Menopause

The U.S. Preventive Services Task Force moved forward their recommendations for using hormone therapy to prevent chronic conditions in postmenopausal women by keeping them the same.

The central message of the new recommendations, released on Nov. 1 as a statement published in JAMA, remains unchanged from the last update in 2017.

The message also remains simple: Don’t use hormone therapy for preventing chronic conditions, such as cardiovascular disease, cancer, and osteoporosis, or bone fracture.

The USPSTF summarized its recommendations in two brief statements: the group “recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons” and “recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.”

This wording is identical to that used in the 2017 guidance (except it now refers to postmenopausal persons instead of specifically women). The recommendation against use of estrogen and progestin for prevention of chronic conditions in postmenopausal women was first made by the USPSTF in 2002.

An editorial accompanying the 2022 revision notes that the evidence cited by the USPSTF includes “only two additional, modest-sized trials” (that focused on the effects of hormone therapy on cognition and brain structure) compared with 2017, “as well as ancillary analyses of previous trials.”
 

A standard 5-year update

The 2022 revision and revisiting of the evidence base by the Task Force regarding the benefits and risks of postmenopausal hormone therapy occurred “as part of the Task Force’s standard approach, which includes updating each recommendation approximately every 5 years,” explained Carol M. Mangione, MD, who is USPSTF chair and chief of the division of general internal medicine and health services research at the University of California, Los Angeles.

“In our review we again found that while hormone therapy may reduce the risk of some conditions, it can also lead to serious harms such as an increase in the risk of blood clots and stroke,” Dr. Mangione said in an interview. “The harms cancel out any potential benefits overall.”

This new statement only applies to using menopausal hormone treatment for preventing chronic conditions in asymptomatic people but does not speak to using this treatment in managing people with perimenopausal symptoms such as hot flashes or vaginal dryness or treating people with premature or surgical menopause, Dr. Mangione highlighted.
 

No review for treating menopausal symptoms

“The Task Force encourages people who are experiencing symptoms of menopause to talk with their health care professional about the best treatment for them,” explained Dr. Mangione. “The Task Force did not review the evidence on the use of hormone therapy to treat symptoms of menopause.”

Osteoporosis and increased risk for bone fracture were among the conditions that accompany menopause reviewed by the USPSTF. The Task Force concluded that while “hormone therapy was associated with decreased risk of fractures,” after weighing the benefits and harms for preventing this condition, “there is no net benefit at the population level.”

This conclusion seems to contrast with the 2022 hormone therapy position statement of the North American Menopause Society (NAMS), released in July, which states: “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome vasomotor symptoms and prevention of bone loss.”
 

USPSTF, NAMS are ‘completely consistent’

However, Stephanie S. Faubion, MD, medical director of NAMS and director of the women’s health clinic at Mayo Clinic, Rochester, Minn., said the new USPSTF recommendations “are completely consistent” with the recent NAMS statement.

“We are entirely aligned with the recommendation to use hormone therapy for management of menopausal symptoms and not for chronic disease prevention or as an anti-aging strategy,” Dr. Faubion commented in an interview.

Dr. Faubion also stressed that “menopausal hormone therapy remains the most effective treatment for menopausal symptoms,” and that “women should not be reflexively directed to other pharmacologic therapies for management of menopausal symptoms.”

The distinction the USPSTF makes between its recommendations against using hormone therapy to prevent chronic conditions and its deferral of comment on use of the same treatment to manage perimenopausal symptoms is often forgotten, note Alison J. Huang, MD, and Deborah Grady, MD, in their editorial.
 

A problem of conflation

“Many patients and clinicians conflate these two different indications,” they write.

The notion that the net harms of menopausal hormone therapy outweigh the benefits “is now widely adopted as a rationale for foregoing menopausal hormone therapy for symptomatic treatment,” even though “nonhormonal treatments that are as effective as menopausal hormone therapy have not yet been identified,” say Dr. Huang and Dr. Grady, both physicians at the University of California, San Francisco.

In addition, alternative, nonhormonal options for treating perimenopausal symptoms have not received the same level of scrutiny as hormonal treatment, they say.

“It is arguably problematic to avoid menopausal hormone therapy and favor potentially less effective treatments, when the longer-term implications of those treatments for health have not been evaluated,” Dr. Huang and Dr. Grady write in their editorial.

In short, during menopause, people are at risk of being “frightened away from considering using menopausal hormone therapy for distressing symptoms,” they say.

“We can’t speak to whether or how often clinicians might be conflating the role of hormone therapy in treating symptoms and preventing chronic conditions,” answered Dr. Mangione.

“We hope to ensure that health professionals know that hormone therapy is not a beneficial way to reduce the risk of chronic conditions such as heart disease, cancer, and strokes,” she added. The new recommendations are an effort to “raise awareness about the value of considering other safe and effective ways for people to reduce their risk of chronic health problems as they age.”
 

The issue of timing

Another critique offered by Dr. Huang and Dr. Grady in their editorial is that “the scientific and medical community should let go of the past,” and should no longer invest additional resources in “trying to parse out subsets of menopausal patients who may derive some preventive benefit from menopausal hormone therapy for a limited amount of time.”

But Dr. Mangione disagreed.

The USPSTF “calls for more research that can help us understand whether health outcomes – both benefits and harms – differ depending on a person’s age or when they started hormone therapy related to when they went through menopause,” she said.

Dr. Mangione also highlighted the need for additional research on whether the benefits and risks of menopausal hormone therapy vary across racial and ethnic groups.

USPSTF receives no commercial funding. Dr. Mangione, Dr. Huang, and Dr. Grady have reported no relevant financial relationships.

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

The U.S. Preventive Services Task Force moved forward their recommendations for using hormone therapy to prevent chronic conditions in postmenopausal women by keeping them the same.

The central message of the new recommendations, released on Nov. 1 as a statement published in JAMA, remains unchanged from the last update in 2017.

The message also remains simple: Don’t use hormone therapy for preventing chronic conditions, such as cardiovascular disease, cancer, and osteoporosis, or bone fracture.

The USPSTF summarized its recommendations in two brief statements: the group “recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons” and “recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.”

This wording is identical to that used in the 2017 guidance (except it now refers to postmenopausal persons instead of specifically women). The recommendation against use of estrogen and progestin for prevention of chronic conditions in postmenopausal women was first made by the USPSTF in 2002.

An editorial accompanying the 2022 revision notes that the evidence cited by the USPSTF includes “only two additional, modest-sized trials” (that focused on the effects of hormone therapy on cognition and brain structure) compared with 2017, “as well as ancillary analyses of previous trials.”
 

A standard 5-year update

The 2022 revision and revisiting of the evidence base by the Task Force regarding the benefits and risks of postmenopausal hormone therapy occurred “as part of the Task Force’s standard approach, which includes updating each recommendation approximately every 5 years,” explained Carol M. Mangione, MD, who is USPSTF chair and chief of the division of general internal medicine and health services research at the University of California, Los Angeles.

“In our review we again found that while hormone therapy may reduce the risk of some conditions, it can also lead to serious harms such as an increase in the risk of blood clots and stroke,” Dr. Mangione said in an interview. “The harms cancel out any potential benefits overall.”

This new statement only applies to using menopausal hormone treatment for preventing chronic conditions in asymptomatic people but does not speak to using this treatment in managing people with perimenopausal symptoms such as hot flashes or vaginal dryness or treating people with premature or surgical menopause, Dr. Mangione highlighted.
 

No review for treating menopausal symptoms

“The Task Force encourages people who are experiencing symptoms of menopause to talk with their health care professional about the best treatment for them,” explained Dr. Mangione. “The Task Force did not review the evidence on the use of hormone therapy to treat symptoms of menopause.”

Osteoporosis and increased risk for bone fracture were among the conditions that accompany menopause reviewed by the USPSTF. The Task Force concluded that while “hormone therapy was associated with decreased risk of fractures,” after weighing the benefits and harms for preventing this condition, “there is no net benefit at the population level.”

This conclusion seems to contrast with the 2022 hormone therapy position statement of the North American Menopause Society (NAMS), released in July, which states: “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome vasomotor symptoms and prevention of bone loss.”
 

USPSTF, NAMS are ‘completely consistent’

However, Stephanie S. Faubion, MD, medical director of NAMS and director of the women’s health clinic at Mayo Clinic, Rochester, Minn., said the new USPSTF recommendations “are completely consistent” with the recent NAMS statement.

“We are entirely aligned with the recommendation to use hormone therapy for management of menopausal symptoms and not for chronic disease prevention or as an anti-aging strategy,” Dr. Faubion commented in an interview.

Dr. Faubion also stressed that “menopausal hormone therapy remains the most effective treatment for menopausal symptoms,” and that “women should not be reflexively directed to other pharmacologic therapies for management of menopausal symptoms.”

The distinction the USPSTF makes between its recommendations against using hormone therapy to prevent chronic conditions and its deferral of comment on use of the same treatment to manage perimenopausal symptoms is often forgotten, note Alison J. Huang, MD, and Deborah Grady, MD, in their editorial.
 

A problem of conflation

“Many patients and clinicians conflate these two different indications,” they write.

The notion that the net harms of menopausal hormone therapy outweigh the benefits “is now widely adopted as a rationale for foregoing menopausal hormone therapy for symptomatic treatment,” even though “nonhormonal treatments that are as effective as menopausal hormone therapy have not yet been identified,” say Dr. Huang and Dr. Grady, both physicians at the University of California, San Francisco.

In addition, alternative, nonhormonal options for treating perimenopausal symptoms have not received the same level of scrutiny as hormonal treatment, they say.

“It is arguably problematic to avoid menopausal hormone therapy and favor potentially less effective treatments, when the longer-term implications of those treatments for health have not been evaluated,” Dr. Huang and Dr. Grady write in their editorial.

In short, during menopause, people are at risk of being “frightened away from considering using menopausal hormone therapy for distressing symptoms,” they say.

“We can’t speak to whether or how often clinicians might be conflating the role of hormone therapy in treating symptoms and preventing chronic conditions,” answered Dr. Mangione.

“We hope to ensure that health professionals know that hormone therapy is not a beneficial way to reduce the risk of chronic conditions such as heart disease, cancer, and strokes,” she added. The new recommendations are an effort to “raise awareness about the value of considering other safe and effective ways for people to reduce their risk of chronic health problems as they age.”
 

The issue of timing

Another critique offered by Dr. Huang and Dr. Grady in their editorial is that “the scientific and medical community should let go of the past,” and should no longer invest additional resources in “trying to parse out subsets of menopausal patients who may derive some preventive benefit from menopausal hormone therapy for a limited amount of time.”

But Dr. Mangione disagreed.

The USPSTF “calls for more research that can help us understand whether health outcomes – both benefits and harms – differ depending on a person’s age or when they started hormone therapy related to when they went through menopause,” she said.

Dr. Mangione also highlighted the need for additional research on whether the benefits and risks of menopausal hormone therapy vary across racial and ethnic groups.

USPSTF receives no commercial funding. Dr. Mangione, Dr. Huang, and Dr. Grady have reported no relevant financial relationships.

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

The U.S. Preventive Services Task Force moved forward their recommendations for using hormone therapy to prevent chronic conditions in postmenopausal women by keeping them the same.

The central message of the new recommendations, released on Nov. 1 as a statement published in JAMA, remains unchanged from the last update in 2017.

The message also remains simple: Don’t use hormone therapy for preventing chronic conditions, such as cardiovascular disease, cancer, and osteoporosis, or bone fracture.

The USPSTF summarized its recommendations in two brief statements: the group “recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons” and “recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.”

This wording is identical to that used in the 2017 guidance (except it now refers to postmenopausal persons instead of specifically women). The recommendation against use of estrogen and progestin for prevention of chronic conditions in postmenopausal women was first made by the USPSTF in 2002.

An editorial accompanying the 2022 revision notes that the evidence cited by the USPSTF includes “only two additional, modest-sized trials” (that focused on the effects of hormone therapy on cognition and brain structure) compared with 2017, “as well as ancillary analyses of previous trials.”
 

A standard 5-year update

The 2022 revision and revisiting of the evidence base by the Task Force regarding the benefits and risks of postmenopausal hormone therapy occurred “as part of the Task Force’s standard approach, which includes updating each recommendation approximately every 5 years,” explained Carol M. Mangione, MD, who is USPSTF chair and chief of the division of general internal medicine and health services research at the University of California, Los Angeles.

“In our review we again found that while hormone therapy may reduce the risk of some conditions, it can also lead to serious harms such as an increase in the risk of blood clots and stroke,” Dr. Mangione said in an interview. “The harms cancel out any potential benefits overall.”

This new statement only applies to using menopausal hormone treatment for preventing chronic conditions in asymptomatic people but does not speak to using this treatment in managing people with perimenopausal symptoms such as hot flashes or vaginal dryness or treating people with premature or surgical menopause, Dr. Mangione highlighted.
 

No review for treating menopausal symptoms

“The Task Force encourages people who are experiencing symptoms of menopause to talk with their health care professional about the best treatment for them,” explained Dr. Mangione. “The Task Force did not review the evidence on the use of hormone therapy to treat symptoms of menopause.”

Osteoporosis and increased risk for bone fracture were among the conditions that accompany menopause reviewed by the USPSTF. The Task Force concluded that while “hormone therapy was associated with decreased risk of fractures,” after weighing the benefits and harms for preventing this condition, “there is no net benefit at the population level.”

This conclusion seems to contrast with the 2022 hormone therapy position statement of the North American Menopause Society (NAMS), released in July, which states: “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for treatment of bothersome vasomotor symptoms and prevention of bone loss.”
 

USPSTF, NAMS are ‘completely consistent’

However, Stephanie S. Faubion, MD, medical director of NAMS and director of the women’s health clinic at Mayo Clinic, Rochester, Minn., said the new USPSTF recommendations “are completely consistent” with the recent NAMS statement.

“We are entirely aligned with the recommendation to use hormone therapy for management of menopausal symptoms and not for chronic disease prevention or as an anti-aging strategy,” Dr. Faubion commented in an interview.

Dr. Faubion also stressed that “menopausal hormone therapy remains the most effective treatment for menopausal symptoms,” and that “women should not be reflexively directed to other pharmacologic therapies for management of menopausal symptoms.”

The distinction the USPSTF makes between its recommendations against using hormone therapy to prevent chronic conditions and its deferral of comment on use of the same treatment to manage perimenopausal symptoms is often forgotten, note Alison J. Huang, MD, and Deborah Grady, MD, in their editorial.
 

A problem of conflation

“Many patients and clinicians conflate these two different indications,” they write.

The notion that the net harms of menopausal hormone therapy outweigh the benefits “is now widely adopted as a rationale for foregoing menopausal hormone therapy for symptomatic treatment,” even though “nonhormonal treatments that are as effective as menopausal hormone therapy have not yet been identified,” say Dr. Huang and Dr. Grady, both physicians at the University of California, San Francisco.

In addition, alternative, nonhormonal options for treating perimenopausal symptoms have not received the same level of scrutiny as hormonal treatment, they say.

“It is arguably problematic to avoid menopausal hormone therapy and favor potentially less effective treatments, when the longer-term implications of those treatments for health have not been evaluated,” Dr. Huang and Dr. Grady write in their editorial.

In short, during menopause, people are at risk of being “frightened away from considering using menopausal hormone therapy for distressing symptoms,” they say.

“We can’t speak to whether or how often clinicians might be conflating the role of hormone therapy in treating symptoms and preventing chronic conditions,” answered Dr. Mangione.

“We hope to ensure that health professionals know that hormone therapy is not a beneficial way to reduce the risk of chronic conditions such as heart disease, cancer, and strokes,” she added. The new recommendations are an effort to “raise awareness about the value of considering other safe and effective ways for people to reduce their risk of chronic health problems as they age.”
 

The issue of timing

Another critique offered by Dr. Huang and Dr. Grady in their editorial is that “the scientific and medical community should let go of the past,” and should no longer invest additional resources in “trying to parse out subsets of menopausal patients who may derive some preventive benefit from menopausal hormone therapy for a limited amount of time.”

But Dr. Mangione disagreed.

The USPSTF “calls for more research that can help us understand whether health outcomes – both benefits and harms – differ depending on a person’s age or when they started hormone therapy related to when they went through menopause,” she said.

Dr. Mangione also highlighted the need for additional research on whether the benefits and risks of menopausal hormone therapy vary across racial and ethnic groups.

USPSTF receives no commercial funding. Dr. Mangione, Dr. Huang, and Dr. Grady have reported no relevant financial relationships.

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

An analysis of more than 800,000 women in Denmark offers more insight into the murky links between female hormones and midlife mental illness in women: It hints that hormone therapy (HT) may boost the risk of depression, have no effect, or lower it – all depending on how it’s administered and when.

Women who took systemic HT had a higher risk of depression from age 48 to 50 (adjusted hazard ratio, 1.50; 95% confidence interval, 1.24-1.81), researchers reported in JAMA Network Open. However, there was no overall link between depression and locally administered HT (aHR, 1.15; 95% CI, 0.70-1.87) – except when HT was begun between ages 54 and 60, when there were signs of a protective effect (aHR, 0.80; 95% CI, 0.70-0.91).

“Women in menopause who initiate systemically administered HT should be aware of depression as a potential adverse effect,” epidemiologist and study corresponding author Merete Osler, MD, PhD, DMSc, of Bispebjerg and Frederiksberg (Denmark) Hospitals and the University of Copenhagen, said in an interview. ”Further, women and clinicians alike should be aware of any misinterpretation of symptoms of depression as menopausal disturbances.”

Dr. Osler said the researchers launched the study to better understand potential hormone-depression links in light of suspicions that lower levels of estrogen in menopause may contribute to depression.

Several randomized clinical trials and cohort and cross-sectional studies have explored whether systemic HT affects depression during menopause, Dr. Osler said, “but the results from these studies have been inconsistent, and few have explored the role of the route of administration.”

For the new registry-based study, researchers retrospectively tracked all women in Denmark who were aged 45 between 1995 and 2017 without prior oophorectomy, certain kinds of cancer, prior use of HT, or ongoing depression.

During follow-up to a mean age of 56, 23% of the women began HT (at a median age of 55), and 1.6% were hospitalized for depression. Of those on HT, 65.8% received locally administered HT.

Researchers adjusted hazard ratios for a long list of factors such as educational level, marital status, number of still births or live births, prior use of hormonal contraceptives, several medical conditions, and prior depression.

“We were surprised by our findings, which to some degree contradicted our prior hypothesis that systemic HT with estrogen would not be associated with first-time depression diagnosis in women aged 45 and above, while HT with progesterone would be associated with a slightly increased risk,” Dr. Osler said. “In our study, systemically administered HT was associated with an increased risk of depression with no difference between estrogen alone or in combination with progestin. As findings from previous studies have been inconsistent, our findings fit with some but not all previous studies.”

Why might the mode of administration make a difference? It’s possible that local administration may contribute less to the systemic circulation, Dr. Osler said, “or that menopausal symptoms including depression are more likely to be treated with systemic HT.”

As for age differences, Dr. Osler said “it is possible that women are more sensitive to the influence of HT on mood around menopause than at later ages. However, it should be noted that in the present study it was not possible to calculate precise risk estimates for use of systemic HT in menopausal women above age 54 because less than 1% initiated treatment with systemic HT after age 54 years.”

In an interview, psychiatrist Natalie Rasgon, MD, PhD, of Stanford (Calif.) University, who’s studied hormones and depression, said the study is “remarkably large and consistently executed.”

She cautioned, however, that the findings don’t prove any causality. “Saying that estrogen therapy or hormone therapy causes depression is patently incorrect.”

How can the findings be useful for medical professionals? “Women and physicians alike need to be very mindful of pre-existing mood disorders,” Dr. Rasgon said. “Women who in the past had anxiety disorders, mood swings, PTSD, or prior episodes of depression might have a differential response to hormone therapy in menopause.”

Also keep in mind, she said, that the transition from menopause to post menopause is “very volatile,” and depression may break through even in women undergoing treatment for the condition.

For her part, Dr. Osler said this study and others “emphasize the need for clinical guidelines to further consider the psychological side effects of systemic HT.”

Funding information was not provided. The study authors and Dr. Rasgon have no disclosures.

An analysis of more than 800,000 women in Denmark offers more insight into the murky links between female hormones and midlife mental illness in women: It hints that hormone therapy (HT) may boost the risk of depression, have no effect, or lower it – all depending on how it’s administered and when.

Women who took systemic HT had a higher risk of depression from age 48 to 50 (adjusted hazard ratio, 1.50; 95% confidence interval, 1.24-1.81), researchers reported in JAMA Network Open. However, there was no overall link between depression and locally administered HT (aHR, 1.15; 95% CI, 0.70-1.87) – except when HT was begun between ages 54 and 60, when there were signs of a protective effect (aHR, 0.80; 95% CI, 0.70-0.91).

“Women in menopause who initiate systemically administered HT should be aware of depression as a potential adverse effect,” epidemiologist and study corresponding author Merete Osler, MD, PhD, DMSc, of Bispebjerg and Frederiksberg (Denmark) Hospitals and the University of Copenhagen, said in an interview. ”Further, women and clinicians alike should be aware of any misinterpretation of symptoms of depression as menopausal disturbances.”

Dr. Osler said the researchers launched the study to better understand potential hormone-depression links in light of suspicions that lower levels of estrogen in menopause may contribute to depression.

Several randomized clinical trials and cohort and cross-sectional studies have explored whether systemic HT affects depression during menopause, Dr. Osler said, “but the results from these studies have been inconsistent, and few have explored the role of the route of administration.”

For the new registry-based study, researchers retrospectively tracked all women in Denmark who were aged 45 between 1995 and 2017 without prior oophorectomy, certain kinds of cancer, prior use of HT, or ongoing depression.

During follow-up to a mean age of 56, 23% of the women began HT (at a median age of 55), and 1.6% were hospitalized for depression. Of those on HT, 65.8% received locally administered HT.

Researchers adjusted hazard ratios for a long list of factors such as educational level, marital status, number of still births or live births, prior use of hormonal contraceptives, several medical conditions, and prior depression.

“We were surprised by our findings, which to some degree contradicted our prior hypothesis that systemic HT with estrogen would not be associated with first-time depression diagnosis in women aged 45 and above, while HT with progesterone would be associated with a slightly increased risk,” Dr. Osler said. “In our study, systemically administered HT was associated with an increased risk of depression with no difference between estrogen alone or in combination with progestin. As findings from previous studies have been inconsistent, our findings fit with some but not all previous studies.”

Why might the mode of administration make a difference? It’s possible that local administration may contribute less to the systemic circulation, Dr. Osler said, “or that menopausal symptoms including depression are more likely to be treated with systemic HT.”

As for age differences, Dr. Osler said “it is possible that women are more sensitive to the influence of HT on mood around menopause than at later ages. However, it should be noted that in the present study it was not possible to calculate precise risk estimates for use of systemic HT in menopausal women above age 54 because less than 1% initiated treatment with systemic HT after age 54 years.”

In an interview, psychiatrist Natalie Rasgon, MD, PhD, of Stanford (Calif.) University, who’s studied hormones and depression, said the study is “remarkably large and consistently executed.”

She cautioned, however, that the findings don’t prove any causality. “Saying that estrogen therapy or hormone therapy causes depression is patently incorrect.”

How can the findings be useful for medical professionals? “Women and physicians alike need to be very mindful of pre-existing mood disorders,” Dr. Rasgon said. “Women who in the past had anxiety disorders, mood swings, PTSD, or prior episodes of depression might have a differential response to hormone therapy in menopause.”

Also keep in mind, she said, that the transition from menopause to post menopause is “very volatile,” and depression may break through even in women undergoing treatment for the condition.

For her part, Dr. Osler said this study and others “emphasize the need for clinical guidelines to further consider the psychological side effects of systemic HT.”

Funding information was not provided. The study authors and Dr. Rasgon have no disclosures.

An analysis of more than 800,000 women in Denmark offers more insight into the murky links between female hormones and midlife mental illness in women: It hints that hormone therapy (HT) may boost the risk of depression, have no effect, or lower it – all depending on how it’s administered and when.

Women who took systemic HT had a higher risk of depression from age 48 to 50 (adjusted hazard ratio, 1.50; 95% confidence interval, 1.24-1.81), researchers reported in JAMA Network Open. However, there was no overall link between depression and locally administered HT (aHR, 1.15; 95% CI, 0.70-1.87) – except when HT was begun between ages 54 and 60, when there were signs of a protective effect (aHR, 0.80; 95% CI, 0.70-0.91).

“Women in menopause who initiate systemically administered HT should be aware of depression as a potential adverse effect,” epidemiologist and study corresponding author Merete Osler, MD, PhD, DMSc, of Bispebjerg and Frederiksberg (Denmark) Hospitals and the University of Copenhagen, said in an interview. ”Further, women and clinicians alike should be aware of any misinterpretation of symptoms of depression as menopausal disturbances.”

Dr. Osler said the researchers launched the study to better understand potential hormone-depression links in light of suspicions that lower levels of estrogen in menopause may contribute to depression.

Several randomized clinical trials and cohort and cross-sectional studies have explored whether systemic HT affects depression during menopause, Dr. Osler said, “but the results from these studies have been inconsistent, and few have explored the role of the route of administration.”

For the new registry-based study, researchers retrospectively tracked all women in Denmark who were aged 45 between 1995 and 2017 without prior oophorectomy, certain kinds of cancer, prior use of HT, or ongoing depression.

During follow-up to a mean age of 56, 23% of the women began HT (at a median age of 55), and 1.6% were hospitalized for depression. Of those on HT, 65.8% received locally administered HT.

Researchers adjusted hazard ratios for a long list of factors such as educational level, marital status, number of still births or live births, prior use of hormonal contraceptives, several medical conditions, and prior depression.

“We were surprised by our findings, which to some degree contradicted our prior hypothesis that systemic HT with estrogen would not be associated with first-time depression diagnosis in women aged 45 and above, while HT with progesterone would be associated with a slightly increased risk,” Dr. Osler said. “In our study, systemically administered HT was associated with an increased risk of depression with no difference between estrogen alone or in combination with progestin. As findings from previous studies have been inconsistent, our findings fit with some but not all previous studies.”

Why might the mode of administration make a difference? It’s possible that local administration may contribute less to the systemic circulation, Dr. Osler said, “or that menopausal symptoms including depression are more likely to be treated with systemic HT.”

As for age differences, Dr. Osler said “it is possible that women are more sensitive to the influence of HT on mood around menopause than at later ages. However, it should be noted that in the present study it was not possible to calculate precise risk estimates for use of systemic HT in menopausal women above age 54 because less than 1% initiated treatment with systemic HT after age 54 years.”

In an interview, psychiatrist Natalie Rasgon, MD, PhD, of Stanford (Calif.) University, who’s studied hormones and depression, said the study is “remarkably large and consistently executed.”

She cautioned, however, that the findings don’t prove any causality. “Saying that estrogen therapy or hormone therapy causes depression is patently incorrect.”

How can the findings be useful for medical professionals? “Women and physicians alike need to be very mindful of pre-existing mood disorders,” Dr. Rasgon said. “Women who in the past had anxiety disorders, mood swings, PTSD, or prior episodes of depression might have a differential response to hormone therapy in menopause.”

Also keep in mind, she said, that the transition from menopause to post menopause is “very volatile,” and depression may break through even in women undergoing treatment for the condition.

For her part, Dr. Osler said this study and others “emphasize the need for clinical guidelines to further consider the psychological side effects of systemic HT.”

Funding information was not provided. The study authors and Dr. Rasgon have no disclosures.

Up to 10 different menopausal symptoms were linked to an increased risk of cardiovascular disease when they were moderate to severe in women who initially had no evidence of cardiovascular disease, according to research presented at the North American Menopause Society annual meeting in Atlanta.

“The take-home message is that severe menopausal symptoms may increase the risk of cardiovascular disease,” Matthew Nudy, MD, an assistant professor of medicine at the Heart and Vascular Institute at Penn State University, Hershey, said in an interview about his findings. “Physicians and patients should be aware of this association. Women with severe symptoms may be more likely to see their physician, and this would be an ideal time to have their cardiovascular risk assessed.”

Margaret Nachtigall, MD, a clinical associate professor of obstetrics and gynecology at New York University and at NYU Langone Health, noted that these findings lined up with other studies showing an increased risk of cardiovascular disease in patients who have more symptoms, especially hot flashes.

“Other recent studies showed that an increase in severity of hot flush is associated with worse blood vessel function, leading to heart disease,” Dr. Nachtigall, who was not involved with the study, said in an interview. “The next step that makes sense is to try to eliminate these symptoms and hope that, in turn, would lower cardiovascular disease and improve survival.”

The researchers compared menopausal symptoms with cardiovascular outcomes and all-cause mortality in an observational cohort of 80,278 postmenopausal women for a median 8.2 years of follow-up. None of the women, all enrolled in the Women’s Health Initiative, had known cardiovascular disease at baseline. They had an average age of 63 years and average body mass index (BMI) of 25.9 at baseline. Most participants were White (86.7%), with 7% being Black and 4.1% Hispanic. Cardiovascular disease was a composite outcome that included hospitalized myocardial infarction, definite silent myocardial infarction, coronary death, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization.

The researchers used a four-item Likert scale (0-3) to assess the severity of 15 symptoms experienced within the past 4 weeks at baseline: “night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, [feeling] restless or fidgety, and difficulty concentrating.”

The associations were adjusted for the following covariates: race/ethnicity, blood pressure, education, smoking status, bilateral oophorectomy, menopausal hormone therapy use (never/past/current), sleep duration, statin use, history of high cholesterol, aspirin use, use of antihypertensives, treated diabetes, and family history of heart attack. Continuous variables included age, age at menopause, BMI, blood pressure, and physical activity levels. Because of the high number of multiple comparisons, the researchers also used a Bonferroni correction to reduce the risk of spurious statistical significance.

The researchers found some clustering of symptoms. Among women who had at least two moderate or severe menopausal symptoms, more than half frequently woke up at night, had joint pain, or felt tired, the researchers reported. Those symptoms were also the most commonly reported ones overall. Younger women, between ages 50 and 59, were more likely than older women (60-79 years old) to experience vasomotor symptoms and all cognitive affective symptoms except forgetfulness.

The researchers identified 10 symptoms whose severity was significantly associated with cardiovascular disease. Compared to having no symptoms at all, the following moderate or severe symptoms were associated with an increased risk of a cardiovascular event after adjustment for covariates and corrected for multiple comparisons: night sweats – a 19% increased risk (P = .03), waking up several times at night – 11% increased risk (P = .05), joint pain or stiffness – 27% increased risk (P < .001), heart racing or skipping beats – 55% increased risk (P < .001), dizziness – 34% increased risk (P < .001), feeling tired – 35% increased risk (P < .001), forgetfulness – 25% increased risk (P < .001), mood swings – 21% increased risk (P = .02), feeling restless or fidgety – 29% increased risk (P < .001), and difficulty concentrating – 31% increased risk (P < .001)

In addition, all-cause mortality was associated with these symptoms when they were moderate or severe: heart racing or skipping beats (32% increased risk of all-cause mortality; hazard ratio, 1.32; P =.006), dizziness (HR, 1.58; P < .001), tremors (HR, 1.44; P < .001), feeling tired (HR, 1.26; P < .001), forgetfulness (HR, 1.29; P = .01), mood swings (HR, 1.35; P = .02), feeling restless or fidgety (HR, 1.35; P < .001), and difficulty concentrating (HR, 1.47; P < .001).

The symptom with the greatest association with all-cause mortality was dizziness, which was associated with an increased risk of 58% when rated moderate or severe. Any dizziness at all was linked to a 12% increased risk of cardiovascular disease, compared with no dizziness. Machine learning with the LASSO method determined that the symptoms most predictive of cardiovascular disease were dizziness, heart racing, feeling tired, and joint pain. The symptoms most associated with all-cause mortality, based on the machine learning algorithm, were dizziness, tremors, and feeling tired.

Dr. Nudy said that their study did not look at mitigation strategies. “Women should discuss with their physician the best methods for cardiovascular risk reduction,” he said. He also cautioned that severe menopausal symptoms can also indicate other health conditions that may require investigation.

“It is certainly possible some symptoms may represent other medical conditions we were unable to control for and may not be directly related to menopause,” such as autoimmune diseases, endocrine abnormalities, or subclinical cardiovascular disease, he said. Additional limitations of the study included an older cohort and retrospective assessment of menopausal symptoms only at baseline. In addition, ”we did not assess the cardiovascular risk among women whose symptoms persisted versus resolved during the study period,” Dr. Nudy said.

Dr. Nachtigall said a key message is that people who are experiencing these symptoms should try to get treatment for them and attempt to alleviate them, hopefully reducing the risk of heart disease and death.

”Estrogen treatment is one excellent option for some individuals and should be considered in the appropriate person,” Dr. Nachtigall said. “If estrogen treatment is to be considered, it should be given closer to menopause, within the first 10 years after menopause and in younger individuals (under 59) at start.”

Dr. Nachtigall referred to the NAMS 2022 position statement concluding that, for healthy women within 10 years of menopause who have bothersome menopause symptoms, “the benefits of hormone therapy outweigh its risks, with fewer cardiovascular events in younger versus older women.”

”Menopause and having menopausal symptoms is an opportunity for clinicians and patients to have a conversation about appropriate individualized management options,” Dr. Nachtigall said.

Women may also be able to mitigate their cardiovascular risk with regular exercise, eating a healthy diet, not smoking, and getting adequate sleep, Dr. Nachtigall said. But these healthy behaviors may not adequately treat moderate or severe menopausal symptoms.

“Some health care providers have said that because menopause happens naturally, individuals should just accept the symptoms and try to wait it out and not get treatment, but this study, as well as others, makes it clear that it actually may be beneficial to treat the symptoms,” Dr. Nachtigall said.

The research used no external funding. Dr. Nudy and Dr. Nachtigall had no disclosures.

Up to 10 different menopausal symptoms were linked to an increased risk of cardiovascular disease when they were moderate to severe in women who initially had no evidence of cardiovascular disease, according to research presented at the North American Menopause Society annual meeting in Atlanta.

“The take-home message is that severe menopausal symptoms may increase the risk of cardiovascular disease,” Matthew Nudy, MD, an assistant professor of medicine at the Heart and Vascular Institute at Penn State University, Hershey, said in an interview about his findings. “Physicians and patients should be aware of this association. Women with severe symptoms may be more likely to see their physician, and this would be an ideal time to have their cardiovascular risk assessed.”

Margaret Nachtigall, MD, a clinical associate professor of obstetrics and gynecology at New York University and at NYU Langone Health, noted that these findings lined up with other studies showing an increased risk of cardiovascular disease in patients who have more symptoms, especially hot flashes.

“Other recent studies showed that an increase in severity of hot flush is associated with worse blood vessel function, leading to heart disease,” Dr. Nachtigall, who was not involved with the study, said in an interview. “The next step that makes sense is to try to eliminate these symptoms and hope that, in turn, would lower cardiovascular disease and improve survival.”

The researchers compared menopausal symptoms with cardiovascular outcomes and all-cause mortality in an observational cohort of 80,278 postmenopausal women for a median 8.2 years of follow-up. None of the women, all enrolled in the Women’s Health Initiative, had known cardiovascular disease at baseline. They had an average age of 63 years and average body mass index (BMI) of 25.9 at baseline. Most participants were White (86.7%), with 7% being Black and 4.1% Hispanic. Cardiovascular disease was a composite outcome that included hospitalized myocardial infarction, definite silent myocardial infarction, coronary death, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization.

The researchers used a four-item Likert scale (0-3) to assess the severity of 15 symptoms experienced within the past 4 weeks at baseline: “night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, [feeling] restless or fidgety, and difficulty concentrating.”

The associations were adjusted for the following covariates: race/ethnicity, blood pressure, education, smoking status, bilateral oophorectomy, menopausal hormone therapy use (never/past/current), sleep duration, statin use, history of high cholesterol, aspirin use, use of antihypertensives, treated diabetes, and family history of heart attack. Continuous variables included age, age at menopause, BMI, blood pressure, and physical activity levels. Because of the high number of multiple comparisons, the researchers also used a Bonferroni correction to reduce the risk of spurious statistical significance.

The researchers found some clustering of symptoms. Among women who had at least two moderate or severe menopausal symptoms, more than half frequently woke up at night, had joint pain, or felt tired, the researchers reported. Those symptoms were also the most commonly reported ones overall. Younger women, between ages 50 and 59, were more likely than older women (60-79 years old) to experience vasomotor symptoms and all cognitive affective symptoms except forgetfulness.

The researchers identified 10 symptoms whose severity was significantly associated with cardiovascular disease. Compared to having no symptoms at all, the following moderate or severe symptoms were associated with an increased risk of a cardiovascular event after adjustment for covariates and corrected for multiple comparisons: night sweats – a 19% increased risk (P = .03), waking up several times at night – 11% increased risk (P = .05), joint pain or stiffness – 27% increased risk (P < .001), heart racing or skipping beats – 55% increased risk (P < .001), dizziness – 34% increased risk (P < .001), feeling tired – 35% increased risk (P < .001), forgetfulness – 25% increased risk (P < .001), mood swings – 21% increased risk (P = .02), feeling restless or fidgety – 29% increased risk (P < .001), and difficulty concentrating – 31% increased risk (P < .001)

In addition, all-cause mortality was associated with these symptoms when they were moderate or severe: heart racing or skipping beats (32% increased risk of all-cause mortality; hazard ratio, 1.32; P =.006), dizziness (HR, 1.58; P < .001), tremors (HR, 1.44; P < .001), feeling tired (HR, 1.26; P < .001), forgetfulness (HR, 1.29; P = .01), mood swings (HR, 1.35; P = .02), feeling restless or fidgety (HR, 1.35; P < .001), and difficulty concentrating (HR, 1.47; P < .001).

The symptom with the greatest association with all-cause mortality was dizziness, which was associated with an increased risk of 58% when rated moderate or severe. Any dizziness at all was linked to a 12% increased risk of cardiovascular disease, compared with no dizziness. Machine learning with the LASSO method determined that the symptoms most predictive of cardiovascular disease were dizziness, heart racing, feeling tired, and joint pain. The symptoms most associated with all-cause mortality, based on the machine learning algorithm, were dizziness, tremors, and feeling tired.

Dr. Nudy said that their study did not look at mitigation strategies. “Women should discuss with their physician the best methods for cardiovascular risk reduction,” he said. He also cautioned that severe menopausal symptoms can also indicate other health conditions that may require investigation.

“It is certainly possible some symptoms may represent other medical conditions we were unable to control for and may not be directly related to menopause,” such as autoimmune diseases, endocrine abnormalities, or subclinical cardiovascular disease, he said. Additional limitations of the study included an older cohort and retrospective assessment of menopausal symptoms only at baseline. In addition, ”we did not assess the cardiovascular risk among women whose symptoms persisted versus resolved during the study period,” Dr. Nudy said.

Dr. Nachtigall said a key message is that people who are experiencing these symptoms should try to get treatment for them and attempt to alleviate them, hopefully reducing the risk of heart disease and death.

”Estrogen treatment is one excellent option for some individuals and should be considered in the appropriate person,” Dr. Nachtigall said. “If estrogen treatment is to be considered, it should be given closer to menopause, within the first 10 years after menopause and in younger individuals (under 59) at start.”

Dr. Nachtigall referred to the NAMS 2022 position statement concluding that, for healthy women within 10 years of menopause who have bothersome menopause symptoms, “the benefits of hormone therapy outweigh its risks, with fewer cardiovascular events in younger versus older women.”

”Menopause and having menopausal symptoms is an opportunity for clinicians and patients to have a conversation about appropriate individualized management options,” Dr. Nachtigall said.

Women may also be able to mitigate their cardiovascular risk with regular exercise, eating a healthy diet, not smoking, and getting adequate sleep, Dr. Nachtigall said. But these healthy behaviors may not adequately treat moderate or severe menopausal symptoms.

“Some health care providers have said that because menopause happens naturally, individuals should just accept the symptoms and try to wait it out and not get treatment, but this study, as well as others, makes it clear that it actually may be beneficial to treat the symptoms,” Dr. Nachtigall said.

The research used no external funding. Dr. Nudy and Dr. Nachtigall had no disclosures.

Up to 10 different menopausal symptoms were linked to an increased risk of cardiovascular disease when they were moderate to severe in women who initially had no evidence of cardiovascular disease, according to research presented at the North American Menopause Society annual meeting in Atlanta.

“The take-home message is that severe menopausal symptoms may increase the risk of cardiovascular disease,” Matthew Nudy, MD, an assistant professor of medicine at the Heart and Vascular Institute at Penn State University, Hershey, said in an interview about his findings. “Physicians and patients should be aware of this association. Women with severe symptoms may be more likely to see their physician, and this would be an ideal time to have their cardiovascular risk assessed.”

Margaret Nachtigall, MD, a clinical associate professor of obstetrics and gynecology at New York University and at NYU Langone Health, noted that these findings lined up with other studies showing an increased risk of cardiovascular disease in patients who have more symptoms, especially hot flashes.

“Other recent studies showed that an increase in severity of hot flush is associated with worse blood vessel function, leading to heart disease,” Dr. Nachtigall, who was not involved with the study, said in an interview. “The next step that makes sense is to try to eliminate these symptoms and hope that, in turn, would lower cardiovascular disease and improve survival.”

The researchers compared menopausal symptoms with cardiovascular outcomes and all-cause mortality in an observational cohort of 80,278 postmenopausal women for a median 8.2 years of follow-up. None of the women, all enrolled in the Women’s Health Initiative, had known cardiovascular disease at baseline. They had an average age of 63 years and average body mass index (BMI) of 25.9 at baseline. Most participants were White (86.7%), with 7% being Black and 4.1% Hispanic. Cardiovascular disease was a composite outcome that included hospitalized myocardial infarction, definite silent myocardial infarction, coronary death, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization.

The researchers used a four-item Likert scale (0-3) to assess the severity of 15 symptoms experienced within the past 4 weeks at baseline: “night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, [feeling] restless or fidgety, and difficulty concentrating.”

The associations were adjusted for the following covariates: race/ethnicity, blood pressure, education, smoking status, bilateral oophorectomy, menopausal hormone therapy use (never/past/current), sleep duration, statin use, history of high cholesterol, aspirin use, use of antihypertensives, treated diabetes, and family history of heart attack. Continuous variables included age, age at menopause, BMI, blood pressure, and physical activity levels. Because of the high number of multiple comparisons, the researchers also used a Bonferroni correction to reduce the risk of spurious statistical significance.

The researchers found some clustering of symptoms. Among women who had at least two moderate or severe menopausal symptoms, more than half frequently woke up at night, had joint pain, or felt tired, the researchers reported. Those symptoms were also the most commonly reported ones overall. Younger women, between ages 50 and 59, were more likely than older women (60-79 years old) to experience vasomotor symptoms and all cognitive affective symptoms except forgetfulness.

The researchers identified 10 symptoms whose severity was significantly associated with cardiovascular disease. Compared to having no symptoms at all, the following moderate or severe symptoms were associated with an increased risk of a cardiovascular event after adjustment for covariates and corrected for multiple comparisons: night sweats – a 19% increased risk (P = .03), waking up several times at night – 11% increased risk (P = .05), joint pain or stiffness – 27% increased risk (P < .001), heart racing or skipping beats – 55% increased risk (P < .001), dizziness – 34% increased risk (P < .001), feeling tired – 35% increased risk (P < .001), forgetfulness – 25% increased risk (P < .001), mood swings – 21% increased risk (P = .02), feeling restless or fidgety – 29% increased risk (P < .001), and difficulty concentrating – 31% increased risk (P < .001)

In addition, all-cause mortality was associated with these symptoms when they were moderate or severe: heart racing or skipping beats (32% increased risk of all-cause mortality; hazard ratio, 1.32; P =.006), dizziness (HR, 1.58; P < .001), tremors (HR, 1.44; P < .001), feeling tired (HR, 1.26; P < .001), forgetfulness (HR, 1.29; P = .01), mood swings (HR, 1.35; P = .02), feeling restless or fidgety (HR, 1.35; P < .001), and difficulty concentrating (HR, 1.47; P < .001).

The symptom with the greatest association with all-cause mortality was dizziness, which was associated with an increased risk of 58% when rated moderate or severe. Any dizziness at all was linked to a 12% increased risk of cardiovascular disease, compared with no dizziness. Machine learning with the LASSO method determined that the symptoms most predictive of cardiovascular disease were dizziness, heart racing, feeling tired, and joint pain. The symptoms most associated with all-cause mortality, based on the machine learning algorithm, were dizziness, tremors, and feeling tired.

Dr. Nudy said that their study did not look at mitigation strategies. “Women should discuss with their physician the best methods for cardiovascular risk reduction,” he said. He also cautioned that severe menopausal symptoms can also indicate other health conditions that may require investigation.

“It is certainly possible some symptoms may represent other medical conditions we were unable to control for and may not be directly related to menopause,” such as autoimmune diseases, endocrine abnormalities, or subclinical cardiovascular disease, he said. Additional limitations of the study included an older cohort and retrospective assessment of menopausal symptoms only at baseline. In addition, ”we did not assess the cardiovascular risk among women whose symptoms persisted versus resolved during the study period,” Dr. Nudy said.

Dr. Nachtigall said a key message is that people who are experiencing these symptoms should try to get treatment for them and attempt to alleviate them, hopefully reducing the risk of heart disease and death.

”Estrogen treatment is one excellent option for some individuals and should be considered in the appropriate person,” Dr. Nachtigall said. “If estrogen treatment is to be considered, it should be given closer to menopause, within the first 10 years after menopause and in younger individuals (under 59) at start.”

Dr. Nachtigall referred to the NAMS 2022 position statement concluding that, for healthy women within 10 years of menopause who have bothersome menopause symptoms, “the benefits of hormone therapy outweigh its risks, with fewer cardiovascular events in younger versus older women.”

”Menopause and having menopausal symptoms is an opportunity for clinicians and patients to have a conversation about appropriate individualized management options,” Dr. Nachtigall said.

Women may also be able to mitigate their cardiovascular risk with regular exercise, eating a healthy diet, not smoking, and getting adequate sleep, Dr. Nachtigall said. But these healthy behaviors may not adequately treat moderate or severe menopausal symptoms.

“Some health care providers have said that because menopause happens naturally, individuals should just accept the symptoms and try to wait it out and not get treatment, but this study, as well as others, makes it clear that it actually may be beneficial to treat the symptoms,” Dr. Nachtigall said.

The research used no external funding. Dr. Nudy and Dr. Nachtigall had no disclosures.

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

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

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

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

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

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

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.
 

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years – when the menopausal transition is underway – women were more frequently hospitalized for psychosis, compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, department of neuroscience, University Medical Center of Groningen, the Netherlands, told this news organization.

The study was published online in Schizophrenia Bulletin.
 

Vulnerable period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Dr. Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Dr. Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on a “vulnerable period that all women with schizophrenia will experience.”
 

Detailed, quantitative data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from Jan. 1, 1996, to Dec. 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with the same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (that is, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

• less than 0.4
• 0.4 to 0.6
• 0.6 to 0.9
• 0.9 to less than 1.1
• 1.1 to less than 1.4
• 1.4 to less than 1.6
• 1.6 or more

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.
 

The turning tide

The cohort consisted of more men than women (31,104 vs. 30,785, respectively), with a mean (standard deviation) age of 49.8 (16.6) years in women vs. 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one-quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis, compared with their male peers (all Ps < .00001). 

Women 45 or older had significantly higher risk for relapse associated with standard dose use, compared with the other groups.

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses over 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs, compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d.

“We ... showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.
 

Don’t just raise the dose

Commenting on the research, Mary Seeman, MD, professor emerita, department of psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Dr. Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials, Dr. Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland. The Dutch Medical Research Association supported Dr. Sommer. Dr. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Seeman declares no relevant financial relationships.

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

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.
 

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years – when the menopausal transition is underway – women were more frequently hospitalized for psychosis, compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, department of neuroscience, University Medical Center of Groningen, the Netherlands, told this news organization.

The study was published online in Schizophrenia Bulletin.
 

Vulnerable period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Dr. Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Dr. Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on a “vulnerable period that all women with schizophrenia will experience.”
 

Detailed, quantitative data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from Jan. 1, 1996, to Dec. 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with the same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (that is, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

• less than 0.4
• 0.4 to 0.6
• 0.6 to 0.9
• 0.9 to less than 1.1
• 1.1 to less than 1.4
• 1.4 to less than 1.6
• 1.6 or more

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.
 

The turning tide

The cohort consisted of more men than women (31,104 vs. 30,785, respectively), with a mean (standard deviation) age of 49.8 (16.6) years in women vs. 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one-quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis, compared with their male peers (all Ps < .00001). 

Women 45 or older had significantly higher risk for relapse associated with standard dose use, compared with the other groups.

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses over 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs, compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d.

“We ... showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.
 

Don’t just raise the dose

Commenting on the research, Mary Seeman, MD, professor emerita, department of psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Dr. Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials, Dr. Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland. The Dutch Medical Research Association supported Dr. Sommer. Dr. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Seeman declares no relevant financial relationships.

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

Menopause appears to be an independent risk factor for relapse in women with schizophrenia spectrum disorders (SSDs), new research suggests.
 

Investigators studied a cohort of close to 62,000 people with SSDs, stratifying individuals by sex and age, and found that starting between the ages of 45 and 50 years – when the menopausal transition is underway – women were more frequently hospitalized for psychosis, compared with men and women younger than 45 years.

In addition, the protective effect of antipsychotic medication was highest in women younger than 45 years and lowest in women aged 45 years or older, even at higher doses.

“Women with schizophrenia who are older than 45 are a vulnerable group for relapse, and higher doses of antipsychotics are not the answer,” lead author Iris Sommer, MD, PhD, professor, department of neuroscience, University Medical Center of Groningen, the Netherlands, told this news organization.

The study was published online in Schizophrenia Bulletin.
 

Vulnerable period

There is an association between estrogen levels and disease severity throughout the life stages of women with SSDs, with lower estrogen levels associated with psychosis, for example, during low estrogenic phases of the menstrual cycle, the investigators note.

“After menopause, estrogen levels remain low, which is associated with a deterioration in the clinical course; therefore, women with SSD have sex-specific psychiatric needs that differ according to their life stage,” they add.

“Estrogens inhibit an important liver enzyme (cytochrome P-450 [CYP1A2]), which leads to higher blood levels of several antipsychotics like olanzapine and clozapine,” said Dr. Sommer. In addition, estrogens make the stomach less acidic, “leading to easier resorption of medication.”

As a clinician, Dr. Sommer said that she has “often witnessed a worsening of symptoms [of psychosis] after menopause.” As a researcher, she “knew that estrogens can have ameliorating effects on brain health, especially in schizophrenia.”

She and her colleagues were motivated to research the issue because there is a “remarkable paucity” of quantitative data on a “vulnerable period that all women with schizophrenia will experience.”
 

Detailed, quantitative data

The researchers sought to provide “detailed, quantitative data on life-stage dependent clinical changes occurring in women with SSD, using an intra-individual design to prevent confounding.”

They drew on data from a nationwide, register-based cohort study of all hospitalized patients with SSD between 1972 and 2014 in Finland (n = 61,889), with follow-up from Jan. 1, 1996, to Dec. 31, 2017.

People were stratified according to age (younger than 45 years and 45 years or older), with the same person contributing person-time to both age groups. The cohort was also subdivided into 5-year age groups, starting at age 20 years and ending at age 69 years.

The primary outcome measure was relapse (that is, inpatient hospitalization because of psychosis).

The researchers focused specifically on monotherapies, excluding time periods when two or more antipsychotics were used concomitantly. They also looked at antipsychotic nonuse periods.

Antipsychotic monotherapies were categorized into defined daily doses per day (DDDs/d):

• less than 0.4
• 0.4 to 0.6
• 0.6 to 0.9
• 0.9 to less than 1.1
• 1.1 to less than 1.4
• 1.4 to less than 1.6
• 1.6 or more

The researchers restricted the main analyses to the four most frequently used oral antipsychotic monotherapies: clozapine, olanzapine, quetiapine, and risperidone.
 

The turning tide

The cohort consisted of more men than women (31,104 vs. 30,785, respectively), with a mean (standard deviation) age of 49.8 (16.6) years in women vs. 43.6 (14.8) in men.

Among both sexes, olanzapine was the most prescribed antipsychotic (roughly one-quarter of patients). In women, the next most common antipsychotic was risperidone, followed by quetiapine and clozapine, whereas in men, the second most common antipsychotic was clozapine, followed by risperidone and quetiapine.

When the researchers compared men and women younger than 45 years, there were “few consistent differences” in proportions hospitalized for psychosis.

Starting at age 45 years and continuing through the oldest age group (65-69 years), higher proportions of women were hospitalized for psychosis, compared with their male peers (all Ps < .00001). 

Women 45 or older had significantly higher risk for relapse associated with standard dose use, compared with the other groups.

When the researchers compared men and women older and younger than 45 years, women younger than 45 years showed lower adjusted hazard ratios (aHRs) at doses between of 0.6-0.9 DDDs/d, whereas for doses over 1.1 DDDs/d, women aged 45 years or older showed “remarkably higher” aHRs, compared with women younger than 45 years and men aged 45 years or older, with a difference that increased with increasing dose.

In women, the efficacy of the antipsychotics was decreased at these DDDs/d.

“We ... showed that antipsychotic monotherapy is most effective in preventing relapse in women below 45, as compared to women above that age, and also as compared to men of all ages,” the authors summarize. But after age 45 years, “the tide seems to turn for women,” compared with younger women and with men of the same age group.

One of several study limitations was the use of age as an estimation of menopausal status, they note.
 

Don’t just raise the dose

Commenting on the research, Mary Seeman, MD, professor emerita, department of psychiatry, University of Toronto, noted the study corroborates her group’s findings regarding the effect of menopause on antipsychotic response.

“When the efficacy of previously effective antipsychotic doses wanes at menopause, raising the dose is not the treatment of choice because it increases the risk of weight gain, cardiovascular, and cerebrovascular events,” said Dr. Seeman, who was not involved with the current research.

“Changing to an antipsychotic that is less affected by estrogen loss may work better,” she continued, noting that amisulpride and aripiprazole “work well post menopause.”

Additional interventions may include changing to a depot or skin-patch antipsychotic that “obviates first-pass metabolism,” adding hormone replacement or a selective estrogen receptor modulator or including phytoestrogens (bioidenticals) in the diet.

The study yields research recommendations, including comparing the effectiveness of different antipsychotics in postmenopausal women with SSDs, recruiting pre- and postmenopausal women in trials of antipsychotic drugs, and stratifying by hormonal status when analyzing results of antipsychotic trials, Dr. Seeman said.

This work was supported by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and the Academy of Finland. The Dutch Medical Research Association supported Dr. Sommer. Dr. Sommer declares no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Seeman declares no relevant financial relationships.

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

Women eating a reduced-fat vegan diet combined with a daily serving of soybeans experienced a 78% reduction in frequency of menopausal hot flashes over 12 weeks, in a small, nonblinded, randomized-controlled trial.

“We do not fully understand yet why this combination works, but it seems that these three elements are key: avoiding animal products, reducing fat, and adding a serving of soybeans,” lead researcher Neal Barnard, MD, explained in a press release. “These new results suggest that a diet change should be considered as a first-line treatment for troublesome vasomotor symptoms, including night sweats and hot flashes,” added Dr. Barnard, who is president of the Physicians Committee for Responsible Medicine, and adjunct professor at George Washington University, Washington. 

Elliott O’Donovan Photography

But, while “the findings from this very small study complement everything we know about the benefits of an excellent diet and the health benefits of soy,” they should be interpreted with some caution, commented Susan Reed, MD, president of the North American Menopause Society, and associate program director of the women’s reproductive research program at the University of Washington, Seattle.

For the trial, called WAVS (Women’s Study for the Alleviation of Vasomotor Symptoms), the researchers randomized 84 postmenopausal women with at least two moderate to severe hot flashes daily to either the intervention or usual diet, with a total of 71 subjects completing the 12-week study, published in Menopause. Criteria for exclusion included any cause of vasomotor symptoms other than natural menopause, current use of a low-fat, vegan diet that includes daily soy products, soy allergy, and body mass index < 18.5 kg/m².

Participants in the intervention group were asked to avoid animal-derived foods, minimize their use of oils and fatty foods such as nuts and avocados, and include half a cup (86 g) of cooked soybeans daily in their diets. They were also offered 1-hour virtual group meetings each week, in which a registered dietitian or research staff provided information on food preparation and managing common dietary challenges.

Control group participants were asked to continue their usual diets and attend four 1-hour group sessions.

At baseline and then after the 12-week study period, dietary intake was self-recorded for 2 weekdays and 1 weekend day, hot flash frequency and severity was recorded for 1 week using a mobile app, and the effect of menopausal symptoms on quality of life was measured using the vasomotor, psychosocial, physical, and sexual domains of the Menopause-Specific Quality of Life (MENQOL) questionnaire.

Equol production was also assessed in a subset of 15 intervention and 12 control participants who had urinary isoflavone concentrations measured after eating half a cup (86 g) of soybeans twice daily for 3 days. This was based on the theory that diets such as the intervention in this study “seem to foster the growth of gut bacteria capable of converting daidzein to equol,” noted the authors. The ability to produce equol is detected more frequently in individuals following vegetarian diets than in omnivores and … has been proposed as a factor in soy’s apparent health benefits.”

The study found that total hot flash frequency decreased by 78% in the intervention group (P < .001) and 39% (P < .001) in the control group (between-group P = .003), and moderate to severe hot flashes decreased by 88% versus 34%, respectively (from 5.0 to 0.6 per day, P < .001 vs. from 4.4 to 2.9 per day, P < .001; between-group P < .001). Among participants with at least seven moderate to severe hot flashes per day at baseline, moderate to severe hot flashes decreased by 93% (from 10.6 to 0.7 per day) in the intervention group (P < .001) and 36% (from 9.0 to 5.8 per day) in the control group (P = .01, between-group P < .001). The changes in hot flashes were paralleled by changes in the MENQOL findings, with significant between-group differences in the vasomotor (P = 0.004), physical (P = 0.01), and sexual (P = 0.03) domains.

Changes in frequency of severe hot flashes correlated directly with changes in fat intake, and inversely with changes in carbohydrate and fiber intake, such that “the greater the reduction in fat intake and the greater the increases in carbohydrate and fiber consumption, the greater the reduction in severe hot flashes,” noted the researchers. Mean body weight also decreased by 3.6 kg in the intervention group and 0.2 kg in the control group (P < .001). “Equol-production status had no apparent effect on hot flashes,” they added.

The study is the second phase of WAVS, which comprises two parts, the first of which showed similar results, but was conducted in the fall, raising questions about whether cooler temperatures were partly responsible for the results. Phase 2 of WAVS enrolled participants in the spring “ruling out the effect of outside temperature,” noted the authors.

“Eating a healthy diet at midlife is so important for long-term health and a sense of well-being for peri- and postmenopausal women,” said Dr Reed, but she urged caution in interpreting the findings. “This was an unblinded study,” she told this news organization. “Women were recruited to this study anticipating that they would be in a study on a soy diet. Individuals who sign up for a study are hoping for benefit from the intervention. The controls who don’t get the soy diet are often disappointed, so there is no benefit from a nonblinded control arm for their hot flashes. And that is exactly what we saw here. Blinded studies can hide what you are getting, so everyone in the study (intervention and controls) has the same anticipated benefit.  But you cannot blind a soy diet.”

Dr. Reed also noted that, while the biologic mechanism of benefit should be equol production, this was not shown – given that both equol producers and nonproducers in the soy intervention reported marked symptom reduction.

“Only prior studies with estrogen interventions have observed reductions of hot flashes of the amount reported here,” she concluded. “Hopefully future large studies will clarify the role of soy diet for decreasing hot flashes.”

Dr. Barnard writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources. Dr. Reed has no relevant disclosures.

Women eating a reduced-fat vegan diet combined with a daily serving of soybeans experienced a 78% reduction in frequency of menopausal hot flashes over 12 weeks, in a small, nonblinded, randomized-controlled trial.

“We do not fully understand yet why this combination works, but it seems that these three elements are key: avoiding animal products, reducing fat, and adding a serving of soybeans,” lead researcher Neal Barnard, MD, explained in a press release. “These new results suggest that a diet change should be considered as a first-line treatment for troublesome vasomotor symptoms, including night sweats and hot flashes,” added Dr. Barnard, who is president of the Physicians Committee for Responsible Medicine, and adjunct professor at George Washington University, Washington. 

Elliott O’Donovan Photography

But, while “the findings from this very small study complement everything we know about the benefits of an excellent diet and the health benefits of soy,” they should be interpreted with some caution, commented Susan Reed, MD, president of the North American Menopause Society, and associate program director of the women’s reproductive research program at the University of Washington, Seattle.

For the trial, called WAVS (Women’s Study for the Alleviation of Vasomotor Symptoms), the researchers randomized 84 postmenopausal women with at least two moderate to severe hot flashes daily to either the intervention or usual diet, with a total of 71 subjects completing the 12-week study, published in Menopause. Criteria for exclusion included any cause of vasomotor symptoms other than natural menopause, current use of a low-fat, vegan diet that includes daily soy products, soy allergy, and body mass index < 18.5 kg/m².

Participants in the intervention group were asked to avoid animal-derived foods, minimize their use of oils and fatty foods such as nuts and avocados, and include half a cup (86 g) of cooked soybeans daily in their diets. They were also offered 1-hour virtual group meetings each week, in which a registered dietitian or research staff provided information on food preparation and managing common dietary challenges.

Control group participants were asked to continue their usual diets and attend four 1-hour group sessions.

At baseline and then after the 12-week study period, dietary intake was self-recorded for 2 weekdays and 1 weekend day, hot flash frequency and severity was recorded for 1 week using a mobile app, and the effect of menopausal symptoms on quality of life was measured using the vasomotor, psychosocial, physical, and sexual domains of the Menopause-Specific Quality of Life (MENQOL) questionnaire.

Equol production was also assessed in a subset of 15 intervention and 12 control participants who had urinary isoflavone concentrations measured after eating half a cup (86 g) of soybeans twice daily for 3 days. This was based on the theory that diets such as the intervention in this study “seem to foster the growth of gut bacteria capable of converting daidzein to equol,” noted the authors. The ability to produce equol is detected more frequently in individuals following vegetarian diets than in omnivores and … has been proposed as a factor in soy’s apparent health benefits.”

The study found that total hot flash frequency decreased by 78% in the intervention group (P < .001) and 39% (P < .001) in the control group (between-group P = .003), and moderate to severe hot flashes decreased by 88% versus 34%, respectively (from 5.0 to 0.6 per day, P < .001 vs. from 4.4 to 2.9 per day, P < .001; between-group P < .001). Among participants with at least seven moderate to severe hot flashes per day at baseline, moderate to severe hot flashes decreased by 93% (from 10.6 to 0.7 per day) in the intervention group (P < .001) and 36% (from 9.0 to 5.8 per day) in the control group (P = .01, between-group P < .001). The changes in hot flashes were paralleled by changes in the MENQOL findings, with significant between-group differences in the vasomotor (P = 0.004), physical (P = 0.01), and sexual (P = 0.03) domains.

Changes in frequency of severe hot flashes correlated directly with changes in fat intake, and inversely with changes in carbohydrate and fiber intake, such that “the greater the reduction in fat intake and the greater the increases in carbohydrate and fiber consumption, the greater the reduction in severe hot flashes,” noted the researchers. Mean body weight also decreased by 3.6 kg in the intervention group and 0.2 kg in the control group (P < .001). “Equol-production status had no apparent effect on hot flashes,” they added.

The study is the second phase of WAVS, which comprises two parts, the first of which showed similar results, but was conducted in the fall, raising questions about whether cooler temperatures were partly responsible for the results. Phase 2 of WAVS enrolled participants in the spring “ruling out the effect of outside temperature,” noted the authors.

“Eating a healthy diet at midlife is so important for long-term health and a sense of well-being for peri- and postmenopausal women,” said Dr Reed, but she urged caution in interpreting the findings. “This was an unblinded study,” she told this news organization. “Women were recruited to this study anticipating that they would be in a study on a soy diet. Individuals who sign up for a study are hoping for benefit from the intervention. The controls who don’t get the soy diet are often disappointed, so there is no benefit from a nonblinded control arm for their hot flashes. And that is exactly what we saw here. Blinded studies can hide what you are getting, so everyone in the study (intervention and controls) has the same anticipated benefit.  But you cannot blind a soy diet.”

Dr. Reed also noted that, while the biologic mechanism of benefit should be equol production, this was not shown – given that both equol producers and nonproducers in the soy intervention reported marked symptom reduction.

“Only prior studies with estrogen interventions have observed reductions of hot flashes of the amount reported here,” she concluded. “Hopefully future large studies will clarify the role of soy diet for decreasing hot flashes.”

Dr. Barnard writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources. Dr. Reed has no relevant disclosures.

Women eating a reduced-fat vegan diet combined with a daily serving of soybeans experienced a 78% reduction in frequency of menopausal hot flashes over 12 weeks, in a small, nonblinded, randomized-controlled trial.

“We do not fully understand yet why this combination works, but it seems that these three elements are key: avoiding animal products, reducing fat, and adding a serving of soybeans,” lead researcher Neal Barnard, MD, explained in a press release. “These new results suggest that a diet change should be considered as a first-line treatment for troublesome vasomotor symptoms, including night sweats and hot flashes,” added Dr. Barnard, who is president of the Physicians Committee for Responsible Medicine, and adjunct professor at George Washington University, Washington. 

Elliott O’Donovan Photography

But, while “the findings from this very small study complement everything we know about the benefits of an excellent diet and the health benefits of soy,” they should be interpreted with some caution, commented Susan Reed, MD, president of the North American Menopause Society, and associate program director of the women’s reproductive research program at the University of Washington, Seattle.

For the trial, called WAVS (Women’s Study for the Alleviation of Vasomotor Symptoms), the researchers randomized 84 postmenopausal women with at least two moderate to severe hot flashes daily to either the intervention or usual diet, with a total of 71 subjects completing the 12-week study, published in Menopause. Criteria for exclusion included any cause of vasomotor symptoms other than natural menopause, current use of a low-fat, vegan diet that includes daily soy products, soy allergy, and body mass index < 18.5 kg/m².

Participants in the intervention group were asked to avoid animal-derived foods, minimize their use of oils and fatty foods such as nuts and avocados, and include half a cup (86 g) of cooked soybeans daily in their diets. They were also offered 1-hour virtual group meetings each week, in which a registered dietitian or research staff provided information on food preparation and managing common dietary challenges.

Control group participants were asked to continue their usual diets and attend four 1-hour group sessions.

At baseline and then after the 12-week study period, dietary intake was self-recorded for 2 weekdays and 1 weekend day, hot flash frequency and severity was recorded for 1 week using a mobile app, and the effect of menopausal symptoms on quality of life was measured using the vasomotor, psychosocial, physical, and sexual domains of the Menopause-Specific Quality of Life (MENQOL) questionnaire.

Equol production was also assessed in a subset of 15 intervention and 12 control participants who had urinary isoflavone concentrations measured after eating half a cup (86 g) of soybeans twice daily for 3 days. This was based on the theory that diets such as the intervention in this study “seem to foster the growth of gut bacteria capable of converting daidzein to equol,” noted the authors. The ability to produce equol is detected more frequently in individuals following vegetarian diets than in omnivores and … has been proposed as a factor in soy’s apparent health benefits.”

The study found that total hot flash frequency decreased by 78% in the intervention group (P < .001) and 39% (P < .001) in the control group (between-group P = .003), and moderate to severe hot flashes decreased by 88% versus 34%, respectively (from 5.0 to 0.6 per day, P < .001 vs. from 4.4 to 2.9 per day, P < .001; between-group P < .001). Among participants with at least seven moderate to severe hot flashes per day at baseline, moderate to severe hot flashes decreased by 93% (from 10.6 to 0.7 per day) in the intervention group (P < .001) and 36% (from 9.0 to 5.8 per day) in the control group (P = .01, between-group P < .001). The changes in hot flashes were paralleled by changes in the MENQOL findings, with significant between-group differences in the vasomotor (P = 0.004), physical (P = 0.01), and sexual (P = 0.03) domains.

Changes in frequency of severe hot flashes correlated directly with changes in fat intake, and inversely with changes in carbohydrate and fiber intake, such that “the greater the reduction in fat intake and the greater the increases in carbohydrate and fiber consumption, the greater the reduction in severe hot flashes,” noted the researchers. Mean body weight also decreased by 3.6 kg in the intervention group and 0.2 kg in the control group (P < .001). “Equol-production status had no apparent effect on hot flashes,” they added.

The study is the second phase of WAVS, which comprises two parts, the first of which showed similar results, but was conducted in the fall, raising questions about whether cooler temperatures were partly responsible for the results. Phase 2 of WAVS enrolled participants in the spring “ruling out the effect of outside temperature,” noted the authors.

“Eating a healthy diet at midlife is so important for long-term health and a sense of well-being for peri- and postmenopausal women,” said Dr Reed, but she urged caution in interpreting the findings. “This was an unblinded study,” she told this news organization. “Women were recruited to this study anticipating that they would be in a study on a soy diet. Individuals who sign up for a study are hoping for benefit from the intervention. The controls who don’t get the soy diet are often disappointed, so there is no benefit from a nonblinded control arm for their hot flashes. And that is exactly what we saw here. Blinded studies can hide what you are getting, so everyone in the study (intervention and controls) has the same anticipated benefit.  But you cannot blind a soy diet.”

Dr. Reed also noted that, while the biologic mechanism of benefit should be equol production, this was not shown – given that both equol producers and nonproducers in the soy intervention reported marked symptom reduction.

“Only prior studies with estrogen interventions have observed reductions of hot flashes of the amount reported here,” she concluded. “Hopefully future large studies will clarify the role of soy diet for decreasing hot flashes.”

Dr. Barnard writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources. Dr. Reed has no relevant disclosures.

The relationship between estrogen levels and heart health makes it particularly important for clinicians to be aware of those patients who might be at risk for cardiovascular disease despite not having other traditional risk factors, according to a presentation Oct. 12 at the North American Menopause Society annual meeting in Atlanta.

”Endogenous estrogens are protective for cardiovascular disease in premenopausal women,” Chrisandra L. Shufelt, MD, chair of the division of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Fla., told attendees. Yet, “a substantial population of young women are dying prematurely from cardiovascular disease,” with rates of cardiovascular death increasing in women aged 35-44 even as rates have decreased in postmenopausal women and in men. One potential reason may be premature estrogen loss.

Dr. Shufelt reminded attendees of four major causes of premature estrogen loss: Natural premature menopause, surgical menopause, chemotherapy-induced menopause, and premature ovarian insufficiency. But she would go on to discuss a less widely recognized condition, functional hypothalamic amenorrhea, that also may be contributing to increased cardiovascular risk.

First, Dr. Shufelt reviewed the evidence supporting the relationship between estrogen and cardiovascular health, starting with the Framingham study’s findings that cardiovascular disease is approximately two to four times more common in postmenopausal women than in premenopausal women, depending on the age range.

“Menopause at an early age, particularly under the age of 40, matters,” Dr. Shufelt said. “So we should be discussing this with our patients.”

Surgical menopause makes a difference to cardiovascular health as well, she said. In women under age 35, for example, the risk of a nonfatal heart attack in those with a bilateral oophorectomy was 7.7 times greater than in women who retained both ovaries and their uterus, and 1.5 times greater in women who had a hysterectomy without bilateral oophorectomy.

In a 2019 study, surgical premature menopause was associated with an 87% increased risk of heart disease even after researchers accounted for age, cardiovascular risk factors, and some forms of hormone therapy. The increased risk from natural premature menopause, on the other hand, was lower – a 36% increased risk of heart disease – compared with those producing endogenous hormones. Although randomized controlled trials are unavailable and unlikely to be done, the Nurses’ Health Study and the Danish Nurses Cohort Study, both observational studies, found that heart disease risk was diminished in those taking hormone therapy after surgical premature menopause.

Recommendations for premature or early menopause, from a wide range of different medical societies including NAMS, are that women without contraindications be given estrogen-based hormone therapy until the average age of natural menopause. Though not included in the same guidance, research has also shown that estrogen after oophorectomy does not increase the risk of breast cancer in women with a BRCA1 mutation, Dr. Shufelt said. Hormone therapy for premature or early menopause should adequately replace the levels women have lost and that means younger menopausal women often need higher doses than what older women receive, such as 2 mg/day of oral estradiol rather than the standard doses of 0.5 or 1 mg/day.
 

Functional hypothalamic amenorrhea and cardiovascular risk

Dr. Shufelt then discussed functional hypothalamic amenorrhea (hypogonadotropic hypogonadism), a common type of secondary amenorrhea that affects at least 1.4 million U.S. women. Diagnosis includes lack of a period for at least 3 months in someone who previously menstruated plus lab values below 50 pg/mL for estradiol, below 10 mIU/L for follicle stimulating hormone, and below 10 mIU/L for luteinizing hormone. Causes of this reversible form of infertility can include stress, overexercising, undereating, or some combination of these, plus an underlying genetic predisposition.

“After ruling out polycystic ovary syndrome, prolactinoma, and thyroid dysfunction, clinicians need to consider the diagnosis of hypothalamic amenorrhea,” Dr. Shufelt said. This condition goes beyond low estrogen levels: Women have elevated cortisol, low thyroid levels, low leptin levels, and increased ghrelin.

”This is not going away,” Dr. Shufelt said, sharing data on stress levels among U.S. adults, particularly Gen Z and millennial adults, noting that the ongoing “national mental health crisis” may be contributing to functional hypothalamic amenorrhea.

A 2020 substudy from the Nurses’ Health Study II found an increased risk of premature death in those who didn’t have a period or always had irregular periods starting as early as 14-17 years old. The increased risk of premature death rose with age in those with irregular or absent cycles – a 37% higher risk in 18- to 22-year-olds and a 39% increased risk in 29- to 46-year-olds.

But clinicians aren’t adequately identifying the “phenotype of the hypothalamic women,” Dr. Shufelt said, despite research showing overlap between hypothalamic amenorrhea and a higher risk of cardiovascular disease. Hypothalamic amenorrhea is so understudied that the last original research on the topic was in 2008, Dr. Shufelt said in an interview. ”No research except mine has been done to evaluate heart health in these young women,” she said.

Dr. Shufelt described a study she led involving 30 women with functional hypothalamic amenorrhea, 29 women with normal menstrual cycles, and 30 women who were recently menopausal and not on hormone therapy. The women with hypothalamic amenorrhea had average stress levels but their depression scores were higher than those of the other two groups.

The results showed that women with hypothalamic amenorrhea had lower estradiol and leptin levels and higher testosterone levels compared with the control group, and they had higher cortisol levels than those of both groups. Despite having similar body mass indexes as the control and menopausal groups, women with hypothalamic amenorrhea had lower blood pressure than that of the other two groups, yet they had higher cholesterol levels than those of the control group. EndoPAT^© (Itamar Medical) testing showed that they had poor vascular function.

“In fact, one-third of the women [with hypothalamic amenorrhea] entered the trial with a diagnosis of what would be considered endothelial dysfunction,” Dr. Shufelt said. “Our results demonstrated significantly higher circulating levels of serum proinflammatory cytokines in the women with hypothalamic amenorrhea compared to eumenorrheic controls.”

Dr. Shufelt’s team then tested whether giving estradiol to the women with hypothalamic amenorrhea for 12 weeks would improve their vascular health, but they saw no significant differences between the women who received estrogen and those who received placebo.

“Endothelial function is partly mediated by estrogen, and it was expected that giving back estrogen would ‘fix’ the endothelium, but that is not what happened,” Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado at Denver, Aurora, said in interview. “The mechanisms that maintain vascular function in women are not limited to hormones,” said Dr. Santoro, who was not involved in Dr. Shufelt’s study but attended her lecture. “We need to think beyond the simple model of estrogen-good, no-estrogen-bad.”

Dr. Santoro noted how easy it is to overlook the women who may have cardiovascular risk because of hypothalamic amenorrhea.

“Because many women with functional hypothalamic amenorrhea are super athletic and do not have the typical features of people with cardiometabolic disease – such as glucose intolerance, obesity, abnormal cholesterol or triglycerides, or high blood pressure – clinicians tend to think of them as healthy and to think that simply giving back hormones will fix the problems with bone density and vascular function, but that is not enough,” Dr. Santoro said. “The cognitive-behavioral therapy model for treatment of women with functional hypothalamic amenorrhea addresses the stress-related factors that drive the disorder, and this needs to be considered the standard of care for treatment.”

Stephanie S. Faubion, MD, professor of medicine and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Fla., who was not involved in Dr. Shufelt’s presentation, also emphasized the importance of recognizing functional hypothalamic amenorrhea.

“This is an underrecognized entity to begin with, and the fact that these women appear to be at increased risk for vascular dysfunction and potentially increased risk for cardiovascular disease down the road makes it even more important for clinicians to identify them and provide interventions early on,” Dr. Faubion said in an interview. “These women need to be identified and the etiology of the amenorrhea addressed, whether it relates to overexercising, being underweight, or experiencing significant stressors that have led to the loss of menstrual cycles.”

Dr. Shufelt’s research was funded by the National Institutes of Health. She had no disclosures. Dr. Santoro is a member of the scientific advisory board for Astellas, Menogenix, Amazon Ember, and Que Oncology, and she consults for Ansh Labs. Dr. Faubion had no disclosures.

The relationship between estrogen levels and heart health makes it particularly important for clinicians to be aware of those patients who might be at risk for cardiovascular disease despite not having other traditional risk factors, according to a presentation Oct. 12 at the North American Menopause Society annual meeting in Atlanta.

”Endogenous estrogens are protective for cardiovascular disease in premenopausal women,” Chrisandra L. Shufelt, MD, chair of the division of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Fla., told attendees. Yet, “a substantial population of young women are dying prematurely from cardiovascular disease,” with rates of cardiovascular death increasing in women aged 35-44 even as rates have decreased in postmenopausal women and in men. One potential reason may be premature estrogen loss.

Dr. Shufelt reminded attendees of four major causes of premature estrogen loss: Natural premature menopause, surgical menopause, chemotherapy-induced menopause, and premature ovarian insufficiency. But she would go on to discuss a less widely recognized condition, functional hypothalamic amenorrhea, that also may be contributing to increased cardiovascular risk.

First, Dr. Shufelt reviewed the evidence supporting the relationship between estrogen and cardiovascular health, starting with the Framingham study’s findings that cardiovascular disease is approximately two to four times more common in postmenopausal women than in premenopausal women, depending on the age range.

“Menopause at an early age, particularly under the age of 40, matters,” Dr. Shufelt said. “So we should be discussing this with our patients.”

Surgical menopause makes a difference to cardiovascular health as well, she said. In women under age 35, for example, the risk of a nonfatal heart attack in those with a bilateral oophorectomy was 7.7 times greater than in women who retained both ovaries and their uterus, and 1.5 times greater in women who had a hysterectomy without bilateral oophorectomy.

In a 2019 study, surgical premature menopause was associated with an 87% increased risk of heart disease even after researchers accounted for age, cardiovascular risk factors, and some forms of hormone therapy. The increased risk from natural premature menopause, on the other hand, was lower – a 36% increased risk of heart disease – compared with those producing endogenous hormones. Although randomized controlled trials are unavailable and unlikely to be done, the Nurses’ Health Study and the Danish Nurses Cohort Study, both observational studies, found that heart disease risk was diminished in those taking hormone therapy after surgical premature menopause.

Recommendations for premature or early menopause, from a wide range of different medical societies including NAMS, are that women without contraindications be given estrogen-based hormone therapy until the average age of natural menopause. Though not included in the same guidance, research has also shown that estrogen after oophorectomy does not increase the risk of breast cancer in women with a BRCA1 mutation, Dr. Shufelt said. Hormone therapy for premature or early menopause should adequately replace the levels women have lost and that means younger menopausal women often need higher doses than what older women receive, such as 2 mg/day of oral estradiol rather than the standard doses of 0.5 or 1 mg/day.
 

Functional hypothalamic amenorrhea and cardiovascular risk

Dr. Shufelt then discussed functional hypothalamic amenorrhea (hypogonadotropic hypogonadism), a common type of secondary amenorrhea that affects at least 1.4 million U.S. women. Diagnosis includes lack of a period for at least 3 months in someone who previously menstruated plus lab values below 50 pg/mL for estradiol, below 10 mIU/L for follicle stimulating hormone, and below 10 mIU/L for luteinizing hormone. Causes of this reversible form of infertility can include stress, overexercising, undereating, or some combination of these, plus an underlying genetic predisposition.

“After ruling out polycystic ovary syndrome, prolactinoma, and thyroid dysfunction, clinicians need to consider the diagnosis of hypothalamic amenorrhea,” Dr. Shufelt said. This condition goes beyond low estrogen levels: Women have elevated cortisol, low thyroid levels, low leptin levels, and increased ghrelin.

”This is not going away,” Dr. Shufelt said, sharing data on stress levels among U.S. adults, particularly Gen Z and millennial adults, noting that the ongoing “national mental health crisis” may be contributing to functional hypothalamic amenorrhea.

A 2020 substudy from the Nurses’ Health Study II found an increased risk of premature death in those who didn’t have a period or always had irregular periods starting as early as 14-17 years old. The increased risk of premature death rose with age in those with irregular or absent cycles – a 37% higher risk in 18- to 22-year-olds and a 39% increased risk in 29- to 46-year-olds.

But clinicians aren’t adequately identifying the “phenotype of the hypothalamic women,” Dr. Shufelt said, despite research showing overlap between hypothalamic amenorrhea and a higher risk of cardiovascular disease. Hypothalamic amenorrhea is so understudied that the last original research on the topic was in 2008, Dr. Shufelt said in an interview. ”No research except mine has been done to evaluate heart health in these young women,” she said.

Dr. Shufelt described a study she led involving 30 women with functional hypothalamic amenorrhea, 29 women with normal menstrual cycles, and 30 women who were recently menopausal and not on hormone therapy. The women with hypothalamic amenorrhea had average stress levels but their depression scores were higher than those of the other two groups.

The results showed that women with hypothalamic amenorrhea had lower estradiol and leptin levels and higher testosterone levels compared with the control group, and they had higher cortisol levels than those of both groups. Despite having similar body mass indexes as the control and menopausal groups, women with hypothalamic amenorrhea had lower blood pressure than that of the other two groups, yet they had higher cholesterol levels than those of the control group. EndoPAT^© (Itamar Medical) testing showed that they had poor vascular function.

“In fact, one-third of the women [with hypothalamic amenorrhea] entered the trial with a diagnosis of what would be considered endothelial dysfunction,” Dr. Shufelt said. “Our results demonstrated significantly higher circulating levels of serum proinflammatory cytokines in the women with hypothalamic amenorrhea compared to eumenorrheic controls.”

Dr. Shufelt’s team then tested whether giving estradiol to the women with hypothalamic amenorrhea for 12 weeks would improve their vascular health, but they saw no significant differences between the women who received estrogen and those who received placebo.

“Endothelial function is partly mediated by estrogen, and it was expected that giving back estrogen would ‘fix’ the endothelium, but that is not what happened,” Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado at Denver, Aurora, said in interview. “The mechanisms that maintain vascular function in women are not limited to hormones,” said Dr. Santoro, who was not involved in Dr. Shufelt’s study but attended her lecture. “We need to think beyond the simple model of estrogen-good, no-estrogen-bad.”

Dr. Santoro noted how easy it is to overlook the women who may have cardiovascular risk because of hypothalamic amenorrhea.

“Because many women with functional hypothalamic amenorrhea are super athletic and do not have the typical features of people with cardiometabolic disease – such as glucose intolerance, obesity, abnormal cholesterol or triglycerides, or high blood pressure – clinicians tend to think of them as healthy and to think that simply giving back hormones will fix the problems with bone density and vascular function, but that is not enough,” Dr. Santoro said. “The cognitive-behavioral therapy model for treatment of women with functional hypothalamic amenorrhea addresses the stress-related factors that drive the disorder, and this needs to be considered the standard of care for treatment.”

Stephanie S. Faubion, MD, professor of medicine and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Fla., who was not involved in Dr. Shufelt’s presentation, also emphasized the importance of recognizing functional hypothalamic amenorrhea.

“This is an underrecognized entity to begin with, and the fact that these women appear to be at increased risk for vascular dysfunction and potentially increased risk for cardiovascular disease down the road makes it even more important for clinicians to identify them and provide interventions early on,” Dr. Faubion said in an interview. “These women need to be identified and the etiology of the amenorrhea addressed, whether it relates to overexercising, being underweight, or experiencing significant stressors that have led to the loss of menstrual cycles.”

Dr. Shufelt’s research was funded by the National Institutes of Health. She had no disclosures. Dr. Santoro is a member of the scientific advisory board for Astellas, Menogenix, Amazon Ember, and Que Oncology, and she consults for Ansh Labs. Dr. Faubion had no disclosures.

The relationship between estrogen levels and heart health makes it particularly important for clinicians to be aware of those patients who might be at risk for cardiovascular disease despite not having other traditional risk factors, according to a presentation Oct. 12 at the North American Menopause Society annual meeting in Atlanta.

”Endogenous estrogens are protective for cardiovascular disease in premenopausal women,” Chrisandra L. Shufelt, MD, chair of the division of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Fla., told attendees. Yet, “a substantial population of young women are dying prematurely from cardiovascular disease,” with rates of cardiovascular death increasing in women aged 35-44 even as rates have decreased in postmenopausal women and in men. One potential reason may be premature estrogen loss.

Dr. Shufelt reminded attendees of four major causes of premature estrogen loss: Natural premature menopause, surgical menopause, chemotherapy-induced menopause, and premature ovarian insufficiency. But she would go on to discuss a less widely recognized condition, functional hypothalamic amenorrhea, that also may be contributing to increased cardiovascular risk.

First, Dr. Shufelt reviewed the evidence supporting the relationship between estrogen and cardiovascular health, starting with the Framingham study’s findings that cardiovascular disease is approximately two to four times more common in postmenopausal women than in premenopausal women, depending on the age range.

“Menopause at an early age, particularly under the age of 40, matters,” Dr. Shufelt said. “So we should be discussing this with our patients.”

Surgical menopause makes a difference to cardiovascular health as well, she said. In women under age 35, for example, the risk of a nonfatal heart attack in those with a bilateral oophorectomy was 7.7 times greater than in women who retained both ovaries and their uterus, and 1.5 times greater in women who had a hysterectomy without bilateral oophorectomy.

In a 2019 study, surgical premature menopause was associated with an 87% increased risk of heart disease even after researchers accounted for age, cardiovascular risk factors, and some forms of hormone therapy. The increased risk from natural premature menopause, on the other hand, was lower – a 36% increased risk of heart disease – compared with those producing endogenous hormones. Although randomized controlled trials are unavailable and unlikely to be done, the Nurses’ Health Study and the Danish Nurses Cohort Study, both observational studies, found that heart disease risk was diminished in those taking hormone therapy after surgical premature menopause.

Recommendations for premature or early menopause, from a wide range of different medical societies including NAMS, are that women without contraindications be given estrogen-based hormone therapy until the average age of natural menopause. Though not included in the same guidance, research has also shown that estrogen after oophorectomy does not increase the risk of breast cancer in women with a BRCA1 mutation, Dr. Shufelt said. Hormone therapy for premature or early menopause should adequately replace the levels women have lost and that means younger menopausal women often need higher doses than what older women receive, such as 2 mg/day of oral estradiol rather than the standard doses of 0.5 or 1 mg/day.
 

Functional hypothalamic amenorrhea and cardiovascular risk

Dr. Shufelt then discussed functional hypothalamic amenorrhea (hypogonadotropic hypogonadism), a common type of secondary amenorrhea that affects at least 1.4 million U.S. women. Diagnosis includes lack of a period for at least 3 months in someone who previously menstruated plus lab values below 50 pg/mL for estradiol, below 10 mIU/L for follicle stimulating hormone, and below 10 mIU/L for luteinizing hormone. Causes of this reversible form of infertility can include stress, overexercising, undereating, or some combination of these, plus an underlying genetic predisposition.

“After ruling out polycystic ovary syndrome, prolactinoma, and thyroid dysfunction, clinicians need to consider the diagnosis of hypothalamic amenorrhea,” Dr. Shufelt said. This condition goes beyond low estrogen levels: Women have elevated cortisol, low thyroid levels, low leptin levels, and increased ghrelin.

”This is not going away,” Dr. Shufelt said, sharing data on stress levels among U.S. adults, particularly Gen Z and millennial adults, noting that the ongoing “national mental health crisis” may be contributing to functional hypothalamic amenorrhea.

A 2020 substudy from the Nurses’ Health Study II found an increased risk of premature death in those who didn’t have a period or always had irregular periods starting as early as 14-17 years old. The increased risk of premature death rose with age in those with irregular or absent cycles – a 37% higher risk in 18- to 22-year-olds and a 39% increased risk in 29- to 46-year-olds.

But clinicians aren’t adequately identifying the “phenotype of the hypothalamic women,” Dr. Shufelt said, despite research showing overlap between hypothalamic amenorrhea and a higher risk of cardiovascular disease. Hypothalamic amenorrhea is so understudied that the last original research on the topic was in 2008, Dr. Shufelt said in an interview. ”No research except mine has been done to evaluate heart health in these young women,” she said.

Dr. Shufelt described a study she led involving 30 women with functional hypothalamic amenorrhea, 29 women with normal menstrual cycles, and 30 women who were recently menopausal and not on hormone therapy. The women with hypothalamic amenorrhea had average stress levels but their depression scores were higher than those of the other two groups.

The results showed that women with hypothalamic amenorrhea had lower estradiol and leptin levels and higher testosterone levels compared with the control group, and they had higher cortisol levels than those of both groups. Despite having similar body mass indexes as the control and menopausal groups, women with hypothalamic amenorrhea had lower blood pressure than that of the other two groups, yet they had higher cholesterol levels than those of the control group. EndoPAT^© (Itamar Medical) testing showed that they had poor vascular function.

“In fact, one-third of the women [with hypothalamic amenorrhea] entered the trial with a diagnosis of what would be considered endothelial dysfunction,” Dr. Shufelt said. “Our results demonstrated significantly higher circulating levels of serum proinflammatory cytokines in the women with hypothalamic amenorrhea compared to eumenorrheic controls.”

Dr. Shufelt’s team then tested whether giving estradiol to the women with hypothalamic amenorrhea for 12 weeks would improve their vascular health, but they saw no significant differences between the women who received estrogen and those who received placebo.

“Endothelial function is partly mediated by estrogen, and it was expected that giving back estrogen would ‘fix’ the endothelium, but that is not what happened,” Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado at Denver, Aurora, said in interview. “The mechanisms that maintain vascular function in women are not limited to hormones,” said Dr. Santoro, who was not involved in Dr. Shufelt’s study but attended her lecture. “We need to think beyond the simple model of estrogen-good, no-estrogen-bad.”

Dr. Santoro noted how easy it is to overlook the women who may have cardiovascular risk because of hypothalamic amenorrhea.

“Because many women with functional hypothalamic amenorrhea are super athletic and do not have the typical features of people with cardiometabolic disease – such as glucose intolerance, obesity, abnormal cholesterol or triglycerides, or high blood pressure – clinicians tend to think of them as healthy and to think that simply giving back hormones will fix the problems with bone density and vascular function, but that is not enough,” Dr. Santoro said. “The cognitive-behavioral therapy model for treatment of women with functional hypothalamic amenorrhea addresses the stress-related factors that drive the disorder, and this needs to be considered the standard of care for treatment.”

Stephanie S. Faubion, MD, professor of medicine and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Fla., who was not involved in Dr. Shufelt’s presentation, also emphasized the importance of recognizing functional hypothalamic amenorrhea.

“This is an underrecognized entity to begin with, and the fact that these women appear to be at increased risk for vascular dysfunction and potentially increased risk for cardiovascular disease down the road makes it even more important for clinicians to identify them and provide interventions early on,” Dr. Faubion said in an interview. “These women need to be identified and the etiology of the amenorrhea addressed, whether it relates to overexercising, being underweight, or experiencing significant stressors that have led to the loss of menstrual cycles.”

Dr. Shufelt’s research was funded by the National Institutes of Health. She had no disclosures. Dr. Santoro is a member of the scientific advisory board for Astellas, Menogenix, Amazon Ember, and Que Oncology, and she consults for Ansh Labs. Dr. Faubion had no disclosures.

The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.

The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.

”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.

”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.

Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.

Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”

This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.

The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.

Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.

”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.

The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.

Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.

”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.

”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”

The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.

The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.

The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.

”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.

”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.

Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.

Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”

This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.

The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.

Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.

”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.

The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.

Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.

”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.

”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”

The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.

The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.

The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.

”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.

”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.

Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.

Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”

This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.

The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.

Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.

”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.

The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.

Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.

”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.

”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”

The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.

Symptoms of menopause can significantly disrupt a woman’s ability to work, according to a cross-sectional study presented at the annual meeting of the North American Menopause Society.

The study, by researchers at the Mayo Clinic, found that roughly one in eight women said issues stemming from menopause caused them to miss multiple days of work; reduce hours on the job; and even quit, retire, or be laid off.

“We were shocked to see the significant impact of menopause symptoms in the workplace,” Ekta Kapoor, MD, an associate professor of medicine at the Mayo Clinic in Rochester, Minn. said in an interview. “The potential economic impact of untreated menopause symptoms at the workplace is mind-boggling.”

The findings represent an opportunity to improve the treatment of menopause symptoms in working women and “draw attention to the need for creation of workplace policies that include education of employers, managers, and supervisors in order to support midlife women during this universal life stage transition,” Dr. Kapoor added.

Laurie Jeffers, DNP, certified menopause practitioner and codirector of the Center for Midlife Health and Menopause within the department of obstetrics & gynecology at New York University Langone Health, said the findings agree with the results of previous studies from the Netherlands and elsewhere.

“We know that across different studies up to 80% of women during the menopause transition and early post menopause will have high symptom burden, with vasomotor symptoms being the most common,” Dr. Jeffers said. “Psychological symptoms were notably significant in this study, which is also not surprising given that there can be an exacerbation of anxiety or depression during the menopausal transition due to the variability of hormonal activity during this time.”
 

4,400 women surveyed

Dr. Kapoor and colleagues analyzed data from 4,440 currently employed women, ages 45-60, who were enrolled in the Mayo Clinic Registry of Midlife Women and completed an online questionnaire between March and June 2021 about their menopause symptoms and the symptoms’ effects on their work. The participants all receive their primary care at one of four Mayo Clinic sites in Rochester; Scottsdale, Ariz.; Jacksonville, Fla.; and northwest Wisconsin.

The researchers defined an adverse outcome from a menopausal symptom as one that directly caused women to miss a day from work in the past year or, within the past 6 months, to cut back on work hours, to experience a layoff or job termination, or to quit, retire or change jobs.

Most of the respondents were White (95%), married (77%), and had at least a college degree (59%), and their average age was 54. Their overall average Menopause Rating Scale (MRS) score – including somatic, psychological, and urogenital domains – was 23.1, which indicated a severe level of menopause symptoms.

More than one in eight women (13%) reported having at least one adverse outcome because of menopause symptoms, most commonly missing work (11%).

The women reported missing an average 3 days of work because of menopause symptoms. About half as many (6%) reported cutting back on hours at work in the past 6 months. A small percentage reported being laid off in the past 6 months (0.3%), or quitting, retiring, or changing jobs in the past 6 months (1%) because of menopause symptoms.

Menopause symptoms may well be contributing to the gender wage gap, Dr. Kapoor said, in the same way that other factors affect women’s overall earnings, such as taking time off for having or raising a family, being responsible for a large share of housework, and taking on more mentoring or teaching roles that aren’t as highly valued at work.

“Women going through the menopause transition, and those who are postmenopausal, are at important stages of their careers,” Dr. Kapoor said. “They are often seeking, or already in leadership positions. Any impediments at this important stage in their professional lives can prove to be very costly, resulting in missed opportunities for promotion and leadership roles.”

Unsurprisingly, the higher a woman’s MRS score, the more likely she was to report an adverse work outcome, regardless of the symptom. For example, women whose symptom severity ranked in the top 25% overall were 15.6 times more likely to have an adverse work experience than those with the lowest level of symptoms (P < .001). Psychological symptoms had the greatest effect on work. Women whose psychological symptoms ranked in the top 25% in terms of severity were 21 times more likely to have an adverse work effect, compared with those with the lowest level of severity, according to the researchers.

The results echo findings from a recent survey from Carrot Fertility of 1,000 women, ages 40-55, about the effects of menopause on their careers. In that survey, 79% of respondents described working during menopause as more challenging than other common life stages and life experiences, including starting a new job, starting a family or getting a promotion.

Yet 77% of women felt uncomfortable talking with executives about the problem, and 63% didn’t feel comfortable talking to human resources about the issue. More than half (58%) didn’t want to discuss it with their immediate supervisor. Only 8% said their employer has offered significant support for menopause.

“Menopause symptoms continue to be undertreated for a variety of reasons [and] impact multiple aspects of a woman’s life, including her performance in the workplace,” Dr. Kapoor said. “In addition to focusing our attention on adequate treatment of menopause symptoms, we need advocacy for creation of workplace policies that can help women navigate this important and universal stage of their lives.”

Those policies might include education about menopause to increase knowledge and awareness among employers and managers, Dr. Kapoor said. She also noted the need to improve communication with women in discussing appropriate support and work adjustments during menopause.

"There is also evidence that less than 20%-30% of women seek help for their symptoms,” Dr. Jeffers said. “There are a variety of evidence-based hormonal and nonhormonal options available to ease these symptoms, and knowledgeable clinical management of these symptoms can favorably impact this transition. This study is interesting in that the population of women surveyed presumably had access to high-quality health resources and yet still had a high symptom burden.”

Dr. Kapoor cautioned that the data collection occurred in the midst of the COVID-19 pandemic, “which may have heightened the adverse experiences of women at the workplace. On the other hand, many of these women may have been working from home, which may have made their menopause experience more favorable than it would have been had they been working in actual offices,” thereby again underrepresenting the problem.

Dr. Kapoor added that the study population may not be representative since they all received treatment at a tertiary health care center and were almost all White women.

“Perhaps the impact of menopause symptoms in the minority populations and the community is even greater,” Dr. Kapoor said. “Our data might be underrepresenting the extent of the problem.”

The research did not use external funding. Dr. Kapoor has received grant support from Mithra Pharmaceuticals and consulted for Astellas, Mithra Pharmaceuticals, Scynexis, and Womaness. Dr. Jeffers had no disclosures.

*This story was updated on Nov. 28, 2022.

Symptoms of menopause can significantly disrupt a woman’s ability to work, according to a cross-sectional study presented at the annual meeting of the North American Menopause Society.

The study, by researchers at the Mayo Clinic, found that roughly one in eight women said issues stemming from menopause caused them to miss multiple days of work; reduce hours on the job; and even quit, retire, or be laid off.

“We were shocked to see the significant impact of menopause symptoms in the workplace,” Ekta Kapoor, MD, an associate professor of medicine at the Mayo Clinic in Rochester, Minn. said in an interview. “The potential economic impact of untreated menopause symptoms at the workplace is mind-boggling.”

The findings represent an opportunity to improve the treatment of menopause symptoms in working women and “draw attention to the need for creation of workplace policies that include education of employers, managers, and supervisors in order to support midlife women during this universal life stage transition,” Dr. Kapoor added.

Laurie Jeffers, DNP, certified menopause practitioner and codirector of the Center for Midlife Health and Menopause within the department of obstetrics & gynecology at New York University Langone Health, said the findings agree with the results of previous studies from the Netherlands and elsewhere.

“We know that across different studies up to 80% of women during the menopause transition and early post menopause will have high symptom burden, with vasomotor symptoms being the most common,” Dr. Jeffers said. “Psychological symptoms were notably significant in this study, which is also not surprising given that there can be an exacerbation of anxiety or depression during the menopausal transition due to the variability of hormonal activity during this time.”
 

4,400 women surveyed

Dr. Kapoor and colleagues analyzed data from 4,440 currently employed women, ages 45-60, who were enrolled in the Mayo Clinic Registry of Midlife Women and completed an online questionnaire between March and June 2021 about their menopause symptoms and the symptoms’ effects on their work. The participants all receive their primary care at one of four Mayo Clinic sites in Rochester; Scottsdale, Ariz.; Jacksonville, Fla.; and northwest Wisconsin.

The researchers defined an adverse outcome from a menopausal symptom as one that directly caused women to miss a day from work in the past year or, within the past 6 months, to cut back on work hours, to experience a layoff or job termination, or to quit, retire or change jobs.

Most of the respondents were White (95%), married (77%), and had at least a college degree (59%), and their average age was 54. Their overall average Menopause Rating Scale (MRS) score – including somatic, psychological, and urogenital domains – was 23.1, which indicated a severe level of menopause symptoms.

More than one in eight women (13%) reported having at least one adverse outcome because of menopause symptoms, most commonly missing work (11%).

The women reported missing an average 3 days of work because of menopause symptoms. About half as many (6%) reported cutting back on hours at work in the past 6 months. A small percentage reported being laid off in the past 6 months (0.3%), or quitting, retiring, or changing jobs in the past 6 months (1%) because of menopause symptoms.

Menopause symptoms may well be contributing to the gender wage gap, Dr. Kapoor said, in the same way that other factors affect women’s overall earnings, such as taking time off for having or raising a family, being responsible for a large share of housework, and taking on more mentoring or teaching roles that aren’t as highly valued at work.

“Women going through the menopause transition, and those who are postmenopausal, are at important stages of their careers,” Dr. Kapoor said. “They are often seeking, or already in leadership positions. Any impediments at this important stage in their professional lives can prove to be very costly, resulting in missed opportunities for promotion and leadership roles.”

Unsurprisingly, the higher a woman’s MRS score, the more likely she was to report an adverse work outcome, regardless of the symptom. For example, women whose symptom severity ranked in the top 25% overall were 15.6 times more likely to have an adverse work experience than those with the lowest level of symptoms (P < .001). Psychological symptoms had the greatest effect on work. Women whose psychological symptoms ranked in the top 25% in terms of severity were 21 times more likely to have an adverse work effect, compared with those with the lowest level of severity, according to the researchers.

The results echo findings from a recent survey from Carrot Fertility of 1,000 women, ages 40-55, about the effects of menopause on their careers. In that survey, 79% of respondents described working during menopause as more challenging than other common life stages and life experiences, including starting a new job, starting a family or getting a promotion.

Yet 77% of women felt uncomfortable talking with executives about the problem, and 63% didn’t feel comfortable talking to human resources about the issue. More than half (58%) didn’t want to discuss it with their immediate supervisor. Only 8% said their employer has offered significant support for menopause.

“Menopause symptoms continue to be undertreated for a variety of reasons [and] impact multiple aspects of a woman’s life, including her performance in the workplace,” Dr. Kapoor said. “In addition to focusing our attention on adequate treatment of menopause symptoms, we need advocacy for creation of workplace policies that can help women navigate this important and universal stage of their lives.”

Those policies might include education about menopause to increase knowledge and awareness among employers and managers, Dr. Kapoor said. She also noted the need to improve communication with women in discussing appropriate support and work adjustments during menopause.

"There is also evidence that less than 20%-30% of women seek help for their symptoms,” Dr. Jeffers said. “There are a variety of evidence-based hormonal and nonhormonal options available to ease these symptoms, and knowledgeable clinical management of these symptoms can favorably impact this transition. This study is interesting in that the population of women surveyed presumably had access to high-quality health resources and yet still had a high symptom burden.”

Dr. Kapoor cautioned that the data collection occurred in the midst of the COVID-19 pandemic, “which may have heightened the adverse experiences of women at the workplace. On the other hand, many of these women may have been working from home, which may have made their menopause experience more favorable than it would have been had they been working in actual offices,” thereby again underrepresenting the problem.

Dr. Kapoor added that the study population may not be representative since they all received treatment at a tertiary health care center and were almost all White women.

“Perhaps the impact of menopause symptoms in the minority populations and the community is even greater,” Dr. Kapoor said. “Our data might be underrepresenting the extent of the problem.”

The research did not use external funding. Dr. Kapoor has received grant support from Mithra Pharmaceuticals and consulted for Astellas, Mithra Pharmaceuticals, Scynexis, and Womaness. Dr. Jeffers had no disclosures.

*This story was updated on Nov. 28, 2022.

Symptoms of menopause can significantly disrupt a woman’s ability to work, according to a cross-sectional study presented at the annual meeting of the North American Menopause Society.

The study, by researchers at the Mayo Clinic, found that roughly one in eight women said issues stemming from menopause caused them to miss multiple days of work; reduce hours on the job; and even quit, retire, or be laid off.

“We were shocked to see the significant impact of menopause symptoms in the workplace,” Ekta Kapoor, MD, an associate professor of medicine at the Mayo Clinic in Rochester, Minn. said in an interview. “The potential economic impact of untreated menopause symptoms at the workplace is mind-boggling.”

The findings represent an opportunity to improve the treatment of menopause symptoms in working women and “draw attention to the need for creation of workplace policies that include education of employers, managers, and supervisors in order to support midlife women during this universal life stage transition,” Dr. Kapoor added.

Laurie Jeffers, DNP, certified menopause practitioner and codirector of the Center for Midlife Health and Menopause within the department of obstetrics & gynecology at New York University Langone Health, said the findings agree with the results of previous studies from the Netherlands and elsewhere.

“We know that across different studies up to 80% of women during the menopause transition and early post menopause will have high symptom burden, with vasomotor symptoms being the most common,” Dr. Jeffers said. “Psychological symptoms were notably significant in this study, which is also not surprising given that there can be an exacerbation of anxiety or depression during the menopausal transition due to the variability of hormonal activity during this time.”
 

4,400 women surveyed

Dr. Kapoor and colleagues analyzed data from 4,440 currently employed women, ages 45-60, who were enrolled in the Mayo Clinic Registry of Midlife Women and completed an online questionnaire between March and June 2021 about their menopause symptoms and the symptoms’ effects on their work. The participants all receive their primary care at one of four Mayo Clinic sites in Rochester; Scottsdale, Ariz.; Jacksonville, Fla.; and northwest Wisconsin.

The researchers defined an adverse outcome from a menopausal symptom as one that directly caused women to miss a day from work in the past year or, within the past 6 months, to cut back on work hours, to experience a layoff or job termination, or to quit, retire or change jobs.

Most of the respondents were White (95%), married (77%), and had at least a college degree (59%), and their average age was 54. Their overall average Menopause Rating Scale (MRS) score – including somatic, psychological, and urogenital domains – was 23.1, which indicated a severe level of menopause symptoms.

More than one in eight women (13%) reported having at least one adverse outcome because of menopause symptoms, most commonly missing work (11%).

The women reported missing an average 3 days of work because of menopause symptoms. About half as many (6%) reported cutting back on hours at work in the past 6 months. A small percentage reported being laid off in the past 6 months (0.3%), or quitting, retiring, or changing jobs in the past 6 months (1%) because of menopause symptoms.

Menopause symptoms may well be contributing to the gender wage gap, Dr. Kapoor said, in the same way that other factors affect women’s overall earnings, such as taking time off for having or raising a family, being responsible for a large share of housework, and taking on more mentoring or teaching roles that aren’t as highly valued at work.

“Women going through the menopause transition, and those who are postmenopausal, are at important stages of their careers,” Dr. Kapoor said. “They are often seeking, or already in leadership positions. Any impediments at this important stage in their professional lives can prove to be very costly, resulting in missed opportunities for promotion and leadership roles.”

Unsurprisingly, the higher a woman’s MRS score, the more likely she was to report an adverse work outcome, regardless of the symptom. For example, women whose symptom severity ranked in the top 25% overall were 15.6 times more likely to have an adverse work experience than those with the lowest level of symptoms (P < .001). Psychological symptoms had the greatest effect on work. Women whose psychological symptoms ranked in the top 25% in terms of severity were 21 times more likely to have an adverse work effect, compared with those with the lowest level of severity, according to the researchers.

The results echo findings from a recent survey from Carrot Fertility of 1,000 women, ages 40-55, about the effects of menopause on their careers. In that survey, 79% of respondents described working during menopause as more challenging than other common life stages and life experiences, including starting a new job, starting a family or getting a promotion.

Yet 77% of women felt uncomfortable talking with executives about the problem, and 63% didn’t feel comfortable talking to human resources about the issue. More than half (58%) didn’t want to discuss it with their immediate supervisor. Only 8% said their employer has offered significant support for menopause.

“Menopause symptoms continue to be undertreated for a variety of reasons [and] impact multiple aspects of a woman’s life, including her performance in the workplace,” Dr. Kapoor said. “In addition to focusing our attention on adequate treatment of menopause symptoms, we need advocacy for creation of workplace policies that can help women navigate this important and universal stage of their lives.”

Those policies might include education about menopause to increase knowledge and awareness among employers and managers, Dr. Kapoor said. She also noted the need to improve communication with women in discussing appropriate support and work adjustments during menopause.

"There is also evidence that less than 20%-30% of women seek help for their symptoms,” Dr. Jeffers said. “There are a variety of evidence-based hormonal and nonhormonal options available to ease these symptoms, and knowledgeable clinical management of these symptoms can favorably impact this transition. This study is interesting in that the population of women surveyed presumably had access to high-quality health resources and yet still had a high symptom burden.”

Dr. Kapoor cautioned that the data collection occurred in the midst of the COVID-19 pandemic, “which may have heightened the adverse experiences of women at the workplace. On the other hand, many of these women may have been working from home, which may have made their menopause experience more favorable than it would have been had they been working in actual offices,” thereby again underrepresenting the problem.

Dr. Kapoor added that the study population may not be representative since they all received treatment at a tertiary health care center and were almost all White women.

“Perhaps the impact of menopause symptoms in the minority populations and the community is even greater,” Dr. Kapoor said. “Our data might be underrepresenting the extent of the problem.”

The research did not use external funding. Dr. Kapoor has received grant support from Mithra Pharmaceuticals and consulted for Astellas, Mithra Pharmaceuticals, Scynexis, and Womaness. Dr. Jeffers had no disclosures.

*This story was updated on Nov. 28, 2022.

Despite a lack of evidence and high cost, laser therapy continues to attract many women seeking “vaginal rejuvenation” to help reverse the physical symptoms of menopause.

Recent reviews of the medical literature continue to show that laser treatment appears to be less effective than estrogen at improving vaginal dryness and pain during sex, according to Cheryl B. Iglesia, MD, a professor of ob.gyn. and urology at Georgetown University, Washington.

“Laser for GSM [genitourinary syndrome of menopause] is showing some promise, but patients need to be offered [Food and Drug Administration]–approved treatments prior to considering laser, and users need to know how to do speculum and pelvic exams and understand vulvovaginal anatomy and pathology,” Dr. Iglesia, who directs the section of female pelvic medicine and reconstructive surgery at MedStar Washington Hospital Center, said in an interview, adding that patients should avoid “vaginal rejuvenation” treatments offered at med-spas.

Dr. Iglesia reviewed how these lasers work and then discussed the controversy over their marketing and the evidence for their use at the annual meeting of the North American Menopause Society.

By 3 years after menopause, more than half of women experience atrophy in their vagina resulting from a lack of estrogen. Marked by a thinning of the epithelium, reduced blood supply, and loss of glycogen, vulvovaginal atrophy is to blame for GSM.

Vaginal laser therapy has been a popular option for women for the last decade, despite a lack of evidence supporting its use or approval from regulators.

The FDA has issued broad clearance for laser therapy for incision, ablation, vaporization, and coagulation of body soft tissues, such as dysplasia, vulvar or anal neoplasia, endometriosis, condylomas, and other disorders. However, the agency has not approved the use of laser therapy for vulvovaginal atrophy, GSM, vaginal dryness, or dyspareunia.
 

Evidence regarding vaginal laser therapy

According to Dr. Iglesia, the evidence for vaginal laser therapy is mixed and of generally low quality. A systematic review published in the Journal of Sexual Medicine (2022 Jan 29. doi: 10.1016/j.jsxm.2021.12.010) presented mostly low-quality evidence from 25 studies and found promising data for genitourinary symptoms but not enough to justify its use for genitourinary symptoms just yet. Dr. Iglesia discussed her own small, multisite study of 62 participants, which compared vaginal laser with vaginal estrogen and found no differences between the two for multiple outcomes. (The study would have been larger if not for interruption from an FDA warning for an Investigational Device Exemption.)

A JAMA study from Australia found no difference between laser therapy and sham laser therapy, but the most recent systematic review, from JAMA Network Open, found no significant difference between vaginal laser and vaginal estrogen for vaginal and sexual function symptoms. This review, however, covered only the six existing randomized controlled trials, including Dr. Iglesia’s, which were small and had a follow-up period of only 3-6 months.

“There have only been a few randomized controlled trials comparing laser to vaginal estrogen therapy, and most of those did not include a placebo or sham arm,” Monica Christmas, MD, director of the Center for Women’s Integrated Health at the University of Chicago Medicine, said in an interview. “This is extremely important, as most of the trials that did include a sham arm did not find that laser was better than the sham.” Dr. Christmas was not a part of the presentation but attended it at NAMS.

The bottom line, she said, is that “current evidence is not sufficient to make conclusions on long-term safety or sustainability, nor is there compelling evidence to make claims on equivalence to vaginal estrogen therapy.” Currently, committee opinions from a half-dozen medical societies, including NAMS, oppose using vaginal laser therapy until rigorous, robust trials on long-term safety and efficacy have been conducted. The International Continence Society and International Society for the Study of Vulvovaginal Disease issued a joint statement in 2018 that emphasized that histologic changes from lasers do not necessarily equate with changes in function. The statement noted the lack of evidence for laser treatment of incontinence and prolapse and stated that it should not be used for vulvodynia or lichen sclerosus.

A 2020 statement from NAMS found “insufficient placebo-controlled trials of energy-based therapies, including laser, to draw conclusions of efficacy or safety or to make treatment recommendations.” A slightly more optimistic statement from the American Urogynecologic Society concluded that energy-based devices have shown short-term efficacy for menopause-related vaginal atrophy and dyspareunia, including effects lasting up to 1 year from fractionated laser for treat dyspareunia, but also noted that studies up to that time were small and measure various outcomes.
 

Recommendations on vaginal laser therapy

Given this landscape of uneven and poor-quality evidence, Dr. Iglesia provided several “common sense” recommendations for energy-based therapies, starting with the need for any practitioner to have working knowledge of vulvovaginal anatomy. Contraindications for laser therapy include any malignancy – especially gynecologic – undiagnosed bleeding, active herpes or other infections, radiation, and vaginal mesh, particularly transvaginal mesh. The provider also must discuss the limited data on long-term function and treatment alternatives, including FDA-approved therapies like topical estrogen, dehydroepiandrosterone sulfate (DHEA-S), ospemifene, and moisturizers, Dr. Iglesia said.

Adverse events associated with laser therapy, such as scarring or burning, are rare but do occur, and cost remains an issue, Dr. Iglesia said.

“Vaginal estrogen therapy is well established as a safe and effective treatment option based on high quality evidence,” Dr. Christmas said. “This is not the case for laser therapy. Rare, but serious harms are reported with vaginal laser, including burns, scarring, dyspareunia, pain, and potential irreversible damage.”

Dr. Iglesia also cautioned that clinicians should take extra care with vulnerable populations, particularly cancer patients and others with contraindications for estrogen treatment.

For those in whom vaginal estrogen is contraindicated, Dr. Christmas recommended vaginal moisturizers, lubricants, dilators, and physical therapy for the pelvic floor.

“In patients who fail those nonhormonal approaches, short courses of vaginal estrogen therapy or DHEA-S suppository may be employed with approval from their oncologist,” Dr. Christmas said.

Dr. Iglesia finally reviewed the major research questions that remain with laser therapy:

• What are outcomes for laser versus sham studies?
• What are long-term outcomes (beyond 6 months)
• What pretreatment is necessary?
• Could laser be used as a drug delivery mechanism for estrogen, and could this provide a synergistic effect?
• What is the optimal number and interval for laser treatments?

Dr. Iglesia had no industry disclosures but received honoraria for consulting at UpToDate. Dr. Christmas is a consultant for Materna. The presentation did not rely on any external funding.

Despite a lack of evidence and high cost, laser therapy continues to attract many women seeking “vaginal rejuvenation” to help reverse the physical symptoms of menopause.

Recent reviews of the medical literature continue to show that laser treatment appears to be less effective than estrogen at improving vaginal dryness and pain during sex, according to Cheryl B. Iglesia, MD, a professor of ob.gyn. and urology at Georgetown University, Washington.

“Laser for GSM [genitourinary syndrome of menopause] is showing some promise, but patients need to be offered [Food and Drug Administration]–approved treatments prior to considering laser, and users need to know how to do speculum and pelvic exams and understand vulvovaginal anatomy and pathology,” Dr. Iglesia, who directs the section of female pelvic medicine and reconstructive surgery at MedStar Washington Hospital Center, said in an interview, adding that patients should avoid “vaginal rejuvenation” treatments offered at med-spas.

Dr. Iglesia reviewed how these lasers work and then discussed the controversy over their marketing and the evidence for their use at the annual meeting of the North American Menopause Society.

By 3 years after menopause, more than half of women experience atrophy in their vagina resulting from a lack of estrogen. Marked by a thinning of the epithelium, reduced blood supply, and loss of glycogen, vulvovaginal atrophy is to blame for GSM.

Vaginal laser therapy has been a popular option for women for the last decade, despite a lack of evidence supporting its use or approval from regulators.

The FDA has issued broad clearance for laser therapy for incision, ablation, vaporization, and coagulation of body soft tissues, such as dysplasia, vulvar or anal neoplasia, endometriosis, condylomas, and other disorders. However, the agency has not approved the use of laser therapy for vulvovaginal atrophy, GSM, vaginal dryness, or dyspareunia.
 

Evidence regarding vaginal laser therapy

According to Dr. Iglesia, the evidence for vaginal laser therapy is mixed and of generally low quality. A systematic review published in the Journal of Sexual Medicine (2022 Jan 29. doi: 10.1016/j.jsxm.2021.12.010) presented mostly low-quality evidence from 25 studies and found promising data for genitourinary symptoms but not enough to justify its use for genitourinary symptoms just yet. Dr. Iglesia discussed her own small, multisite study of 62 participants, which compared vaginal laser with vaginal estrogen and found no differences between the two for multiple outcomes. (The study would have been larger if not for interruption from an FDA warning for an Investigational Device Exemption.)

A JAMA study from Australia found no difference between laser therapy and sham laser therapy, but the most recent systematic review, from JAMA Network Open, found no significant difference between vaginal laser and vaginal estrogen for vaginal and sexual function symptoms. This review, however, covered only the six existing randomized controlled trials, including Dr. Iglesia’s, which were small and had a follow-up period of only 3-6 months.

“There have only been a few randomized controlled trials comparing laser to vaginal estrogen therapy, and most of those did not include a placebo or sham arm,” Monica Christmas, MD, director of the Center for Women’s Integrated Health at the University of Chicago Medicine, said in an interview. “This is extremely important, as most of the trials that did include a sham arm did not find that laser was better than the sham.” Dr. Christmas was not a part of the presentation but attended it at NAMS.

The bottom line, she said, is that “current evidence is not sufficient to make conclusions on long-term safety or sustainability, nor is there compelling evidence to make claims on equivalence to vaginal estrogen therapy.” Currently, committee opinions from a half-dozen medical societies, including NAMS, oppose using vaginal laser therapy until rigorous, robust trials on long-term safety and efficacy have been conducted. The International Continence Society and International Society for the Study of Vulvovaginal Disease issued a joint statement in 2018 that emphasized that histologic changes from lasers do not necessarily equate with changes in function. The statement noted the lack of evidence for laser treatment of incontinence and prolapse and stated that it should not be used for vulvodynia or lichen sclerosus.

A 2020 statement from NAMS found “insufficient placebo-controlled trials of energy-based therapies, including laser, to draw conclusions of efficacy or safety or to make treatment recommendations.” A slightly more optimistic statement from the American Urogynecologic Society concluded that energy-based devices have shown short-term efficacy for menopause-related vaginal atrophy and dyspareunia, including effects lasting up to 1 year from fractionated laser for treat dyspareunia, but also noted that studies up to that time were small and measure various outcomes.
 

Recommendations on vaginal laser therapy

Given this landscape of uneven and poor-quality evidence, Dr. Iglesia provided several “common sense” recommendations for energy-based therapies, starting with the need for any practitioner to have working knowledge of vulvovaginal anatomy. Contraindications for laser therapy include any malignancy – especially gynecologic – undiagnosed bleeding, active herpes or other infections, radiation, and vaginal mesh, particularly transvaginal mesh. The provider also must discuss the limited data on long-term function and treatment alternatives, including FDA-approved therapies like topical estrogen, dehydroepiandrosterone sulfate (DHEA-S), ospemifene, and moisturizers, Dr. Iglesia said.

Adverse events associated with laser therapy, such as scarring or burning, are rare but do occur, and cost remains an issue, Dr. Iglesia said.

“Vaginal estrogen therapy is well established as a safe and effective treatment option based on high quality evidence,” Dr. Christmas said. “This is not the case for laser therapy. Rare, but serious harms are reported with vaginal laser, including burns, scarring, dyspareunia, pain, and potential irreversible damage.”

Dr. Iglesia also cautioned that clinicians should take extra care with vulnerable populations, particularly cancer patients and others with contraindications for estrogen treatment.

For those in whom vaginal estrogen is contraindicated, Dr. Christmas recommended vaginal moisturizers, lubricants, dilators, and physical therapy for the pelvic floor.

“In patients who fail those nonhormonal approaches, short courses of vaginal estrogen therapy or DHEA-S suppository may be employed with approval from their oncologist,” Dr. Christmas said.

Dr. Iglesia finally reviewed the major research questions that remain with laser therapy:

• What are outcomes for laser versus sham studies?
• What are long-term outcomes (beyond 6 months)
• What pretreatment is necessary?
• Could laser be used as a drug delivery mechanism for estrogen, and could this provide a synergistic effect?
• What is the optimal number and interval for laser treatments?

Dr. Iglesia had no industry disclosures but received honoraria for consulting at UpToDate. Dr. Christmas is a consultant for Materna. The presentation did not rely on any external funding.

Despite a lack of evidence and high cost, laser therapy continues to attract many women seeking “vaginal rejuvenation” to help reverse the physical symptoms of menopause.

Recent reviews of the medical literature continue to show that laser treatment appears to be less effective than estrogen at improving vaginal dryness and pain during sex, according to Cheryl B. Iglesia, MD, a professor of ob.gyn. and urology at Georgetown University, Washington.

“Laser for GSM [genitourinary syndrome of menopause] is showing some promise, but patients need to be offered [Food and Drug Administration]–approved treatments prior to considering laser, and users need to know how to do speculum and pelvic exams and understand vulvovaginal anatomy and pathology,” Dr. Iglesia, who directs the section of female pelvic medicine and reconstructive surgery at MedStar Washington Hospital Center, said in an interview, adding that patients should avoid “vaginal rejuvenation” treatments offered at med-spas.

Dr. Iglesia reviewed how these lasers work and then discussed the controversy over their marketing and the evidence for their use at the annual meeting of the North American Menopause Society.

By 3 years after menopause, more than half of women experience atrophy in their vagina resulting from a lack of estrogen. Marked by a thinning of the epithelium, reduced blood supply, and loss of glycogen, vulvovaginal atrophy is to blame for GSM.

Vaginal laser therapy has been a popular option for women for the last decade, despite a lack of evidence supporting its use or approval from regulators.

The FDA has issued broad clearance for laser therapy for incision, ablation, vaporization, and coagulation of body soft tissues, such as dysplasia, vulvar or anal neoplasia, endometriosis, condylomas, and other disorders. However, the agency has not approved the use of laser therapy for vulvovaginal atrophy, GSM, vaginal dryness, or dyspareunia.
 

Evidence regarding vaginal laser therapy

According to Dr. Iglesia, the evidence for vaginal laser therapy is mixed and of generally low quality. A systematic review published in the Journal of Sexual Medicine (2022 Jan 29. doi: 10.1016/j.jsxm.2021.12.010) presented mostly low-quality evidence from 25 studies and found promising data for genitourinary symptoms but not enough to justify its use for genitourinary symptoms just yet. Dr. Iglesia discussed her own small, multisite study of 62 participants, which compared vaginal laser with vaginal estrogen and found no differences between the two for multiple outcomes. (The study would have been larger if not for interruption from an FDA warning for an Investigational Device Exemption.)

A JAMA study from Australia found no difference between laser therapy and sham laser therapy, but the most recent systematic review, from JAMA Network Open, found no significant difference between vaginal laser and vaginal estrogen for vaginal and sexual function symptoms. This review, however, covered only the six existing randomized controlled trials, including Dr. Iglesia’s, which were small and had a follow-up period of only 3-6 months.

“There have only been a few randomized controlled trials comparing laser to vaginal estrogen therapy, and most of those did not include a placebo or sham arm,” Monica Christmas, MD, director of the Center for Women’s Integrated Health at the University of Chicago Medicine, said in an interview. “This is extremely important, as most of the trials that did include a sham arm did not find that laser was better than the sham.” Dr. Christmas was not a part of the presentation but attended it at NAMS.

The bottom line, she said, is that “current evidence is not sufficient to make conclusions on long-term safety or sustainability, nor is there compelling evidence to make claims on equivalence to vaginal estrogen therapy.” Currently, committee opinions from a half-dozen medical societies, including NAMS, oppose using vaginal laser therapy until rigorous, robust trials on long-term safety and efficacy have been conducted. The International Continence Society and International Society for the Study of Vulvovaginal Disease issued a joint statement in 2018 that emphasized that histologic changes from lasers do not necessarily equate with changes in function. The statement noted the lack of evidence for laser treatment of incontinence and prolapse and stated that it should not be used for vulvodynia or lichen sclerosus.

A 2020 statement from NAMS found “insufficient placebo-controlled trials of energy-based therapies, including laser, to draw conclusions of efficacy or safety or to make treatment recommendations.” A slightly more optimistic statement from the American Urogynecologic Society concluded that energy-based devices have shown short-term efficacy for menopause-related vaginal atrophy and dyspareunia, including effects lasting up to 1 year from fractionated laser for treat dyspareunia, but also noted that studies up to that time were small and measure various outcomes.
 

Recommendations on vaginal laser therapy

Given this landscape of uneven and poor-quality evidence, Dr. Iglesia provided several “common sense” recommendations for energy-based therapies, starting with the need for any practitioner to have working knowledge of vulvovaginal anatomy. Contraindications for laser therapy include any malignancy – especially gynecologic – undiagnosed bleeding, active herpes or other infections, radiation, and vaginal mesh, particularly transvaginal mesh. The provider also must discuss the limited data on long-term function and treatment alternatives, including FDA-approved therapies like topical estrogen, dehydroepiandrosterone sulfate (DHEA-S), ospemifene, and moisturizers, Dr. Iglesia said.

Adverse events associated with laser therapy, such as scarring or burning, are rare but do occur, and cost remains an issue, Dr. Iglesia said.

“Vaginal estrogen therapy is well established as a safe and effective treatment option based on high quality evidence,” Dr. Christmas said. “This is not the case for laser therapy. Rare, but serious harms are reported with vaginal laser, including burns, scarring, dyspareunia, pain, and potential irreversible damage.”

Dr. Iglesia also cautioned that clinicians should take extra care with vulnerable populations, particularly cancer patients and others with contraindications for estrogen treatment.

For those in whom vaginal estrogen is contraindicated, Dr. Christmas recommended vaginal moisturizers, lubricants, dilators, and physical therapy for the pelvic floor.

“In patients who fail those nonhormonal approaches, short courses of vaginal estrogen therapy or DHEA-S suppository may be employed with approval from their oncologist,” Dr. Christmas said.

Dr. Iglesia finally reviewed the major research questions that remain with laser therapy:

• What are outcomes for laser versus sham studies?
• What are long-term outcomes (beyond 6 months)
• What pretreatment is necessary?
• Could laser be used as a drug delivery mechanism for estrogen, and could this provide a synergistic effect?
• What is the optimal number and interval for laser treatments?

Dr. Iglesia had no industry disclosures but received honoraria for consulting at UpToDate. Dr. Christmas is a consultant for Materna. The presentation did not rely on any external funding.