommended longer waits before returning to manual labor.

The authors of the survey noted a lack of consensus guidelines and wide variations in recommendations for postoperative restrictions after minimally invasive gynecologic and pelvic reconstructive surgery, which the researchers called a “largely unstudied field.”

Dr. Wang said, “The majority of patients may need more than 2 weeks to return to work and normal activities even following minimally invasive outpatient surgeries such as midurethral sling.”

Dr. Wang is scheduled to present the findings June 18 at the annual meeting of the American Urogynecologic Society.

For the new study, Dr. Wang and a colleague examined how patients answered questions about their activity levels during recovery after sling procedures. The patients were enrolled in the Trial of Mid-Urethral Slings (TOMUS), a randomized controlled trial that compared two types of midurethral slings used for the treatment of stress urinary incontinence: the retropubic midurethral mesh sling and the transobturator midurethral sling. Results of the trial were published in 2010.

Of 597 women enrolled in TOMUS, 441 were included in the new analysis. Patients who underwent another surgery at the same time as their sling procedure were excluded from the analysis.

As part of the trial, patients were asked how many paid workdays they took off after surgery; whether they had returned to full normal activities of daily life, including work, if applicable; and how much time it took for them to fully return to normal activities of daily life, including work.

The researchers found that 183 (41.5%) returned to normal activities within 2 weeks of the procedure. Among those patients, the median recovery time was 6 days. Within 6 weeks of surgery, 308 (70%) had returned to normal activities, including work. After 6 months, 407 (98.3%) were back to their normal routines, the study showed.

Multivariate regression analysis yielded no factor that predicted the timing of returning to normal activity and work. Nor did the researchers observe any significant differences in failure rates and adverse outcomes between patients who returned within 2 weeks or after 2 weeks.
 

Essential information for patient planning

Dr. Wang said she expects that the findings will help physicians in counseling patients and setting postoperative recovery expectations. “For patients planning elective surgery, one of the most important quality-of-life issues is the time they will need to take off from work and recover,” she said.

Although most patients needed more than 2 weeks to recover, the median paid time off after surgery was 4 days. “Many patients would have taken unpaid days off or used vacation time for their postoperative recovery,” Dr. Wang said.

She added that more research is needed to explore whether that discrepancy disproportionately affects women in jobs with fewer employee benefits. “We did not find that age, race/ethnicity, marital status, occupation, symptom severity, and duration of surgery significantly predicted the timing of return to work or normal activities,” she said. “But are there other factors, such as geographic location, insurance status, [or] income, that may affect this timing?”

Sarah Boyd, MD, an assistant professor in the Division of Female Pelvic Medicine and Reconstructive Surgery at Penn State College of Medicine, Hershey, said the new findings add concrete information that can guide patients in planning their recovery.

“Previously, surgeons could only provide general estimates to these patients based on the experience of their patients,” Dr. Boyd, who was not involved in the study, told this news organization.

The analysis has not been published in a peer-reviewed journal, and Dr. Boyd said that the findings may not pertain to all individuals who undergo midurethral sling procedures, such as people who have had prior surgery for incontinence or those who undergo surgery for other pelvic floor disorders at the same time.

Dr. Wang and Dr. Boyd reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Surgeons may significantly underestimate how long it will take women to return to normal activities following sling surgery to correct stress urinary incontinence, a new study has found.

The researchers found that just over 40% of women reported returning to work and other normal activities within 2 weeks of having undergone midurethral sling procedures – a much less optimistic forecast than what surgeons typically provide in these cases.

“This is in contrast to a published survey of physicians that showed the majority of surgeons suggested patients return to work within 2 weeks,” Rui Wang, MD, a fellow in female pelvic medicine and reconstructive surgery at Hartford Hospital, Conn., said in an interview.

Dr. Wang referred to a published survey of 135 physicians that was conducted at a 2018 meeting of the Society of Gynecologic Surgeons. In that survey, 88% of respondents indicated that patients could return to sedentary work within 2 weeks after undergoing sling surgery. Most recommended longer waits before returning to manual labor.

The authors of the survey noted a lack of consensus guidelines and wide variations in recommendations for postoperative restrictions after minimally invasive gynecologic and pelvic reconstructive surgery, which the researchers called a “largely unstudied field.”

Dr. Wang said, “The majority of patients may need more than 2 weeks to return to work and normal activities even following minimally invasive outpatient surgeries such as midurethral sling.”

Dr. Wang is scheduled to present the findings June 18 at the annual meeting of the American Urogynecologic Society.

For the new study, Dr. Wang and a colleague examined how patients answered questions about their activity levels during recovery after sling procedures. The patients were enrolled in the Trial of Mid-Urethral Slings (TOMUS), a randomized controlled trial that compared two types of midurethral slings used for the treatment of stress urinary incontinence: the retropubic midurethral mesh sling and the transobturator midurethral sling. Results of the trial were published in 2010.

Of 597 women enrolled in TOMUS, 441 were included in the new analysis. Patients who underwent another surgery at the same time as their sling procedure were excluded from the analysis.

As part of the trial, patients were asked how many paid workdays they took off after surgery; whether they had returned to full normal activities of daily life, including work, if applicable; and how much time it took for them to fully return to normal activities of daily life, including work.

The researchers found that 183 (41.5%) returned to normal activities within 2 weeks of the procedure. Among those patients, the median recovery time was 6 days. Within 6 weeks of surgery, 308 (70%) had returned to normal activities, including work. After 6 months, 407 (98.3%) were back to their normal routines, the study showed.

Multivariate regression analysis yielded no factor that predicted the timing of returning to normal activity and work. Nor did the researchers observe any significant differences in failure rates and adverse outcomes between patients who returned within 2 weeks or after 2 weeks.
 

Essential information for patient planning

Dr. Wang said she expects that the findings will help physicians in counseling patients and setting postoperative recovery expectations. “For patients planning elective surgery, one of the most important quality-of-life issues is the time they will need to take off from work and recover,” she said.

Although most patients needed more than 2 weeks to recover, the median paid time off after surgery was 4 days. “Many patients would have taken unpaid days off or used vacation time for their postoperative recovery,” Dr. Wang said.

She added that more research is needed to explore whether that discrepancy disproportionately affects women in jobs with fewer employee benefits. “We did not find that age, race/ethnicity, marital status, occupation, symptom severity, and duration of surgery significantly predicted the timing of return to work or normal activities,” she said. “But are there other factors, such as geographic location, insurance status, [or] income, that may affect this timing?”

Sarah Boyd, MD, an assistant professor in the Division of Female Pelvic Medicine and Reconstructive Surgery at Penn State College of Medicine, Hershey, said the new findings add concrete information that can guide patients in planning their recovery.

“Previously, surgeons could only provide general estimates to these patients based on the experience of their patients,” Dr. Boyd, who was not involved in the study, told this news organization.

The analysis has not been published in a peer-reviewed journal, and Dr. Boyd said that the findings may not pertain to all individuals who undergo midurethral sling procedures, such as people who have had prior surgery for incontinence or those who undergo surgery for other pelvic floor disorders at the same time.

Dr. Wang and Dr. Boyd reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Surgeons may significantly underestimate how long it will take women to return to normal activities following sling surgery to correct stress urinary incontinence, a new study has found.

The researchers found that just over 40% of women reported returning to work and other normal activities within 2 weeks of having undergone midurethral sling procedures – a much less optimistic forecast than what surgeons typically provide in these cases.

“This is in contrast to a published survey of physicians that showed the majority of surgeons suggested patients return to work within 2 weeks,” Rui Wang, MD, a fellow in female pelvic medicine and reconstructive surgery at Hartford Hospital, Conn., said in an interview.

Dr. Wang referred to a published survey of 135 physicians that was conducted at a 2018 meeting of the Society of Gynecologic Surgeons. In that survey, 88% of respondents indicated that patients could return to sedentary work within 2 weeks after undergoing sling surgery. Most recommended longer waits before returning to manual labor.

The authors of the survey noted a lack of consensus guidelines and wide variations in recommendations for postoperative restrictions after minimally invasive gynecologic and pelvic reconstructive surgery, which the researchers called a “largely unstudied field.”

Dr. Wang said, “The majority of patients may need more than 2 weeks to return to work and normal activities even following minimally invasive outpatient surgeries such as midurethral sling.”

Dr. Wang is scheduled to present the findings June 18 at the annual meeting of the American Urogynecologic Society.

For the new study, Dr. Wang and a colleague examined how patients answered questions about their activity levels during recovery after sling procedures. The patients were enrolled in the Trial of Mid-Urethral Slings (TOMUS), a randomized controlled trial that compared two types of midurethral slings used for the treatment of stress urinary incontinence: the retropubic midurethral mesh sling and the transobturator midurethral sling. Results of the trial were published in 2010.

Of 597 women enrolled in TOMUS, 441 were included in the new analysis. Patients who underwent another surgery at the same time as their sling procedure were excluded from the analysis.

As part of the trial, patients were asked how many paid workdays they took off after surgery; whether they had returned to full normal activities of daily life, including work, if applicable; and how much time it took for them to fully return to normal activities of daily life, including work.

The researchers found that 183 (41.5%) returned to normal activities within 2 weeks of the procedure. Among those patients, the median recovery time was 6 days. Within 6 weeks of surgery, 308 (70%) had returned to normal activities, including work. After 6 months, 407 (98.3%) were back to their normal routines, the study showed.

Multivariate regression analysis yielded no factor that predicted the timing of returning to normal activity and work. Nor did the researchers observe any significant differences in failure rates and adverse outcomes between patients who returned within 2 weeks or after 2 weeks.
 

Essential information for patient planning

Dr. Wang said she expects that the findings will help physicians in counseling patients and setting postoperative recovery expectations. “For patients planning elective surgery, one of the most important quality-of-life issues is the time they will need to take off from work and recover,” she said.

Although most patients needed more than 2 weeks to recover, the median paid time off after surgery was 4 days. “Many patients would have taken unpaid days off or used vacation time for their postoperative recovery,” Dr. Wang said.

She added that more research is needed to explore whether that discrepancy disproportionately affects women in jobs with fewer employee benefits. “We did not find that age, race/ethnicity, marital status, occupation, symptom severity, and duration of surgery significantly predicted the timing of return to work or normal activities,” she said. “But are there other factors, such as geographic location, insurance status, [or] income, that may affect this timing?”

Sarah Boyd, MD, an assistant professor in the Division of Female Pelvic Medicine and Reconstructive Surgery at Penn State College of Medicine, Hershey, said the new findings add concrete information that can guide patients in planning their recovery.

“Previously, surgeons could only provide general estimates to these patients based on the experience of their patients,” Dr. Boyd, who was not involved in the study, told this news organization.

The analysis has not been published in a peer-reviewed journal, and Dr. Boyd said that the findings may not pertain to all individuals who undergo midurethral sling procedures, such as people who have had prior surgery for incontinence or those who undergo surgery for other pelvic floor disorders at the same time.

Dr. Wang and Dr. Boyd reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The transition to menopause begins with ovarian fluctuation and hormonal changes, often beginning before significant changes in menstruation. Reproductive aging with loss of follicular activity progresses over a wide age range (42 to 58 years) with an average onset at approximately age 47, ranging from 4 to 8 years. Although most women have heard about menopause, defined as 12 months after the last period, they often lack understanding about perimenopause or that the menopausal transition usually begins 5 years before menopause.¹

Perimenopause, defined as early and late menopause transition stages, may be viewed as a window of potential vulnerability for women who develop or have worsening menstrual-related mood disorders. Over time, hormonal fluctuations often lead to menstrual cycle irregularity (either shorter or longer). Changes occurring during perimenopause may be confusing as it may not be clear whether symptoms are related to menopause, aging, or stress. Often not recognized or treated adequately, perimenopausal symptoms may be challenging to navigate for both women and clinicians.

The perimenopausal process is often even more confusing for women with early menopause—whether due to bilateral oophorectomy, chemotherapy or radiation therapy, genetics, or an autoimmune process—because of lack of recognition that an early menopausal transition is occurring or what solutions are available for symptoms. While there is support in the workplace for women during pregnancy and breastfeeding, there remains little support or recognition for the oft challenging perimenopausal transition leading to menopause.

Perimenopause: Common symptoms and treatments

Symptoms may be related to either estrogen level deficiency or excess during perimenopause, and these level changes may even occur within the same cycle.

Cyclic breast tenderness may develop, worsened by caffeine or high salt intake (which can be potentially improved, although without clinical trial evidence, with decreased caffeine or a trial of evening primrose oil or vitamin E).

Changes in menstrual flow and frequency of menses are typical. Flow may be lighter or heavier, longer or shorter, and there may be cycle variability, missed menses, or midcycle spotting.² Bleeding may be heavy, with or without cramping. In addition to imaging with vaginal ultrasonography or hysteroscopy to identify structural issues, symptoms may be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy (HT) with short hormone-free interval contraceptives, oral progestogens, or progestin intrauterine systems. Newer medical treatments include antifibrinolytic drugs and selective progesterone-receptor modulators. Uterine ablation to decrease or stop bleeding is effective if there are no structural abnormalities, such as fibroids or polyps or the presence of adenomyosis, where glands will regrow into the endometrium after ablation. Endometrial biopsy is indicated for persistent abnormal uterine bleeding or those with risk factors such as chronic anovulation.

Worsening headaches or menstrual migraines may be triggered by hormonal changes, which may respond to NSAIDs; dihydroergotamine; triptans; the combination of aspirin, acetaminophen, and caffeine; or estrogen the week before menses. For women taking oral contraceptives (OCPs), adding estradiol the week before menses, or using the OCP continuously, may decrease headache frequency. These short-term prophylactic strategies during the perimenstrual time are often effective. If not, preventive therapy is available for women with frequent, severe headaches.

Mood complaints and poor sleep are independently associated with menstrual irregularity, and can lead to fatigue or anxiety, worsening premenstrual syndrome, or depressive moods. Sleep is disrupted premenstrually for up to one-third of women, and sleep disruption is particularly prevalent in those with premenstrual mood disorders and worsens during perimenopause.³

Reproductive hormones act on the neurotransmitter systems in the brain involved in mood regulation and emotion. The fluctuating hormones occurring during perimenopause may exacerbate pre-existing menstrual-related mood disorders. A subset of women experience depressive moods due to perimenopausal elevations in ovarian hormones.⁴ Others may exhibit increased mood sensitivity with the ovarian hormone withdrawal accompanying late menopause transition and early postmenopausal phase.⁵ There is significant comorbidity between premenstrual mood disorder (PMDD) and postpartum depression.⁶ During perimenopause and early menopause, clinicians should ask about prior hormonally-related depression (puberty, postpartum) and recognize that current or past premenstrual syndrome may worsen into a more severe premenstrual dysphoric disorder. Evidence-based treatments for PMDD include selective serotonin reuptake inhibitors (SSRIs); either taken continuously or only during the luteal phase; drospirenone-containing oral contraceptives, often with shorter pill-free intervals; GnRH analogues with or without hormone add-back; and cognitive behavioral therapy.⁷ For women whose perimenopausal moods improve with HT or develop worsened mood sensitivity with ovarian hormone withdrawal, clinicians should recognize that mood may worsen when treatment is ceased.⁵

Continue to: Menopausal symptoms...

Vasomotor symptoms (VMS), hot flashes, or night sweats occur in up to 75% of women as they develop more menstrual irregularity and move closer to their final period and menopause.

Hot flashes are transient episodes of flushing with the sensation of warmth (up to intense heat) on the upper body and face or head, often associated with sweating, chills or flushing, an increase in heart rate, and lowered blood pressure. Hot flashes can sometimes be preceded by an intense feeling of dread, followed by rapid heat dissipation. The etiology of hot flashes is still not clear, but the neurokinin receptors are involved. They are related to small fluctuations in core body temperature superimposed on a narrow thermoneutral zone in symptomatic women. Hot flashes are triggered when core body temperature rises above the upper (sweating) threshold. Shivering occurs if the core body temperature falls below the lower threshold. Sleep may be disrupted, with less rapid eye movement (REM) sleep, and associated with throwing covers on and off or changing sheets or nightclothes. On average, hot flashes last 7.2 years,⁸ and they are more bothersome if night sweats interfere with sleep or disrupt performance during the day.

In the Stages of Reproductive Aging Workshop (STRAW + 10), women reported VMS within 1-3 years after the menopausal transition.⁸ Four trajectories of hot flashes were identified in the Study of Women’s Health Across the Nation (SWAN) trial,⁹ including low levels throughout the menopause transition, early onset, late onset, and a group which had frequent hot flashes, starting early and lasting longer. Serum estrogen levels were not predictive of hot flash frequency or severity.

Hot flashes have been associated with low levels of exercise, cigarette smoking, high follicle-stimulating hormone levels and low estradiol levels, increasing body mass index, ethnicity (with hot flashes more common among Black and Hispanic women), low socioeconomic status, prior PMDD, anxiety, perceived stress, and depression.⁸ Women with a history of premenstrual syndrome, stress, sexual dysfunction, physical inactivity, or hot flashes are more vulnerable to depressive symptoms during perimenopause and early menopause.⁵

Depression may co-occur or overlap with menopause symptoms. Diagnosis involves menopausal stage, co-occurring psychiatric and menopause symptoms, psychosocial stressors, and a validated screening tool such as PQ9. Treatments for perimenopausal depression, such as antidepressants, psychotherapy, or cognitive behavioral therapy, are recommended first line for perimenopausal depression. Estrogen therapy has not been approved to treat perimenopausal depression but appears to have antidepressant effects in perimenopausal women, particularly those with bothersome vasomotor symptoms.⁵

Anxiety can worsen during menopause, and may respond to calming apps, meditation, cognitive behavioral therapy, hypnosis, yoga or tai chi, HT, or antianxiety medications.

Weight gain around the abdomen (ie, belly fat) is a common complaint during the menopausal transition, despite women reporting not changing their eating or exercise patterns. Increasing exercise or bursts of higher intensity, decreasing portion sizes or limiting carbohydrates and alcohol may help.

Memory and concentration problems, described as brain fog, tend to be more of an issue in perimenopause and level out after menopause. Counsel midlife women that these changes are not due to dementia but are related to normal aging, hormonal changes, mood, stress, or other life circumstances. Identifying and addressing sleep issues and mood disorders may help mitigate brain fog, as can advising women to avoid excess caffeine, alcohol, nicotine, and eating before bed. Improvements in memory, cognition, and health have been found with the Mediterranean diet, regular exercise, avoiding multitasking, and engaging in mentally stimulating activities.

Sleeping concerns in peri- and postmenopausal women include sleeping less and more frequent insomnia. Women are more likely to use prescription sleeping aids during these times of their lives. The data from SWAN⁸ show that the menopausal transition is related to self-reported difficulty sleeping, independent of age. Sleep latency interval is increased while REM sleep decreases. Night sweats can trigger awakenings in the first half of the night. The perceived decline in sleep quality also may be attributed to general aging effects, nocturnal urination, sleep-related disorders such as sleep apnea or restless legs, or chronic pain, stress, or depression.¹⁰ Suggestions for management include sleep apps, cognitive behavioral therapy, low-dose antidepressant therapy, addressing sleep routines, and HT. Hypnotics should be avoided.

Sexuality issues are common complaints during the menopausal transition. Cross-sectional data reported from a longitudinal, population-based Australian cohort of women aged 45 to 55 years, found a decrease in sexual responsivity, sexual frequency, libido, vaginal dyspareunia, and more partner problems.¹¹ Low libido may be related to relationship issues, dyspareunia with vaginal narrowing, loss of lubrication, levator spasm, stress, anxiety, exhaustion or mood disorder, lowered hormone levels, excess alcohol intake, underlying health concerns, or a side effect of medications for depression or pain. There is no direct correlation between testosterone levels and libido.

When HT at menopause may be helpful

For healthy symptomatic women without contraindications who are younger than age 60, or within 10 years of menopause onset, the benefits of initiating HT most likely outweigh the risks to relieve bothersome hot flashes and night sweats.^12-17 For older women, or for those further from menopause, the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia, in general, outweigh the potential benefits.^12-17 Extended durations of HT have less safety and efficacy data and should be considered primarily for those with persistent menopausal symptoms, with periodic re-evaluation.^13,14 For bothersome genitourinary syndrome of menopause symptoms that do not respond to vaginal moisturizers or lubricants, low-dose vaginal HTs are encouraged.^13-17

Continue to: Early-onset menopause...

Early-onset menopause

According to observational studies,¹⁸ early menopause is associated with a higher risk of osteoporosis, coronary heart disease, cognitive changes, vaginal dryness, loss of libido, and mood changes. Studies have shown that women with early menopause who take HT, without contraindications, to the average age of menopause (age 52) decrease the health risks of early menopause (bone loss, heart disease, mood, and cognition changes).^13,14,18

Women with early menopause, whether spontaneous or following bilateral oophorectomy or cancer treatment, should be counseled to get adequate calcium (dietary recommended over supplementation) and vitamin D intake, eat a healthy diet, and exercise regularly. Evaluation should include risk for bone loss, heart disease, mood changes, and vaginal changes.

Extended use of HT

Up to 8% of women have hot flashes for 20 years or more after menopause.¹⁹ The decision to continue or to stop HT is not always clear for women:

• with persistent hot flashes after a trial period of HT discontinuation
• with bone loss that cannot be treated with bone-specific medications
• who request continuation for quality of life.

Extended use of HT should include an ongoing assessment of its risks and benefits, periodic trials off of HT, and documentation of rationale and informed discussions about continuing. Lower doses and transdermal therapies appear safer, as does micronized progesterone instead of more potent synthetic progestins.^13-17

Genitourinary syndrome of menopause

Once women are further into menopause, they may notice vaginal dryness, vulvar itching or burning, bothersome vaginal discharge, or urinary urgency or frequency. The development of painful intercourse frequently occurs, a combination of the loss of estrogen with thinning of the vaginal mucosa, a loss of the acidic vaginal milieu with less elasticity, and spasm of the levator muscles. Some women develop urinary tract infections after intercourse or have more frequent reoccurrences. First-line therapy is often vaginal moisturizers and lubricants. Vaginal therapies (estradiol, conjugated estrogen, or dehydroepiandrosterone) or oral selective estrogen-receptor modulators (SERMs; ospemifene) improve vaginal dryness and dyspareunia.^13,14 Pelvic therapy has also proved valuable for incontinence, pelvic floor dysfunction, and levator spasms.²⁰

Where are there gaps in clinician knowledge?

Studies on emotional health, mood, and sleep need to incorporate measures of menstrual timing into data collection and analyses. Does the sleep disruption occurring premenstrually during perimenopause disproportionately contribute to a woman’s vulnerability to depressive disorders? The risk of clinically significant depressive symptoms increases 1.5- to 2.9-fold in the menopause transition.⁵ Research into premenstrual dysphoria during the menopause transition may identify different trajectories in the timing of symptoms related to either cycle itself or the ovarian hormone fluctuations or both.²¹ Gamma-aminobutyric acid (GABA)-modulating drugs, such as sepranolone, which blocks allopregnanolone’s actions at the GABAA receptor, may allow treatment of menstrual-related mood disorders without the need for hormonal interventions.²¹

Despite extended observational trial data, more data are needed to inform us about the long-term risks and benefits of using menopausal HT, particularly when initiated at menopause and to help address the timing of HT discontinuation. Furthermore, there are many unanswered questions. For instance:

• How much safer are lower dose and transdermal therapies?
• Do untreated hot flashes increase the risk of cardiovascular disease or dementia?
• Will newer non-HT options, such as the neurokinin receptor antagonists that are in testing but are not yet available, lower cardiovascular or dementia risks?
• What will be the risks and benefits for the newer estrogen in testing (estetrol, or E4), considered a natural estrogen and which appears to have lower thrombotic risks?
• What will be the role of intravaginal energy-based therapies, such as vaginal laser or radiofrequency devices?
• How do we address diverse populations and the effects of menopause on race, gender, culture, prior trauma, and socioeconomic status?

Lack of recognition of menopausal symptoms, particularly in the workplace

Clinicians need to understand the varied physical and emotional symptoms that may occur with hormonal changes as women traverse perimenopause and early menopause. We need to recognize that the lack of discussion about women’s health during this time may make women feel ashamed and fearful of bringing up their symptoms due to fear of being dismissed or stigmatized.²² Women may not seek help until a crisis at home or work occurs, as they may fear that admitting symptoms or a need for help or time away from work will threaten how they are viewed at work or affect their chances of promotion. Although there are economic costs around menopause for appointments, tests, therapies, and missed time at work, not addressing menopausal health leads to poorer performance, workplace absences, and additional medical costs.²²

Conclusion

Menopause occurs naturally as a part of a woman’s life cycle. However, women need assistance navigating perimenopausal hormonal fluctuations and decisions about HT once in menopause. Increased awareness and education about perimenopause and menopause will allow compassionate, individualized, informed care, including lifestyle changes, behavioral or complementary strategies, or medical therapies, hormonal or nonhormonal.²⁷ As a medical society, we need to challenge the stigma associated with aging and menopause and educate ourselves and our patients to help women navigate this challenging time. ●

The transition to menopause begins with ovarian fluctuation and hormonal changes, often beginning before significant changes in menstruation. Reproductive aging with loss of follicular activity progresses over a wide age range (42 to 58 years) with an average onset at approximately age 47, ranging from 4 to 8 years. Although most women have heard about menopause, defined as 12 months after the last period, they often lack understanding about perimenopause or that the menopausal transition usually begins 5 years before menopause.¹

Perimenopause, defined as early and late menopause transition stages, may be viewed as a window of potential vulnerability for women who develop or have worsening menstrual-related mood disorders. Over time, hormonal fluctuations often lead to menstrual cycle irregularity (either shorter or longer). Changes occurring during perimenopause may be confusing as it may not be clear whether symptoms are related to menopause, aging, or stress. Often not recognized or treated adequately, perimenopausal symptoms may be challenging to navigate for both women and clinicians.

The perimenopausal process is often even more confusing for women with early menopause—whether due to bilateral oophorectomy, chemotherapy or radiation therapy, genetics, or an autoimmune process—because of lack of recognition that an early menopausal transition is occurring or what solutions are available for symptoms. While there is support in the workplace for women during pregnancy and breastfeeding, there remains little support or recognition for the oft challenging perimenopausal transition leading to menopause.

Perimenopause: Common symptoms and treatments

Symptoms may be related to either estrogen level deficiency or excess during perimenopause, and these level changes may even occur within the same cycle.

Cyclic breast tenderness may develop, worsened by caffeine or high salt intake (which can be potentially improved, although without clinical trial evidence, with decreased caffeine or a trial of evening primrose oil or vitamin E).

Changes in menstrual flow and frequency of menses are typical. Flow may be lighter or heavier, longer or shorter, and there may be cycle variability, missed menses, or midcycle spotting.² Bleeding may be heavy, with or without cramping. In addition to imaging with vaginal ultrasonography or hysteroscopy to identify structural issues, symptoms may be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy (HT) with short hormone-free interval contraceptives, oral progestogens, or progestin intrauterine systems. Newer medical treatments include antifibrinolytic drugs and selective progesterone-receptor modulators. Uterine ablation to decrease or stop bleeding is effective if there are no structural abnormalities, such as fibroids or polyps or the presence of adenomyosis, where glands will regrow into the endometrium after ablation. Endometrial biopsy is indicated for persistent abnormal uterine bleeding or those with risk factors such as chronic anovulation.

Worsening headaches or menstrual migraines may be triggered by hormonal changes, which may respond to NSAIDs; dihydroergotamine; triptans; the combination of aspirin, acetaminophen, and caffeine; or estrogen the week before menses. For women taking oral contraceptives (OCPs), adding estradiol the week before menses, or using the OCP continuously, may decrease headache frequency. These short-term prophylactic strategies during the perimenstrual time are often effective. If not, preventive therapy is available for women with frequent, severe headaches.

Mood complaints and poor sleep are independently associated with menstrual irregularity, and can lead to fatigue or anxiety, worsening premenstrual syndrome, or depressive moods. Sleep is disrupted premenstrually for up to one-third of women, and sleep disruption is particularly prevalent in those with premenstrual mood disorders and worsens during perimenopause.³

Reproductive hormones act on the neurotransmitter systems in the brain involved in mood regulation and emotion. The fluctuating hormones occurring during perimenopause may exacerbate pre-existing menstrual-related mood disorders. A subset of women experience depressive moods due to perimenopausal elevations in ovarian hormones.⁴ Others may exhibit increased mood sensitivity with the ovarian hormone withdrawal accompanying late menopause transition and early postmenopausal phase.⁵ There is significant comorbidity between premenstrual mood disorder (PMDD) and postpartum depression.⁶ During perimenopause and early menopause, clinicians should ask about prior hormonally-related depression (puberty, postpartum) and recognize that current or past premenstrual syndrome may worsen into a more severe premenstrual dysphoric disorder. Evidence-based treatments for PMDD include selective serotonin reuptake inhibitors (SSRIs); either taken continuously or only during the luteal phase; drospirenone-containing oral contraceptives, often with shorter pill-free intervals; GnRH analogues with or without hormone add-back; and cognitive behavioral therapy.⁷ For women whose perimenopausal moods improve with HT or develop worsened mood sensitivity with ovarian hormone withdrawal, clinicians should recognize that mood may worsen when treatment is ceased.⁵

Continue to: Menopausal symptoms...

Vasomotor symptoms (VMS), hot flashes, or night sweats occur in up to 75% of women as they develop more menstrual irregularity and move closer to their final period and menopause.

Hot flashes are transient episodes of flushing with the sensation of warmth (up to intense heat) on the upper body and face or head, often associated with sweating, chills or flushing, an increase in heart rate, and lowered blood pressure. Hot flashes can sometimes be preceded by an intense feeling of dread, followed by rapid heat dissipation. The etiology of hot flashes is still not clear, but the neurokinin receptors are involved. They are related to small fluctuations in core body temperature superimposed on a narrow thermoneutral zone in symptomatic women. Hot flashes are triggered when core body temperature rises above the upper (sweating) threshold. Shivering occurs if the core body temperature falls below the lower threshold. Sleep may be disrupted, with less rapid eye movement (REM) sleep, and associated with throwing covers on and off or changing sheets or nightclothes. On average, hot flashes last 7.2 years,⁸ and they are more bothersome if night sweats interfere with sleep or disrupt performance during the day.

In the Stages of Reproductive Aging Workshop (STRAW + 10), women reported VMS within 1-3 years after the menopausal transition.⁸ Four trajectories of hot flashes were identified in the Study of Women’s Health Across the Nation (SWAN) trial,⁹ including low levels throughout the menopause transition, early onset, late onset, and a group which had frequent hot flashes, starting early and lasting longer. Serum estrogen levels were not predictive of hot flash frequency or severity.

Hot flashes have been associated with low levels of exercise, cigarette smoking, high follicle-stimulating hormone levels and low estradiol levels, increasing body mass index, ethnicity (with hot flashes more common among Black and Hispanic women), low socioeconomic status, prior PMDD, anxiety, perceived stress, and depression.⁸ Women with a history of premenstrual syndrome, stress, sexual dysfunction, physical inactivity, or hot flashes are more vulnerable to depressive symptoms during perimenopause and early menopause.⁵

Depression may co-occur or overlap with menopause symptoms. Diagnosis involves menopausal stage, co-occurring psychiatric and menopause symptoms, psychosocial stressors, and a validated screening tool such as PQ9. Treatments for perimenopausal depression, such as antidepressants, psychotherapy, or cognitive behavioral therapy, are recommended first line for perimenopausal depression. Estrogen therapy has not been approved to treat perimenopausal depression but appears to have antidepressant effects in perimenopausal women, particularly those with bothersome vasomotor symptoms.⁵

Anxiety can worsen during menopause, and may respond to calming apps, meditation, cognitive behavioral therapy, hypnosis, yoga or tai chi, HT, or antianxiety medications.

Weight gain around the abdomen (ie, belly fat) is a common complaint during the menopausal transition, despite women reporting not changing their eating or exercise patterns. Increasing exercise or bursts of higher intensity, decreasing portion sizes or limiting carbohydrates and alcohol may help.

Memory and concentration problems, described as brain fog, tend to be more of an issue in perimenopause and level out after menopause. Counsel midlife women that these changes are not due to dementia but are related to normal aging, hormonal changes, mood, stress, or other life circumstances. Identifying and addressing sleep issues and mood disorders may help mitigate brain fog, as can advising women to avoid excess caffeine, alcohol, nicotine, and eating before bed. Improvements in memory, cognition, and health have been found with the Mediterranean diet, regular exercise, avoiding multitasking, and engaging in mentally stimulating activities.

Sleeping concerns in peri- and postmenopausal women include sleeping less and more frequent insomnia. Women are more likely to use prescription sleeping aids during these times of their lives. The data from SWAN⁸ show that the menopausal transition is related to self-reported difficulty sleeping, independent of age. Sleep latency interval is increased while REM sleep decreases. Night sweats can trigger awakenings in the first half of the night. The perceived decline in sleep quality also may be attributed to general aging effects, nocturnal urination, sleep-related disorders such as sleep apnea or restless legs, or chronic pain, stress, or depression.¹⁰ Suggestions for management include sleep apps, cognitive behavioral therapy, low-dose antidepressant therapy, addressing sleep routines, and HT. Hypnotics should be avoided.

Sexuality issues are common complaints during the menopausal transition. Cross-sectional data reported from a longitudinal, population-based Australian cohort of women aged 45 to 55 years, found a decrease in sexual responsivity, sexual frequency, libido, vaginal dyspareunia, and more partner problems.¹¹ Low libido may be related to relationship issues, dyspareunia with vaginal narrowing, loss of lubrication, levator spasm, stress, anxiety, exhaustion or mood disorder, lowered hormone levels, excess alcohol intake, underlying health concerns, or a side effect of medications for depression or pain. There is no direct correlation between testosterone levels and libido.

When HT at menopause may be helpful

For healthy symptomatic women without contraindications who are younger than age 60, or within 10 years of menopause onset, the benefits of initiating HT most likely outweigh the risks to relieve bothersome hot flashes and night sweats.^12-17 For older women, or for those further from menopause, the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia, in general, outweigh the potential benefits.^12-17 Extended durations of HT have less safety and efficacy data and should be considered primarily for those with persistent menopausal symptoms, with periodic re-evaluation.^13,14 For bothersome genitourinary syndrome of menopause symptoms that do not respond to vaginal moisturizers or lubricants, low-dose vaginal HTs are encouraged.^13-17

Continue to: Early-onset menopause...

Early-onset menopause

According to observational studies,¹⁸ early menopause is associated with a higher risk of osteoporosis, coronary heart disease, cognitive changes, vaginal dryness, loss of libido, and mood changes. Studies have shown that women with early menopause who take HT, without contraindications, to the average age of menopause (age 52) decrease the health risks of early menopause (bone loss, heart disease, mood, and cognition changes).^13,14,18

Women with early menopause, whether spontaneous or following bilateral oophorectomy or cancer treatment, should be counseled to get adequate calcium (dietary recommended over supplementation) and vitamin D intake, eat a healthy diet, and exercise regularly. Evaluation should include risk for bone loss, heart disease, mood changes, and vaginal changes.

Extended use of HT

Up to 8% of women have hot flashes for 20 years or more after menopause.¹⁹ The decision to continue or to stop HT is not always clear for women:

• with persistent hot flashes after a trial period of HT discontinuation
• with bone loss that cannot be treated with bone-specific medications
• who request continuation for quality of life.

Extended use of HT should include an ongoing assessment of its risks and benefits, periodic trials off of HT, and documentation of rationale and informed discussions about continuing. Lower doses and transdermal therapies appear safer, as does micronized progesterone instead of more potent synthetic progestins.^13-17

Genitourinary syndrome of menopause

Once women are further into menopause, they may notice vaginal dryness, vulvar itching or burning, bothersome vaginal discharge, or urinary urgency or frequency. The development of painful intercourse frequently occurs, a combination of the loss of estrogen with thinning of the vaginal mucosa, a loss of the acidic vaginal milieu with less elasticity, and spasm of the levator muscles. Some women develop urinary tract infections after intercourse or have more frequent reoccurrences. First-line therapy is often vaginal moisturizers and lubricants. Vaginal therapies (estradiol, conjugated estrogen, or dehydroepiandrosterone) or oral selective estrogen-receptor modulators (SERMs; ospemifene) improve vaginal dryness and dyspareunia.^13,14 Pelvic therapy has also proved valuable for incontinence, pelvic floor dysfunction, and levator spasms.²⁰

Where are there gaps in clinician knowledge?

Studies on emotional health, mood, and sleep need to incorporate measures of menstrual timing into data collection and analyses. Does the sleep disruption occurring premenstrually during perimenopause disproportionately contribute to a woman’s vulnerability to depressive disorders? The risk of clinically significant depressive symptoms increases 1.5- to 2.9-fold in the menopause transition.⁵ Research into premenstrual dysphoria during the menopause transition may identify different trajectories in the timing of symptoms related to either cycle itself or the ovarian hormone fluctuations or both.²¹ Gamma-aminobutyric acid (GABA)-modulating drugs, such as sepranolone, which blocks allopregnanolone’s actions at the GABAA receptor, may allow treatment of menstrual-related mood disorders without the need for hormonal interventions.²¹

Despite extended observational trial data, more data are needed to inform us about the long-term risks and benefits of using menopausal HT, particularly when initiated at menopause and to help address the timing of HT discontinuation. Furthermore, there are many unanswered questions. For instance:

• How much safer are lower dose and transdermal therapies?
• Do untreated hot flashes increase the risk of cardiovascular disease or dementia?
• Will newer non-HT options, such as the neurokinin receptor antagonists that are in testing but are not yet available, lower cardiovascular or dementia risks?
• What will be the risks and benefits for the newer estrogen in testing (estetrol, or E4), considered a natural estrogen and which appears to have lower thrombotic risks?
• What will be the role of intravaginal energy-based therapies, such as vaginal laser or radiofrequency devices?
• How do we address diverse populations and the effects of menopause on race, gender, culture, prior trauma, and socioeconomic status?

Lack of recognition of menopausal symptoms, particularly in the workplace

Clinicians need to understand the varied physical and emotional symptoms that may occur with hormonal changes as women traverse perimenopause and early menopause. We need to recognize that the lack of discussion about women’s health during this time may make women feel ashamed and fearful of bringing up their symptoms due to fear of being dismissed or stigmatized.²² Women may not seek help until a crisis at home or work occurs, as they may fear that admitting symptoms or a need for help or time away from work will threaten how they are viewed at work or affect their chances of promotion. Although there are economic costs around menopause for appointments, tests, therapies, and missed time at work, not addressing menopausal health leads to poorer performance, workplace absences, and additional medical costs.²²

Conclusion

Menopause occurs naturally as a part of a woman’s life cycle. However, women need assistance navigating perimenopausal hormonal fluctuations and decisions about HT once in menopause. Increased awareness and education about perimenopause and menopause will allow compassionate, individualized, informed care, including lifestyle changes, behavioral or complementary strategies, or medical therapies, hormonal or nonhormonal.²⁷ As a medical society, we need to challenge the stigma associated with aging and menopause and educate ourselves and our patients to help women navigate this challenging time. ●

The transition to menopause begins with ovarian fluctuation and hormonal changes, often beginning before significant changes in menstruation. Reproductive aging with loss of follicular activity progresses over a wide age range (42 to 58 years) with an average onset at approximately age 47, ranging from 4 to 8 years. Although most women have heard about menopause, defined as 12 months after the last period, they often lack understanding about perimenopause or that the menopausal transition usually begins 5 years before menopause.¹

Perimenopause, defined as early and late menopause transition stages, may be viewed as a window of potential vulnerability for women who develop or have worsening menstrual-related mood disorders. Over time, hormonal fluctuations often lead to menstrual cycle irregularity (either shorter or longer). Changes occurring during perimenopause may be confusing as it may not be clear whether symptoms are related to menopause, aging, or stress. Often not recognized or treated adequately, perimenopausal symptoms may be challenging to navigate for both women and clinicians.

The perimenopausal process is often even more confusing for women with early menopause—whether due to bilateral oophorectomy, chemotherapy or radiation therapy, genetics, or an autoimmune process—because of lack of recognition that an early menopausal transition is occurring or what solutions are available for symptoms. While there is support in the workplace for women during pregnancy and breastfeeding, there remains little support or recognition for the oft challenging perimenopausal transition leading to menopause.

Perimenopause: Common symptoms and treatments

Symptoms may be related to either estrogen level deficiency or excess during perimenopause, and these level changes may even occur within the same cycle.

Cyclic breast tenderness may develop, worsened by caffeine or high salt intake (which can be potentially improved, although without clinical trial evidence, with decreased caffeine or a trial of evening primrose oil or vitamin E).

Changes in menstrual flow and frequency of menses are typical. Flow may be lighter or heavier, longer or shorter, and there may be cycle variability, missed menses, or midcycle spotting.² Bleeding may be heavy, with or without cramping. In addition to imaging with vaginal ultrasonography or hysteroscopy to identify structural issues, symptoms may be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal therapy (HT) with short hormone-free interval contraceptives, oral progestogens, or progestin intrauterine systems. Newer medical treatments include antifibrinolytic drugs and selective progesterone-receptor modulators. Uterine ablation to decrease or stop bleeding is effective if there are no structural abnormalities, such as fibroids or polyps or the presence of adenomyosis, where glands will regrow into the endometrium after ablation. Endometrial biopsy is indicated for persistent abnormal uterine bleeding or those with risk factors such as chronic anovulation.

Worsening headaches or menstrual migraines may be triggered by hormonal changes, which may respond to NSAIDs; dihydroergotamine; triptans; the combination of aspirin, acetaminophen, and caffeine; or estrogen the week before menses. For women taking oral contraceptives (OCPs), adding estradiol the week before menses, or using the OCP continuously, may decrease headache frequency. These short-term prophylactic strategies during the perimenstrual time are often effective. If not, preventive therapy is available for women with frequent, severe headaches.

Mood complaints and poor sleep are independently associated with menstrual irregularity, and can lead to fatigue or anxiety, worsening premenstrual syndrome, or depressive moods. Sleep is disrupted premenstrually for up to one-third of women, and sleep disruption is particularly prevalent in those with premenstrual mood disorders and worsens during perimenopause.³

Reproductive hormones act on the neurotransmitter systems in the brain involved in mood regulation and emotion. The fluctuating hormones occurring during perimenopause may exacerbate pre-existing menstrual-related mood disorders. A subset of women experience depressive moods due to perimenopausal elevations in ovarian hormones.⁴ Others may exhibit increased mood sensitivity with the ovarian hormone withdrawal accompanying late menopause transition and early postmenopausal phase.⁵ There is significant comorbidity between premenstrual mood disorder (PMDD) and postpartum depression.⁶ During perimenopause and early menopause, clinicians should ask about prior hormonally-related depression (puberty, postpartum) and recognize that current or past premenstrual syndrome may worsen into a more severe premenstrual dysphoric disorder. Evidence-based treatments for PMDD include selective serotonin reuptake inhibitors (SSRIs); either taken continuously or only during the luteal phase; drospirenone-containing oral contraceptives, often with shorter pill-free intervals; GnRH analogues with or without hormone add-back; and cognitive behavioral therapy.⁷ For women whose perimenopausal moods improve with HT or develop worsened mood sensitivity with ovarian hormone withdrawal, clinicians should recognize that mood may worsen when treatment is ceased.⁵

Continue to: Menopausal symptoms...

Vasomotor symptoms (VMS), hot flashes, or night sweats occur in up to 75% of women as they develop more menstrual irregularity and move closer to their final period and menopause.

Hot flashes are transient episodes of flushing with the sensation of warmth (up to intense heat) on the upper body and face or head, often associated with sweating, chills or flushing, an increase in heart rate, and lowered blood pressure. Hot flashes can sometimes be preceded by an intense feeling of dread, followed by rapid heat dissipation. The etiology of hot flashes is still not clear, but the neurokinin receptors are involved. They are related to small fluctuations in core body temperature superimposed on a narrow thermoneutral zone in symptomatic women. Hot flashes are triggered when core body temperature rises above the upper (sweating) threshold. Shivering occurs if the core body temperature falls below the lower threshold. Sleep may be disrupted, with less rapid eye movement (REM) sleep, and associated with throwing covers on and off or changing sheets or nightclothes. On average, hot flashes last 7.2 years,⁸ and they are more bothersome if night sweats interfere with sleep or disrupt performance during the day.

In the Stages of Reproductive Aging Workshop (STRAW + 10), women reported VMS within 1-3 years after the menopausal transition.⁸ Four trajectories of hot flashes were identified in the Study of Women’s Health Across the Nation (SWAN) trial,⁹ including low levels throughout the menopause transition, early onset, late onset, and a group which had frequent hot flashes, starting early and lasting longer. Serum estrogen levels were not predictive of hot flash frequency or severity.

Hot flashes have been associated with low levels of exercise, cigarette smoking, high follicle-stimulating hormone levels and low estradiol levels, increasing body mass index, ethnicity (with hot flashes more common among Black and Hispanic women), low socioeconomic status, prior PMDD, anxiety, perceived stress, and depression.⁸ Women with a history of premenstrual syndrome, stress, sexual dysfunction, physical inactivity, or hot flashes are more vulnerable to depressive symptoms during perimenopause and early menopause.⁵

Depression may co-occur or overlap with menopause symptoms. Diagnosis involves menopausal stage, co-occurring psychiatric and menopause symptoms, psychosocial stressors, and a validated screening tool such as PQ9. Treatments for perimenopausal depression, such as antidepressants, psychotherapy, or cognitive behavioral therapy, are recommended first line for perimenopausal depression. Estrogen therapy has not been approved to treat perimenopausal depression but appears to have antidepressant effects in perimenopausal women, particularly those with bothersome vasomotor symptoms.⁵

Anxiety can worsen during menopause, and may respond to calming apps, meditation, cognitive behavioral therapy, hypnosis, yoga or tai chi, HT, or antianxiety medications.

Weight gain around the abdomen (ie, belly fat) is a common complaint during the menopausal transition, despite women reporting not changing their eating or exercise patterns. Increasing exercise or bursts of higher intensity, decreasing portion sizes or limiting carbohydrates and alcohol may help.

Memory and concentration problems, described as brain fog, tend to be more of an issue in perimenopause and level out after menopause. Counsel midlife women that these changes are not due to dementia but are related to normal aging, hormonal changes, mood, stress, or other life circumstances. Identifying and addressing sleep issues and mood disorders may help mitigate brain fog, as can advising women to avoid excess caffeine, alcohol, nicotine, and eating before bed. Improvements in memory, cognition, and health have been found with the Mediterranean diet, regular exercise, avoiding multitasking, and engaging in mentally stimulating activities.

Sleeping concerns in peri- and postmenopausal women include sleeping less and more frequent insomnia. Women are more likely to use prescription sleeping aids during these times of their lives. The data from SWAN⁸ show that the menopausal transition is related to self-reported difficulty sleeping, independent of age. Sleep latency interval is increased while REM sleep decreases. Night sweats can trigger awakenings in the first half of the night. The perceived decline in sleep quality also may be attributed to general aging effects, nocturnal urination, sleep-related disorders such as sleep apnea or restless legs, or chronic pain, stress, or depression.¹⁰ Suggestions for management include sleep apps, cognitive behavioral therapy, low-dose antidepressant therapy, addressing sleep routines, and HT. Hypnotics should be avoided.

Sexuality issues are common complaints during the menopausal transition. Cross-sectional data reported from a longitudinal, population-based Australian cohort of women aged 45 to 55 years, found a decrease in sexual responsivity, sexual frequency, libido, vaginal dyspareunia, and more partner problems.¹¹ Low libido may be related to relationship issues, dyspareunia with vaginal narrowing, loss of lubrication, levator spasm, stress, anxiety, exhaustion or mood disorder, lowered hormone levels, excess alcohol intake, underlying health concerns, or a side effect of medications for depression or pain. There is no direct correlation between testosterone levels and libido.

When HT at menopause may be helpful

For healthy symptomatic women without contraindications who are younger than age 60, or within 10 years of menopause onset, the benefits of initiating HT most likely outweigh the risks to relieve bothersome hot flashes and night sweats.^12-17 For older women, or for those further from menopause, the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia, in general, outweigh the potential benefits.^12-17 Extended durations of HT have less safety and efficacy data and should be considered primarily for those with persistent menopausal symptoms, with periodic re-evaluation.^13,14 For bothersome genitourinary syndrome of menopause symptoms that do not respond to vaginal moisturizers or lubricants, low-dose vaginal HTs are encouraged.^13-17

Continue to: Early-onset menopause...

Early-onset menopause

According to observational studies,¹⁸ early menopause is associated with a higher risk of osteoporosis, coronary heart disease, cognitive changes, vaginal dryness, loss of libido, and mood changes. Studies have shown that women with early menopause who take HT, without contraindications, to the average age of menopause (age 52) decrease the health risks of early menopause (bone loss, heart disease, mood, and cognition changes).^13,14,18

Women with early menopause, whether spontaneous or following bilateral oophorectomy or cancer treatment, should be counseled to get adequate calcium (dietary recommended over supplementation) and vitamin D intake, eat a healthy diet, and exercise regularly. Evaluation should include risk for bone loss, heart disease, mood changes, and vaginal changes.

Extended use of HT

Up to 8% of women have hot flashes for 20 years or more after menopause.¹⁹ The decision to continue or to stop HT is not always clear for women:

• with persistent hot flashes after a trial period of HT discontinuation
• with bone loss that cannot be treated with bone-specific medications
• who request continuation for quality of life.

Extended use of HT should include an ongoing assessment of its risks and benefits, periodic trials off of HT, and documentation of rationale and informed discussions about continuing. Lower doses and transdermal therapies appear safer, as does micronized progesterone instead of more potent synthetic progestins.^13-17

Genitourinary syndrome of menopause

Once women are further into menopause, they may notice vaginal dryness, vulvar itching or burning, bothersome vaginal discharge, or urinary urgency or frequency. The development of painful intercourse frequently occurs, a combination of the loss of estrogen with thinning of the vaginal mucosa, a loss of the acidic vaginal milieu with less elasticity, and spasm of the levator muscles. Some women develop urinary tract infections after intercourse or have more frequent reoccurrences. First-line therapy is often vaginal moisturizers and lubricants. Vaginal therapies (estradiol, conjugated estrogen, or dehydroepiandrosterone) or oral selective estrogen-receptor modulators (SERMs; ospemifene) improve vaginal dryness and dyspareunia.^13,14 Pelvic therapy has also proved valuable for incontinence, pelvic floor dysfunction, and levator spasms.²⁰

Where are there gaps in clinician knowledge?

Studies on emotional health, mood, and sleep need to incorporate measures of menstrual timing into data collection and analyses. Does the sleep disruption occurring premenstrually during perimenopause disproportionately contribute to a woman’s vulnerability to depressive disorders? The risk of clinically significant depressive symptoms increases 1.5- to 2.9-fold in the menopause transition.⁵ Research into premenstrual dysphoria during the menopause transition may identify different trajectories in the timing of symptoms related to either cycle itself or the ovarian hormone fluctuations or both.²¹ Gamma-aminobutyric acid (GABA)-modulating drugs, such as sepranolone, which blocks allopregnanolone’s actions at the GABAA receptor, may allow treatment of menstrual-related mood disorders without the need for hormonal interventions.²¹

Despite extended observational trial data, more data are needed to inform us about the long-term risks and benefits of using menopausal HT, particularly when initiated at menopause and to help address the timing of HT discontinuation. Furthermore, there are many unanswered questions. For instance:

• How much safer are lower dose and transdermal therapies?
• Do untreated hot flashes increase the risk of cardiovascular disease or dementia?
• Will newer non-HT options, such as the neurokinin receptor antagonists that are in testing but are not yet available, lower cardiovascular or dementia risks?
• What will be the risks and benefits for the newer estrogen in testing (estetrol, or E4), considered a natural estrogen and which appears to have lower thrombotic risks?
• What will be the role of intravaginal energy-based therapies, such as vaginal laser or radiofrequency devices?
• How do we address diverse populations and the effects of menopause on race, gender, culture, prior trauma, and socioeconomic status?

Lack of recognition of menopausal symptoms, particularly in the workplace

Clinicians need to understand the varied physical and emotional symptoms that may occur with hormonal changes as women traverse perimenopause and early menopause. We need to recognize that the lack of discussion about women’s health during this time may make women feel ashamed and fearful of bringing up their symptoms due to fear of being dismissed or stigmatized.²² Women may not seek help until a crisis at home or work occurs, as they may fear that admitting symptoms or a need for help or time away from work will threaten how they are viewed at work or affect their chances of promotion. Although there are economic costs around menopause for appointments, tests, therapies, and missed time at work, not addressing menopausal health leads to poorer performance, workplace absences, and additional medical costs.²²

Conclusion

Menopause occurs naturally as a part of a woman’s life cycle. However, women need assistance navigating perimenopausal hormonal fluctuations and decisions about HT once in menopause. Increased awareness and education about perimenopause and menopause will allow compassionate, individualized, informed care, including lifestyle changes, behavioral or complementary strategies, or medical therapies, hormonal or nonhormonal.²⁷ As a medical society, we need to challenge the stigma associated with aging and menopause and educate ourselves and our patients to help women navigate this challenging time. ●

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

A version of this article first appeared on Medscape.com.

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

A version of this article first appeared on Medscape.com.

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

A version of this article first appeared on Medscape.com.

Transvaginal mesh was found to be safe and effective for patients with pelvic organ prolapse (POP) when compared with native tissue repair (NTR) in a 3-year trial.

Researchers, led by Bruce S. Kahn, MD, with the department of obstetrics & gynecology at Scripps Clinic in San Diego evaluated the two surgical treatment methods and published their findings in Obstetrics & Gynecology.

At completion of the 3-year follow-up in 2016, there were 401 participants in the transvaginal mesh group and 171 in the NTR group.

The prospective, nonrandomized, parallel-cohort, 27-site trial used a primary composite endpoint of anatomical success; subjective success (vaginal bulging); retreatment measures; and serious device-related or serious procedure-related adverse events.

The secondary endpoint was a composite outcome similar to the primary composite outcome but with anatomical success more stringently defined as POP quantification (POP-Q) point Ba < 0 and/or C < 0.

The secondary outcome was added to this trial because investigators had criticized the primary endpoint, set by the Food and Drug Administration, because it included anatomic outcome measures that were the same for inclusion criteria (POP-Q point Ba < 0 and/or C < 0.)

The secondary-outcome composite also included quality-of-life measures, mesh exposure, and mesh- and procedure-related complications.
 

Outcomes similar for both groups

The primary outcome demonstrated transvaginal mesh was not superior to native tissue repair (P =.056).

In the secondary outcome, superiority of transvaginal mesh over native tissue repair was shown (P =.009), with a propensity score–adjusted difference of 10.6% (90% confidence interval, 3.3%-17.9%) in favor of transvaginal mesh.

The authors noted that subjective success regarding vaginal bulging, which is important in patient satisfaction, was high and not statistically different between the two groups.

Additionally, transvaginal mesh repair was as safe as NTR regarding serious device-related and/or serious procedure-related side effects.

For the primary safety endpoint, 3.1% in the mesh group and 2.7% in the native tissue repair group experienced serious adverse events, demonstrating that mesh was noninferior to NTR.
 

Research results have been mixed

Unanswered questions surround surgical options for POP, which, the authors wrote, “affects 3%-6% of women based on symptoms and up to 50% of women based on vaginal examination.”

The FDA in 2011 issued 522 postmarket surveillance study orders for companies that market transvaginal mesh for POP.

Research results have varied and contentious debate has continued in the field. Some studies have shown that mesh has better subjective and objective outcomes than NTR in the anterior compartment. Others have found more complications with transvaginal mesh, such as mesh exposure and painful intercourse.

Complicating comparisons, early versions of the mesh used were larger and denser than today’s versions.

In this postmarket study, patients received either the Uphold LITE brand of transvaginal mesh or native tissue repair for surgical treatment of POP.
 

Expert: This study unlikely to change minds

In an accompanying editorial, John O.L. DeLancey, MD, professor of gynecology at the University of Michigan, Ann Arbor, pointed out that so far there’s been a lack of randomized trials that could answer whether mesh surgeries result in fewer symptoms or result in sufficient improvements in anatomy to justify their additional risk.

This study may not help with the decision. Dr. DeLancey wrote: “Will this study change the minds of either side of this debate? Probably not. The two sides are deeply entrenched in their positions.”

Two considerations are important in thinking about the issue, he said. Surgical outcomes for POP are “not as good as we would hope.” Also, many women have had serious complications with mesh operations.

He wrote: “Mesh litigation has resulted in more $8 billion in settlements, which is many times the $1 billion annual national cost of providing care for prolapse. Those of us who practice in referral centers have seen women with devastating problems, even though they probably represent a small fraction of cases.”

Dr. DeLancey highlighted some limitations of the study by Dr. Kahn and colleagues, especially regarding differences in the groups studied and the design of the study.

“For example,” he explained, “65% of individuals in the mesh-repair group had a prior hysterectomy as opposed to 30% in the native tissue repair group. In addition, some of the operations in the native tissue group are not typical choices; for example, hysteropexy was used for some patients and had a 47% failure rate.”

He said the all-or-nothing approach to surgical solutions may be clouding the debate – in other words mesh or no mesh for women as a group.

“Rather than asking whether mesh is better than no mesh, knowing which women (if any) stand to benefit from mesh is the critical question. We need to understand, for each woman, what structural failures exist so that we can target our interventions to correct them,” he wrote.

This study was sponsored by Boston Scientific. Dr. Kahn disclosed research support from Solaire, payments from AbbVie and Douchenay as a speaker, payments from Caldera and Cytuity (Boston Scientific) as a medical consultant, and payment from Johnson & Johnson as an expert witness. One coauthor disclosed that money was paid to her institution from Medtronic and Boston Scientific (both unrestricted educational grants for cadaveric lab). Another is chief medical officer at Axonics. One study coauthor receives research funding from Axonics and is a consultant for Group Dynamics, Medpace, and FirstThought. One coauthor received research support, is a consultant for Boston Scientific, and is an expert witness for Johnson & Johnson. Dr. DeLancey declared no relevant financial relationships.

Transvaginal mesh was found to be safe and effective for patients with pelvic organ prolapse (POP) when compared with native tissue repair (NTR) in a 3-year trial.

Researchers, led by Bruce S. Kahn, MD, with the department of obstetrics & gynecology at Scripps Clinic in San Diego evaluated the two surgical treatment methods and published their findings in Obstetrics & Gynecology.

At completion of the 3-year follow-up in 2016, there were 401 participants in the transvaginal mesh group and 171 in the NTR group.

The prospective, nonrandomized, parallel-cohort, 27-site trial used a primary composite endpoint of anatomical success; subjective success (vaginal bulging); retreatment measures; and serious device-related or serious procedure-related adverse events.

The secondary endpoint was a composite outcome similar to the primary composite outcome but with anatomical success more stringently defined as POP quantification (POP-Q) point Ba < 0 and/or C < 0.

The secondary outcome was added to this trial because investigators had criticized the primary endpoint, set by the Food and Drug Administration, because it included anatomic outcome measures that were the same for inclusion criteria (POP-Q point Ba < 0 and/or C < 0.)

The secondary-outcome composite also included quality-of-life measures, mesh exposure, and mesh- and procedure-related complications.
 

Outcomes similar for both groups

The primary outcome demonstrated transvaginal mesh was not superior to native tissue repair (P =.056).

In the secondary outcome, superiority of transvaginal mesh over native tissue repair was shown (P =.009), with a propensity score–adjusted difference of 10.6% (90% confidence interval, 3.3%-17.9%) in favor of transvaginal mesh.

The authors noted that subjective success regarding vaginal bulging, which is important in patient satisfaction, was high and not statistically different between the two groups.

Additionally, transvaginal mesh repair was as safe as NTR regarding serious device-related and/or serious procedure-related side effects.

For the primary safety endpoint, 3.1% in the mesh group and 2.7% in the native tissue repair group experienced serious adverse events, demonstrating that mesh was noninferior to NTR.
 

Research results have been mixed

Unanswered questions surround surgical options for POP, which, the authors wrote, “affects 3%-6% of women based on symptoms and up to 50% of women based on vaginal examination.”

The FDA in 2011 issued 522 postmarket surveillance study orders for companies that market transvaginal mesh for POP.

Research results have varied and contentious debate has continued in the field. Some studies have shown that mesh has better subjective and objective outcomes than NTR in the anterior compartment. Others have found more complications with transvaginal mesh, such as mesh exposure and painful intercourse.

Complicating comparisons, early versions of the mesh used were larger and denser than today’s versions.

In this postmarket study, patients received either the Uphold LITE brand of transvaginal mesh or native tissue repair for surgical treatment of POP.
 

Expert: This study unlikely to change minds

In an accompanying editorial, John O.L. DeLancey, MD, professor of gynecology at the University of Michigan, Ann Arbor, pointed out that so far there’s been a lack of randomized trials that could answer whether mesh surgeries result in fewer symptoms or result in sufficient improvements in anatomy to justify their additional risk.

This study may not help with the decision. Dr. DeLancey wrote: “Will this study change the minds of either side of this debate? Probably not. The two sides are deeply entrenched in their positions.”

Two considerations are important in thinking about the issue, he said. Surgical outcomes for POP are “not as good as we would hope.” Also, many women have had serious complications with mesh operations.

He wrote: “Mesh litigation has resulted in more $8 billion in settlements, which is many times the $1 billion annual national cost of providing care for prolapse. Those of us who practice in referral centers have seen women with devastating problems, even though they probably represent a small fraction of cases.”

Dr. DeLancey highlighted some limitations of the study by Dr. Kahn and colleagues, especially regarding differences in the groups studied and the design of the study.

“For example,” he explained, “65% of individuals in the mesh-repair group had a prior hysterectomy as opposed to 30% in the native tissue repair group. In addition, some of the operations in the native tissue group are not typical choices; for example, hysteropexy was used for some patients and had a 47% failure rate.”

He said the all-or-nothing approach to surgical solutions may be clouding the debate – in other words mesh or no mesh for women as a group.

“Rather than asking whether mesh is better than no mesh, knowing which women (if any) stand to benefit from mesh is the critical question. We need to understand, for each woman, what structural failures exist so that we can target our interventions to correct them,” he wrote.

This study was sponsored by Boston Scientific. Dr. Kahn disclosed research support from Solaire, payments from AbbVie and Douchenay as a speaker, payments from Caldera and Cytuity (Boston Scientific) as a medical consultant, and payment from Johnson & Johnson as an expert witness. One coauthor disclosed that money was paid to her institution from Medtronic and Boston Scientific (both unrestricted educational grants for cadaveric lab). Another is chief medical officer at Axonics. One study coauthor receives research funding from Axonics and is a consultant for Group Dynamics, Medpace, and FirstThought. One coauthor received research support, is a consultant for Boston Scientific, and is an expert witness for Johnson & Johnson. Dr. DeLancey declared no relevant financial relationships.

Transvaginal mesh was found to be safe and effective for patients with pelvic organ prolapse (POP) when compared with native tissue repair (NTR) in a 3-year trial.

Researchers, led by Bruce S. Kahn, MD, with the department of obstetrics & gynecology at Scripps Clinic in San Diego evaluated the two surgical treatment methods and published their findings in Obstetrics & Gynecology.

At completion of the 3-year follow-up in 2016, there were 401 participants in the transvaginal mesh group and 171 in the NTR group.

The prospective, nonrandomized, parallel-cohort, 27-site trial used a primary composite endpoint of anatomical success; subjective success (vaginal bulging); retreatment measures; and serious device-related or serious procedure-related adverse events.

The secondary endpoint was a composite outcome similar to the primary composite outcome but with anatomical success more stringently defined as POP quantification (POP-Q) point Ba < 0 and/or C < 0.

The secondary outcome was added to this trial because investigators had criticized the primary endpoint, set by the Food and Drug Administration, because it included anatomic outcome measures that were the same for inclusion criteria (POP-Q point Ba < 0 and/or C < 0.)

The secondary-outcome composite also included quality-of-life measures, mesh exposure, and mesh- and procedure-related complications.
 

Outcomes similar for both groups

The primary outcome demonstrated transvaginal mesh was not superior to native tissue repair (P =.056).

In the secondary outcome, superiority of transvaginal mesh over native tissue repair was shown (P =.009), with a propensity score–adjusted difference of 10.6% (90% confidence interval, 3.3%-17.9%) in favor of transvaginal mesh.

The authors noted that subjective success regarding vaginal bulging, which is important in patient satisfaction, was high and not statistically different between the two groups.

Additionally, transvaginal mesh repair was as safe as NTR regarding serious device-related and/or serious procedure-related side effects.

For the primary safety endpoint, 3.1% in the mesh group and 2.7% in the native tissue repair group experienced serious adverse events, demonstrating that mesh was noninferior to NTR.
 

Research results have been mixed

Unanswered questions surround surgical options for POP, which, the authors wrote, “affects 3%-6% of women based on symptoms and up to 50% of women based on vaginal examination.”

The FDA in 2011 issued 522 postmarket surveillance study orders for companies that market transvaginal mesh for POP.

Research results have varied and contentious debate has continued in the field. Some studies have shown that mesh has better subjective and objective outcomes than NTR in the anterior compartment. Others have found more complications with transvaginal mesh, such as mesh exposure and painful intercourse.

Complicating comparisons, early versions of the mesh used were larger and denser than today’s versions.

In this postmarket study, patients received either the Uphold LITE brand of transvaginal mesh or native tissue repair for surgical treatment of POP.
 

Expert: This study unlikely to change minds

In an accompanying editorial, John O.L. DeLancey, MD, professor of gynecology at the University of Michigan, Ann Arbor, pointed out that so far there’s been a lack of randomized trials that could answer whether mesh surgeries result in fewer symptoms or result in sufficient improvements in anatomy to justify their additional risk.

This study may not help with the decision. Dr. DeLancey wrote: “Will this study change the minds of either side of this debate? Probably not. The two sides are deeply entrenched in their positions.”

Two considerations are important in thinking about the issue, he said. Surgical outcomes for POP are “not as good as we would hope.” Also, many women have had serious complications with mesh operations.

He wrote: “Mesh litigation has resulted in more $8 billion in settlements, which is many times the $1 billion annual national cost of providing care for prolapse. Those of us who practice in referral centers have seen women with devastating problems, even though they probably represent a small fraction of cases.”

Dr. DeLancey highlighted some limitations of the study by Dr. Kahn and colleagues, especially regarding differences in the groups studied and the design of the study.

“For example,” he explained, “65% of individuals in the mesh-repair group had a prior hysterectomy as opposed to 30% in the native tissue repair group. In addition, some of the operations in the native tissue group are not typical choices; for example, hysteropexy was used for some patients and had a 47% failure rate.”

He said the all-or-nothing approach to surgical solutions may be clouding the debate – in other words mesh or no mesh for women as a group.

“Rather than asking whether mesh is better than no mesh, knowing which women (if any) stand to benefit from mesh is the critical question. We need to understand, for each woman, what structural failures exist so that we can target our interventions to correct them,” he wrote.

This study was sponsored by Boston Scientific. Dr. Kahn disclosed research support from Solaire, payments from AbbVie and Douchenay as a speaker, payments from Caldera and Cytuity (Boston Scientific) as a medical consultant, and payment from Johnson & Johnson as an expert witness. One coauthor disclosed that money was paid to her institution from Medtronic and Boston Scientific (both unrestricted educational grants for cadaveric lab). Another is chief medical officer at Axonics. One study coauthor receives research funding from Axonics and is a consultant for Group Dynamics, Medpace, and FirstThought. One coauthor received research support, is a consultant for Boston Scientific, and is an expert witness for Johnson & Johnson. Dr. DeLancey declared no relevant financial relationships.

In the presentation of secondary amenorrhea, pregnancy is the No. 1 differential diagnosis. Once this has been excluded, an algorithm is initiated to determine the etiology, including an assessment of the hypothalamic-pituitary-ovarian axis. While the early onset of ovarian failure can be physically and psychologically disrupting, the effect on fertility is an especially devastating event. Previously identified by terms including premature ovarian failure and premature menopause, “primary ovarian insufficiency” (POI) is now the preferred designation. This month’s article will address the diagnosis, evaluation, and management of POI.

The definition of POI is the development of primary hypogonadism before the age of 40 years. Spontaneous POI occurs in approximately 1 in 250 women by age 35 years and 1 in 100 by age 40 years. After excluding pregnancy, the clinician should determine signs and symptoms that can lead to expedited and cost-efficient testing.

Consequences

POI is an important risk factor for bone loss and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass. At the time of diagnosis of POI, a bone density test (dual-energy x-ray absorptiometry) should be obtained. Women with POI may also develop depression and anxiety as well as experience an increased risk for cardiovascular morbidity and mortality, possibly related to endothelial dysfunction.

Young women with spontaneous POI are at increased risk of developing autoimmune adrenal insufficiency (AAI), a potentially fatal disorder. Consequently, to diagnose AAI, serum adrenal cortical and 21-hydroxylase antibodies should be measured in all women who have a karyotype of 46,XX and experience spontaneous POI. Women with AAI have a 50% risk of developing adrenal insufficiency. Despite initial normal adrenal function, women with positive adrenal cortical antibodies should be followed annually.
 

Causes (see table for a more complete list)

Iatrogenic

Known causes of POI include chemotherapy/radiation often in the setting of cancer treatment. The three most commonly used drugs, cyclophosphamide, cisplatin, and doxorubicin, cause POI by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. The most damaging agents are alkylating drugs. A cyclophosphamide equivalent dose calculator has been established for ovarian failure risk stratification from chemotherapy based on the cumulative dose of alkylating agents received.

One study estimated the radiosensitivity of the oocyte to be less than 2 Gy. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5% of patients as follows:

• 20.3 Gy at birth
• 18.4 Gy at age 10 years
• 16.5 Gy at age 20 years
• 14.3 Gy at age 30 years

Genetic

Approximately 10% of cases are familial. A family history of POI raises concern for a fragile X premutation. Fragile X syndrome is an X-linked form of intellectual disability that is one of the most common causes of mental retardation worldwide. There is a strong relationship between age at menopause, including POI, and premutations for fragile X syndrome. The American College of Obstetricians and Gynecologists recommends that women with POI or an elevated follicle-stimulating hormone (FSH) level before age 40 years without known cause be screened for FMR1 premutations. Approximately 6% of cases of POI are associated with premutations in the FMR1 gene.

Turner syndrome is one of the most common causes of POI and results from the lack of a second X chromosome. The most common chromosomal defect in humans, TS occurs in up to 1.5% of conceptions, 10% of spontaneous abortions, and 1 of 2,500 live births.

Serum antiadrenal and/or anti–21-hydroxylase antibodies and antithyroid antiperoxidase antibodies, can aid in the diagnosis of adrenal gland, ovary, and thyroid autoimmune causes, which is found in 4% of women with spontaneous POI. Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in women with proven spontaneous POI.

The etiology of POI remains unknown in approximately 75%-90% of cases. However, studies using whole exome or whole genome sequencing have identified genetic variants in approximately 30%-35% of these patients.
 

Risk factors

Factors that are thought to play a role in determining the age of menopause, include genetics (e.g., FMR1 premutation and mosaic Turner syndrome), ethnicity (earlier among Hispanic women and later in Japanese American women when compared with White women), and smoking (reduced by approximately 2 years ).

Regarding ovarian aging, the holy grail of the reproductive life span is to predict menopause. While the definitive age eludes us, anti-Müllerian hormone levels appear to show promise. An ultrasensitive anti-Müllerian hormone assay (< 0.01 ng/mL) predicted a 79% probability of menopause within 12 months for women aged 51 and above; the probability was 51% for women below age 48.
 

Diagnosis

The three P’s of secondary amenorrhea are physiological, pharmacological, or pathological and can guide the clinician to a targeted evaluation. Physiological causes are pregnancy, the first 6 months of continuous breastfeeding (from elevated prolactin), and natural menopause. Pharmacological etiologies, excluding hormonal treatment that suppresses ovulation (combined oral contraceptives, gonadotropin-releasing hormone agonist/antagonist, or danazol), include agents that inhibit dopamine thereby increasing serum prolactin, such as metoclopramide; phenothiazine antipsychotics, such as haloperidol; and tardive dystonia dopamine-depleting medications, such as reserpine. Pathological causes include pituitary adenomas, thyroid disease, functional hypothalamic amenorrhea from changes in weight, exercise regimen, and stress.

Management

About 50%-75% of women with 46,XX spontaneous POI experience intermittent ovarian function and 5%-10% of women remain able to conceive. Anecdotally, a 32-year-old woman presented to me with primary infertility, secondary amenorrhea, and suspected POI based on vasomotor symptoms and elevated FSH levels. Pelvic ultrasound showed a hemorrhagic cyst, suspicious for a corpus luteum. Two weeks thereafter she reported a positive home urine human chorionic gonadotropin test and ultimately delivered twins. Her diagnosis of POI with amenorrhea remained postpartum.

Unless there is an absolute contraindication, estrogen therapy should be prescribed to women with POI to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy as well as to maintain sexual health and quality of life. For those with an intact uterus, women should receive progesterone because of the risk of endometrial hyperplasia from unopposed estrogen. Rather than oral estrogen, the use of transdermal or vaginal delivery of estrogen is a more physiological approach and provides lower risks of venous thromboembolism and gallbladder disease. Of note, standard postmenopausal hormone therapy, which has a much lower dose of estrogen than combined estrogen-progestin contraceptives, does not provide effective contraception. Per ACOG, systemic hormone treatment should be prescribed until age 50-51 years to all women with POI.

For fertility, women with spontaneous POI can be offered oocyte or embryo donation. The uterus does not age reproductively, unlike oocytes, therefore women can achieve reasonable pregnancy success rates through egg donation despite experiencing menopause.
 

Future potential options

Female germline stem cells have been isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes. Further experiments are needed before the implications for humans can be determined.

Emotionally traumatic for most women, POI disrupts life plans, hopes, and dreams of raising a family. The approach to the patient with POI involves the above evidence-based testing along with empathy from the health care provider.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

In the presentation of secondary amenorrhea, pregnancy is the No. 1 differential diagnosis. Once this has been excluded, an algorithm is initiated to determine the etiology, including an assessment of the hypothalamic-pituitary-ovarian axis. While the early onset of ovarian failure can be physically and psychologically disrupting, the effect on fertility is an especially devastating event. Previously identified by terms including premature ovarian failure and premature menopause, “primary ovarian insufficiency” (POI) is now the preferred designation. This month’s article will address the diagnosis, evaluation, and management of POI.

The definition of POI is the development of primary hypogonadism before the age of 40 years. Spontaneous POI occurs in approximately 1 in 250 women by age 35 years and 1 in 100 by age 40 years. After excluding pregnancy, the clinician should determine signs and symptoms that can lead to expedited and cost-efficient testing.

Consequences

POI is an important risk factor for bone loss and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass. At the time of diagnosis of POI, a bone density test (dual-energy x-ray absorptiometry) should be obtained. Women with POI may also develop depression and anxiety as well as experience an increased risk for cardiovascular morbidity and mortality, possibly related to endothelial dysfunction.

Young women with spontaneous POI are at increased risk of developing autoimmune adrenal insufficiency (AAI), a potentially fatal disorder. Consequently, to diagnose AAI, serum adrenal cortical and 21-hydroxylase antibodies should be measured in all women who have a karyotype of 46,XX and experience spontaneous POI. Women with AAI have a 50% risk of developing adrenal insufficiency. Despite initial normal adrenal function, women with positive adrenal cortical antibodies should be followed annually.
 

Causes (see table for a more complete list)

Iatrogenic

Known causes of POI include chemotherapy/radiation often in the setting of cancer treatment. The three most commonly used drugs, cyclophosphamide, cisplatin, and doxorubicin, cause POI by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. The most damaging agents are alkylating drugs. A cyclophosphamide equivalent dose calculator has been established for ovarian failure risk stratification from chemotherapy based on the cumulative dose of alkylating agents received.

One study estimated the radiosensitivity of the oocyte to be less than 2 Gy. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5% of patients as follows:

• 20.3 Gy at birth
• 18.4 Gy at age 10 years
• 16.5 Gy at age 20 years
• 14.3 Gy at age 30 years

Genetic

Approximately 10% of cases are familial. A family history of POI raises concern for a fragile X premutation. Fragile X syndrome is an X-linked form of intellectual disability that is one of the most common causes of mental retardation worldwide. There is a strong relationship between age at menopause, including POI, and premutations for fragile X syndrome. The American College of Obstetricians and Gynecologists recommends that women with POI or an elevated follicle-stimulating hormone (FSH) level before age 40 years without known cause be screened for FMR1 premutations. Approximately 6% of cases of POI are associated with premutations in the FMR1 gene.

Turner syndrome is one of the most common causes of POI and results from the lack of a second X chromosome. The most common chromosomal defect in humans, TS occurs in up to 1.5% of conceptions, 10% of spontaneous abortions, and 1 of 2,500 live births.

Serum antiadrenal and/or anti–21-hydroxylase antibodies and antithyroid antiperoxidase antibodies, can aid in the diagnosis of adrenal gland, ovary, and thyroid autoimmune causes, which is found in 4% of women with spontaneous POI. Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in women with proven spontaneous POI.

The etiology of POI remains unknown in approximately 75%-90% of cases. However, studies using whole exome or whole genome sequencing have identified genetic variants in approximately 30%-35% of these patients.
 

Risk factors

Factors that are thought to play a role in determining the age of menopause, include genetics (e.g., FMR1 premutation and mosaic Turner syndrome), ethnicity (earlier among Hispanic women and later in Japanese American women when compared with White women), and smoking (reduced by approximately 2 years ).

Regarding ovarian aging, the holy grail of the reproductive life span is to predict menopause. While the definitive age eludes us, anti-Müllerian hormone levels appear to show promise. An ultrasensitive anti-Müllerian hormone assay (< 0.01 ng/mL) predicted a 79% probability of menopause within 12 months for women aged 51 and above; the probability was 51% for women below age 48.
 

Diagnosis

The three P’s of secondary amenorrhea are physiological, pharmacological, or pathological and can guide the clinician to a targeted evaluation. Physiological causes are pregnancy, the first 6 months of continuous breastfeeding (from elevated prolactin), and natural menopause. Pharmacological etiologies, excluding hormonal treatment that suppresses ovulation (combined oral contraceptives, gonadotropin-releasing hormone agonist/antagonist, or danazol), include agents that inhibit dopamine thereby increasing serum prolactin, such as metoclopramide; phenothiazine antipsychotics, such as haloperidol; and tardive dystonia dopamine-depleting medications, such as reserpine. Pathological causes include pituitary adenomas, thyroid disease, functional hypothalamic amenorrhea from changes in weight, exercise regimen, and stress.

Management

About 50%-75% of women with 46,XX spontaneous POI experience intermittent ovarian function and 5%-10% of women remain able to conceive. Anecdotally, a 32-year-old woman presented to me with primary infertility, secondary amenorrhea, and suspected POI based on vasomotor symptoms and elevated FSH levels. Pelvic ultrasound showed a hemorrhagic cyst, suspicious for a corpus luteum. Two weeks thereafter she reported a positive home urine human chorionic gonadotropin test and ultimately delivered twins. Her diagnosis of POI with amenorrhea remained postpartum.

Unless there is an absolute contraindication, estrogen therapy should be prescribed to women with POI to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy as well as to maintain sexual health and quality of life. For those with an intact uterus, women should receive progesterone because of the risk of endometrial hyperplasia from unopposed estrogen. Rather than oral estrogen, the use of transdermal or vaginal delivery of estrogen is a more physiological approach and provides lower risks of venous thromboembolism and gallbladder disease. Of note, standard postmenopausal hormone therapy, which has a much lower dose of estrogen than combined estrogen-progestin contraceptives, does not provide effective contraception. Per ACOG, systemic hormone treatment should be prescribed until age 50-51 years to all women with POI.

For fertility, women with spontaneous POI can be offered oocyte or embryo donation. The uterus does not age reproductively, unlike oocytes, therefore women can achieve reasonable pregnancy success rates through egg donation despite experiencing menopause.
 

Future potential options

Female germline stem cells have been isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes. Further experiments are needed before the implications for humans can be determined.

Emotionally traumatic for most women, POI disrupts life plans, hopes, and dreams of raising a family. The approach to the patient with POI involves the above evidence-based testing along with empathy from the health care provider.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

In the presentation of secondary amenorrhea, pregnancy is the No. 1 differential diagnosis. Once this has been excluded, an algorithm is initiated to determine the etiology, including an assessment of the hypothalamic-pituitary-ovarian axis. While the early onset of ovarian failure can be physically and psychologically disrupting, the effect on fertility is an especially devastating event. Previously identified by terms including premature ovarian failure and premature menopause, “primary ovarian insufficiency” (POI) is now the preferred designation. This month’s article will address the diagnosis, evaluation, and management of POI.

The definition of POI is the development of primary hypogonadism before the age of 40 years. Spontaneous POI occurs in approximately 1 in 250 women by age 35 years and 1 in 100 by age 40 years. After excluding pregnancy, the clinician should determine signs and symptoms that can lead to expedited and cost-efficient testing.

Consequences

POI is an important risk factor for bone loss and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass. At the time of diagnosis of POI, a bone density test (dual-energy x-ray absorptiometry) should be obtained. Women with POI may also develop depression and anxiety as well as experience an increased risk for cardiovascular morbidity and mortality, possibly related to endothelial dysfunction.

Young women with spontaneous POI are at increased risk of developing autoimmune adrenal insufficiency (AAI), a potentially fatal disorder. Consequently, to diagnose AAI, serum adrenal cortical and 21-hydroxylase antibodies should be measured in all women who have a karyotype of 46,XX and experience spontaneous POI. Women with AAI have a 50% risk of developing adrenal insufficiency. Despite initial normal adrenal function, women with positive adrenal cortical antibodies should be followed annually.
 

Causes (see table for a more complete list)

Iatrogenic

Known causes of POI include chemotherapy/radiation often in the setting of cancer treatment. The three most commonly used drugs, cyclophosphamide, cisplatin, and doxorubicin, cause POI by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. The most damaging agents are alkylating drugs. A cyclophosphamide equivalent dose calculator has been established for ovarian failure risk stratification from chemotherapy based on the cumulative dose of alkylating agents received.

One study estimated the radiosensitivity of the oocyte to be less than 2 Gy. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5% of patients as follows:

• 20.3 Gy at birth
• 18.4 Gy at age 10 years
• 16.5 Gy at age 20 years
• 14.3 Gy at age 30 years

Genetic

Approximately 10% of cases are familial. A family history of POI raises concern for a fragile X premutation. Fragile X syndrome is an X-linked form of intellectual disability that is one of the most common causes of mental retardation worldwide. There is a strong relationship between age at menopause, including POI, and premutations for fragile X syndrome. The American College of Obstetricians and Gynecologists recommends that women with POI or an elevated follicle-stimulating hormone (FSH) level before age 40 years without known cause be screened for FMR1 premutations. Approximately 6% of cases of POI are associated with premutations in the FMR1 gene.

Turner syndrome is one of the most common causes of POI and results from the lack of a second X chromosome. The most common chromosomal defect in humans, TS occurs in up to 1.5% of conceptions, 10% of spontaneous abortions, and 1 of 2,500 live births.

Serum antiadrenal and/or anti–21-hydroxylase antibodies and antithyroid antiperoxidase antibodies, can aid in the diagnosis of adrenal gland, ovary, and thyroid autoimmune causes, which is found in 4% of women with spontaneous POI. Testing for the presence of 21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in women with proven spontaneous POI.

The etiology of POI remains unknown in approximately 75%-90% of cases. However, studies using whole exome or whole genome sequencing have identified genetic variants in approximately 30%-35% of these patients.
 

Risk factors

Factors that are thought to play a role in determining the age of menopause, include genetics (e.g., FMR1 premutation and mosaic Turner syndrome), ethnicity (earlier among Hispanic women and later in Japanese American women when compared with White women), and smoking (reduced by approximately 2 years ).

Regarding ovarian aging, the holy grail of the reproductive life span is to predict menopause. While the definitive age eludes us, anti-Müllerian hormone levels appear to show promise. An ultrasensitive anti-Müllerian hormone assay (< 0.01 ng/mL) predicted a 79% probability of menopause within 12 months for women aged 51 and above; the probability was 51% for women below age 48.
 

Diagnosis

The three P’s of secondary amenorrhea are physiological, pharmacological, or pathological and can guide the clinician to a targeted evaluation. Physiological causes are pregnancy, the first 6 months of continuous breastfeeding (from elevated prolactin), and natural menopause. Pharmacological etiologies, excluding hormonal treatment that suppresses ovulation (combined oral contraceptives, gonadotropin-releasing hormone agonist/antagonist, or danazol), include agents that inhibit dopamine thereby increasing serum prolactin, such as metoclopramide; phenothiazine antipsychotics, such as haloperidol; and tardive dystonia dopamine-depleting medications, such as reserpine. Pathological causes include pituitary adenomas, thyroid disease, functional hypothalamic amenorrhea from changes in weight, exercise regimen, and stress.

Management

About 50%-75% of women with 46,XX spontaneous POI experience intermittent ovarian function and 5%-10% of women remain able to conceive. Anecdotally, a 32-year-old woman presented to me with primary infertility, secondary amenorrhea, and suspected POI based on vasomotor symptoms and elevated FSH levels. Pelvic ultrasound showed a hemorrhagic cyst, suspicious for a corpus luteum. Two weeks thereafter she reported a positive home urine human chorionic gonadotropin test and ultimately delivered twins. Her diagnosis of POI with amenorrhea remained postpartum.

Unless there is an absolute contraindication, estrogen therapy should be prescribed to women with POI to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy as well as to maintain sexual health and quality of life. For those with an intact uterus, women should receive progesterone because of the risk of endometrial hyperplasia from unopposed estrogen. Rather than oral estrogen, the use of transdermal or vaginal delivery of estrogen is a more physiological approach and provides lower risks of venous thromboembolism and gallbladder disease. Of note, standard postmenopausal hormone therapy, which has a much lower dose of estrogen than combined estrogen-progestin contraceptives, does not provide effective contraception. Per ACOG, systemic hormone treatment should be prescribed until age 50-51 years to all women with POI.

For fertility, women with spontaneous POI can be offered oocyte or embryo donation. The uterus does not age reproductively, unlike oocytes, therefore women can achieve reasonable pregnancy success rates through egg donation despite experiencing menopause.
 

Future potential options

Female germline stem cells have been isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes. Further experiments are needed before the implications for humans can be determined.

Emotionally traumatic for most women, POI disrupts life plans, hopes, and dreams of raising a family. The approach to the patient with POI involves the above evidence-based testing along with empathy from the health care provider.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Women in midlife exposed to combinations of perfluoroalkyl and polyfluoroalkyl substances (PFASs), dubbed “forever and everywhere chemicals”, are at increased risk of developing diabetes, similar to the magnitude of risk associated with overweight and even greater than the risk associated with smoking, new research shows.

“This is the first study to examine the joint effect of PFAS on incident diabetes,” first author Sung Kyun Park, ScD, MPH, told this news organization.

“We showed that multiple PFAS as mixtures have larger effects than individual PFAS,” said Dr. Park, of the department of epidemiology, School of Public Health, University of Michigan, Ann Arbor.

The results suggest that, “given that 1.5 million Americans are newly diagnosed with diabetes each year in the USA, approximately 370,000 new cases of diabetes annually in the U.S. are attributable to PFAS exposure,” Dr. Park and authors note in the study, published in Diabetologia.

However, Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., told the UK Science Media Centre: “[Some] doubt about cause still remains. Yes, this study does show that PFAS may increase diabetes risk in middle-aged women, but it certainly can’t rule out other explanations for its findings.”
 

Is there any way to reduce exposure?

PFASs, known to be ubiquitous in the environment and also often dubbed “endocrine-disrupting” chemicals, have structures similar to fatty acids. They have been detected in the blood of most people and linked to health concerns including pre-eclampsia, altered levels of liver enzymes, inflammation, and altered lipid and glucose metabolism.

Sources of PFAS exposure can run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

The authors note a recent Consumer Reports investigation of 118 food packaging products, for instance, which reported finding PFAS chemicals in the packaging of every fast-food chain and retailer examined, including Burger King, McDonald’s, and even more health-focused chains, such as Trader Joe’s.

While efforts to pressure industry to limit PFAS in products are ongoing, Dr. Park asserted that “PFAS exposure reduction at the individual-level is very limited, so a more important way is to change policies and to limit PFAS in the air, drinking water, and foods, etc.”

“It is impossible to completely avoid exposure to PFAS, but I think it is important to acknowledge such sources and change our mindset,” he said.

In terms of clinical practice, the authors add that “it is also important for clinicians to be aware of PFAS as unrecognized risk factors for diabetes and to be prepared to counsel patients in terms of sources of exposure and potential health effects.”
 

Prospective findings from the SWAN-MPS study

The findings come from a prospective study of 1,237 women, with a median age of 49.4 years, who were diabetes-free upon entering the Study of Women’s Health Across the Nation – Multi-Pollutant Study (SWAN-MPS) between 1999 and 2000 and followed until 2017.

Blood samples taken throughout the study were analyzed for serum concentrations of seven PFASs.

Over the study period, there were 102 cases of incident diabetes, representing a rate of 6 cases per 1,000 person-years. Type of diabetes was not determined, but given the age of study participants, most were assumed to have type 2 diabetes, Dr. Park and colleagues note.

namiroz/iStock/Getty Images

A version of this article first appeared on Medscape.com.

Women in midlife exposed to combinations of perfluoroalkyl and polyfluoroalkyl substances (PFASs), dubbed “forever and everywhere chemicals”, are at increased risk of developing diabetes, similar to the magnitude of risk associated with overweight and even greater than the risk associated with smoking, new research shows.

“This is the first study to examine the joint effect of PFAS on incident diabetes,” first author Sung Kyun Park, ScD, MPH, told this news organization.

“We showed that multiple PFAS as mixtures have larger effects than individual PFAS,” said Dr. Park, of the department of epidemiology, School of Public Health, University of Michigan, Ann Arbor.

The results suggest that, “given that 1.5 million Americans are newly diagnosed with diabetes each year in the USA, approximately 370,000 new cases of diabetes annually in the U.S. are attributable to PFAS exposure,” Dr. Park and authors note in the study, published in Diabetologia.

However, Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., told the UK Science Media Centre: “[Some] doubt about cause still remains. Yes, this study does show that PFAS may increase diabetes risk in middle-aged women, but it certainly can’t rule out other explanations for its findings.”
 

Is there any way to reduce exposure?

PFASs, known to be ubiquitous in the environment and also often dubbed “endocrine-disrupting” chemicals, have structures similar to fatty acids. They have been detected in the blood of most people and linked to health concerns including pre-eclampsia, altered levels of liver enzymes, inflammation, and altered lipid and glucose metabolism.

Sources of PFAS exposure can run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

The authors note a recent Consumer Reports investigation of 118 food packaging products, for instance, which reported finding PFAS chemicals in the packaging of every fast-food chain and retailer examined, including Burger King, McDonald’s, and even more health-focused chains, such as Trader Joe’s.

While efforts to pressure industry to limit PFAS in products are ongoing, Dr. Park asserted that “PFAS exposure reduction at the individual-level is very limited, so a more important way is to change policies and to limit PFAS in the air, drinking water, and foods, etc.”

“It is impossible to completely avoid exposure to PFAS, but I think it is important to acknowledge such sources and change our mindset,” he said.

In terms of clinical practice, the authors add that “it is also important for clinicians to be aware of PFAS as unrecognized risk factors for diabetes and to be prepared to counsel patients in terms of sources of exposure and potential health effects.”
 

Prospective findings from the SWAN-MPS study

The findings come from a prospective study of 1,237 women, with a median age of 49.4 years, who were diabetes-free upon entering the Study of Women’s Health Across the Nation – Multi-Pollutant Study (SWAN-MPS) between 1999 and 2000 and followed until 2017.

Blood samples taken throughout the study were analyzed for serum concentrations of seven PFASs.

Over the study period, there were 102 cases of incident diabetes, representing a rate of 6 cases per 1,000 person-years. Type of diabetes was not determined, but given the age of study participants, most were assumed to have type 2 diabetes, Dr. Park and colleagues note.

namiroz/iStock/Getty Images

A version of this article first appeared on Medscape.com.

Women in midlife exposed to combinations of perfluoroalkyl and polyfluoroalkyl substances (PFASs), dubbed “forever and everywhere chemicals”, are at increased risk of developing diabetes, similar to the magnitude of risk associated with overweight and even greater than the risk associated with smoking, new research shows.

“This is the first study to examine the joint effect of PFAS on incident diabetes,” first author Sung Kyun Park, ScD, MPH, told this news organization.

“We showed that multiple PFAS as mixtures have larger effects than individual PFAS,” said Dr. Park, of the department of epidemiology, School of Public Health, University of Michigan, Ann Arbor.

The results suggest that, “given that 1.5 million Americans are newly diagnosed with diabetes each year in the USA, approximately 370,000 new cases of diabetes annually in the U.S. are attributable to PFAS exposure,” Dr. Park and authors note in the study, published in Diabetologia.

However, Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., told the UK Science Media Centre: “[Some] doubt about cause still remains. Yes, this study does show that PFAS may increase diabetes risk in middle-aged women, but it certainly can’t rule out other explanations for its findings.”
 

Is there any way to reduce exposure?

PFASs, known to be ubiquitous in the environment and also often dubbed “endocrine-disrupting” chemicals, have structures similar to fatty acids. They have been detected in the blood of most people and linked to health concerns including pre-eclampsia, altered levels of liver enzymes, inflammation, and altered lipid and glucose metabolism.

Sources of PFAS exposure can run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

The authors note a recent Consumer Reports investigation of 118 food packaging products, for instance, which reported finding PFAS chemicals in the packaging of every fast-food chain and retailer examined, including Burger King, McDonald’s, and even more health-focused chains, such as Trader Joe’s.

While efforts to pressure industry to limit PFAS in products are ongoing, Dr. Park asserted that “PFAS exposure reduction at the individual-level is very limited, so a more important way is to change policies and to limit PFAS in the air, drinking water, and foods, etc.”

“It is impossible to completely avoid exposure to PFAS, but I think it is important to acknowledge such sources and change our mindset,” he said.

In terms of clinical practice, the authors add that “it is also important for clinicians to be aware of PFAS as unrecognized risk factors for diabetes and to be prepared to counsel patients in terms of sources of exposure and potential health effects.”
 

Prospective findings from the SWAN-MPS study

The findings come from a prospective study of 1,237 women, with a median age of 49.4 years, who were diabetes-free upon entering the Study of Women’s Health Across the Nation – Multi-Pollutant Study (SWAN-MPS) between 1999 and 2000 and followed until 2017.

Blood samples taken throughout the study were analyzed for serum concentrations of seven PFASs.

Over the study period, there were 102 cases of incident diabetes, representing a rate of 6 cases per 1,000 person-years. Type of diabetes was not determined, but given the age of study participants, most were assumed to have type 2 diabetes, Dr. Park and colleagues note.

namiroz/iStock/Getty Images

A version of this article first appeared on Medscape.com.