Menopause

It’s important for clinicians to ask women whether they are experiencing symptoms of genitourinary syndrome of menopause (GSM) before and after menopause, according to a new statement from the North American Menopause Society.

Stephanie Faubion, MD, MBA, medical director of NAMS, presented the updated statement at the virtual annual meeting of the North American Menopause Society.

“The one thing we tried to emphasize is proactive counseling and proactive inquiry, educating women when they hit perimenopause that this is a thing and that there are treatments,” Dr. Faubion said in an interview.

“I think women sometimes think there’s nothing they can do, which is not true. There’s the misperception that it’s just part of getting old, which it’s not,” said Dr. Faubion, who is also director of the Mayo Clinic Center for Women’s Health in Rochester, Minn., and chair of the department of medicine at the Mayo Clinic in Jacksonville, Fla.
 

Changes from previous statement

The GSM statement describes the symptoms and signs resulting from estrogen deficiency on the genitourinary tract, Dr. Faubion explained. The biggest change from the earlier version, published in 2013, is the condition’s new name. Formerly known as vulvovaginal atrophy, the condition’s new term was developed in 2014 and is now preferred by NAMS and the American College of Obstetricians and Gynecologists because it’s more comprehensive. Rather than just a physical description of the condition, GSM encompasses the many related symptoms and the urinary tract changes that occur, and it clearly associates the condition with menopause.

“Women don’t always associate these changes with menopause and don’t recognize that there’s something that can be done about it,” Dr. Faubion said. “We like to emphasize that sex should never be painful, but it’s not just about sex. It’s about comfort.”

Other changes include a review of evidence related to vaginal laser therapy for GSM and the availability of Imvexxy vaginal inserts with lower doses (4 mcg and 10 mpg) of estrogen.
 

Etiology and diagnosis of GSM

The presence of endogenous estrogen keeps the vaginal lining thick, rugated, well vascularized, and lubricated. As estrogen levels decline during postmenopause, the epithelial lining becomes thinner, with reduced blood supply and loss of glycogen.

The most common symptoms of GSM include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge, but the symptoms may not always correlate with physical findings. In women with surgical menopause, the symptoms tend to be more severe. The most distressing symptoms to women are often those that affect sexual function.

“Clinicians must be proactive in asking menopausal women if GSM symptoms are present, even before menopause begins,” Dr. Faubion said.

Taking a women’s history during evaluation may help identify contributing factors, other causes, or potentially effective treatments based on what has worked in the past. History should include a description of symptoms, their onset and duration, how distressing they are, and their effect on the woman’s quality of life. A sexual history, such as lubricants the woman has used, can also be useful in determining management strategies.

Signs of GSM include labial atrophy, vaginal dryness, introital stenosis, clitoral atrophy, phimosis of the prepuce, reduced mons pubis and labia majora bulk, reduced labia minora tissue and pigmentation, and changes in the urethra, including erythema of the urethral meatus and commonly a urethral caruncle, a benign outgrown of inflammatory tissue that likely results from low estrogen levels and can be treated effectively with topical hormonal therapies.

A diagnosis of GSM requires both physical findings and bothersome symptoms, though not necessarily specific vaginal maturation index or vaginal pH values. The differential diagnosis speaks to the importance of taking a good history: allergic or inflammatory conditions, infection, trauma, presence of a foreign body, malignancy, vulvodynia, chronic pelvic pain, or provoked pelvic floor hypertonia.

If first-line therapies of over-the-counter lubricants do not sufficiently treat GSM, other effective treatments include low-dose vaginal estrogen therapy, systemic estrogen therapy if other menopause symptoms are present, vaginal dehydroepiandrosterone (DHEA), and ospemifene.
 

Management of GSM

First-line therapy of GSM involves over-the-counter lubricants and moisturizers, which are often adequate to alleviate or eliminate women’s symptoms. However, the panel that developed the statement found no evidence that hyaluronic acid was any more effective than other lubricants or moisturizers, and no herbal products were found to effectively treat GSM.

While emerging evidence suggests that energy-based therapies, such as treatments with vaginal laser or radiofrequency devices, show some promise, more evidence is needed to show safety and efficacy before the panel can recommend routine use.

When over-the-counter therapies are not effective, vaginal estrogen usually relieves GSM with little absorption and is preferred over systemic therapy if GSM is the only bothersome menopausal symptom. Options include topical creams, a slow-release estradiol intravaginal ring, and estradiol vaginal tablets and inserts.

“However, when systemic hormone therapy is needed to treat other menopause symptoms, usually a woman will derive benefit and resolution of the GSM at the same time,” Dr. Faubion said. “However, for some women, additional low-dose vaginal estrogen may be added to systemic estrogen if needed, and that could include vaginal DHEA.”

All the approved vaginal products have shown efficacy, compared with placebo in clinical trials, and a Cochrane review comparing the different therapies found them to be similarly efficacious in treating vaginal dryness and dyspareunia with no significant differences in adverse events.
 

Preparing patients for the boxed warning

As vaginal estrogen doses are significantly lower than systemic estrogen, their safety profile is better, with serum estrogen levels remaining within the postmenopausal range when low-dose vaginal estrogen therapy is used. That said, some studies have shown that vaginal estrogen cream can be a large enough dose to involve systemic absorption and lead to symptoms such as vaginal bleeding, breast pain, and nausea.

However, package inserts for vaginal estrogen have the same boxed warning as seen in systemic hormone therapy inserts regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and “probable dementia” despite these conditions not being linked to vaginal estrogen in trials. Neither has venous thromboembolism been linked to vaginal estrogen.

“The panel felt it was very important that women be educated about the differences between low-dose vaginal estrogen and systemic estrogen therapy and be prepared for this boxed warning,” Dr. Faubion told attendees. “It’s really important to say: ‘You’re going to get this, it’s going to look scary, and there’s no evidence these same warnings apply to the low-dose vaginal estrogen products.’ ”

This point particularly resonated with NAMS attendee Juliana (Jewel) Kling, MD, MPH, an associate professor of medicine at the Mayo Clinic Arizona, Scottsdale.

“The point about educating women about the differences between low-dose vaginal estrogen products and systemic treatments and being prepared for the boxed warning is important and I hope reaches many practitioners,” Dr. Kling said in an interview.

The panel did not recommend using progestogen with low-dose vaginal estrogen therapy or doing routine endometrial surveillance in women using vaginal estrogen. But endometrial surveillance may be worth considering in women with increased risk of endometrial cancer.

Estrogen insufficiency from premature menopause or primary ovarian insufficiency is linked to more severe sexual dysfunction, which can be particularly upsetting for younger women with vaginal atrophy and dyspareunia. A meta-analysis showed that vaginal estrogen appeared to slightly outperform over-the-counter lubricants in bringing back sexual function.

Undiagnosed vaginal or uterine bleeding is a contraindication for vaginal estrogen until the cause has been determined, and providers should use caution in prescribing vaginal estrogen to women with estrogen-dependent neoplasia. Dr. Faubion noted that GSM is common in women with breast cancer, especially if they are receiving endocrine treatments or aromatase inhibitors.

“For women with a hormone-dependent cancer, GSM management depends on each woman’s preference in consultants with her oncologist,” she said. GSM management in women with a nonhormone-dependent cancer, however, is no different than in women without cancer.

DHEA is a steroid that effectively improves vaginal maturation index, vaginal pH, dyspareunia, and vaginal dryness. The most common side effect is vaginal discharge.

Ospemifene, an estrogen agonist available in the United States but not in Canada, is the only oral product approved to treat vaginal dryness and dyspareunia. An observational study also found it effective in reducing recurrent UTIs. The most common side effect is vasomotor symptoms, and it should not be used in patients with breast cancer because it hasn’t been studied in this population.

“This updated information and position statement was needed and will be very clinically relevant in treating midlife women,” Dr. Kling said in an interview. “Dr. Faubion presented a high-level overview of the position statement with clinically relevant points, including treatment for sexual dysfunction related to GSM, GSM treatment in cancer patients, and emphasized the efficacy and low-risk safety profile of low-dose vaginal estrogen, compared to systemic [hormone therapy], for treatment of GSM.”

Dr. Faubion and Dr. Kling disclosed no relevant financial relationships.

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

It’s important for clinicians to ask women whether they are experiencing symptoms of genitourinary syndrome of menopause (GSM) before and after menopause, according to a new statement from the North American Menopause Society.

Stephanie Faubion, MD, MBA, medical director of NAMS, presented the updated statement at the virtual annual meeting of the North American Menopause Society.

“The one thing we tried to emphasize is proactive counseling and proactive inquiry, educating women when they hit perimenopause that this is a thing and that there are treatments,” Dr. Faubion said in an interview.

“I think women sometimes think there’s nothing they can do, which is not true. There’s the misperception that it’s just part of getting old, which it’s not,” said Dr. Faubion, who is also director of the Mayo Clinic Center for Women’s Health in Rochester, Minn., and chair of the department of medicine at the Mayo Clinic in Jacksonville, Fla.
 

Changes from previous statement

The GSM statement describes the symptoms and signs resulting from estrogen deficiency on the genitourinary tract, Dr. Faubion explained. The biggest change from the earlier version, published in 2013, is the condition’s new name. Formerly known as vulvovaginal atrophy, the condition’s new term was developed in 2014 and is now preferred by NAMS and the American College of Obstetricians and Gynecologists because it’s more comprehensive. Rather than just a physical description of the condition, GSM encompasses the many related symptoms and the urinary tract changes that occur, and it clearly associates the condition with menopause.

“Women don’t always associate these changes with menopause and don’t recognize that there’s something that can be done about it,” Dr. Faubion said. “We like to emphasize that sex should never be painful, but it’s not just about sex. It’s about comfort.”

Other changes include a review of evidence related to vaginal laser therapy for GSM and the availability of Imvexxy vaginal inserts with lower doses (4 mcg and 10 mpg) of estrogen.
 

Etiology and diagnosis of GSM

The presence of endogenous estrogen keeps the vaginal lining thick, rugated, well vascularized, and lubricated. As estrogen levels decline during postmenopause, the epithelial lining becomes thinner, with reduced blood supply and loss of glycogen.

The most common symptoms of GSM include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge, but the symptoms may not always correlate with physical findings. In women with surgical menopause, the symptoms tend to be more severe. The most distressing symptoms to women are often those that affect sexual function.

“Clinicians must be proactive in asking menopausal women if GSM symptoms are present, even before menopause begins,” Dr. Faubion said.

Taking a women’s history during evaluation may help identify contributing factors, other causes, or potentially effective treatments based on what has worked in the past. History should include a description of symptoms, their onset and duration, how distressing they are, and their effect on the woman’s quality of life. A sexual history, such as lubricants the woman has used, can also be useful in determining management strategies.

Signs of GSM include labial atrophy, vaginal dryness, introital stenosis, clitoral atrophy, phimosis of the prepuce, reduced mons pubis and labia majora bulk, reduced labia minora tissue and pigmentation, and changes in the urethra, including erythema of the urethral meatus and commonly a urethral caruncle, a benign outgrown of inflammatory tissue that likely results from low estrogen levels and can be treated effectively with topical hormonal therapies.

A diagnosis of GSM requires both physical findings and bothersome symptoms, though not necessarily specific vaginal maturation index or vaginal pH values. The differential diagnosis speaks to the importance of taking a good history: allergic or inflammatory conditions, infection, trauma, presence of a foreign body, malignancy, vulvodynia, chronic pelvic pain, or provoked pelvic floor hypertonia.

If first-line therapies of over-the-counter lubricants do not sufficiently treat GSM, other effective treatments include low-dose vaginal estrogen therapy, systemic estrogen therapy if other menopause symptoms are present, vaginal dehydroepiandrosterone (DHEA), and ospemifene.
 

Management of GSM

First-line therapy of GSM involves over-the-counter lubricants and moisturizers, which are often adequate to alleviate or eliminate women’s symptoms. However, the panel that developed the statement found no evidence that hyaluronic acid was any more effective than other lubricants or moisturizers, and no herbal products were found to effectively treat GSM.

While emerging evidence suggests that energy-based therapies, such as treatments with vaginal laser or radiofrequency devices, show some promise, more evidence is needed to show safety and efficacy before the panel can recommend routine use.

When over-the-counter therapies are not effective, vaginal estrogen usually relieves GSM with little absorption and is preferred over systemic therapy if GSM is the only bothersome menopausal symptom. Options include topical creams, a slow-release estradiol intravaginal ring, and estradiol vaginal tablets and inserts.

“However, when systemic hormone therapy is needed to treat other menopause symptoms, usually a woman will derive benefit and resolution of the GSM at the same time,” Dr. Faubion said. “However, for some women, additional low-dose vaginal estrogen may be added to systemic estrogen if needed, and that could include vaginal DHEA.”

All the approved vaginal products have shown efficacy, compared with placebo in clinical trials, and a Cochrane review comparing the different therapies found them to be similarly efficacious in treating vaginal dryness and dyspareunia with no significant differences in adverse events.
 

Preparing patients for the boxed warning

As vaginal estrogen doses are significantly lower than systemic estrogen, their safety profile is better, with serum estrogen levels remaining within the postmenopausal range when low-dose vaginal estrogen therapy is used. That said, some studies have shown that vaginal estrogen cream can be a large enough dose to involve systemic absorption and lead to symptoms such as vaginal bleeding, breast pain, and nausea.

However, package inserts for vaginal estrogen have the same boxed warning as seen in systemic hormone therapy inserts regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and “probable dementia” despite these conditions not being linked to vaginal estrogen in trials. Neither has venous thromboembolism been linked to vaginal estrogen.

“The panel felt it was very important that women be educated about the differences between low-dose vaginal estrogen and systemic estrogen therapy and be prepared for this boxed warning,” Dr. Faubion told attendees. “It’s really important to say: ‘You’re going to get this, it’s going to look scary, and there’s no evidence these same warnings apply to the low-dose vaginal estrogen products.’ ”

This point particularly resonated with NAMS attendee Juliana (Jewel) Kling, MD, MPH, an associate professor of medicine at the Mayo Clinic Arizona, Scottsdale.

“The point about educating women about the differences between low-dose vaginal estrogen products and systemic treatments and being prepared for the boxed warning is important and I hope reaches many practitioners,” Dr. Kling said in an interview.

The panel did not recommend using progestogen with low-dose vaginal estrogen therapy or doing routine endometrial surveillance in women using vaginal estrogen. But endometrial surveillance may be worth considering in women with increased risk of endometrial cancer.

Estrogen insufficiency from premature menopause or primary ovarian insufficiency is linked to more severe sexual dysfunction, which can be particularly upsetting for younger women with vaginal atrophy and dyspareunia. A meta-analysis showed that vaginal estrogen appeared to slightly outperform over-the-counter lubricants in bringing back sexual function.

Undiagnosed vaginal or uterine bleeding is a contraindication for vaginal estrogen until the cause has been determined, and providers should use caution in prescribing vaginal estrogen to women with estrogen-dependent neoplasia. Dr. Faubion noted that GSM is common in women with breast cancer, especially if they are receiving endocrine treatments or aromatase inhibitors.

“For women with a hormone-dependent cancer, GSM management depends on each woman’s preference in consultants with her oncologist,” she said. GSM management in women with a nonhormone-dependent cancer, however, is no different than in women without cancer.

DHEA is a steroid that effectively improves vaginal maturation index, vaginal pH, dyspareunia, and vaginal dryness. The most common side effect is vaginal discharge.

Ospemifene, an estrogen agonist available in the United States but not in Canada, is the only oral product approved to treat vaginal dryness and dyspareunia. An observational study also found it effective in reducing recurrent UTIs. The most common side effect is vasomotor symptoms, and it should not be used in patients with breast cancer because it hasn’t been studied in this population.

“This updated information and position statement was needed and will be very clinically relevant in treating midlife women,” Dr. Kling said in an interview. “Dr. Faubion presented a high-level overview of the position statement with clinically relevant points, including treatment for sexual dysfunction related to GSM, GSM treatment in cancer patients, and emphasized the efficacy and low-risk safety profile of low-dose vaginal estrogen, compared to systemic [hormone therapy], for treatment of GSM.”

Dr. Faubion and Dr. Kling disclosed no relevant financial relationships.

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

It’s important for clinicians to ask women whether they are experiencing symptoms of genitourinary syndrome of menopause (GSM) before and after menopause, according to a new statement from the North American Menopause Society.

Stephanie Faubion, MD, MBA, medical director of NAMS, presented the updated statement at the virtual annual meeting of the North American Menopause Society.

“The one thing we tried to emphasize is proactive counseling and proactive inquiry, educating women when they hit perimenopause that this is a thing and that there are treatments,” Dr. Faubion said in an interview.

“I think women sometimes think there’s nothing they can do, which is not true. There’s the misperception that it’s just part of getting old, which it’s not,” said Dr. Faubion, who is also director of the Mayo Clinic Center for Women’s Health in Rochester, Minn., and chair of the department of medicine at the Mayo Clinic in Jacksonville, Fla.
 

Changes from previous statement

The GSM statement describes the symptoms and signs resulting from estrogen deficiency on the genitourinary tract, Dr. Faubion explained. The biggest change from the earlier version, published in 2013, is the condition’s new name. Formerly known as vulvovaginal atrophy, the condition’s new term was developed in 2014 and is now preferred by NAMS and the American College of Obstetricians and Gynecologists because it’s more comprehensive. Rather than just a physical description of the condition, GSM encompasses the many related symptoms and the urinary tract changes that occur, and it clearly associates the condition with menopause.

“Women don’t always associate these changes with menopause and don’t recognize that there’s something that can be done about it,” Dr. Faubion said. “We like to emphasize that sex should never be painful, but it’s not just about sex. It’s about comfort.”

Other changes include a review of evidence related to vaginal laser therapy for GSM and the availability of Imvexxy vaginal inserts with lower doses (4 mcg and 10 mpg) of estrogen.
 

Etiology and diagnosis of GSM

The presence of endogenous estrogen keeps the vaginal lining thick, rugated, well vascularized, and lubricated. As estrogen levels decline during postmenopause, the epithelial lining becomes thinner, with reduced blood supply and loss of glycogen.

The most common symptoms of GSM include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge, but the symptoms may not always correlate with physical findings. In women with surgical menopause, the symptoms tend to be more severe. The most distressing symptoms to women are often those that affect sexual function.

“Clinicians must be proactive in asking menopausal women if GSM symptoms are present, even before menopause begins,” Dr. Faubion said.

Taking a women’s history during evaluation may help identify contributing factors, other causes, or potentially effective treatments based on what has worked in the past. History should include a description of symptoms, their onset and duration, how distressing they are, and their effect on the woman’s quality of life. A sexual history, such as lubricants the woman has used, can also be useful in determining management strategies.

Signs of GSM include labial atrophy, vaginal dryness, introital stenosis, clitoral atrophy, phimosis of the prepuce, reduced mons pubis and labia majora bulk, reduced labia minora tissue and pigmentation, and changes in the urethra, including erythema of the urethral meatus and commonly a urethral caruncle, a benign outgrown of inflammatory tissue that likely results from low estrogen levels and can be treated effectively with topical hormonal therapies.

A diagnosis of GSM requires both physical findings and bothersome symptoms, though not necessarily specific vaginal maturation index or vaginal pH values. The differential diagnosis speaks to the importance of taking a good history: allergic or inflammatory conditions, infection, trauma, presence of a foreign body, malignancy, vulvodynia, chronic pelvic pain, or provoked pelvic floor hypertonia.

If first-line therapies of over-the-counter lubricants do not sufficiently treat GSM, other effective treatments include low-dose vaginal estrogen therapy, systemic estrogen therapy if other menopause symptoms are present, vaginal dehydroepiandrosterone (DHEA), and ospemifene.
 

Management of GSM

First-line therapy of GSM involves over-the-counter lubricants and moisturizers, which are often adequate to alleviate or eliminate women’s symptoms. However, the panel that developed the statement found no evidence that hyaluronic acid was any more effective than other lubricants or moisturizers, and no herbal products were found to effectively treat GSM.

While emerging evidence suggests that energy-based therapies, such as treatments with vaginal laser or radiofrequency devices, show some promise, more evidence is needed to show safety and efficacy before the panel can recommend routine use.

When over-the-counter therapies are not effective, vaginal estrogen usually relieves GSM with little absorption and is preferred over systemic therapy if GSM is the only bothersome menopausal symptom. Options include topical creams, a slow-release estradiol intravaginal ring, and estradiol vaginal tablets and inserts.

“However, when systemic hormone therapy is needed to treat other menopause symptoms, usually a woman will derive benefit and resolution of the GSM at the same time,” Dr. Faubion said. “However, for some women, additional low-dose vaginal estrogen may be added to systemic estrogen if needed, and that could include vaginal DHEA.”

All the approved vaginal products have shown efficacy, compared with placebo in clinical trials, and a Cochrane review comparing the different therapies found them to be similarly efficacious in treating vaginal dryness and dyspareunia with no significant differences in adverse events.
 

Preparing patients for the boxed warning

As vaginal estrogen doses are significantly lower than systemic estrogen, their safety profile is better, with serum estrogen levels remaining within the postmenopausal range when low-dose vaginal estrogen therapy is used. That said, some studies have shown that vaginal estrogen cream can be a large enough dose to involve systemic absorption and lead to symptoms such as vaginal bleeding, breast pain, and nausea.

However, package inserts for vaginal estrogen have the same boxed warning as seen in systemic hormone therapy inserts regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and “probable dementia” despite these conditions not being linked to vaginal estrogen in trials. Neither has venous thromboembolism been linked to vaginal estrogen.

“The panel felt it was very important that women be educated about the differences between low-dose vaginal estrogen and systemic estrogen therapy and be prepared for this boxed warning,” Dr. Faubion told attendees. “It’s really important to say: ‘You’re going to get this, it’s going to look scary, and there’s no evidence these same warnings apply to the low-dose vaginal estrogen products.’ ”

This point particularly resonated with NAMS attendee Juliana (Jewel) Kling, MD, MPH, an associate professor of medicine at the Mayo Clinic Arizona, Scottsdale.

“The point about educating women about the differences between low-dose vaginal estrogen products and systemic treatments and being prepared for the boxed warning is important and I hope reaches many practitioners,” Dr. Kling said in an interview.

The panel did not recommend using progestogen with low-dose vaginal estrogen therapy or doing routine endometrial surveillance in women using vaginal estrogen. But endometrial surveillance may be worth considering in women with increased risk of endometrial cancer.

Estrogen insufficiency from premature menopause or primary ovarian insufficiency is linked to more severe sexual dysfunction, which can be particularly upsetting for younger women with vaginal atrophy and dyspareunia. A meta-analysis showed that vaginal estrogen appeared to slightly outperform over-the-counter lubricants in bringing back sexual function.

Undiagnosed vaginal or uterine bleeding is a contraindication for vaginal estrogen until the cause has been determined, and providers should use caution in prescribing vaginal estrogen to women with estrogen-dependent neoplasia. Dr. Faubion noted that GSM is common in women with breast cancer, especially if they are receiving endocrine treatments or aromatase inhibitors.

“For women with a hormone-dependent cancer, GSM management depends on each woman’s preference in consultants with her oncologist,” she said. GSM management in women with a nonhormone-dependent cancer, however, is no different than in women without cancer.

DHEA is a steroid that effectively improves vaginal maturation index, vaginal pH, dyspareunia, and vaginal dryness. The most common side effect is vaginal discharge.

Ospemifene, an estrogen agonist available in the United States but not in Canada, is the only oral product approved to treat vaginal dryness and dyspareunia. An observational study also found it effective in reducing recurrent UTIs. The most common side effect is vasomotor symptoms, and it should not be used in patients with breast cancer because it hasn’t been studied in this population.

“This updated information and position statement was needed and will be very clinically relevant in treating midlife women,” Dr. Kling said in an interview. “Dr. Faubion presented a high-level overview of the position statement with clinically relevant points, including treatment for sexual dysfunction related to GSM, GSM treatment in cancer patients, and emphasized the efficacy and low-risk safety profile of low-dose vaginal estrogen, compared to systemic [hormone therapy], for treatment of GSM.”

Dr. Faubion and Dr. Kling disclosed no relevant financial relationships.

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

Hormone therapy for menopausal symptoms has come a long way in the past decade, but some low risks remain, particularly for certain groups of women. But new naturally occurring estrogens are on the horizon and may provide safer options with similar efficacy for treating hot flashes and other symptoms, researchers report.

“Unfortunately, there is no such thing as the perfect estrogen that has all the things that makes it favorable and none of the negative,” Hugh S. Taylor, MD, told attendees at the virtual annual meeting of the North American Menopause Society. “It probably doesn’t exist. But there’s an opportunity for us to design better estrogens or take advantage of other naturally occurring estrogens that come closer to that goal of the ideal estrogen,” said Dr. Taylor, professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn.

Those naturally occurring estrogens are the fetal estrogens, estetrol and estriol, which are produced almost exclusively during pregnancy. Only estetrol has been investigated in clinical trials, and it does show some promise, Dr. Taylor said.

“If there’s a better cardiovascular effect without the breast cancer risk, this could be something everyone would want to take,” Dr. Taylor said in an interview. “It’s the first new estrogen we’ve had in many years, and it makes so much sense that we go back to a naturally occurring estrogen. We’ve never really been able to get a synthetic estrogen [that works].”
 

Hormone therapy still most effective for vasomotor symptoms

The primary benefits of hormone therapy for postmenopausal women are decreased hot flashes and night sweats and the prevention of bone loss, vaginal dryness, and vaginal atrophy. But as women age, particularly past age 70 years, the risks for stroke, heart disease, and breast cancer associated with hormone therapy begin to outweigh the benefits.

That leaves women who are still experiencing those symptoms in a quandary.

“Some people will take on substantial risks because they want to continue taking hormones,” Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, said in an interview. “If they understand what they’re doing and they tell me that they are that miserable, then I will continue their hormones.”

Dr. Santoro, who was not involved in Taylor’s work, said some patients have seen her because their primary care providers refused to continue prescribing them hormones at their age, despite serious vasomotor symptoms that interfered with their daily life.

“Women are sometimes not taken seriously, and I think that’s a problem,” Dr. Santoro said. “Women need to be able to make an informed choice about what kinds of risk they’re taking on. Many physicians’ rationales are that hot flashes never killed anybody. Well, they can sure make you miserable.”

Dr. Taylor echoed the importance of taking women’s symptoms seriously and helping them choose the most effective treatments to manage their symptoms.

“The rush of adrenaline, the anxiety, the palpitations, the heart racing, the sweating, all the night sweats [that mean] you can’t sleep at night, and the lack of adequate REM sleep – all these things add up and can really be disruptive to someone’s life,” Dr. Taylor said in an interview. “I think it’s important that we raise awareness of how severe it can be, about just how low the risks [of hormone therapy] are, and get people more comfortable using hormone therapy, but also continue to search for safer, better products that will eliminate even those low risks.”

A major development toward that goal in the past decade has been therapies that combine an estrogen with a selective estrogen receptor modulator (SERM), which have antiestrogen effects in the endometrium and breast without blocking estrogen in the bones and brain.

One such tissue-selective estrogen complex (TSEC) is the combination of bazedoxifene (20 mg) and conjugated estrogens (0.45 mg). Clinical trials showed that this TSEC reduced the frequency of hot flashes by 74%, compared with 47% with placebo. In addition, TSEC reduced the severity of hot flashes by 39%, compared with 13% with placebo. The combination also improved bone density at the spine and hip without promoting endometrial hyperplasia.

“It looks like it does exactly what we want,” Dr. Taylor told NAMS attendees. “The SERM is antagonizing the effects of the estrogens in the endometrium but not in the bone or brain.” It also led to a decrease in total cholesterol, and there was no increase in breast stimulation or density.

Another advance in recent years has been more choices and more precision with dosing, Dr. Santoro said.

“Where inroads have been made is in having women be aware of all the options they have and in getting the most convenient compounds to people,” she said, despite the confusion and misinformation that have arisen from the proliferation of bioidenticals. “You can dial in a dose for just about anybody.”
 

New estrogens in the pipeline

Neither of these developments, however, have eliminated the risks associated with hormone therapy for women of older age or for women at high risk for breast cancer. Although total elimination of risk may not be possible, recent research suggests that the naturally occurring fetal estrogens estriol and estetrol appear to have SERM-like properties, Dr. Taylor said. These estrogens are made only in pregnancy and appear to have evolved for a purpose different from that of estrone and estradiol.

“While both are weak estrogens by traditional standards, both have unique properties that make them very interesting for therapeutic use,” Dr. Taylor said. In particular, estetrol has a much longer half-life than estriol, making it more appropriate for therapeutic investigation.

A study of estetrol that was published in Menopause in August 2020 showed encouraging results. Despite a fairly sizable placebo effect, there was also a dose-response effect from estetrol on vasomotor symptoms. Low doses did not have much effect, but with higher doses (15 mg), there was a robust, significant improvement in the frequency and severity of hot flashes. So far, Dr. Taylor said, it looks like estetrol can be a highly effective treatment for vasomotor symptoms.

In addition, preclinical research suggests that estetrol may have a better safety profile than currently available therapies, though much more work is needed to know for sure. For example, a 2015 study found that it requires extremely high doses – well above therapeutic levels – for tumor growth to occur. Similarly, a 2019 study found that very high doses of estetrol or estriol were needed before it would stimulate breast cancer cell growth, likely because these are such weak estrogens, compared with estradiol, Dr. Taylor said.

There is currently less information on estetrol’s potential cardiovascular effects, but an animal model suggests positive effects, he said. Giving a mouse estetrol led to an increase in blood vessel dilation with increased blood flow.

The reason these estrogens appear to pose less risk yet still show therapeutic effects appears related to how they bind to the estrogen receptor and what their purpose is, Dr. Taylor told attendees.

“These fetal estrogens are really there probably for developmental programming,” he said. “It’s no wonder they may have some unique and favorable properties for therapeutic use. I’m really enthusiastic to see this explored further as a potential new hormonal therapy.”

Dr. Taylor disclosed no relevant financial relationships. Dr. Santoro reported stock ownership in Menogenix and consulting or advising for Ansh Labs, Menogenix, and Ogeda/Astellas.

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

Hormone therapy for menopausal symptoms has come a long way in the past decade, but some low risks remain, particularly for certain groups of women. But new naturally occurring estrogens are on the horizon and may provide safer options with similar efficacy for treating hot flashes and other symptoms, researchers report.

“Unfortunately, there is no such thing as the perfect estrogen that has all the things that makes it favorable and none of the negative,” Hugh S. Taylor, MD, told attendees at the virtual annual meeting of the North American Menopause Society. “It probably doesn’t exist. But there’s an opportunity for us to design better estrogens or take advantage of other naturally occurring estrogens that come closer to that goal of the ideal estrogen,” said Dr. Taylor, professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn.

Those naturally occurring estrogens are the fetal estrogens, estetrol and estriol, which are produced almost exclusively during pregnancy. Only estetrol has been investigated in clinical trials, and it does show some promise, Dr. Taylor said.

“If there’s a better cardiovascular effect without the breast cancer risk, this could be something everyone would want to take,” Dr. Taylor said in an interview. “It’s the first new estrogen we’ve had in many years, and it makes so much sense that we go back to a naturally occurring estrogen. We’ve never really been able to get a synthetic estrogen [that works].”
 

Hormone therapy still most effective for vasomotor symptoms

The primary benefits of hormone therapy for postmenopausal women are decreased hot flashes and night sweats and the prevention of bone loss, vaginal dryness, and vaginal atrophy. But as women age, particularly past age 70 years, the risks for stroke, heart disease, and breast cancer associated with hormone therapy begin to outweigh the benefits.

That leaves women who are still experiencing those symptoms in a quandary.

“Some people will take on substantial risks because they want to continue taking hormones,” Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, said in an interview. “If they understand what they’re doing and they tell me that they are that miserable, then I will continue their hormones.”

Dr. Santoro, who was not involved in Taylor’s work, said some patients have seen her because their primary care providers refused to continue prescribing them hormones at their age, despite serious vasomotor symptoms that interfered with their daily life.

“Women are sometimes not taken seriously, and I think that’s a problem,” Dr. Santoro said. “Women need to be able to make an informed choice about what kinds of risk they’re taking on. Many physicians’ rationales are that hot flashes never killed anybody. Well, they can sure make you miserable.”

Dr. Taylor echoed the importance of taking women’s symptoms seriously and helping them choose the most effective treatments to manage their symptoms.

“The rush of adrenaline, the anxiety, the palpitations, the heart racing, the sweating, all the night sweats [that mean] you can’t sleep at night, and the lack of adequate REM sleep – all these things add up and can really be disruptive to someone’s life,” Dr. Taylor said in an interview. “I think it’s important that we raise awareness of how severe it can be, about just how low the risks [of hormone therapy] are, and get people more comfortable using hormone therapy, but also continue to search for safer, better products that will eliminate even those low risks.”

A major development toward that goal in the past decade has been therapies that combine an estrogen with a selective estrogen receptor modulator (SERM), which have antiestrogen effects in the endometrium and breast without blocking estrogen in the bones and brain.

One such tissue-selective estrogen complex (TSEC) is the combination of bazedoxifene (20 mg) and conjugated estrogens (0.45 mg). Clinical trials showed that this TSEC reduced the frequency of hot flashes by 74%, compared with 47% with placebo. In addition, TSEC reduced the severity of hot flashes by 39%, compared with 13% with placebo. The combination also improved bone density at the spine and hip without promoting endometrial hyperplasia.

“It looks like it does exactly what we want,” Dr. Taylor told NAMS attendees. “The SERM is antagonizing the effects of the estrogens in the endometrium but not in the bone or brain.” It also led to a decrease in total cholesterol, and there was no increase in breast stimulation or density.

Another advance in recent years has been more choices and more precision with dosing, Dr. Santoro said.

“Where inroads have been made is in having women be aware of all the options they have and in getting the most convenient compounds to people,” she said, despite the confusion and misinformation that have arisen from the proliferation of bioidenticals. “You can dial in a dose for just about anybody.”
 

New estrogens in the pipeline

Neither of these developments, however, have eliminated the risks associated with hormone therapy for women of older age or for women at high risk for breast cancer. Although total elimination of risk may not be possible, recent research suggests that the naturally occurring fetal estrogens estriol and estetrol appear to have SERM-like properties, Dr. Taylor said. These estrogens are made only in pregnancy and appear to have evolved for a purpose different from that of estrone and estradiol.

“While both are weak estrogens by traditional standards, both have unique properties that make them very interesting for therapeutic use,” Dr. Taylor said. In particular, estetrol has a much longer half-life than estriol, making it more appropriate for therapeutic investigation.

A study of estetrol that was published in Menopause in August 2020 showed encouraging results. Despite a fairly sizable placebo effect, there was also a dose-response effect from estetrol on vasomotor symptoms. Low doses did not have much effect, but with higher doses (15 mg), there was a robust, significant improvement in the frequency and severity of hot flashes. So far, Dr. Taylor said, it looks like estetrol can be a highly effective treatment for vasomotor symptoms.

In addition, preclinical research suggests that estetrol may have a better safety profile than currently available therapies, though much more work is needed to know for sure. For example, a 2015 study found that it requires extremely high doses – well above therapeutic levels – for tumor growth to occur. Similarly, a 2019 study found that very high doses of estetrol or estriol were needed before it would stimulate breast cancer cell growth, likely because these are such weak estrogens, compared with estradiol, Dr. Taylor said.

There is currently less information on estetrol’s potential cardiovascular effects, but an animal model suggests positive effects, he said. Giving a mouse estetrol led to an increase in blood vessel dilation with increased blood flow.

The reason these estrogens appear to pose less risk yet still show therapeutic effects appears related to how they bind to the estrogen receptor and what their purpose is, Dr. Taylor told attendees.

“These fetal estrogens are really there probably for developmental programming,” he said. “It’s no wonder they may have some unique and favorable properties for therapeutic use. I’m really enthusiastic to see this explored further as a potential new hormonal therapy.”

Dr. Taylor disclosed no relevant financial relationships. Dr. Santoro reported stock ownership in Menogenix and consulting or advising for Ansh Labs, Menogenix, and Ogeda/Astellas.

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

Hormone therapy for menopausal symptoms has come a long way in the past decade, but some low risks remain, particularly for certain groups of women. But new naturally occurring estrogens are on the horizon and may provide safer options with similar efficacy for treating hot flashes and other symptoms, researchers report.

“Unfortunately, there is no such thing as the perfect estrogen that has all the things that makes it favorable and none of the negative,” Hugh S. Taylor, MD, told attendees at the virtual annual meeting of the North American Menopause Society. “It probably doesn’t exist. But there’s an opportunity for us to design better estrogens or take advantage of other naturally occurring estrogens that come closer to that goal of the ideal estrogen,” said Dr. Taylor, professor and chair of ob.gyn. and reproductive sciences at Yale University, New Haven, Conn.

Those naturally occurring estrogens are the fetal estrogens, estetrol and estriol, which are produced almost exclusively during pregnancy. Only estetrol has been investigated in clinical trials, and it does show some promise, Dr. Taylor said.

“If there’s a better cardiovascular effect without the breast cancer risk, this could be something everyone would want to take,” Dr. Taylor said in an interview. “It’s the first new estrogen we’ve had in many years, and it makes so much sense that we go back to a naturally occurring estrogen. We’ve never really been able to get a synthetic estrogen [that works].”
 

Hormone therapy still most effective for vasomotor symptoms

The primary benefits of hormone therapy for postmenopausal women are decreased hot flashes and night sweats and the prevention of bone loss, vaginal dryness, and vaginal atrophy. But as women age, particularly past age 70 years, the risks for stroke, heart disease, and breast cancer associated with hormone therapy begin to outweigh the benefits.

That leaves women who are still experiencing those symptoms in a quandary.

“Some people will take on substantial risks because they want to continue taking hormones,” Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, said in an interview. “If they understand what they’re doing and they tell me that they are that miserable, then I will continue their hormones.”

Dr. Santoro, who was not involved in Taylor’s work, said some patients have seen her because their primary care providers refused to continue prescribing them hormones at their age, despite serious vasomotor symptoms that interfered with their daily life.

“Women are sometimes not taken seriously, and I think that’s a problem,” Dr. Santoro said. “Women need to be able to make an informed choice about what kinds of risk they’re taking on. Many physicians’ rationales are that hot flashes never killed anybody. Well, they can sure make you miserable.”

Dr. Taylor echoed the importance of taking women’s symptoms seriously and helping them choose the most effective treatments to manage their symptoms.

“The rush of adrenaline, the anxiety, the palpitations, the heart racing, the sweating, all the night sweats [that mean] you can’t sleep at night, and the lack of adequate REM sleep – all these things add up and can really be disruptive to someone’s life,” Dr. Taylor said in an interview. “I think it’s important that we raise awareness of how severe it can be, about just how low the risks [of hormone therapy] are, and get people more comfortable using hormone therapy, but also continue to search for safer, better products that will eliminate even those low risks.”

A major development toward that goal in the past decade has been therapies that combine an estrogen with a selective estrogen receptor modulator (SERM), which have antiestrogen effects in the endometrium and breast without blocking estrogen in the bones and brain.

One such tissue-selective estrogen complex (TSEC) is the combination of bazedoxifene (20 mg) and conjugated estrogens (0.45 mg). Clinical trials showed that this TSEC reduced the frequency of hot flashes by 74%, compared with 47% with placebo. In addition, TSEC reduced the severity of hot flashes by 39%, compared with 13% with placebo. The combination also improved bone density at the spine and hip without promoting endometrial hyperplasia.

“It looks like it does exactly what we want,” Dr. Taylor told NAMS attendees. “The SERM is antagonizing the effects of the estrogens in the endometrium but not in the bone or brain.” It also led to a decrease in total cholesterol, and there was no increase in breast stimulation or density.

Another advance in recent years has been more choices and more precision with dosing, Dr. Santoro said.

“Where inroads have been made is in having women be aware of all the options they have and in getting the most convenient compounds to people,” she said, despite the confusion and misinformation that have arisen from the proliferation of bioidenticals. “You can dial in a dose for just about anybody.”
 

New estrogens in the pipeline

Neither of these developments, however, have eliminated the risks associated with hormone therapy for women of older age or for women at high risk for breast cancer. Although total elimination of risk may not be possible, recent research suggests that the naturally occurring fetal estrogens estriol and estetrol appear to have SERM-like properties, Dr. Taylor said. These estrogens are made only in pregnancy and appear to have evolved for a purpose different from that of estrone and estradiol.

“While both are weak estrogens by traditional standards, both have unique properties that make them very interesting for therapeutic use,” Dr. Taylor said. In particular, estetrol has a much longer half-life than estriol, making it more appropriate for therapeutic investigation.

A study of estetrol that was published in Menopause in August 2020 showed encouraging results. Despite a fairly sizable placebo effect, there was also a dose-response effect from estetrol on vasomotor symptoms. Low doses did not have much effect, but with higher doses (15 mg), there was a robust, significant improvement in the frequency and severity of hot flashes. So far, Dr. Taylor said, it looks like estetrol can be a highly effective treatment for vasomotor symptoms.

In addition, preclinical research suggests that estetrol may have a better safety profile than currently available therapies, though much more work is needed to know for sure. For example, a 2015 study found that it requires extremely high doses – well above therapeutic levels – for tumor growth to occur. Similarly, a 2019 study found that very high doses of estetrol or estriol were needed before it would stimulate breast cancer cell growth, likely because these are such weak estrogens, compared with estradiol, Dr. Taylor said.

There is currently less information on estetrol’s potential cardiovascular effects, but an animal model suggests positive effects, he said. Giving a mouse estetrol led to an increase in blood vessel dilation with increased blood flow.

The reason these estrogens appear to pose less risk yet still show therapeutic effects appears related to how they bind to the estrogen receptor and what their purpose is, Dr. Taylor told attendees.

“These fetal estrogens are really there probably for developmental programming,” he said. “It’s no wonder they may have some unique and favorable properties for therapeutic use. I’m really enthusiastic to see this explored further as a potential new hormonal therapy.”

Dr. Taylor disclosed no relevant financial relationships. Dr. Santoro reported stock ownership in Menogenix and consulting or advising for Ansh Labs, Menogenix, and Ogeda/Astellas.

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

A new group of nonhormonal drugs currently in clinical trials shows strong promise for treating menopausal hot flashes as effectively as hormones, researchers told attendees at the virtual North American Menopause Society 2020 Annual Meeting.

“The KNDy [kisspeptin/neurokinin B/dynorphin] neuron manipulation is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms, though we’re still looking at the safety in phase 3 trials,” reported Susan D. Reed, MD, MPH, director of the Women’s Reproductive Health Research Program at the University of Washington, Seattle.

“If we continue to see good safety data, these are going to be the greatest things since sliced bread,” Dr. Reed said in an interview. “I don’t think we’ve seen anything like this in menopause therapeutics in a long time.”

While several nonhormonal drugs are already used to treat vasomotor symptoms in menopausal women with and without breast cancer, none are as effective as hormone treatments.

“For now, the SSRIs, SNRIs [serotonin norepinephrine reuptake inhibitors], and GABAergics are the best frontline nonhormonal options with a moderate effect, and clonidine and oxybutynin are effective, but we see more side effects with these,” Dr. Reed said. She noted the importance of considering patients’ mood, sleep, pain, sexual function, weight gain, overactive bladder, blood pressure, and individual quality of life (QOL) goals in tailoring those therapies.

But women still need more nonhormonal options that are at least as effective as hormonal options, Dr. Reed said. Some women are unable to take hormonal options because they are at risk for blood clots or breast cancer.

“Then there’s preference,” she said. “Sometimes people don’t like the way they feel when they take hormones, or they just don’t want hormones in their body. It’s absolutely critical to have these options available for women.”

Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, who was not involved in the presentation, said in an interview that physicians may not always realize the extent to which vasomotor symptoms interfere with women’s daily lives.

“They have an eroding effect on QOL that is not appreciated sometimes,” she said. Though hot flashes eventually subside in most women, others may continue to experience them into their 70s, when hormonal therapies can begin causing more harm than benefit.

“It goes underappreciated that, for a proportion of women, hot flashes will never go away, and they’re just as bad [as] when they were in their 50s,” Dr. Santoro said. “They need to be treated, and the nonhormonal treatments do not work for everybody.”
 

Promising KNDy therapeutics

Autopsy studies of postmenopausal women revealed that a complex of neurons in the hypothalamus was “massively hypertrophied” and sits right next to the thermoregulatory center of the brain, Dr. Reed explained.

The complex produces three types of molecules: kisspeptin (a neuropeptide), neurokinin B (a neuropeptide), and dynorphin (a kappa opioid), collectively referred to as the KNDy. The KNDy neural complex is located in the same place as the majority of hormone receptors in the arcuate nucleus, a collection of nerve cells in the hypothalamus.

The current hypothesis is that the KNDy neurons, which communicate with each other, become hyperactivated and cause hot flashes by spilling over to and triggering the thermoregulatory center next door. NKB (kisspeptin and neurokinin B) agonists activate KNDy neurons and dynorphin agonists inactivate KNDy, so the expectation is that NKB antagonists or dynorphin agonists would stop hot flashes.

Indeed, research published in 2015 showed that women taking kappa agonists experienced fewer hot flashes than women in the placebo group. However, no peripherally restricted kappa agonists are currently in clinical trials, so their future as therapeutics is unclear.

Right now, three different NK antagonists are in the pipeline for reducing vasomotor symptoms: MLE 4901 (pavinetant) and ESN364 (fezolinetant) are both NK3R antagonists, and NT-814 is a dual NK1R/NK3R antagonist. All three of these drugs were originally developed to treat schizophrenia.

Phase 2 clinical trials of pavinetant were discontinued in November 2017 by Millendo Therapeutics because 3 of 28 women experienced abnormal liver function, which normalized within 90 days. However, the study had shown an 80% decrease in hot flashes in women taking pavinetant, compared with a 30% decrease in the placebo group.

Fezolinetant, currently in phase 3 trials with Astellas, showed a dose response effect on reproductive hormones in phase 1 studies and a short half-life (4-6 hours) in women. It also showed no concerning side effects.

“There was, in fact, a decrease in the endometrial thickness, a delayed or impeded ovulation and a prolonged cycle duration,” Reed said.

The subsequent phase 2a study showed a reduction of five hot flashes a day (93% decrease), compared with placebo (54% decrease, P <.001) “with an abrupt return to baseline hot flash frequency after cessation,” she said. Improvements also occurred in sleep quality, quality of life, disability, and interference of hot flashes in daily life.

The phase 2b study found no difference in effects between once-daily versus twice-daily doses. However, two severe adverse events occurred: a drug-induced liver injury in one woman and cholelithiasis in another, both on the 60-mg, once-daily dose. Additionally, five women on varying doses had transient increases (above 1000 U/L) in creatinine kinase, though apparently without dose response.

A 52-week, three-arm, phase 3 trial of fezolinetant is currently under way with a goal of enrolling 1,740 participants, and plans to be completed by December 2021. Participants will undergo regular adverse event screening first biweekly, then monthly, with vital signs, blood, and urine monitoring.

Meanwhile, NT-814 from KaNDy Therapeutics, has completed phase 2a and phase 2b trials with phase 3 slated to begin in 2021. Adverse events in phase 1 included sleepiness and headache, and it had a long half-life (about 26 hours) and rapid absorption (an hour).

The phase 2a trial found a reduction of five hot flashes a day, compared with placebo, with main side effects again being sleepiness and headache. No events of abnormal liver function occurred. Phase 2b results have not been published.

So far, existing research suggests that KNDy interventions will involve a single daily oral dose that begins taking effect within 3 days and is fully in effect within 1-2 weeks. The reduction in hot flashes, about five fewer a day, is more effective than any other currently used nonhormonal medications for vasomotor symptoms. SSRIs and SNRIs tend to result in 1.5-2 fewer hot flashes a day, and gabapentin results in about 3 fewer per day. It will take longer-term studies, however, and paying attention to liver concerns for the NK3R antagonists to move into clinic.

“We want to keep our eye on the [luteinizing hormone] because if it decreases too much, it could adversely affect sexual function, and this does appear to be a dose-response finding,” Dr. Reed said. It would also be ideal, she said, to target only the KNDy neurons with NK3 antagonists without effects on the NK3 receptors in the liver.
 

Other nonhormonal options

Oxybutynin is another a nonhormonal agent under investigation for vasomotor symptoms. It’s an anticholinergic that resulted in 80% fewer hot flashes, compared with 30% with placebo in a 2016 trial, but 52% of women complained of dry mouth. A more recent study similarly found high efficacy – a 60%-80% drop in hot flashes, compared with 30% with placebo – but also side effects of dry mouth, difficulty urinating, and abdominal pain.

Finally, Dr. Reed mentioned three other agents under investigation as possible nonhormonal therapeutics, though she has little information about them. They include MT-8554 by Mitsubishi Tanabe; FP-101 by Fervent Pharmaceuticals; and Q-122 by QUE Oncology with Emory University, Atlanta, and the University of Queensland, Brisbane, Australia. 

None of the currently available nonhormonal options provide as high efficacy as hormones, but they do reduce symptoms:

Clonidine is an off-label option some physicians already use as a nonhormonal treatment for vasomotor symptoms, but again, the side effects are problematic: dry mouth, constipation, drowsiness, postural hypotension, and poor sleep.

Paroxetine, at 7.5-10 mg, is the only FDA-approved nonhormonal treatment for vasomotor symptoms, but she listed other off-label options found effective in evidence reviews: gabapentin (100-2,400 mg), venlafaxine (37.5-75 mg), citalopram (10 mg), desvenlafaxine (150 mg), and escitalopram (10 mg).

“I want you to take note of the lower doses in all of these products that are efficacious above those doses that might be used for mood,” Dr. Reed added.

Dr. Reed receives royalties from UpToDate and research funding from Bayer. Dr. Santoro owns stock in MenoGeniX and serves as a consultant or advisor to Ansh Labs, MenoGeniX, and Ogeda/Astellas.

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

A new group of nonhormonal drugs currently in clinical trials shows strong promise for treating menopausal hot flashes as effectively as hormones, researchers told attendees at the virtual North American Menopause Society 2020 Annual Meeting.

“The KNDy [kisspeptin/neurokinin B/dynorphin] neuron manipulation is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms, though we’re still looking at the safety in phase 3 trials,” reported Susan D. Reed, MD, MPH, director of the Women’s Reproductive Health Research Program at the University of Washington, Seattle.

“If we continue to see good safety data, these are going to be the greatest things since sliced bread,” Dr. Reed said in an interview. “I don’t think we’ve seen anything like this in menopause therapeutics in a long time.”

While several nonhormonal drugs are already used to treat vasomotor symptoms in menopausal women with and without breast cancer, none are as effective as hormone treatments.

“For now, the SSRIs, SNRIs [serotonin norepinephrine reuptake inhibitors], and GABAergics are the best frontline nonhormonal options with a moderate effect, and clonidine and oxybutynin are effective, but we see more side effects with these,” Dr. Reed said. She noted the importance of considering patients’ mood, sleep, pain, sexual function, weight gain, overactive bladder, blood pressure, and individual quality of life (QOL) goals in tailoring those therapies.

But women still need more nonhormonal options that are at least as effective as hormonal options, Dr. Reed said. Some women are unable to take hormonal options because they are at risk for blood clots or breast cancer.

“Then there’s preference,” she said. “Sometimes people don’t like the way they feel when they take hormones, or they just don’t want hormones in their body. It’s absolutely critical to have these options available for women.”

Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, who was not involved in the presentation, said in an interview that physicians may not always realize the extent to which vasomotor symptoms interfere with women’s daily lives.

“They have an eroding effect on QOL that is not appreciated sometimes,” she said. Though hot flashes eventually subside in most women, others may continue to experience them into their 70s, when hormonal therapies can begin causing more harm than benefit.

“It goes underappreciated that, for a proportion of women, hot flashes will never go away, and they’re just as bad [as] when they were in their 50s,” Dr. Santoro said. “They need to be treated, and the nonhormonal treatments do not work for everybody.”
 

Promising KNDy therapeutics

Autopsy studies of postmenopausal women revealed that a complex of neurons in the hypothalamus was “massively hypertrophied” and sits right next to the thermoregulatory center of the brain, Dr. Reed explained.

The complex produces three types of molecules: kisspeptin (a neuropeptide), neurokinin B (a neuropeptide), and dynorphin (a kappa opioid), collectively referred to as the KNDy. The KNDy neural complex is located in the same place as the majority of hormone receptors in the arcuate nucleus, a collection of nerve cells in the hypothalamus.

The current hypothesis is that the KNDy neurons, which communicate with each other, become hyperactivated and cause hot flashes by spilling over to and triggering the thermoregulatory center next door. NKB (kisspeptin and neurokinin B) agonists activate KNDy neurons and dynorphin agonists inactivate KNDy, so the expectation is that NKB antagonists or dynorphin agonists would stop hot flashes.

Indeed, research published in 2015 showed that women taking kappa agonists experienced fewer hot flashes than women in the placebo group. However, no peripherally restricted kappa agonists are currently in clinical trials, so their future as therapeutics is unclear.

Right now, three different NK antagonists are in the pipeline for reducing vasomotor symptoms: MLE 4901 (pavinetant) and ESN364 (fezolinetant) are both NK3R antagonists, and NT-814 is a dual NK1R/NK3R antagonist. All three of these drugs were originally developed to treat schizophrenia.

Phase 2 clinical trials of pavinetant were discontinued in November 2017 by Millendo Therapeutics because 3 of 28 women experienced abnormal liver function, which normalized within 90 days. However, the study had shown an 80% decrease in hot flashes in women taking pavinetant, compared with a 30% decrease in the placebo group.

Fezolinetant, currently in phase 3 trials with Astellas, showed a dose response effect on reproductive hormones in phase 1 studies and a short half-life (4-6 hours) in women. It also showed no concerning side effects.

“There was, in fact, a decrease in the endometrial thickness, a delayed or impeded ovulation and a prolonged cycle duration,” Reed said.

The subsequent phase 2a study showed a reduction of five hot flashes a day (93% decrease), compared with placebo (54% decrease, P <.001) “with an abrupt return to baseline hot flash frequency after cessation,” she said. Improvements also occurred in sleep quality, quality of life, disability, and interference of hot flashes in daily life.

The phase 2b study found no difference in effects between once-daily versus twice-daily doses. However, two severe adverse events occurred: a drug-induced liver injury in one woman and cholelithiasis in another, both on the 60-mg, once-daily dose. Additionally, five women on varying doses had transient increases (above 1000 U/L) in creatinine kinase, though apparently without dose response.

A 52-week, three-arm, phase 3 trial of fezolinetant is currently under way with a goal of enrolling 1,740 participants, and plans to be completed by December 2021. Participants will undergo regular adverse event screening first biweekly, then monthly, with vital signs, blood, and urine monitoring.

Meanwhile, NT-814 from KaNDy Therapeutics, has completed phase 2a and phase 2b trials with phase 3 slated to begin in 2021. Adverse events in phase 1 included sleepiness and headache, and it had a long half-life (about 26 hours) and rapid absorption (an hour).

The phase 2a trial found a reduction of five hot flashes a day, compared with placebo, with main side effects again being sleepiness and headache. No events of abnormal liver function occurred. Phase 2b results have not been published.

So far, existing research suggests that KNDy interventions will involve a single daily oral dose that begins taking effect within 3 days and is fully in effect within 1-2 weeks. The reduction in hot flashes, about five fewer a day, is more effective than any other currently used nonhormonal medications for vasomotor symptoms. SSRIs and SNRIs tend to result in 1.5-2 fewer hot flashes a day, and gabapentin results in about 3 fewer per day. It will take longer-term studies, however, and paying attention to liver concerns for the NK3R antagonists to move into clinic.

“We want to keep our eye on the [luteinizing hormone] because if it decreases too much, it could adversely affect sexual function, and this does appear to be a dose-response finding,” Dr. Reed said. It would also be ideal, she said, to target only the KNDy neurons with NK3 antagonists without effects on the NK3 receptors in the liver.
 

Other nonhormonal options

Oxybutynin is another a nonhormonal agent under investigation for vasomotor symptoms. It’s an anticholinergic that resulted in 80% fewer hot flashes, compared with 30% with placebo in a 2016 trial, but 52% of women complained of dry mouth. A more recent study similarly found high efficacy – a 60%-80% drop in hot flashes, compared with 30% with placebo – but also side effects of dry mouth, difficulty urinating, and abdominal pain.

Finally, Dr. Reed mentioned three other agents under investigation as possible nonhormonal therapeutics, though she has little information about them. They include MT-8554 by Mitsubishi Tanabe; FP-101 by Fervent Pharmaceuticals; and Q-122 by QUE Oncology with Emory University, Atlanta, and the University of Queensland, Brisbane, Australia. 

None of the currently available nonhormonal options provide as high efficacy as hormones, but they do reduce symptoms:

Clonidine is an off-label option some physicians already use as a nonhormonal treatment for vasomotor symptoms, but again, the side effects are problematic: dry mouth, constipation, drowsiness, postural hypotension, and poor sleep.

Paroxetine, at 7.5-10 mg, is the only FDA-approved nonhormonal treatment for vasomotor symptoms, but she listed other off-label options found effective in evidence reviews: gabapentin (100-2,400 mg), venlafaxine (37.5-75 mg), citalopram (10 mg), desvenlafaxine (150 mg), and escitalopram (10 mg).

“I want you to take note of the lower doses in all of these products that are efficacious above those doses that might be used for mood,” Dr. Reed added.

Dr. Reed receives royalties from UpToDate and research funding from Bayer. Dr. Santoro owns stock in MenoGeniX and serves as a consultant or advisor to Ansh Labs, MenoGeniX, and Ogeda/Astellas.

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

A new group of nonhormonal drugs currently in clinical trials shows strong promise for treating menopausal hot flashes as effectively as hormones, researchers told attendees at the virtual North American Menopause Society 2020 Annual Meeting.

“The KNDy [kisspeptin/neurokinin B/dynorphin] neuron manipulation is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms, though we’re still looking at the safety in phase 3 trials,” reported Susan D. Reed, MD, MPH, director of the Women’s Reproductive Health Research Program at the University of Washington, Seattle.

“If we continue to see good safety data, these are going to be the greatest things since sliced bread,” Dr. Reed said in an interview. “I don’t think we’ve seen anything like this in menopause therapeutics in a long time.”

While several nonhormonal drugs are already used to treat vasomotor symptoms in menopausal women with and without breast cancer, none are as effective as hormone treatments.

“For now, the SSRIs, SNRIs [serotonin norepinephrine reuptake inhibitors], and GABAergics are the best frontline nonhormonal options with a moderate effect, and clonidine and oxybutynin are effective, but we see more side effects with these,” Dr. Reed said. She noted the importance of considering patients’ mood, sleep, pain, sexual function, weight gain, overactive bladder, blood pressure, and individual quality of life (QOL) goals in tailoring those therapies.

But women still need more nonhormonal options that are at least as effective as hormonal options, Dr. Reed said. Some women are unable to take hormonal options because they are at risk for blood clots or breast cancer.

“Then there’s preference,” she said. “Sometimes people don’t like the way they feel when they take hormones, or they just don’t want hormones in their body. It’s absolutely critical to have these options available for women.”

Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, who was not involved in the presentation, said in an interview that physicians may not always realize the extent to which vasomotor symptoms interfere with women’s daily lives.

“They have an eroding effect on QOL that is not appreciated sometimes,” she said. Though hot flashes eventually subside in most women, others may continue to experience them into their 70s, when hormonal therapies can begin causing more harm than benefit.

“It goes underappreciated that, for a proportion of women, hot flashes will never go away, and they’re just as bad [as] when they were in their 50s,” Dr. Santoro said. “They need to be treated, and the nonhormonal treatments do not work for everybody.”
 

Promising KNDy therapeutics

Autopsy studies of postmenopausal women revealed that a complex of neurons in the hypothalamus was “massively hypertrophied” and sits right next to the thermoregulatory center of the brain, Dr. Reed explained.

The complex produces three types of molecules: kisspeptin (a neuropeptide), neurokinin B (a neuropeptide), and dynorphin (a kappa opioid), collectively referred to as the KNDy. The KNDy neural complex is located in the same place as the majority of hormone receptors in the arcuate nucleus, a collection of nerve cells in the hypothalamus.

The current hypothesis is that the KNDy neurons, which communicate with each other, become hyperactivated and cause hot flashes by spilling over to and triggering the thermoregulatory center next door. NKB (kisspeptin and neurokinin B) agonists activate KNDy neurons and dynorphin agonists inactivate KNDy, so the expectation is that NKB antagonists or dynorphin agonists would stop hot flashes.

Indeed, research published in 2015 showed that women taking kappa agonists experienced fewer hot flashes than women in the placebo group. However, no peripherally restricted kappa agonists are currently in clinical trials, so their future as therapeutics is unclear.

Right now, three different NK antagonists are in the pipeline for reducing vasomotor symptoms: MLE 4901 (pavinetant) and ESN364 (fezolinetant) are both NK3R antagonists, and NT-814 is a dual NK1R/NK3R antagonist. All three of these drugs were originally developed to treat schizophrenia.

Phase 2 clinical trials of pavinetant were discontinued in November 2017 by Millendo Therapeutics because 3 of 28 women experienced abnormal liver function, which normalized within 90 days. However, the study had shown an 80% decrease in hot flashes in women taking pavinetant, compared with a 30% decrease in the placebo group.

Fezolinetant, currently in phase 3 trials with Astellas, showed a dose response effect on reproductive hormones in phase 1 studies and a short half-life (4-6 hours) in women. It also showed no concerning side effects.

“There was, in fact, a decrease in the endometrial thickness, a delayed or impeded ovulation and a prolonged cycle duration,” Reed said.

The subsequent phase 2a study showed a reduction of five hot flashes a day (93% decrease), compared with placebo (54% decrease, P <.001) “with an abrupt return to baseline hot flash frequency after cessation,” she said. Improvements also occurred in sleep quality, quality of life, disability, and interference of hot flashes in daily life.

The phase 2b study found no difference in effects between once-daily versus twice-daily doses. However, two severe adverse events occurred: a drug-induced liver injury in one woman and cholelithiasis in another, both on the 60-mg, once-daily dose. Additionally, five women on varying doses had transient increases (above 1000 U/L) in creatinine kinase, though apparently without dose response.

A 52-week, three-arm, phase 3 trial of fezolinetant is currently under way with a goal of enrolling 1,740 participants, and plans to be completed by December 2021. Participants will undergo regular adverse event screening first biweekly, then monthly, with vital signs, blood, and urine monitoring.

Meanwhile, NT-814 from KaNDy Therapeutics, has completed phase 2a and phase 2b trials with phase 3 slated to begin in 2021. Adverse events in phase 1 included sleepiness and headache, and it had a long half-life (about 26 hours) and rapid absorption (an hour).

The phase 2a trial found a reduction of five hot flashes a day, compared with placebo, with main side effects again being sleepiness and headache. No events of abnormal liver function occurred. Phase 2b results have not been published.

So far, existing research suggests that KNDy interventions will involve a single daily oral dose that begins taking effect within 3 days and is fully in effect within 1-2 weeks. The reduction in hot flashes, about five fewer a day, is more effective than any other currently used nonhormonal medications for vasomotor symptoms. SSRIs and SNRIs tend to result in 1.5-2 fewer hot flashes a day, and gabapentin results in about 3 fewer per day. It will take longer-term studies, however, and paying attention to liver concerns for the NK3R antagonists to move into clinic.

“We want to keep our eye on the [luteinizing hormone] because if it decreases too much, it could adversely affect sexual function, and this does appear to be a dose-response finding,” Dr. Reed said. It would also be ideal, she said, to target only the KNDy neurons with NK3 antagonists without effects on the NK3 receptors in the liver.
 

Other nonhormonal options

Oxybutynin is another a nonhormonal agent under investigation for vasomotor symptoms. It’s an anticholinergic that resulted in 80% fewer hot flashes, compared with 30% with placebo in a 2016 trial, but 52% of women complained of dry mouth. A more recent study similarly found high efficacy – a 60%-80% drop in hot flashes, compared with 30% with placebo – but also side effects of dry mouth, difficulty urinating, and abdominal pain.

Finally, Dr. Reed mentioned three other agents under investigation as possible nonhormonal therapeutics, though she has little information about them. They include MT-8554 by Mitsubishi Tanabe; FP-101 by Fervent Pharmaceuticals; and Q-122 by QUE Oncology with Emory University, Atlanta, and the University of Queensland, Brisbane, Australia. 

None of the currently available nonhormonal options provide as high efficacy as hormones, but they do reduce symptoms:

Clonidine is an off-label option some physicians already use as a nonhormonal treatment for vasomotor symptoms, but again, the side effects are problematic: dry mouth, constipation, drowsiness, postural hypotension, and poor sleep.

Paroxetine, at 7.5-10 mg, is the only FDA-approved nonhormonal treatment for vasomotor symptoms, but she listed other off-label options found effective in evidence reviews: gabapentin (100-2,400 mg), venlafaxine (37.5-75 mg), citalopram (10 mg), desvenlafaxine (150 mg), and escitalopram (10 mg).

“I want you to take note of the lower doses in all of these products that are efficacious above those doses that might be used for mood,” Dr. Reed added.

Dr. Reed receives royalties from UpToDate and research funding from Bayer. Dr. Santoro owns stock in MenoGeniX and serves as a consultant or advisor to Ansh Labs, MenoGeniX, and Ogeda/Astellas.

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

The emergence of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in December 2019, has resulted in a global pandemic that has challenged the medical community and will continue to represent a public health emergency for the next several months.¹ It has rapidly spread globally, infecting many individuals in an unprecedented rate of infection and worldwide reach. On March 11, 2020, the World Health Organization designated COVID-19 as a pandemic. While the majority of infected individuals are asymptomatic or develop only mild symptoms, some have an unfortunate clinical course resulting in multi-organ failure and death.²

It is accepted that the virus mainly spreads during close contact and via respiratory droplets.³ The average time from infection to onset of symptoms ranges from 2 to 14 days, with an average of 5 days.⁴ Recommended measures to prevent the spread of the infection include social distancing (at least 6 feet from others), meticulous hand hygiene, and wearing a mask covering the mouth and nose when in public.⁵ Aiming to mitigate the risk of viral dissemination for patients and health care providers, and to preserve hospital resources, all nonessential medical interventions were initially suspended. Recently, the American College of Surgeons in a joint statement with 9 women’s health care societies have provided recommendations on how to resume clinical activities as we recover from the pandemic.⁶

As we reinitiate clinical activities, gynecologists have been alerted of the potential risk of viral dissemination during gynecologic minimally invasive surgical procedures due to the presence of the virus in blood, stool, and the potential risk of aerosolization of the virus, especially when using smoke-generating devices.^7,8 This risk is not limited to intubation and extubation of the airway during anesthesia; the risk also presents itself during other aerosol-generating procedures, such as laparoscopy or robotic surgery.^9,10

Hysteroscopy is considered the gold standard procedure for the diagnosis and management of intrauterine pathologies.¹¹ It is frequently performed in an office setting without the use of anesthesia.^11,12 It is usually well tolerated, with only a few patients reporting discomfort.¹² It allows for immediate treatment (using the “see and treat” approach) while avoiding not only the risk of anesthesia, as stated, but also the need for intubation—which has a high risk of droplet contamination in COVID-19–infected individuals.¹³

Is there risk of viral dissemination during hysteroscopic procedures?

The novel and rapidly changing nature of the COVID-19 pandemic present many challenges to the gynecologist. Significant concerns have been raised regarding potential risk of viral dissemination during laparoscopic surgery due to aerosolization of viral particles and the presence of the virus in blood and the gastrointestinal tract of infected patients.⁷ Diagnostic, and some simple, hysteroscopic procedures are commonly performed in an outpatient setting, with the patient awake. Complex hysteroscopic interventions, however, are generally performed in the operating room, typically with the use of general anesthesia. Hysteroscopy has the theoretical risks of viral dissemination when performed in COVID-19–positive patients. Two important questions must be addressed to better understand the potential risk of COVID-19 viral dissemination during hysteroscopic procedures.

Continue to: 1. Is the virus present in the vaginal fluid of women infected with COVID-19?...

1. Is the virus present in the vaginal fluid of women infected with COVID-19?

Recent studies have confirmed the presence of viral particles in urine, feces, blood, and tears in addition to the respiratory tract in patients infected with COVID-19.^3,14,15 The presence of the SARS-CoV-2 virus in the female genital system is currently unknown. Previous studies, of other epidemic viral infections, have demonstrated the presence of the virus in the female genital tract in affected patients of Zika virus and Ebola.^16,17 However, 2 recent studies have failed to demonstrate the presence of the SARS-CoV-2 virus in the vaginal fluid of pregnant¹⁴ and not pregnant¹⁸ women with severe COVID-19 infection.

2. Is there risk of viral dissemination during hysteroscopy if using electrosurgery?

There are significant concerns with possible risk of COVID-19 transmission to health care providers in direct contact with infected patients during minimally invasive gynecologic procedures due to direct contamination and aerosolization of the virus.^10,19 Current data on COVID-19 transmission during surgery are limited. However, it is important to recognize that viral aerosolization has been documented with other viral diseases, such as human papillomavirus and hepatitis B.²⁰ A recent report called for awareness in the surgical community about the potential risks of COVID-19 viral dissemination during laparoscopic surgery. Among other recommendations, international experts advised minimizing the use of electrosurgery to reduce the creation of surgical plume, decreasing the pneumoperitoneum pressure to minimum levels, and using suction devices in a closed system.²¹ Although these preventive measures apply to laparoscopic surgery, it is important to consider that hysteroscopy is performed in a unique environment.

During hysteroscopy the uterine cavity is distended with a liquid medium (normal saline or electrolyte-free solutions); this is opposed to gynecologic laparoscopy, in which the peritoneal cavity is distended with carbon dioxide.²² The smoke produced with the use of hysteroscopic electrosurgical instruments generates bubbles that are immediately cooled down to the temperature of the distention media and subsequently dissolve into it. Therefore, there are no bubbles generated during hysteroscopic surgery that are subsequently released into the air. This results in a low risk for viral dissemination during hysteroscopic procedures. Nevertheless, the necessary precautions to minimize the risk of COVID-19 transmission during hysteroscopic intervention are extremely important.

Recommendations for hysteroscopic procedures during the COVID-19 pandemic

We provide our overall recommendations for hysteroscopy, as well as those specific to the office and hospital setting.

Recommendations: General

Limit hysteroscopic procedures to COVID-19–negative patients and to those patients in whom delaying the procedure could result in adverse clinical outcomes.²³

Universally screen for potential COVID-19 infection. When possible, a phone interview to triage patients based on their symptoms and infection exposure status should take place before the patient arrives to the health care center. Patients with suspected or confirmed COVID-19 infection who require immediate evaluation should be directed to COVID-19–designated emergency areas.

Universally test for SARS-CoV-2 before procedures performed in the operating room (OR). Using nasopharyngeal swabs for the detection of viral RNA, employing molecular methods such as polymerase chain reaction (PCR), within 48 to 72 hours prior to all OR hysteroscopic procedures is strongly recommended. Adopting this testing strategy will aid to identify asymptomatic SARS-CoV-2‒infected patients, allowing to defer the procedure, if possible, among patients testing positive. If tests are limited, testing only patients scheduled for hysteroscopic procedures in which general or regional anesthesia will be required is acceptable.

Universal SARS-CoV-2 testing of patients undergoing in-office hysteroscopic diagnostic or minor operative procedures without the use of anesthesia is not required.

Limit the presence of a companion. It is understood that visitor policies may vary at the discretion of each institution’s guidelines. Children and individuals over the age of 60 years should not be granted access to the center. Companions will be subjected to the same screening criteria as patients.

Provide for social distancing and other precautionary measures. If more than one patient is scheduled to be at the facility at the same time, ensure that the facility provides adequate space to allow the appropriate social distancing recommendations between patients. Hand sanitizers and facemasks should be available for patients and companions.

Provide PPE for clinicians. All health care providers in close contact with the patient must wear personal protective equipment (PPE), which includes an apron and gown, a surgical mask, eye protection, and gloves. Health care providers should wear PPE deemed appropriate by their regulatory institutions following their local and national guidelines during clinical patient interactions.

Restrict surgical attendees to vital personnel. The participation of learners by physical presence in the office or operating room should be restricted.

Continue to: Recommendations: Office setting...

Preprocedural recommendations

• Advise patients to come to the office alone. If the patient requires a companion, a maximum of one adult companion under the age of 60 should be accepted.
• Limit the number of health care team members present in the procedure room.

Intraprocedural recommendations

• Choose the appropriate device(s) that will allow for an effective and fast procedure.
• Use the recommended PPE for all clinicians.
• Limit the movement of staff members in and out of the procedure room.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same procedure room, allow enough time in between cases to grant a thorough OR decontamination.
• Allow for patients to recover from the procedure in the same room as the procedure took place in order to avoid potential contamination of multiple rooms.
• Expedite patient discharge.
• Follow up after the procedure by phone or telemedicine.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Continue to: Recommendations: Operating room setting...

Preprocedural recommendations

• Perform adequate patient screening for potential COVID-19 infection. (Screening should be independent of symptoms and not be limited to those with clinical symptoms.)
• Limit the number of health care team members in the operating procedure room.
• To minimize unnecessary staff exposure, have surgeons and staff not needed for intubation remain outside the OR until intubation is completed and leave the OR before extubation.

Intraprocedure recommendations

• Limit personnel in the OR to a minimum.
• Staff should not enter or leave the room during the procedure.
• When possible, use conscious sedation or regional anesthesia to avoid the risk of viral dissemination at the time of intubation/extubation.
• Choose the device that will allow an effective and fast procedure.
• Favor non–smoke-generating devices, such as hysteroscopic scissors, graspers, and tissue retrieval systems.
• Connect active suction to the outflow, especially when using smoke-generating instruments, to facilitate the extraction of surgical smoke.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same room, allow enough time in between cases to grant a thorough OR decontamination.
• Expedite postprocedure recovery and patient discharge.
• After completion of the procedure, staff should remove scrubs and change into clean clothing.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Conclusions

The COVID-19 pandemic has caused a global health emergency. Our knowledge of this devastating virus is constantly evolving as we continue to fight this overwhelming disease. Theoretical risk of “viral” dissemination is considered extremely low, or negligible, during hysterosocopy. Hysteroscopic procedures in COVID-19–positive patients with life-threatening conditions or in patients in whom delaying the procedure could worsen outcomes should be performed taking appropriate measures. Patients who test negative for COVID-19 (confirmed by PCR) and require hysteroscopic procedures, should be treated using universal precautions. ●

The emergence of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in December 2019, has resulted in a global pandemic that has challenged the medical community and will continue to represent a public health emergency for the next several months.¹ It has rapidly spread globally, infecting many individuals in an unprecedented rate of infection and worldwide reach. On March 11, 2020, the World Health Organization designated COVID-19 as a pandemic. While the majority of infected individuals are asymptomatic or develop only mild symptoms, some have an unfortunate clinical course resulting in multi-organ failure and death.²

It is accepted that the virus mainly spreads during close contact and via respiratory droplets.³ The average time from infection to onset of symptoms ranges from 2 to 14 days, with an average of 5 days.⁴ Recommended measures to prevent the spread of the infection include social distancing (at least 6 feet from others), meticulous hand hygiene, and wearing a mask covering the mouth and nose when in public.⁵ Aiming to mitigate the risk of viral dissemination for patients and health care providers, and to preserve hospital resources, all nonessential medical interventions were initially suspended. Recently, the American College of Surgeons in a joint statement with 9 women’s health care societies have provided recommendations on how to resume clinical activities as we recover from the pandemic.⁶

As we reinitiate clinical activities, gynecologists have been alerted of the potential risk of viral dissemination during gynecologic minimally invasive surgical procedures due to the presence of the virus in blood, stool, and the potential risk of aerosolization of the virus, especially when using smoke-generating devices.^7,8 This risk is not limited to intubation and extubation of the airway during anesthesia; the risk also presents itself during other aerosol-generating procedures, such as laparoscopy or robotic surgery.^9,10

Hysteroscopy is considered the gold standard procedure for the diagnosis and management of intrauterine pathologies.¹¹ It is frequently performed in an office setting without the use of anesthesia.^11,12 It is usually well tolerated, with only a few patients reporting discomfort.¹² It allows for immediate treatment (using the “see and treat” approach) while avoiding not only the risk of anesthesia, as stated, but also the need for intubation—which has a high risk of droplet contamination in COVID-19–infected individuals.¹³

Is there risk of viral dissemination during hysteroscopic procedures?

The novel and rapidly changing nature of the COVID-19 pandemic present many challenges to the gynecologist. Significant concerns have been raised regarding potential risk of viral dissemination during laparoscopic surgery due to aerosolization of viral particles and the presence of the virus in blood and the gastrointestinal tract of infected patients.⁷ Diagnostic, and some simple, hysteroscopic procedures are commonly performed in an outpatient setting, with the patient awake. Complex hysteroscopic interventions, however, are generally performed in the operating room, typically with the use of general anesthesia. Hysteroscopy has the theoretical risks of viral dissemination when performed in COVID-19–positive patients. Two important questions must be addressed to better understand the potential risk of COVID-19 viral dissemination during hysteroscopic procedures.

Continue to: 1. Is the virus present in the vaginal fluid of women infected with COVID-19?...

1. Is the virus present in the vaginal fluid of women infected with COVID-19?

Recent studies have confirmed the presence of viral particles in urine, feces, blood, and tears in addition to the respiratory tract in patients infected with COVID-19.^3,14,15 The presence of the SARS-CoV-2 virus in the female genital system is currently unknown. Previous studies, of other epidemic viral infections, have demonstrated the presence of the virus in the female genital tract in affected patients of Zika virus and Ebola.^16,17 However, 2 recent studies have failed to demonstrate the presence of the SARS-CoV-2 virus in the vaginal fluid of pregnant¹⁴ and not pregnant¹⁸ women with severe COVID-19 infection.

2. Is there risk of viral dissemination during hysteroscopy if using electrosurgery?

There are significant concerns with possible risk of COVID-19 transmission to health care providers in direct contact with infected patients during minimally invasive gynecologic procedures due to direct contamination and aerosolization of the virus.^10,19 Current data on COVID-19 transmission during surgery are limited. However, it is important to recognize that viral aerosolization has been documented with other viral diseases, such as human papillomavirus and hepatitis B.²⁰ A recent report called for awareness in the surgical community about the potential risks of COVID-19 viral dissemination during laparoscopic surgery. Among other recommendations, international experts advised minimizing the use of electrosurgery to reduce the creation of surgical plume, decreasing the pneumoperitoneum pressure to minimum levels, and using suction devices in a closed system.²¹ Although these preventive measures apply to laparoscopic surgery, it is important to consider that hysteroscopy is performed in a unique environment.

During hysteroscopy the uterine cavity is distended with a liquid medium (normal saline or electrolyte-free solutions); this is opposed to gynecologic laparoscopy, in which the peritoneal cavity is distended with carbon dioxide.²² The smoke produced with the use of hysteroscopic electrosurgical instruments generates bubbles that are immediately cooled down to the temperature of the distention media and subsequently dissolve into it. Therefore, there are no bubbles generated during hysteroscopic surgery that are subsequently released into the air. This results in a low risk for viral dissemination during hysteroscopic procedures. Nevertheless, the necessary precautions to minimize the risk of COVID-19 transmission during hysteroscopic intervention are extremely important.

Recommendations for hysteroscopic procedures during the COVID-19 pandemic

We provide our overall recommendations for hysteroscopy, as well as those specific to the office and hospital setting.

Recommendations: General

Limit hysteroscopic procedures to COVID-19–negative patients and to those patients in whom delaying the procedure could result in adverse clinical outcomes.²³

Universally screen for potential COVID-19 infection. When possible, a phone interview to triage patients based on their symptoms and infection exposure status should take place before the patient arrives to the health care center. Patients with suspected or confirmed COVID-19 infection who require immediate evaluation should be directed to COVID-19–designated emergency areas.

Universally test for SARS-CoV-2 before procedures performed in the operating room (OR). Using nasopharyngeal swabs for the detection of viral RNA, employing molecular methods such as polymerase chain reaction (PCR), within 48 to 72 hours prior to all OR hysteroscopic procedures is strongly recommended. Adopting this testing strategy will aid to identify asymptomatic SARS-CoV-2‒infected patients, allowing to defer the procedure, if possible, among patients testing positive. If tests are limited, testing only patients scheduled for hysteroscopic procedures in which general or regional anesthesia will be required is acceptable.

Universal SARS-CoV-2 testing of patients undergoing in-office hysteroscopic diagnostic or minor operative procedures without the use of anesthesia is not required.

Limit the presence of a companion. It is understood that visitor policies may vary at the discretion of each institution’s guidelines. Children and individuals over the age of 60 years should not be granted access to the center. Companions will be subjected to the same screening criteria as patients.

Provide for social distancing and other precautionary measures. If more than one patient is scheduled to be at the facility at the same time, ensure that the facility provides adequate space to allow the appropriate social distancing recommendations between patients. Hand sanitizers and facemasks should be available for patients and companions.

Provide PPE for clinicians. All health care providers in close contact with the patient must wear personal protective equipment (PPE), which includes an apron and gown, a surgical mask, eye protection, and gloves. Health care providers should wear PPE deemed appropriate by their regulatory institutions following their local and national guidelines during clinical patient interactions.

Restrict surgical attendees to vital personnel. The participation of learners by physical presence in the office or operating room should be restricted.

Continue to: Recommendations: Office setting...

Preprocedural recommendations

• Advise patients to come to the office alone. If the patient requires a companion, a maximum of one adult companion under the age of 60 should be accepted.
• Limit the number of health care team members present in the procedure room.

Intraprocedural recommendations

• Choose the appropriate device(s) that will allow for an effective and fast procedure.
• Use the recommended PPE for all clinicians.
• Limit the movement of staff members in and out of the procedure room.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same procedure room, allow enough time in between cases to grant a thorough OR decontamination.
• Allow for patients to recover from the procedure in the same room as the procedure took place in order to avoid potential contamination of multiple rooms.
• Expedite patient discharge.
• Follow up after the procedure by phone or telemedicine.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Continue to: Recommendations: Operating room setting...

Preprocedural recommendations

• Perform adequate patient screening for potential COVID-19 infection. (Screening should be independent of symptoms and not be limited to those with clinical symptoms.)
• Limit the number of health care team members in the operating procedure room.
• To minimize unnecessary staff exposure, have surgeons and staff not needed for intubation remain outside the OR until intubation is completed and leave the OR before extubation.

Intraprocedure recommendations

• Limit personnel in the OR to a minimum.
• Staff should not enter or leave the room during the procedure.
• When possible, use conscious sedation or regional anesthesia to avoid the risk of viral dissemination at the time of intubation/extubation.
• Choose the device that will allow an effective and fast procedure.
• Favor non–smoke-generating devices, such as hysteroscopic scissors, graspers, and tissue retrieval systems.
• Connect active suction to the outflow, especially when using smoke-generating instruments, to facilitate the extraction of surgical smoke.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same room, allow enough time in between cases to grant a thorough OR decontamination.
• Expedite postprocedure recovery and patient discharge.
• After completion of the procedure, staff should remove scrubs and change into clean clothing.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Conclusions

The COVID-19 pandemic has caused a global health emergency. Our knowledge of this devastating virus is constantly evolving as we continue to fight this overwhelming disease. Theoretical risk of “viral” dissemination is considered extremely low, or negligible, during hysterosocopy. Hysteroscopic procedures in COVID-19–positive patients with life-threatening conditions or in patients in whom delaying the procedure could worsen outcomes should be performed taking appropriate measures. Patients who test negative for COVID-19 (confirmed by PCR) and require hysteroscopic procedures, should be treated using universal precautions. ●

The emergence of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in December 2019, has resulted in a global pandemic that has challenged the medical community and will continue to represent a public health emergency for the next several months.¹ It has rapidly spread globally, infecting many individuals in an unprecedented rate of infection and worldwide reach. On March 11, 2020, the World Health Organization designated COVID-19 as a pandemic. While the majority of infected individuals are asymptomatic or develop only mild symptoms, some have an unfortunate clinical course resulting in multi-organ failure and death.²

It is accepted that the virus mainly spreads during close contact and via respiratory droplets.³ The average time from infection to onset of symptoms ranges from 2 to 14 days, with an average of 5 days.⁴ Recommended measures to prevent the spread of the infection include social distancing (at least 6 feet from others), meticulous hand hygiene, and wearing a mask covering the mouth and nose when in public.⁵ Aiming to mitigate the risk of viral dissemination for patients and health care providers, and to preserve hospital resources, all nonessential medical interventions were initially suspended. Recently, the American College of Surgeons in a joint statement with 9 women’s health care societies have provided recommendations on how to resume clinical activities as we recover from the pandemic.⁶

As we reinitiate clinical activities, gynecologists have been alerted of the potential risk of viral dissemination during gynecologic minimally invasive surgical procedures due to the presence of the virus in blood, stool, and the potential risk of aerosolization of the virus, especially when using smoke-generating devices.^7,8 This risk is not limited to intubation and extubation of the airway during anesthesia; the risk also presents itself during other aerosol-generating procedures, such as laparoscopy or robotic surgery.^9,10

Hysteroscopy is considered the gold standard procedure for the diagnosis and management of intrauterine pathologies.¹¹ It is frequently performed in an office setting without the use of anesthesia.^11,12 It is usually well tolerated, with only a few patients reporting discomfort.¹² It allows for immediate treatment (using the “see and treat” approach) while avoiding not only the risk of anesthesia, as stated, but also the need for intubation—which has a high risk of droplet contamination in COVID-19–infected individuals.¹³

Is there risk of viral dissemination during hysteroscopic procedures?

The novel and rapidly changing nature of the COVID-19 pandemic present many challenges to the gynecologist. Significant concerns have been raised regarding potential risk of viral dissemination during laparoscopic surgery due to aerosolization of viral particles and the presence of the virus in blood and the gastrointestinal tract of infected patients.⁷ Diagnostic, and some simple, hysteroscopic procedures are commonly performed in an outpatient setting, with the patient awake. Complex hysteroscopic interventions, however, are generally performed in the operating room, typically with the use of general anesthesia. Hysteroscopy has the theoretical risks of viral dissemination when performed in COVID-19–positive patients. Two important questions must be addressed to better understand the potential risk of COVID-19 viral dissemination during hysteroscopic procedures.

Continue to: 1. Is the virus present in the vaginal fluid of women infected with COVID-19?...

1. Is the virus present in the vaginal fluid of women infected with COVID-19?

Recent studies have confirmed the presence of viral particles in urine, feces, blood, and tears in addition to the respiratory tract in patients infected with COVID-19.^3,14,15 The presence of the SARS-CoV-2 virus in the female genital system is currently unknown. Previous studies, of other epidemic viral infections, have demonstrated the presence of the virus in the female genital tract in affected patients of Zika virus and Ebola.^16,17 However, 2 recent studies have failed to demonstrate the presence of the SARS-CoV-2 virus in the vaginal fluid of pregnant¹⁴ and not pregnant¹⁸ women with severe COVID-19 infection.

2. Is there risk of viral dissemination during hysteroscopy if using electrosurgery?

There are significant concerns with possible risk of COVID-19 transmission to health care providers in direct contact with infected patients during minimally invasive gynecologic procedures due to direct contamination and aerosolization of the virus.^10,19 Current data on COVID-19 transmission during surgery are limited. However, it is important to recognize that viral aerosolization has been documented with other viral diseases, such as human papillomavirus and hepatitis B.²⁰ A recent report called for awareness in the surgical community about the potential risks of COVID-19 viral dissemination during laparoscopic surgery. Among other recommendations, international experts advised minimizing the use of electrosurgery to reduce the creation of surgical plume, decreasing the pneumoperitoneum pressure to minimum levels, and using suction devices in a closed system.²¹ Although these preventive measures apply to laparoscopic surgery, it is important to consider that hysteroscopy is performed in a unique environment.

During hysteroscopy the uterine cavity is distended with a liquid medium (normal saline or electrolyte-free solutions); this is opposed to gynecologic laparoscopy, in which the peritoneal cavity is distended with carbon dioxide.²² The smoke produced with the use of hysteroscopic electrosurgical instruments generates bubbles that are immediately cooled down to the temperature of the distention media and subsequently dissolve into it. Therefore, there are no bubbles generated during hysteroscopic surgery that are subsequently released into the air. This results in a low risk for viral dissemination during hysteroscopic procedures. Nevertheless, the necessary precautions to minimize the risk of COVID-19 transmission during hysteroscopic intervention are extremely important.

Recommendations for hysteroscopic procedures during the COVID-19 pandemic

We provide our overall recommendations for hysteroscopy, as well as those specific to the office and hospital setting.

Recommendations: General

Limit hysteroscopic procedures to COVID-19–negative patients and to those patients in whom delaying the procedure could result in adverse clinical outcomes.²³

Universally screen for potential COVID-19 infection. When possible, a phone interview to triage patients based on their symptoms and infection exposure status should take place before the patient arrives to the health care center. Patients with suspected or confirmed COVID-19 infection who require immediate evaluation should be directed to COVID-19–designated emergency areas.

Universally test for SARS-CoV-2 before procedures performed in the operating room (OR). Using nasopharyngeal swabs for the detection of viral RNA, employing molecular methods such as polymerase chain reaction (PCR), within 48 to 72 hours prior to all OR hysteroscopic procedures is strongly recommended. Adopting this testing strategy will aid to identify asymptomatic SARS-CoV-2‒infected patients, allowing to defer the procedure, if possible, among patients testing positive. If tests are limited, testing only patients scheduled for hysteroscopic procedures in which general or regional anesthesia will be required is acceptable.

Universal SARS-CoV-2 testing of patients undergoing in-office hysteroscopic diagnostic or minor operative procedures without the use of anesthesia is not required.

Limit the presence of a companion. It is understood that visitor policies may vary at the discretion of each institution’s guidelines. Children and individuals over the age of 60 years should not be granted access to the center. Companions will be subjected to the same screening criteria as patients.

Provide for social distancing and other precautionary measures. If more than one patient is scheduled to be at the facility at the same time, ensure that the facility provides adequate space to allow the appropriate social distancing recommendations between patients. Hand sanitizers and facemasks should be available for patients and companions.

Provide PPE for clinicians. All health care providers in close contact with the patient must wear personal protective equipment (PPE), which includes an apron and gown, a surgical mask, eye protection, and gloves. Health care providers should wear PPE deemed appropriate by their regulatory institutions following their local and national guidelines during clinical patient interactions.

Restrict surgical attendees to vital personnel. The participation of learners by physical presence in the office or operating room should be restricted.

Continue to: Recommendations: Office setting...

Preprocedural recommendations

• Advise patients to come to the office alone. If the patient requires a companion, a maximum of one adult companion under the age of 60 should be accepted.
• Limit the number of health care team members present in the procedure room.

Intraprocedural recommendations

• Choose the appropriate device(s) that will allow for an effective and fast procedure.
• Use the recommended PPE for all clinicians.
• Limit the movement of staff members in and out of the procedure room.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same procedure room, allow enough time in between cases to grant a thorough OR decontamination.
• Allow for patients to recover from the procedure in the same room as the procedure took place in order to avoid potential contamination of multiple rooms.
• Expedite patient discharge.
• Follow up after the procedure by phone or telemedicine.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Continue to: Recommendations: Operating room setting...

Preprocedural recommendations

• Perform adequate patient screening for potential COVID-19 infection. (Screening should be independent of symptoms and not be limited to those with clinical symptoms.)
• Limit the number of health care team members in the operating procedure room.
• To minimize unnecessary staff exposure, have surgeons and staff not needed for intubation remain outside the OR until intubation is completed and leave the OR before extubation.

Intraprocedure recommendations

• Limit personnel in the OR to a minimum.
• Staff should not enter or leave the room during the procedure.
• When possible, use conscious sedation or regional anesthesia to avoid the risk of viral dissemination at the time of intubation/extubation.
• Choose the device that will allow an effective and fast procedure.
• Favor non–smoke-generating devices, such as hysteroscopic scissors, graspers, and tissue retrieval systems.
• Connect active suction to the outflow, especially when using smoke-generating instruments, to facilitate the extraction of surgical smoke.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same room, allow enough time in between cases to grant a thorough OR decontamination.
• Expedite postprocedure recovery and patient discharge.
• After completion of the procedure, staff should remove scrubs and change into clean clothing.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Conclusions

The COVID-19 pandemic has caused a global health emergency. Our knowledge of this devastating virus is constantly evolving as we continue to fight this overwhelming disease. Theoretical risk of “viral” dissemination is considered extremely low, or negligible, during hysterosocopy. Hysteroscopic procedures in COVID-19–positive patients with life-threatening conditions or in patients in whom delaying the procedure could worsen outcomes should be performed taking appropriate measures. Patients who test negative for COVID-19 (confirmed by PCR) and require hysteroscopic procedures, should be treated using universal precautions. ●

Women facing issues related to perimenopause and menopause can consult their primary care physicians or ob.gyns. through telemedicine visits, but a new online portal, the Cusp, offers an alternative model with a focus on menopause and access to experts for a monthly membership fee.

The Cusp doesn’t claim to replace routine gynecologic care. Rather, it focuses on perimenopause and menopause symptoms specifically, and states that its physicians, some of whom are certified by the North American Menopause Society, provide expertise in menopause beyond what patients might receive as part of a typical ob.gyn. visit.

The Cusp is a for-profit organization, a group of physicians, nurse practitioners, and technologists who focus on integrated care for women in perimenopause and beyond. The aim is to leverage technology as a way to connect women to the care platform to book physician and nurse practitioner visits virtually and to have all of the information about their care centralized in one place.

According to the website, most patients who sign up for a care plan check in with their providers at least once a month to monitor their symptoms and tweak treatment strategies. Patients who sign up are prompted to download an app, which then becomes the main tool for scheduling future visits, tracking symptoms, and communicating with providers.

The Cusp launched in early 2019, before the advent of the COVID-19 pandemic, but the pandemic has accelerated the acceptance across medical specialties, suggesting that telemedicine is here to stay, according to Mindy Goldman, MD, professor of gynecology and gynecologic surgery at the University of California, San Francisco, and director of the Gynecology Center for Cancer Survivors and At-Risk Women at UCSF, who also serves as a medical adviser to the Cusp.

Partnering with technology companies allows opportunities to provide care in areas where there are gaps, such as menopause management, she said. Many clinicians in primary care and ob.gyn. care don’t have the time or training to discuss menopause management in depth with patients, and patient interviews conducted by the Cusp before launching the site showed that this was an area of need.

“One thing that is really unique about the Cusp is that we brought together experts to provide care in both in an evidence-based and holistic fashion,” Dr. Goldman emphasized.

The Cusp’s medical team includes physician and nurse practitioner menopause experts with backgrounds including not only ob.gyn. but also psychiatry, integrative medicine, and naturopathic medicine, with plans to add endocrinology and dermatology as well. This holistic approach allows the Cusp to tailor care based on what each woman is looking for, with evidence-based expertise to support treatment decisions, said Dr. Goldman, whose advisory role includes helping to develop patient treatment protocols and services.

If a woman wants to begin treating symptoms with a naturopathic approach, the team will provide protocols that take current guidelines into account. Regular visits, approximately once a month or as needed, allow for collaboration with the Cusp’s specialists to provide consistent care that is very comprehensive, she said.

One of the benefits of the Cusp is the opportunity for “frequent touchpoints” in which providers reach out to patients via text, email, or video. Although a traditional medical visit may include some initial discussion of menopause and treatment plans, the Cusp offers “a more seamless way to address needs on an ongoing basis,” to provide more complete patient care, Dr. Goldman said.

“We are constantly asking women what they are looking for in menopause care,” and a recurring question was about hormone testing, she said. Nontraditional practitioners may offer hormone testing as a way of individualizing care that also involves compounded formulations, and other treatments that are not standard of care. “In all of our protocols we follow what is recommended by standard organizations such as ACOG [American College of Obstetricians and Gynecologists] and NAMS.”

The Cusp’s newest service is an at-home hormone test currently for women in New York and California, but the company plans to expand this service. The hormone test, while not essential, is another tool to guide menopause management, and having a sense of when menopause will occur “gives us a chance to talk to people about behavioral changes and time to personalize a treatment protocol,” Dr. Goldman said.

The test is based in part on the anti-Müllerian hormone, which recent studies have shown is useful in predicting time to menopause. This, in combination with other hormone tests and other clinical information, will allow the Cusp’s menopause specialists to help women in perimenopause gain perspective on their symptoms and design a treatment plan that can evolve as their needs change, she explained.

“The more information you know about when menopause is going to be happening, you can tailor your treatment plan,” Dr. Goldman said. For example, a woman who may be 2 years away from menopause might consider a naturopathic approach at first, and switch to a different therapy as menopause occurs. “We know that the risks of cardiovascular disease and bone loss increase after menopause, and knowing the time to menopause gives us more guidance when educating patients about healthy lifestyle habits such as exercise and dietary changes that can help reduce these risks.”

The Cusp allows patients to use money in flexible spending accounts or health savings accounts to pay for the program. If doctors require lab tests or other procedures, these are covered through the patients’ regular health insurance as they would be if requested by a primary care physician or other health care professional.

Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn., commented that part of the value in a telehealth site such as the Cusp is to serve as “a resource for reproductively aging women to understand what is happening to them.”

Any way to improve education on the topic of menopause is empowering to women, said Dr. Pal, professor of obstetrics, gynecology, and reproductive sciences at Yale. “This is an opportunity for patients to have access to a directed evaluation” of menopause-related symptoms. Then, when women visit their regular health care provider in person, they are well-equipped with knowledge to ask more informed questions and discuss a wide range of treatment options.

Dr. Pal noted that the hormone test is less valuable than the interaction between physicians and patients, whether online or in person.

“Menopause is a Monday morning quarterback diagnosis,” she said, emphasizing that, not only is a year without menses part of the diagnosis of menopause, many women in perimenopause can have wide fluctuations in hormone levels, so a test is more of a snapshot than a diagnostic tool, and that the results might cause unnecessary angst and concerns for patients.

However, part of the value of a telehealth site that focuses on menopause is that it gives women a place to learn more about their biology and to clarify their questions about symptoms and become aware of a range of treatment options. Telehealth consultations also can help women recognize how other factors such as lifestyle modifications can play a role in menopause symptoms, and how modifying these factors may provide some relief, she said.

Dr. Pal said she would be cautious about the idea of prescribing without seeing the patient in person, but noted that telehealth sites such as the Cusp can be a win-win to enhance women’s health when used in combination with regular in-person visits to an ob.gyn. The added value in patients’ being able to discuss their concerns and to learn more about their symptoms means that they will be better informed to develop a menopause management strategy in partnership with their providers, said Dr. Pal, who is not associated with the Cusp.

Dr. Goldman disclosed receiving compensation from the Cusp for her advisory work. She also holds stock options in the company. Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board, had no financial conflicts to disclose.

Women facing issues related to perimenopause and menopause can consult their primary care physicians or ob.gyns. through telemedicine visits, but a new online portal, the Cusp, offers an alternative model with a focus on menopause and access to experts for a monthly membership fee.

The Cusp doesn’t claim to replace routine gynecologic care. Rather, it focuses on perimenopause and menopause symptoms specifically, and states that its physicians, some of whom are certified by the North American Menopause Society, provide expertise in menopause beyond what patients might receive as part of a typical ob.gyn. visit.

The Cusp is a for-profit organization, a group of physicians, nurse practitioners, and technologists who focus on integrated care for women in perimenopause and beyond. The aim is to leverage technology as a way to connect women to the care platform to book physician and nurse practitioner visits virtually and to have all of the information about their care centralized in one place.

According to the website, most patients who sign up for a care plan check in with their providers at least once a month to monitor their symptoms and tweak treatment strategies. Patients who sign up are prompted to download an app, which then becomes the main tool for scheduling future visits, tracking symptoms, and communicating with providers.

The Cusp launched in early 2019, before the advent of the COVID-19 pandemic, but the pandemic has accelerated the acceptance across medical specialties, suggesting that telemedicine is here to stay, according to Mindy Goldman, MD, professor of gynecology and gynecologic surgery at the University of California, San Francisco, and director of the Gynecology Center for Cancer Survivors and At-Risk Women at UCSF, who also serves as a medical adviser to the Cusp.

Partnering with technology companies allows opportunities to provide care in areas where there are gaps, such as menopause management, she said. Many clinicians in primary care and ob.gyn. care don’t have the time or training to discuss menopause management in depth with patients, and patient interviews conducted by the Cusp before launching the site showed that this was an area of need.

“One thing that is really unique about the Cusp is that we brought together experts to provide care in both in an evidence-based and holistic fashion,” Dr. Goldman emphasized.

The Cusp’s medical team includes physician and nurse practitioner menopause experts with backgrounds including not only ob.gyn. but also psychiatry, integrative medicine, and naturopathic medicine, with plans to add endocrinology and dermatology as well. This holistic approach allows the Cusp to tailor care based on what each woman is looking for, with evidence-based expertise to support treatment decisions, said Dr. Goldman, whose advisory role includes helping to develop patient treatment protocols and services.

If a woman wants to begin treating symptoms with a naturopathic approach, the team will provide protocols that take current guidelines into account. Regular visits, approximately once a month or as needed, allow for collaboration with the Cusp’s specialists to provide consistent care that is very comprehensive, she said.

One of the benefits of the Cusp is the opportunity for “frequent touchpoints” in which providers reach out to patients via text, email, or video. Although a traditional medical visit may include some initial discussion of menopause and treatment plans, the Cusp offers “a more seamless way to address needs on an ongoing basis,” to provide more complete patient care, Dr. Goldman said.

“We are constantly asking women what they are looking for in menopause care,” and a recurring question was about hormone testing, she said. Nontraditional practitioners may offer hormone testing as a way of individualizing care that also involves compounded formulations, and other treatments that are not standard of care. “In all of our protocols we follow what is recommended by standard organizations such as ACOG [American College of Obstetricians and Gynecologists] and NAMS.”

The Cusp’s newest service is an at-home hormone test currently for women in New York and California, but the company plans to expand this service. The hormone test, while not essential, is another tool to guide menopause management, and having a sense of when menopause will occur “gives us a chance to talk to people about behavioral changes and time to personalize a treatment protocol,” Dr. Goldman said.

The test is based in part on the anti-Müllerian hormone, which recent studies have shown is useful in predicting time to menopause. This, in combination with other hormone tests and other clinical information, will allow the Cusp’s menopause specialists to help women in perimenopause gain perspective on their symptoms and design a treatment plan that can evolve as their needs change, she explained.

“The more information you know about when menopause is going to be happening, you can tailor your treatment plan,” Dr. Goldman said. For example, a woman who may be 2 years away from menopause might consider a naturopathic approach at first, and switch to a different therapy as menopause occurs. “We know that the risks of cardiovascular disease and bone loss increase after menopause, and knowing the time to menopause gives us more guidance when educating patients about healthy lifestyle habits such as exercise and dietary changes that can help reduce these risks.”

The Cusp allows patients to use money in flexible spending accounts or health savings accounts to pay for the program. If doctors require lab tests or other procedures, these are covered through the patients’ regular health insurance as they would be if requested by a primary care physician or other health care professional.

Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn., commented that part of the value in a telehealth site such as the Cusp is to serve as “a resource for reproductively aging women to understand what is happening to them.”

Any way to improve education on the topic of menopause is empowering to women, said Dr. Pal, professor of obstetrics, gynecology, and reproductive sciences at Yale. “This is an opportunity for patients to have access to a directed evaluation” of menopause-related symptoms. Then, when women visit their regular health care provider in person, they are well-equipped with knowledge to ask more informed questions and discuss a wide range of treatment options.

Dr. Pal noted that the hormone test is less valuable than the interaction between physicians and patients, whether online or in person.

“Menopause is a Monday morning quarterback diagnosis,” she said, emphasizing that, not only is a year without menses part of the diagnosis of menopause, many women in perimenopause can have wide fluctuations in hormone levels, so a test is more of a snapshot than a diagnostic tool, and that the results might cause unnecessary angst and concerns for patients.

However, part of the value of a telehealth site that focuses on menopause is that it gives women a place to learn more about their biology and to clarify their questions about symptoms and become aware of a range of treatment options. Telehealth consultations also can help women recognize how other factors such as lifestyle modifications can play a role in menopause symptoms, and how modifying these factors may provide some relief, she said.

Dr. Pal said she would be cautious about the idea of prescribing without seeing the patient in person, but noted that telehealth sites such as the Cusp can be a win-win to enhance women’s health when used in combination with regular in-person visits to an ob.gyn. The added value in patients’ being able to discuss their concerns and to learn more about their symptoms means that they will be better informed to develop a menopause management strategy in partnership with their providers, said Dr. Pal, who is not associated with the Cusp.

Dr. Goldman disclosed receiving compensation from the Cusp for her advisory work. She also holds stock options in the company. Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board, had no financial conflicts to disclose.

Women facing issues related to perimenopause and menopause can consult their primary care physicians or ob.gyns. through telemedicine visits, but a new online portal, the Cusp, offers an alternative model with a focus on menopause and access to experts for a monthly membership fee.

The Cusp doesn’t claim to replace routine gynecologic care. Rather, it focuses on perimenopause and menopause symptoms specifically, and states that its physicians, some of whom are certified by the North American Menopause Society, provide expertise in menopause beyond what patients might receive as part of a typical ob.gyn. visit.

The Cusp is a for-profit organization, a group of physicians, nurse practitioners, and technologists who focus on integrated care for women in perimenopause and beyond. The aim is to leverage technology as a way to connect women to the care platform to book physician and nurse practitioner visits virtually and to have all of the information about their care centralized in one place.

According to the website, most patients who sign up for a care plan check in with their providers at least once a month to monitor their symptoms and tweak treatment strategies. Patients who sign up are prompted to download an app, which then becomes the main tool for scheduling future visits, tracking symptoms, and communicating with providers.

The Cusp launched in early 2019, before the advent of the COVID-19 pandemic, but the pandemic has accelerated the acceptance across medical specialties, suggesting that telemedicine is here to stay, according to Mindy Goldman, MD, professor of gynecology and gynecologic surgery at the University of California, San Francisco, and director of the Gynecology Center for Cancer Survivors and At-Risk Women at UCSF, who also serves as a medical adviser to the Cusp.

Partnering with technology companies allows opportunities to provide care in areas where there are gaps, such as menopause management, she said. Many clinicians in primary care and ob.gyn. care don’t have the time or training to discuss menopause management in depth with patients, and patient interviews conducted by the Cusp before launching the site showed that this was an area of need.

“One thing that is really unique about the Cusp is that we brought together experts to provide care in both in an evidence-based and holistic fashion,” Dr. Goldman emphasized.

The Cusp’s medical team includes physician and nurse practitioner menopause experts with backgrounds including not only ob.gyn. but also psychiatry, integrative medicine, and naturopathic medicine, with plans to add endocrinology and dermatology as well. This holistic approach allows the Cusp to tailor care based on what each woman is looking for, with evidence-based expertise to support treatment decisions, said Dr. Goldman, whose advisory role includes helping to develop patient treatment protocols and services.

If a woman wants to begin treating symptoms with a naturopathic approach, the team will provide protocols that take current guidelines into account. Regular visits, approximately once a month or as needed, allow for collaboration with the Cusp’s specialists to provide consistent care that is very comprehensive, she said.

One of the benefits of the Cusp is the opportunity for “frequent touchpoints” in which providers reach out to patients via text, email, or video. Although a traditional medical visit may include some initial discussion of menopause and treatment plans, the Cusp offers “a more seamless way to address needs on an ongoing basis,” to provide more complete patient care, Dr. Goldman said.

“We are constantly asking women what they are looking for in menopause care,” and a recurring question was about hormone testing, she said. Nontraditional practitioners may offer hormone testing as a way of individualizing care that also involves compounded formulations, and other treatments that are not standard of care. “In all of our protocols we follow what is recommended by standard organizations such as ACOG [American College of Obstetricians and Gynecologists] and NAMS.”

The Cusp’s newest service is an at-home hormone test currently for women in New York and California, but the company plans to expand this service. The hormone test, while not essential, is another tool to guide menopause management, and having a sense of when menopause will occur “gives us a chance to talk to people about behavioral changes and time to personalize a treatment protocol,” Dr. Goldman said.

The test is based in part on the anti-Müllerian hormone, which recent studies have shown is useful in predicting time to menopause. This, in combination with other hormone tests and other clinical information, will allow the Cusp’s menopause specialists to help women in perimenopause gain perspective on their symptoms and design a treatment plan that can evolve as their needs change, she explained.

“The more information you know about when menopause is going to be happening, you can tailor your treatment plan,” Dr. Goldman said. For example, a woman who may be 2 years away from menopause might consider a naturopathic approach at first, and switch to a different therapy as menopause occurs. “We know that the risks of cardiovascular disease and bone loss increase after menopause, and knowing the time to menopause gives us more guidance when educating patients about healthy lifestyle habits such as exercise and dietary changes that can help reduce these risks.”

The Cusp allows patients to use money in flexible spending accounts or health savings accounts to pay for the program. If doctors require lab tests or other procedures, these are covered through the patients’ regular health insurance as they would be if requested by a primary care physician or other health care professional.

Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn., commented that part of the value in a telehealth site such as the Cusp is to serve as “a resource for reproductively aging women to understand what is happening to them.”

Any way to improve education on the topic of menopause is empowering to women, said Dr. Pal, professor of obstetrics, gynecology, and reproductive sciences at Yale. “This is an opportunity for patients to have access to a directed evaluation” of menopause-related symptoms. Then, when women visit their regular health care provider in person, they are well-equipped with knowledge to ask more informed questions and discuss a wide range of treatment options.

Dr. Pal noted that the hormone test is less valuable than the interaction between physicians and patients, whether online or in person.

“Menopause is a Monday morning quarterback diagnosis,” she said, emphasizing that, not only is a year without menses part of the diagnosis of menopause, many women in perimenopause can have wide fluctuations in hormone levels, so a test is more of a snapshot than a diagnostic tool, and that the results might cause unnecessary angst and concerns for patients.

However, part of the value of a telehealth site that focuses on menopause is that it gives women a place to learn more about their biology and to clarify their questions about symptoms and become aware of a range of treatment options. Telehealth consultations also can help women recognize how other factors such as lifestyle modifications can play a role in menopause symptoms, and how modifying these factors may provide some relief, she said.

Dr. Pal said she would be cautious about the idea of prescribing without seeing the patient in person, but noted that telehealth sites such as the Cusp can be a win-win to enhance women’s health when used in combination with regular in-person visits to an ob.gyn. The added value in patients’ being able to discuss their concerns and to learn more about their symptoms means that they will be better informed to develop a menopause management strategy in partnership with their providers, said Dr. Pal, who is not associated with the Cusp.

Dr. Goldman disclosed receiving compensation from the Cusp for her advisory work. She also holds stock options in the company. Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board, had no financial conflicts to disclose.

A new follow-up study of menopausal hormone therapy found that prior use of conjugated equine estrogen (CEE) decreased both breast cancer incidence and mortality, while prior use of CEE plus medroxyprogesterone acetate (MPA) was associated with an increase in incidence.

“Prior use of CEE alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer,” wrote Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute for Biomedical Innovation in Torrance, Calif., and his coauthors. The study was published July 28 in JAMA.

To further investigate the outcomes of the Women’s Health Initiative in regard to hormone therapy and breast cancer risk, the researchers analyzed the long-term follow-up of two randomized trials that included 27,347 postmenopausal women with no prior breast cancer and negative mammograms at baseline. Their mean (SD) age was 63.4 (7.2) years. Enrollment took place from 1993 to 1998; participants were contacted for follow-up every 6 months through 2005 and annually from then on. Mortality data were gathered from follow-up and the National Death Index.

The first trial included 16,608 women with a uterus. Among these women, 8,506 received 0.625 mg/day of CEE plus 2.5 mg/day of MPA, and 8,102 received placebo. The second trial included 10,739 women who’d gotten a hysterectomy, 5,310 of whom received 0.625 mg/day of CEE alone and 5,429 of whom received placebo. The first trial ended in 2002 after a median intervention period of 5.6 years, and the second trial ended in 2004 after a period of 7.2 years.

An analysis in 2015 found that CEE alone was associated with lower risk of breast cancer and CEE plus MPA was associated with increased risk.

The current analysis confirmed that, after a median of 20.3 years of follow-up, and with mortality data now available for more than 98% of participants, CEE alone was associated with fewer cases of breast cancer (238 cases, annualized rate 0.30%), compared with placebo (296 cases, annualized rate 0.37%; hazard ratio 0.78; 95% confidence interval, 0.65-0.93; P = .005).

Furthermore, CEE alone was also associated with lower mortality (30 deaths, annualized mortality rate 0.031%), compared with placebo (46 deaths, annualized mortality rate 0.046%; HR 0.60; 95% CI, 0.37-0.97; P = .04).

By comparison, CEE plus MPA was linked with more cases of breast cancer (584 cases, annualized rate 0.45%) than placebo (447 cases, annualized rate 0.36%; HR 1.28; 95% CI, 1.13-1.45; P < .001). In regard to mortality, there was no statistically significant difference between CEE plus MPA (71 deaths, annualized mortality rate 0.045%) and placebo (53 deaths, annualized mortality rate 0.035%; HR 1.35; 95% CI, 0.94-1.95; P = .11).

“The big thing to think about is estrogen alone reducing breast cancer mortality by 40%,” said Dr. Chlebowski in an interview. “None of the other interventions, including tamoxifen, had any change on mortality. This should change the way we look at breast cancer prevention, though we might have to be a little creative about it. I think you have to be a little away from menopause for it to reduce breast cancer. But we wanted to start that debate.

“On the other hand,” he said, “a woman takes estrogen plus progestin and when you look at that curve, it’s staying about 25% increased. You take it for 5.6 years and the increase continues through 20 years, so you’re maybe buying a lifetime of increase in breast cancer by taking estrogen plus progestin for 5 years.”

He also highlighted the comprehensiveness of the mortality data, noting that “when you hook up to the National Death Index, they find 98% of all deaths in the United States. That’s really remarkable; you retain the whole power of the randomization. It means our data, between the death index and our follow-up of participants, is essentially complete.”

Use of hormone therapy, and decoding the outcomes, remains ‘complex’

Decades after the data were gathered from the Women’s Health Initiative clinical trials, they continue to assist researchers and patients alike, wrote Christina A. Minami, MD, of Brigham and Women’s Hospital in Boston and Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute in Boston, in an accompanying editorial.

That said, in regard to the findings of this latest analysis, “many questions still remain on whether (and how) a hormone therapy intervention that occurred many years earlier may continue to affect breast cancer risk and mortality at 20 years,” they wrote. They noted that it’s “impossible” to isolate how exposure to certain therapies can impact long-term outcomes, and that a high percentage of patients who discontinued the drugs during each trial muddy the waters even further.

“Decisions to initiate these medications remain complex,” they added, emphasizing that breast cancer risk is just one of many factors that physicians must consider when considering hormone therapy for their patients.

Dr. Chlebowski and his coauthors acknowledged their study’s limitations, including the use of very specifically administered and formulated dosages making their findings “not necessarily generalizable to other preparations.” In addition, they noted the significant percentage of patients – 54% with CEE alone and 42% with CEE plus MPA – who discontinued drug usage during their respective trials.

The Women’s Health Initiative is supported by the National Institutes of Health and the Department of Health and Human Services. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various government organizations, foundations, and pharmaceutical companies. The editorial’s authors reported no conflicts of interest.

SOURCE: Chlebowski RT et al. JAMA. 2020 Jul 28. doi: 10.1001/jama.2020.9482.

A new follow-up study of menopausal hormone therapy found that prior use of conjugated equine estrogen (CEE) decreased both breast cancer incidence and mortality, while prior use of CEE plus medroxyprogesterone acetate (MPA) was associated with an increase in incidence.

“Prior use of CEE alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer,” wrote Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute for Biomedical Innovation in Torrance, Calif., and his coauthors. The study was published July 28 in JAMA.

To further investigate the outcomes of the Women’s Health Initiative in regard to hormone therapy and breast cancer risk, the researchers analyzed the long-term follow-up of two randomized trials that included 27,347 postmenopausal women with no prior breast cancer and negative mammograms at baseline. Their mean (SD) age was 63.4 (7.2) years. Enrollment took place from 1993 to 1998; participants were contacted for follow-up every 6 months through 2005 and annually from then on. Mortality data were gathered from follow-up and the National Death Index.

The first trial included 16,608 women with a uterus. Among these women, 8,506 received 0.625 mg/day of CEE plus 2.5 mg/day of MPA, and 8,102 received placebo. The second trial included 10,739 women who’d gotten a hysterectomy, 5,310 of whom received 0.625 mg/day of CEE alone and 5,429 of whom received placebo. The first trial ended in 2002 after a median intervention period of 5.6 years, and the second trial ended in 2004 after a period of 7.2 years.

An analysis in 2015 found that CEE alone was associated with lower risk of breast cancer and CEE plus MPA was associated with increased risk.

The current analysis confirmed that, after a median of 20.3 years of follow-up, and with mortality data now available for more than 98% of participants, CEE alone was associated with fewer cases of breast cancer (238 cases, annualized rate 0.30%), compared with placebo (296 cases, annualized rate 0.37%; hazard ratio 0.78; 95% confidence interval, 0.65-0.93; P = .005).

Furthermore, CEE alone was also associated with lower mortality (30 deaths, annualized mortality rate 0.031%), compared with placebo (46 deaths, annualized mortality rate 0.046%; HR 0.60; 95% CI, 0.37-0.97; P = .04).

By comparison, CEE plus MPA was linked with more cases of breast cancer (584 cases, annualized rate 0.45%) than placebo (447 cases, annualized rate 0.36%; HR 1.28; 95% CI, 1.13-1.45; P < .001). In regard to mortality, there was no statistically significant difference between CEE plus MPA (71 deaths, annualized mortality rate 0.045%) and placebo (53 deaths, annualized mortality rate 0.035%; HR 1.35; 95% CI, 0.94-1.95; P = .11).

“The big thing to think about is estrogen alone reducing breast cancer mortality by 40%,” said Dr. Chlebowski in an interview. “None of the other interventions, including tamoxifen, had any change on mortality. This should change the way we look at breast cancer prevention, though we might have to be a little creative about it. I think you have to be a little away from menopause for it to reduce breast cancer. But we wanted to start that debate.

“On the other hand,” he said, “a woman takes estrogen plus progestin and when you look at that curve, it’s staying about 25% increased. You take it for 5.6 years and the increase continues through 20 years, so you’re maybe buying a lifetime of increase in breast cancer by taking estrogen plus progestin for 5 years.”

He also highlighted the comprehensiveness of the mortality data, noting that “when you hook up to the National Death Index, they find 98% of all deaths in the United States. That’s really remarkable; you retain the whole power of the randomization. It means our data, between the death index and our follow-up of participants, is essentially complete.”

Use of hormone therapy, and decoding the outcomes, remains ‘complex’

Decades after the data were gathered from the Women’s Health Initiative clinical trials, they continue to assist researchers and patients alike, wrote Christina A. Minami, MD, of Brigham and Women’s Hospital in Boston and Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute in Boston, in an accompanying editorial.

That said, in regard to the findings of this latest analysis, “many questions still remain on whether (and how) a hormone therapy intervention that occurred many years earlier may continue to affect breast cancer risk and mortality at 20 years,” they wrote. They noted that it’s “impossible” to isolate how exposure to certain therapies can impact long-term outcomes, and that a high percentage of patients who discontinued the drugs during each trial muddy the waters even further.

“Decisions to initiate these medications remain complex,” they added, emphasizing that breast cancer risk is just one of many factors that physicians must consider when considering hormone therapy for their patients.

Dr. Chlebowski and his coauthors acknowledged their study’s limitations, including the use of very specifically administered and formulated dosages making their findings “not necessarily generalizable to other preparations.” In addition, they noted the significant percentage of patients – 54% with CEE alone and 42% with CEE plus MPA – who discontinued drug usage during their respective trials.

The Women’s Health Initiative is supported by the National Institutes of Health and the Department of Health and Human Services. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various government organizations, foundations, and pharmaceutical companies. The editorial’s authors reported no conflicts of interest.

SOURCE: Chlebowski RT et al. JAMA. 2020 Jul 28. doi: 10.1001/jama.2020.9482.

A new follow-up study of menopausal hormone therapy found that prior use of conjugated equine estrogen (CEE) decreased both breast cancer incidence and mortality, while prior use of CEE plus medroxyprogesterone acetate (MPA) was associated with an increase in incidence.

“Prior use of CEE alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer,” wrote Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute for Biomedical Innovation in Torrance, Calif., and his coauthors. The study was published July 28 in JAMA.

To further investigate the outcomes of the Women’s Health Initiative in regard to hormone therapy and breast cancer risk, the researchers analyzed the long-term follow-up of two randomized trials that included 27,347 postmenopausal women with no prior breast cancer and negative mammograms at baseline. Their mean (SD) age was 63.4 (7.2) years. Enrollment took place from 1993 to 1998; participants were contacted for follow-up every 6 months through 2005 and annually from then on. Mortality data were gathered from follow-up and the National Death Index.

The first trial included 16,608 women with a uterus. Among these women, 8,506 received 0.625 mg/day of CEE plus 2.5 mg/day of MPA, and 8,102 received placebo. The second trial included 10,739 women who’d gotten a hysterectomy, 5,310 of whom received 0.625 mg/day of CEE alone and 5,429 of whom received placebo. The first trial ended in 2002 after a median intervention period of 5.6 years, and the second trial ended in 2004 after a period of 7.2 years.

An analysis in 2015 found that CEE alone was associated with lower risk of breast cancer and CEE plus MPA was associated with increased risk.

The current analysis confirmed that, after a median of 20.3 years of follow-up, and with mortality data now available for more than 98% of participants, CEE alone was associated with fewer cases of breast cancer (238 cases, annualized rate 0.30%), compared with placebo (296 cases, annualized rate 0.37%; hazard ratio 0.78; 95% confidence interval, 0.65-0.93; P = .005).

Furthermore, CEE alone was also associated with lower mortality (30 deaths, annualized mortality rate 0.031%), compared with placebo (46 deaths, annualized mortality rate 0.046%; HR 0.60; 95% CI, 0.37-0.97; P = .04).

By comparison, CEE plus MPA was linked with more cases of breast cancer (584 cases, annualized rate 0.45%) than placebo (447 cases, annualized rate 0.36%; HR 1.28; 95% CI, 1.13-1.45; P < .001). In regard to mortality, there was no statistically significant difference between CEE plus MPA (71 deaths, annualized mortality rate 0.045%) and placebo (53 deaths, annualized mortality rate 0.035%; HR 1.35; 95% CI, 0.94-1.95; P = .11).

“The big thing to think about is estrogen alone reducing breast cancer mortality by 40%,” said Dr. Chlebowski in an interview. “None of the other interventions, including tamoxifen, had any change on mortality. This should change the way we look at breast cancer prevention, though we might have to be a little creative about it. I think you have to be a little away from menopause for it to reduce breast cancer. But we wanted to start that debate.

“On the other hand,” he said, “a woman takes estrogen plus progestin and when you look at that curve, it’s staying about 25% increased. You take it for 5.6 years and the increase continues through 20 years, so you’re maybe buying a lifetime of increase in breast cancer by taking estrogen plus progestin for 5 years.”

He also highlighted the comprehensiveness of the mortality data, noting that “when you hook up to the National Death Index, they find 98% of all deaths in the United States. That’s really remarkable; you retain the whole power of the randomization. It means our data, between the death index and our follow-up of participants, is essentially complete.”

Use of hormone therapy, and decoding the outcomes, remains ‘complex’

Decades after the data were gathered from the Women’s Health Initiative clinical trials, they continue to assist researchers and patients alike, wrote Christina A. Minami, MD, of Brigham and Women’s Hospital in Boston and Rachel A. Freedman, MD, of the Dana-Farber Cancer Institute in Boston, in an accompanying editorial.

That said, in regard to the findings of this latest analysis, “many questions still remain on whether (and how) a hormone therapy intervention that occurred many years earlier may continue to affect breast cancer risk and mortality at 20 years,” they wrote. They noted that it’s “impossible” to isolate how exposure to certain therapies can impact long-term outcomes, and that a high percentage of patients who discontinued the drugs during each trial muddy the waters even further.

“Decisions to initiate these medications remain complex,” they added, emphasizing that breast cancer risk is just one of many factors that physicians must consider when considering hormone therapy for their patients.

Dr. Chlebowski and his coauthors acknowledged their study’s limitations, including the use of very specifically administered and formulated dosages making their findings “not necessarily generalizable to other preparations.” In addition, they noted the significant percentage of patients – 54% with CEE alone and 42% with CEE plus MPA – who discontinued drug usage during their respective trials.

The Women’s Health Initiative is supported by the National Institutes of Health and the Department of Health and Human Services. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various government organizations, foundations, and pharmaceutical companies. The editorial’s authors reported no conflicts of interest.

SOURCE: Chlebowski RT et al. JAMA. 2020 Jul 28. doi: 10.1001/jama.2020.9482.

Use of weight-promoting medications may contribute to postmenopausal abdominal weight gain in women, based on data from more than 76,000 individuals in the Women’s Health Initiative.

“Many of the medications prescribed to treat obesity-related comorbidities such as hypertension, type 2 diabetes, and depression have been linked to weight gain,” but the impact of such medications in relation to changes in body mass index (BMI) and waist circumference in postmenopausal women in particular has not been studied, wrote Fatima Cody Stanford, MD, of Harvard Medical School, Boston, and colleagues.

“Postmenopausal women are of significant interest as those who have obesity and normal weight central obesity are at increased risk for conditions such as invasive breast cancer, sleep disturbances, and type 2 diabetes, as well as mortality,” they wrote.

In a study published in the journal Menopause, the researchers identified 76,252 postmenopausal women aged 50-79 years and measured body mass index at baseline and after 3 years. Medication use was determined by a medication inventory of pill bottles brought to baseline and year-3 visits.

During a 3-year follow-up period, the average BMI increase was 0.37 kg/m² in women taking at least one weight-promoting medication, compared with an average increase of 0.27 kg/m² in women not taking such medications (P = .0045). Weight-promoting medications in the study included antidepressants, beta-blockers, insulin, and/or glucocorticosteroids. The researchers used generalized linear models to assess the impact of these medications on increased BMI and waist circumference.

In addition, the average increase in waist circumference was 1.10 cm in women taking at least one weight-promoting medication, compared with 0.89 cm (P = .0077) for women not on such medications.

“Type of medication, dosage, and race/ethnicity may have important interrelationships,” in postmenopausal weight gain, as do individual susceptibility and genetics, the researchers noted. “Options to mitigate the weight gain may include proactive lifestyle modifications, reduction in dose, change to another agent, or discontinuation of the medication altogether. If alternative medications are not an option, lifestyle factors such as diet quality, physical activity level, and sleep quality and duration warrant emphasis.”

The study findings were limited by several factors, including a lack of data on indications and underlying health conditions surrounding the prescription of various medications, notably psychotropics and antipsychotics, the researchers wrote.

However, the data “may help to inform clinical decision-making and support increased attention to lifestyle modifications and other strategies” to mitigate the potential for weight gain in a population already at risk for overweight and obesity over time, they concluded.

“Given the obesity epidemic, addressing factors contributing to weight gain in midlife [a time associated with weight gain] women is critical,” Stephanie S. Faubion, MD, of the Mayo Clinic in Jacksonville, Fla., said in an interview. Dr. Faubion said that the study findings were not surprising given the widespread use of known weight-promoting medications by midlife women for such as hypertension, diabetes, and depression.

“Clinicians need to ensure that they prescribe medications that are truly needed and utilize the lowest dose required to achieve treatment goals,” Dr. Faubion said. “When possible, alternative therapies that do not cause weight gain should be considered. In addition, patients should be warned of the potential for weight gain, and clinicians should advocate for lifestyle measures aimed at mitigating these effects.”

The findings do not encourage the use of alternative therapies for menopausal symptoms per se, added Dr. Faubion, who is also medical director of the North American Menopause Society. “Hormone therapy is not associated with weight gain, and if anything, it is weight favorable and associated with less weight around the midsection. It is the alternative strategies for management of hot flashes that are associated with weight gain, such as antidepressants and gabapentin.

“We need to focus efforts on strategies to prevent weight gain in midlife to avoid the development of conditions that necessitate initiation of many of these weight-promoting medications,” Dr. Faubion said.

The study was supported by the National Institutes of Health and Massachusetts General Hospital Executive Committee on Research, the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Faubion had no financial conflicts to disclose.

SOURCE: Stanford FC et al. Menopause. 2020 Jul 13. doi: 10.1097/GME.0000000000001589.

Use of weight-promoting medications may contribute to postmenopausal abdominal weight gain in women, based on data from more than 76,000 individuals in the Women’s Health Initiative.

“Many of the medications prescribed to treat obesity-related comorbidities such as hypertension, type 2 diabetes, and depression have been linked to weight gain,” but the impact of such medications in relation to changes in body mass index (BMI) and waist circumference in postmenopausal women in particular has not been studied, wrote Fatima Cody Stanford, MD, of Harvard Medical School, Boston, and colleagues.

“Postmenopausal women are of significant interest as those who have obesity and normal weight central obesity are at increased risk for conditions such as invasive breast cancer, sleep disturbances, and type 2 diabetes, as well as mortality,” they wrote.

In a study published in the journal Menopause, the researchers identified 76,252 postmenopausal women aged 50-79 years and measured body mass index at baseline and after 3 years. Medication use was determined by a medication inventory of pill bottles brought to baseline and year-3 visits.

During a 3-year follow-up period, the average BMI increase was 0.37 kg/m² in women taking at least one weight-promoting medication, compared with an average increase of 0.27 kg/m² in women not taking such medications (P = .0045). Weight-promoting medications in the study included antidepressants, beta-blockers, insulin, and/or glucocorticosteroids. The researchers used generalized linear models to assess the impact of these medications on increased BMI and waist circumference.

In addition, the average increase in waist circumference was 1.10 cm in women taking at least one weight-promoting medication, compared with 0.89 cm (P = .0077) for women not on such medications.

“Type of medication, dosage, and race/ethnicity may have important interrelationships,” in postmenopausal weight gain, as do individual susceptibility and genetics, the researchers noted. “Options to mitigate the weight gain may include proactive lifestyle modifications, reduction in dose, change to another agent, or discontinuation of the medication altogether. If alternative medications are not an option, lifestyle factors such as diet quality, physical activity level, and sleep quality and duration warrant emphasis.”

The study findings were limited by several factors, including a lack of data on indications and underlying health conditions surrounding the prescription of various medications, notably psychotropics and antipsychotics, the researchers wrote.

However, the data “may help to inform clinical decision-making and support increased attention to lifestyle modifications and other strategies” to mitigate the potential for weight gain in a population already at risk for overweight and obesity over time, they concluded.

“Given the obesity epidemic, addressing factors contributing to weight gain in midlife [a time associated with weight gain] women is critical,” Stephanie S. Faubion, MD, of the Mayo Clinic in Jacksonville, Fla., said in an interview. Dr. Faubion said that the study findings were not surprising given the widespread use of known weight-promoting medications by midlife women for such as hypertension, diabetes, and depression.

“Clinicians need to ensure that they prescribe medications that are truly needed and utilize the lowest dose required to achieve treatment goals,” Dr. Faubion said. “When possible, alternative therapies that do not cause weight gain should be considered. In addition, patients should be warned of the potential for weight gain, and clinicians should advocate for lifestyle measures aimed at mitigating these effects.”

The findings do not encourage the use of alternative therapies for menopausal symptoms per se, added Dr. Faubion, who is also medical director of the North American Menopause Society. “Hormone therapy is not associated with weight gain, and if anything, it is weight favorable and associated with less weight around the midsection. It is the alternative strategies for management of hot flashes that are associated with weight gain, such as antidepressants and gabapentin.

“We need to focus efforts on strategies to prevent weight gain in midlife to avoid the development of conditions that necessitate initiation of many of these weight-promoting medications,” Dr. Faubion said.

The study was supported by the National Institutes of Health and Massachusetts General Hospital Executive Committee on Research, the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Faubion had no financial conflicts to disclose.

SOURCE: Stanford FC et al. Menopause. 2020 Jul 13. doi: 10.1097/GME.0000000000001589.

Use of weight-promoting medications may contribute to postmenopausal abdominal weight gain in women, based on data from more than 76,000 individuals in the Women’s Health Initiative.

“Many of the medications prescribed to treat obesity-related comorbidities such as hypertension, type 2 diabetes, and depression have been linked to weight gain,” but the impact of such medications in relation to changes in body mass index (BMI) and waist circumference in postmenopausal women in particular has not been studied, wrote Fatima Cody Stanford, MD, of Harvard Medical School, Boston, and colleagues.

“Postmenopausal women are of significant interest as those who have obesity and normal weight central obesity are at increased risk for conditions such as invasive breast cancer, sleep disturbances, and type 2 diabetes, as well as mortality,” they wrote.

In a study published in the journal Menopause, the researchers identified 76,252 postmenopausal women aged 50-79 years and measured body mass index at baseline and after 3 years. Medication use was determined by a medication inventory of pill bottles brought to baseline and year-3 visits.

During a 3-year follow-up period, the average BMI increase was 0.37 kg/m² in women taking at least one weight-promoting medication, compared with an average increase of 0.27 kg/m² in women not taking such medications (P = .0045). Weight-promoting medications in the study included antidepressants, beta-blockers, insulin, and/or glucocorticosteroids. The researchers used generalized linear models to assess the impact of these medications on increased BMI and waist circumference.

In addition, the average increase in waist circumference was 1.10 cm in women taking at least one weight-promoting medication, compared with 0.89 cm (P = .0077) for women not on such medications.

“Type of medication, dosage, and race/ethnicity may have important interrelationships,” in postmenopausal weight gain, as do individual susceptibility and genetics, the researchers noted. “Options to mitigate the weight gain may include proactive lifestyle modifications, reduction in dose, change to another agent, or discontinuation of the medication altogether. If alternative medications are not an option, lifestyle factors such as diet quality, physical activity level, and sleep quality and duration warrant emphasis.”

The study findings were limited by several factors, including a lack of data on indications and underlying health conditions surrounding the prescription of various medications, notably psychotropics and antipsychotics, the researchers wrote.

However, the data “may help to inform clinical decision-making and support increased attention to lifestyle modifications and other strategies” to mitigate the potential for weight gain in a population already at risk for overweight and obesity over time, they concluded.

“Given the obesity epidemic, addressing factors contributing to weight gain in midlife [a time associated with weight gain] women is critical,” Stephanie S. Faubion, MD, of the Mayo Clinic in Jacksonville, Fla., said in an interview. Dr. Faubion said that the study findings were not surprising given the widespread use of known weight-promoting medications by midlife women for such as hypertension, diabetes, and depression.

“Clinicians need to ensure that they prescribe medications that are truly needed and utilize the lowest dose required to achieve treatment goals,” Dr. Faubion said. “When possible, alternative therapies that do not cause weight gain should be considered. In addition, patients should be warned of the potential for weight gain, and clinicians should advocate for lifestyle measures aimed at mitigating these effects.”

The findings do not encourage the use of alternative therapies for menopausal symptoms per se, added Dr. Faubion, who is also medical director of the North American Menopause Society. “Hormone therapy is not associated with weight gain, and if anything, it is weight favorable and associated with less weight around the midsection. It is the alternative strategies for management of hot flashes that are associated with weight gain, such as antidepressants and gabapentin.

“We need to focus efforts on strategies to prevent weight gain in midlife to avoid the development of conditions that necessitate initiation of many of these weight-promoting medications,” Dr. Faubion said.

The study was supported by the National Institutes of Health and Massachusetts General Hospital Executive Committee on Research, the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Faubion had no financial conflicts to disclose.

SOURCE: Stanford FC et al. Menopause. 2020 Jul 13. doi: 10.1097/GME.0000000000001589.

The use of compounded bioidentical hormone therapies should be limited to patients who are not able to use a hormone therapy product approved by the Food and Drug Administration for reasons of allergy or dosage, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

yacobchuk/Getty Images

In recent years, compounded bioidentical hormone therapies (cBHTs) have been “marketed as a personalized and natural approach to enhanced wellness using tailored preparations that address a myriad of symptoms, including those associated with menopause and aging,” wrote Donald R. Mattison, MD, of the University of Ottawa, and chair of the committee charged with producing the report, and colleagues.

Although both cBHTs and bioidentical hormone therapies (BHTs) contain hormones that are structurally and chemically identical to those in the human body, cBHTs have not undergone the safety, efficacy, and quality control tests of approved FDA products, according to the report.

In addition, cBHTs have no standardization when it comes to medication doses, and the products often are available in topicals such as creams or ointments, as well as pills or pellets. The lack of standards in dosing or form can contribute to the risk of overdose, the report emphasized.

Various cBTH products continue to be marketed to the public for age-related hormone symptoms including hot flashes associated with menopause and decreased muscle mass associated with decreased testosterone. However, cBHTs are not approved by the FDA in part because the individually mixed products are not tested to verify the amount of hormone that may be absorbed.

In response to the increased use of cBHTs, the National Academies convened a Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy and commissioned a report.

The two typical reasons to prescribe cBHT are either to provide a medication in an alternate dose not available in approved products or to omit components of a medication to which a patient is allergic, according to the report.

The report includes an algorithm to help guide clinicians in prescribing FDA-approved products, including off-label use of approved products, before cBHT products. “There is a dearth of high-quality evidence ... available to establish whether cBHT preparations are safe or efficacious for their prescribed uses,” the report states.

Of note, the committee also found no guidelines to recommend the use of cBHT products as a substitute for off-label use of FDA-approved BHT products for patients with female sexual dysfunction or gender dysphoria, two conditions for which no FDA-approved BHT products exist.

“The North American Menopause Society applauds the efforts of the National Academies of Sciences, Engineering, and Medicine (NASEM) and endorses their recommendations on compounded bioidentical hormone therapy,” Stephanie S. Faubion, MD, medical director of The North American Menopause Society, wrote in a statement. “As a society, we remain committed to improving the care of midlife women through the promotion of evidence-based research, education, and clinical care.”

A report on the use of cBHTs was important at this time because of the widespread and largely unregulated use of these products with little data to support their safety and efficacy, Dr. Faubion said in an interview.

“There are no indications for use of custom compounded hormone therapy aside from an allergy to a component in the FDA-approved products or lack of availability of the needed dose, which would be exceedingly rare given the variety of forms and doses available with FDA-approved products,” she said.

Main concerns regarding the use of cBHTs are the lack of safety and efficacy data, Dr. Faubion emphasized. “Women believe these products are safer than FDA-approved products because they do not receive a package insert outlining potential risks as they do with FDA-approved products.” A lack of data and safety monitoring of cBHTs means that adverse effects are not monitored and reported, she said. Also, safety concerns persist regarding some forms of cBHTs such as pellets, which were specifically highlighted in the report.

Dr. Faubion said that she “absolutely” agrees with the report’s limited circumstances in which the used of cBHTs would be appropriate. “There are very few reasons why women would need to use compounded hormones instead of the FDA-approved versions, which are regulated for quality, efficacy and safety, readily available in the local pharmacy, and often covered by insurance.”

In terms of the future, “we need more education for women as consumers and for medical providers on this topic,” Dr. Faubion noted. Also, “clearly, there is a dearth of research on the true efficacy and safety of these compounded hormone therapy products.”

The statement from the National Academies crystallizes what experts have been saying for decades, according to Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn.

The formal recommendations to limit the use of cBHTs “are not novel, but certainly needed,” and the statement “offers guidance regardless of your specialty,” Dr. Pal said in an interview.

There is often a disconnect between consumers’ understanding of compounding and the reality of safety concerns, she said. “We are in a tabloid era,” and education is key to guiding patients toward the FDA-approved treatments with safety data and demonstrated effectiveness, she said. “Safety should be the driving factor.” In compounded products, “there is no consistency that what you get today is the same as what you get tomorrow,” and the lack of standardization of cBHTs increases the risk for adverse events, she emphasized.

For patients with special needs such as allergies or other specialized dosing requirements, as noted in the National Academies statement, clinicians should discuss the options with patients and monitor them regularly to head off potential adverse events such as the development of uterine cancer, said Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board.

The research involved in creating the report was supported by the Food and Drug Administration.

Dr. Faubion had no financial conflicts to disclose. Dr. Pal had no relevant financial disclosures.

[email protected]

SOURCE: Mattison DR et al.; National Academies of Sciences, Engineering, and Medicine. The clinical utility of compounded bioidentical hormone therapy: A review of safety, effectiveness, and use. (Washington, DC: The National Academies Press. 2020.)

The use of compounded bioidentical hormone therapies should be limited to patients who are not able to use a hormone therapy product approved by the Food and Drug Administration for reasons of allergy or dosage, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

yacobchuk/Getty Images

In recent years, compounded bioidentical hormone therapies (cBHTs) have been “marketed as a personalized and natural approach to enhanced wellness using tailored preparations that address a myriad of symptoms, including those associated with menopause and aging,” wrote Donald R. Mattison, MD, of the University of Ottawa, and chair of the committee charged with producing the report, and colleagues.

Although both cBHTs and bioidentical hormone therapies (BHTs) contain hormones that are structurally and chemically identical to those in the human body, cBHTs have not undergone the safety, efficacy, and quality control tests of approved FDA products, according to the report.

In addition, cBHTs have no standardization when it comes to medication doses, and the products often are available in topicals such as creams or ointments, as well as pills or pellets. The lack of standards in dosing or form can contribute to the risk of overdose, the report emphasized.

Various cBTH products continue to be marketed to the public for age-related hormone symptoms including hot flashes associated with menopause and decreased muscle mass associated with decreased testosterone. However, cBHTs are not approved by the FDA in part because the individually mixed products are not tested to verify the amount of hormone that may be absorbed.

In response to the increased use of cBHTs, the National Academies convened a Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy and commissioned a report.

The two typical reasons to prescribe cBHT are either to provide a medication in an alternate dose not available in approved products or to omit components of a medication to which a patient is allergic, according to the report.

The report includes an algorithm to help guide clinicians in prescribing FDA-approved products, including off-label use of approved products, before cBHT products. “There is a dearth of high-quality evidence ... available to establish whether cBHT preparations are safe or efficacious for their prescribed uses,” the report states.

Of note, the committee also found no guidelines to recommend the use of cBHT products as a substitute for off-label use of FDA-approved BHT products for patients with female sexual dysfunction or gender dysphoria, two conditions for which no FDA-approved BHT products exist.

“The North American Menopause Society applauds the efforts of the National Academies of Sciences, Engineering, and Medicine (NASEM) and endorses their recommendations on compounded bioidentical hormone therapy,” Stephanie S. Faubion, MD, medical director of The North American Menopause Society, wrote in a statement. “As a society, we remain committed to improving the care of midlife women through the promotion of evidence-based research, education, and clinical care.”

A report on the use of cBHTs was important at this time because of the widespread and largely unregulated use of these products with little data to support their safety and efficacy, Dr. Faubion said in an interview.

“There are no indications for use of custom compounded hormone therapy aside from an allergy to a component in the FDA-approved products or lack of availability of the needed dose, which would be exceedingly rare given the variety of forms and doses available with FDA-approved products,” she said.

Main concerns regarding the use of cBHTs are the lack of safety and efficacy data, Dr. Faubion emphasized. “Women believe these products are safer than FDA-approved products because they do not receive a package insert outlining potential risks as they do with FDA-approved products.” A lack of data and safety monitoring of cBHTs means that adverse effects are not monitored and reported, she said. Also, safety concerns persist regarding some forms of cBHTs such as pellets, which were specifically highlighted in the report.

Dr. Faubion said that she “absolutely” agrees with the report’s limited circumstances in which the used of cBHTs would be appropriate. “There are very few reasons why women would need to use compounded hormones instead of the FDA-approved versions, which are regulated for quality, efficacy and safety, readily available in the local pharmacy, and often covered by insurance.”

In terms of the future, “we need more education for women as consumers and for medical providers on this topic,” Dr. Faubion noted. Also, “clearly, there is a dearth of research on the true efficacy and safety of these compounded hormone therapy products.”

The statement from the National Academies crystallizes what experts have been saying for decades, according to Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn.

The formal recommendations to limit the use of cBHTs “are not novel, but certainly needed,” and the statement “offers guidance regardless of your specialty,” Dr. Pal said in an interview.

There is often a disconnect between consumers’ understanding of compounding and the reality of safety concerns, she said. “We are in a tabloid era,” and education is key to guiding patients toward the FDA-approved treatments with safety data and demonstrated effectiveness, she said. “Safety should be the driving factor.” In compounded products, “there is no consistency that what you get today is the same as what you get tomorrow,” and the lack of standardization of cBHTs increases the risk for adverse events, she emphasized.

For patients with special needs such as allergies or other specialized dosing requirements, as noted in the National Academies statement, clinicians should discuss the options with patients and monitor them regularly to head off potential adverse events such as the development of uterine cancer, said Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board.

The research involved in creating the report was supported by the Food and Drug Administration.

Dr. Faubion had no financial conflicts to disclose. Dr. Pal had no relevant financial disclosures.

[email protected]

SOURCE: Mattison DR et al.; National Academies of Sciences, Engineering, and Medicine. The clinical utility of compounded bioidentical hormone therapy: A review of safety, effectiveness, and use. (Washington, DC: The National Academies Press. 2020.)

The use of compounded bioidentical hormone therapies should be limited to patients who are not able to use a hormone therapy product approved by the Food and Drug Administration for reasons of allergy or dosage, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

yacobchuk/Getty Images

In recent years, compounded bioidentical hormone therapies (cBHTs) have been “marketed as a personalized and natural approach to enhanced wellness using tailored preparations that address a myriad of symptoms, including those associated with menopause and aging,” wrote Donald R. Mattison, MD, of the University of Ottawa, and chair of the committee charged with producing the report, and colleagues.

Although both cBHTs and bioidentical hormone therapies (BHTs) contain hormones that are structurally and chemically identical to those in the human body, cBHTs have not undergone the safety, efficacy, and quality control tests of approved FDA products, according to the report.

In addition, cBHTs have no standardization when it comes to medication doses, and the products often are available in topicals such as creams or ointments, as well as pills or pellets. The lack of standards in dosing or form can contribute to the risk of overdose, the report emphasized.

Various cBTH products continue to be marketed to the public for age-related hormone symptoms including hot flashes associated with menopause and decreased muscle mass associated with decreased testosterone. However, cBHTs are not approved by the FDA in part because the individually mixed products are not tested to verify the amount of hormone that may be absorbed.

In response to the increased use of cBHTs, the National Academies convened a Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy and commissioned a report.

The two typical reasons to prescribe cBHT are either to provide a medication in an alternate dose not available in approved products or to omit components of a medication to which a patient is allergic, according to the report.

The report includes an algorithm to help guide clinicians in prescribing FDA-approved products, including off-label use of approved products, before cBHT products. “There is a dearth of high-quality evidence ... available to establish whether cBHT preparations are safe or efficacious for their prescribed uses,” the report states.

Of note, the committee also found no guidelines to recommend the use of cBHT products as a substitute for off-label use of FDA-approved BHT products for patients with female sexual dysfunction or gender dysphoria, two conditions for which no FDA-approved BHT products exist.

“The North American Menopause Society applauds the efforts of the National Academies of Sciences, Engineering, and Medicine (NASEM) and endorses their recommendations on compounded bioidentical hormone therapy,” Stephanie S. Faubion, MD, medical director of The North American Menopause Society, wrote in a statement. “As a society, we remain committed to improving the care of midlife women through the promotion of evidence-based research, education, and clinical care.”

A report on the use of cBHTs was important at this time because of the widespread and largely unregulated use of these products with little data to support their safety and efficacy, Dr. Faubion said in an interview.

“There are no indications for use of custom compounded hormone therapy aside from an allergy to a component in the FDA-approved products or lack of availability of the needed dose, which would be exceedingly rare given the variety of forms and doses available with FDA-approved products,” she said.

Main concerns regarding the use of cBHTs are the lack of safety and efficacy data, Dr. Faubion emphasized. “Women believe these products are safer than FDA-approved products because they do not receive a package insert outlining potential risks as they do with FDA-approved products.” A lack of data and safety monitoring of cBHTs means that adverse effects are not monitored and reported, she said. Also, safety concerns persist regarding some forms of cBHTs such as pellets, which were specifically highlighted in the report.

Dr. Faubion said that she “absolutely” agrees with the report’s limited circumstances in which the used of cBHTs would be appropriate. “There are very few reasons why women would need to use compounded hormones instead of the FDA-approved versions, which are regulated for quality, efficacy and safety, readily available in the local pharmacy, and often covered by insurance.”

In terms of the future, “we need more education for women as consumers and for medical providers on this topic,” Dr. Faubion noted. Also, “clearly, there is a dearth of research on the true efficacy and safety of these compounded hormone therapy products.”

The statement from the National Academies crystallizes what experts have been saying for decades, according to Lubna Pal, MBBS, director of the menopause program at Yale University, New Haven, Conn.

The formal recommendations to limit the use of cBHTs “are not novel, but certainly needed,” and the statement “offers guidance regardless of your specialty,” Dr. Pal said in an interview.

There is often a disconnect between consumers’ understanding of compounding and the reality of safety concerns, she said. “We are in a tabloid era,” and education is key to guiding patients toward the FDA-approved treatments with safety data and demonstrated effectiveness, she said. “Safety should be the driving factor.” In compounded products, “there is no consistency that what you get today is the same as what you get tomorrow,” and the lack of standardization of cBHTs increases the risk for adverse events, she emphasized.

For patients with special needs such as allergies or other specialized dosing requirements, as noted in the National Academies statement, clinicians should discuss the options with patients and monitor them regularly to head off potential adverse events such as the development of uterine cancer, said Dr. Pal, who is a member of the Ob.Gyn. News editorial advisory board.

The research involved in creating the report was supported by the Food and Drug Administration.

Dr. Faubion had no financial conflicts to disclose. Dr. Pal had no relevant financial disclosures.

[email protected]

SOURCE: Mattison DR et al.; National Academies of Sciences, Engineering, and Medicine. The clinical utility of compounded bioidentical hormone therapy: A review of safety, effectiveness, and use. (Washington, DC: The National Academies Press. 2020.)

Dairy consumption does not improve bone mineral density (BMD) or reduce the risk of osteoporotic fracture in women starting menopause, a new analysis of the Study of Women’s Health Across the Nation (SWAN) indicates.

copyright/Jupiterimages/Getty Images

And this was regardless of baseline menopausal status, say Taylor Wallace, PhD, of George Mason University, Fairfax, Va., and colleagues in their article published online in Menopause.

“Our previous work indicated a potential premenopausal critical window in regard to the effectiveness of calcium supplements,” they noted.

Clifford Rosen, MD, professor of medicine, Tufts University, Boston, said in an interview that he believes the study reinforces earlier work that dairy intake in women aged 45-55 years does not affect the rate of bone loss or fractures.

“The SWAN study is longitudinal and with sufficient numbers to support their conclusion,” Dr. Rosen said.
 

SWAN study: White women consume the most dairy

As dairy is known to be one of the foremost sources of calcium, along with other bone beneficial nutrients, Dr. Wallace and colleagues decided to examine intake of this food type with long-term bone health using the SWAN data.

The SWAN bone substudy started in 1996 and involved 3,302 pre- or early perimenopausal women aged 42-53 years. The sample size for the annualized rate of BMD loss and fracture analysis involved 1955 women.

A modified food frequency questionnaire was used at baseline, at visit 5, and again at visit 9 to record daily dairy consumption, among many other food items.

“Women were classified into four dairy groups based on this cumulative average dairy intake,” Wallace and colleagues note. Intake was grouped into < 0.5 servings/day; 0.5 to < 1.5 servings/day; 1.5 to < 2.5 servings/day, and ≥ 2.5 servings/day.

“Non-Hispanic white individuals were more likely to consume higher amounts of dairy compared to African American, Chinese, and Japanese individuals,” the authors noted.

They found no significant differences for baseline age, body mass index, femoral neck and lumbar spine BMD, calcium supplement use, or fracture history by dairy intake group.

There were also no differences in the hazard ratios or relative risk of nontraumatic fractures by frequency of daily dairy intake.
 

Findings on dairy and bone are inconsistent

The authors caution that several factors should be taken into account when considering these new findings.

“First, dairy intake was low [overall] among SWAN participants, with 65% reporting consumption of < 1.5 servings/day,” they point out.

Dairy intake was also “particularly low” among racial groups other than whites, which may be due to higher rates of lactose intolerance among ethnic minorities, they speculate.

They previously reported that the use of calcium dietary supplements in SWAN was associated with a lower annualized rate of femoral neck BMD loss as well as BMD loss at the lumbar spine over 10 years of follow-up, mainly in women who were premenopausal at baseline.

But no associations were observed in the risk of bone fracture in any women in that analysis, regardless of menopausal status.

In this new analysis, there were no significant differences in calcium supplement use across the dairy intake groups.

Dr. Wallace and colleagues also noted that the relevance of dairy product intake for bone health has been in question as some observational studies have even “suggested consumption to be associated with an increased risk of fractures.”

The lead author of one of these studies, Karl Michaelsson, MD, PhD, of Uppsala (Sweden) University, said in an interview that his study had looked only at milk intake, and the lack of benefit on bone health from high milk consumption may not apply to all dairy products.

We “may need to look at different types of dairy products,” he said.

Summing up, Stephanie Faubion, MD, MBA, medical director of the North American Menopause Society, said the new SWAN findings do add to the evidence base, “albeit inconsistent ... suggesting a lack of benefit from dairy intake on BMD and fracture risk.”
 

Vitamin D data were not available; dairy may help in this respect

Dr. Rosen also noted that no information was available on vitamin D levels in patients involved in SWAN, which he believes is a limitation of the study.

Nevertheless, “it is important to recognize that elderly individuals who increase their dairy intake may have health benefits as recognized in the Nurses’ Health Study, possibly due to increased protein intake, higher vitamin D levels, or greater calcium intake,” he observed.

A randomized trial of enhanced dairy intake in long-term care residents is currently underway, which should provide answers for a much more vulnerable population than those in the SWAN cohort, Dr. Rosen concluded.

Dr. Wallace has reported serving on the scientific advisory board of the Vitamin Shoppe and has received research support from the National Dairy Council and scientific consulting fees from several food companies. Dr. Rosen has reported no relevant financial relationships.

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

Dairy consumption does not improve bone mineral density (BMD) or reduce the risk of osteoporotic fracture in women starting menopause, a new analysis of the Study of Women’s Health Across the Nation (SWAN) indicates.

copyright/Jupiterimages/Getty Images

And this was regardless of baseline menopausal status, say Taylor Wallace, PhD, of George Mason University, Fairfax, Va., and colleagues in their article published online in Menopause.

“Our previous work indicated a potential premenopausal critical window in regard to the effectiveness of calcium supplements,” they noted.

Clifford Rosen, MD, professor of medicine, Tufts University, Boston, said in an interview that he believes the study reinforces earlier work that dairy intake in women aged 45-55 years does not affect the rate of bone loss or fractures.

“The SWAN study is longitudinal and with sufficient numbers to support their conclusion,” Dr. Rosen said.
 

SWAN study: White women consume the most dairy

As dairy is known to be one of the foremost sources of calcium, along with other bone beneficial nutrients, Dr. Wallace and colleagues decided to examine intake of this food type with long-term bone health using the SWAN data.

The SWAN bone substudy started in 1996 and involved 3,302 pre- or early perimenopausal women aged 42-53 years. The sample size for the annualized rate of BMD loss and fracture analysis involved 1955 women.

A modified food frequency questionnaire was used at baseline, at visit 5, and again at visit 9 to record daily dairy consumption, among many other food items.

“Women were classified into four dairy groups based on this cumulative average dairy intake,” Wallace and colleagues note. Intake was grouped into < 0.5 servings/day; 0.5 to < 1.5 servings/day; 1.5 to < 2.5 servings/day, and ≥ 2.5 servings/day.

“Non-Hispanic white individuals were more likely to consume higher amounts of dairy compared to African American, Chinese, and Japanese individuals,” the authors noted.

They found no significant differences for baseline age, body mass index, femoral neck and lumbar spine BMD, calcium supplement use, or fracture history by dairy intake group.

There were also no differences in the hazard ratios or relative risk of nontraumatic fractures by frequency of daily dairy intake.
 

Findings on dairy and bone are inconsistent

The authors caution that several factors should be taken into account when considering these new findings.

“First, dairy intake was low [overall] among SWAN participants, with 65% reporting consumption of < 1.5 servings/day,” they point out.

Dairy intake was also “particularly low” among racial groups other than whites, which may be due to higher rates of lactose intolerance among ethnic minorities, they speculate.

They previously reported that the use of calcium dietary supplements in SWAN was associated with a lower annualized rate of femoral neck BMD loss as well as BMD loss at the lumbar spine over 10 years of follow-up, mainly in women who were premenopausal at baseline.

But no associations were observed in the risk of bone fracture in any women in that analysis, regardless of menopausal status.

In this new analysis, there were no significant differences in calcium supplement use across the dairy intake groups.

Dr. Wallace and colleagues also noted that the relevance of dairy product intake for bone health has been in question as some observational studies have even “suggested consumption to be associated with an increased risk of fractures.”

The lead author of one of these studies, Karl Michaelsson, MD, PhD, of Uppsala (Sweden) University, said in an interview that his study had looked only at milk intake, and the lack of benefit on bone health from high milk consumption may not apply to all dairy products.

We “may need to look at different types of dairy products,” he said.

Summing up, Stephanie Faubion, MD, MBA, medical director of the North American Menopause Society, said the new SWAN findings do add to the evidence base, “albeit inconsistent ... suggesting a lack of benefit from dairy intake on BMD and fracture risk.”
 

Vitamin D data were not available; dairy may help in this respect

Dr. Rosen also noted that no information was available on vitamin D levels in patients involved in SWAN, which he believes is a limitation of the study.

Nevertheless, “it is important to recognize that elderly individuals who increase their dairy intake may have health benefits as recognized in the Nurses’ Health Study, possibly due to increased protein intake, higher vitamin D levels, or greater calcium intake,” he observed.

A randomized trial of enhanced dairy intake in long-term care residents is currently underway, which should provide answers for a much more vulnerable population than those in the SWAN cohort, Dr. Rosen concluded.

Dr. Wallace has reported serving on the scientific advisory board of the Vitamin Shoppe and has received research support from the National Dairy Council and scientific consulting fees from several food companies. Dr. Rosen has reported no relevant financial relationships.

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

Dairy consumption does not improve bone mineral density (BMD) or reduce the risk of osteoporotic fracture in women starting menopause, a new analysis of the Study of Women’s Health Across the Nation (SWAN) indicates.

copyright/Jupiterimages/Getty Images

And this was regardless of baseline menopausal status, say Taylor Wallace, PhD, of George Mason University, Fairfax, Va., and colleagues in their article published online in Menopause.

“Our previous work indicated a potential premenopausal critical window in regard to the effectiveness of calcium supplements,” they noted.

Clifford Rosen, MD, professor of medicine, Tufts University, Boston, said in an interview that he believes the study reinforces earlier work that dairy intake in women aged 45-55 years does not affect the rate of bone loss or fractures.

“The SWAN study is longitudinal and with sufficient numbers to support their conclusion,” Dr. Rosen said.
 

SWAN study: White women consume the most dairy

As dairy is known to be one of the foremost sources of calcium, along with other bone beneficial nutrients, Dr. Wallace and colleagues decided to examine intake of this food type with long-term bone health using the SWAN data.

The SWAN bone substudy started in 1996 and involved 3,302 pre- or early perimenopausal women aged 42-53 years. The sample size for the annualized rate of BMD loss and fracture analysis involved 1955 women.

A modified food frequency questionnaire was used at baseline, at visit 5, and again at visit 9 to record daily dairy consumption, among many other food items.

“Women were classified into four dairy groups based on this cumulative average dairy intake,” Wallace and colleagues note. Intake was grouped into < 0.5 servings/day; 0.5 to < 1.5 servings/day; 1.5 to < 2.5 servings/day, and ≥ 2.5 servings/day.

“Non-Hispanic white individuals were more likely to consume higher amounts of dairy compared to African American, Chinese, and Japanese individuals,” the authors noted.

They found no significant differences for baseline age, body mass index, femoral neck and lumbar spine BMD, calcium supplement use, or fracture history by dairy intake group.

There were also no differences in the hazard ratios or relative risk of nontraumatic fractures by frequency of daily dairy intake.
 

Findings on dairy and bone are inconsistent

The authors caution that several factors should be taken into account when considering these new findings.

“First, dairy intake was low [overall] among SWAN participants, with 65% reporting consumption of < 1.5 servings/day,” they point out.

Dairy intake was also “particularly low” among racial groups other than whites, which may be due to higher rates of lactose intolerance among ethnic minorities, they speculate.

They previously reported that the use of calcium dietary supplements in SWAN was associated with a lower annualized rate of femoral neck BMD loss as well as BMD loss at the lumbar spine over 10 years of follow-up, mainly in women who were premenopausal at baseline.

But no associations were observed in the risk of bone fracture in any women in that analysis, regardless of menopausal status.

In this new analysis, there were no significant differences in calcium supplement use across the dairy intake groups.

Dr. Wallace and colleagues also noted that the relevance of dairy product intake for bone health has been in question as some observational studies have even “suggested consumption to be associated with an increased risk of fractures.”

The lead author of one of these studies, Karl Michaelsson, MD, PhD, of Uppsala (Sweden) University, said in an interview that his study had looked only at milk intake, and the lack of benefit on bone health from high milk consumption may not apply to all dairy products.

We “may need to look at different types of dairy products,” he said.

Summing up, Stephanie Faubion, MD, MBA, medical director of the North American Menopause Society, said the new SWAN findings do add to the evidence base, “albeit inconsistent ... suggesting a lack of benefit from dairy intake on BMD and fracture risk.”
 

Vitamin D data were not available; dairy may help in this respect

Dr. Rosen also noted that no information was available on vitamin D levels in patients involved in SWAN, which he believes is a limitation of the study.

Nevertheless, “it is important to recognize that elderly individuals who increase their dairy intake may have health benefits as recognized in the Nurses’ Health Study, possibly due to increased protein intake, higher vitamin D levels, or greater calcium intake,” he observed.

A randomized trial of enhanced dairy intake in long-term care residents is currently underway, which should provide answers for a much more vulnerable population than those in the SWAN cohort, Dr. Rosen concluded.

Dr. Wallace has reported serving on the scientific advisory board of the Vitamin Shoppe and has received research support from the National Dairy Council and scientific consulting fees from several food companies. Dr. Rosen has reported no relevant financial relationships.

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

In a national sample of U.S. women in their mid-40s to mid-50s, those with high serum levels of per- and polyfluoroalkyl substances (PFAS) were likely to enter menopause 2 years earlier than those with low levels of these chemicals.

That is, the median age of natural menopause was 52.8 years versus 50.8 years in women with high versus low serum levels of these chemicals in an analysis of data from more than 1,100 women in the Study of Women’s Health Across the Nation (SWAN) Multi-Pollutant Study, which excluded women with premature menopause (before age 40) or early menopause (before age 45).

“This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life,” Ning Ding, PhD, MPH, University of Michigan, Ann Arbor, and colleagues concluded in their article, published online June 3 in the Journal of Clinical Endocrinology & Metabolism.

“Even menopause a few years earlier than usual could have a significant impact on cardiovascular and bone health, quality of life, and overall health in general among women,” senior author Sung Kyun Park, ScD, MPH, from the same institution, added in a statement.

PFAS don’t break down in the body, build up with time

PFAS have been widely used in many consumer and industrial products such as nonstick cookware, stain-repellent carpets, waterproof rain gear, microwave popcorn bags, and firefighting foam, the authors explained.

These have been dubbed “forever chemicals” because they do not degrade. Household water for an estimated 110 million Americans (one in three) may be contaminated with these chemicals, according to an Endocrine Society press release.

“PFAS are everywhere. Once they enter the body, they don’t break down and [they] build up over time,” said Dr. Ding. “Because of their persistence in humans and potentially detrimental effects on ovarian function, it is important to raise awareness of this issue and reduce exposure to these chemicals.”

Environmental exposure and accelerated ovarian aging

Earlier menopause has been associated with an increased risk of cardiovascular disease, osteoporosis, and earlier cardiovascular and overall mortality, and environmental exposure may accelerate ovarian aging, the authors wrote.

PFAS, especially the most studied types – perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) – are plausible endocrine-disrupting chemicals, but findings so far have been inconsistent.

A study of people in Ohio exposed to contaminated water found that women with earlier natural menopause had higher serum PFOA and PFOS levels (J Clin Endocriniol Metab. 2011;96:1747-53).

But in research based on National Health and Nutrition Survey Examination data, higher PFOA, PFOS, or perfluorononanoic acid (PFNA) levels were not linked to earlier menopause, although higher levels of perfluorohexane sulfonic acid (PFHxS) were (Environ Health Perspect. 2014;122:145-50).

There may have been reverse causation, where postmenopausal women had higher PFAS levels because they were not excreting these chemicals in menstrual blood.

In a third study, PFOA exposure was not linked with age at menopause onset, but this was based on recall from 10 years earlier (Environ Res. 2016;146:323-30).

The current analysis examined data from 1,120 premenopausal women who were aged 45-56 years from 1999 to 2000.

The women were seen at five sites (Boston; Detroit; Los Angeles; Oakland, Calif.; and Pittsburgh) and were ethnically diverse (577 white, 235 black, 142 Chinese, and 166 Japanese).

Baseline serum PFAS levels were measured using high performance liquid chromatography-mass spectrometry. The women were followed up to 2017 and incident menopause (12 consecutive months with no menstruation) was determined from annual interviews.

Of the 1,120 women and 5,466 person-years of follow-up, 578 women had a known date of natural incident menopause and were included in the analysis. The remaining 542 women were excluded mainly because their date of final menstruation was unknown because of hormone therapy (451) or they had a hysterectomy, or did not enter menopause during the study.

Compared with women in the lowest tertile of PFOS levels, women in the highest tertile had a significant 26%-27% greater risk of incident menopause – after adjusting for age, body mass index, and prior hormone use, race/ethnicity, study site, education, physical activity, smoking status, and parity.

Higher PFOA and PFNA levels but not higher PFHxS levels were also associated with increased risk.

Compared with women with a low overall PFAS level, those with a high level had a 63% increased risk of incident menopause (hazard ratio, 1.63; 95% confidence interval, 1.08-2.45), equivalent to having menopause a median of 2 years earlier.

Although production and use of some types of PFAS in the United States are declining, Dr. Ding and colleagues wrote, exposure continues, along with associated potential hazards to human reproductive health.

“Due to PFAS widespread use and environmental persistence, their potential adverse effects remain a public health concern,” they concluded.

SWAN was supported by the National Institutes of Health, Department of Health & Human Services through the National Institute on Aging, National Institute of Nursing Research, NIH Office of Research on Women’s Health, and the SWAN repository. The current article was supported by the National Center for Research Resources and National Center for Advancing Translational Sciences, NIH, National Institute of Environmental Health Sciences, and Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The authors have reported no relevant financial relationships.

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

In a national sample of U.S. women in their mid-40s to mid-50s, those with high serum levels of per- and polyfluoroalkyl substances (PFAS) were likely to enter menopause 2 years earlier than those with low levels of these chemicals.

That is, the median age of natural menopause was 52.8 years versus 50.8 years in women with high versus low serum levels of these chemicals in an analysis of data from more than 1,100 women in the Study of Women’s Health Across the Nation (SWAN) Multi-Pollutant Study, which excluded women with premature menopause (before age 40) or early menopause (before age 45).

“This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life,” Ning Ding, PhD, MPH, University of Michigan, Ann Arbor, and colleagues concluded in their article, published online June 3 in the Journal of Clinical Endocrinology & Metabolism.

“Even menopause a few years earlier than usual could have a significant impact on cardiovascular and bone health, quality of life, and overall health in general among women,” senior author Sung Kyun Park, ScD, MPH, from the same institution, added in a statement.

PFAS don’t break down in the body, build up with time

PFAS have been widely used in many consumer and industrial products such as nonstick cookware, stain-repellent carpets, waterproof rain gear, microwave popcorn bags, and firefighting foam, the authors explained.

These have been dubbed “forever chemicals” because they do not degrade. Household water for an estimated 110 million Americans (one in three) may be contaminated with these chemicals, according to an Endocrine Society press release.

“PFAS are everywhere. Once they enter the body, they don’t break down and [they] build up over time,” said Dr. Ding. “Because of their persistence in humans and potentially detrimental effects on ovarian function, it is important to raise awareness of this issue and reduce exposure to these chemicals.”

Environmental exposure and accelerated ovarian aging

Earlier menopause has been associated with an increased risk of cardiovascular disease, osteoporosis, and earlier cardiovascular and overall mortality, and environmental exposure may accelerate ovarian aging, the authors wrote.

PFAS, especially the most studied types – perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) – are plausible endocrine-disrupting chemicals, but findings so far have been inconsistent.

A study of people in Ohio exposed to contaminated water found that women with earlier natural menopause had higher serum PFOA and PFOS levels (J Clin Endocriniol Metab. 2011;96:1747-53).

But in research based on National Health and Nutrition Survey Examination data, higher PFOA, PFOS, or perfluorononanoic acid (PFNA) levels were not linked to earlier menopause, although higher levels of perfluorohexane sulfonic acid (PFHxS) were (Environ Health Perspect. 2014;122:145-50).

There may have been reverse causation, where postmenopausal women had higher PFAS levels because they were not excreting these chemicals in menstrual blood.

In a third study, PFOA exposure was not linked with age at menopause onset, but this was based on recall from 10 years earlier (Environ Res. 2016;146:323-30).

The current analysis examined data from 1,120 premenopausal women who were aged 45-56 years from 1999 to 2000.

The women were seen at five sites (Boston; Detroit; Los Angeles; Oakland, Calif.; and Pittsburgh) and were ethnically diverse (577 white, 235 black, 142 Chinese, and 166 Japanese).

Baseline serum PFAS levels were measured using high performance liquid chromatography-mass spectrometry. The women were followed up to 2017 and incident menopause (12 consecutive months with no menstruation) was determined from annual interviews.

Of the 1,120 women and 5,466 person-years of follow-up, 578 women had a known date of natural incident menopause and were included in the analysis. The remaining 542 women were excluded mainly because their date of final menstruation was unknown because of hormone therapy (451) or they had a hysterectomy, or did not enter menopause during the study.

Compared with women in the lowest tertile of PFOS levels, women in the highest tertile had a significant 26%-27% greater risk of incident menopause – after adjusting for age, body mass index, and prior hormone use, race/ethnicity, study site, education, physical activity, smoking status, and parity.

Higher PFOA and PFNA levels but not higher PFHxS levels were also associated with increased risk.

Compared with women with a low overall PFAS level, those with a high level had a 63% increased risk of incident menopause (hazard ratio, 1.63; 95% confidence interval, 1.08-2.45), equivalent to having menopause a median of 2 years earlier.

Although production and use of some types of PFAS in the United States are declining, Dr. Ding and colleagues wrote, exposure continues, along with associated potential hazards to human reproductive health.

“Due to PFAS widespread use and environmental persistence, their potential adverse effects remain a public health concern,” they concluded.

SWAN was supported by the National Institutes of Health, Department of Health & Human Services through the National Institute on Aging, National Institute of Nursing Research, NIH Office of Research on Women’s Health, and the SWAN repository. The current article was supported by the National Center for Research Resources and National Center for Advancing Translational Sciences, NIH, National Institute of Environmental Health Sciences, and Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The authors have reported no relevant financial relationships.

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

In a national sample of U.S. women in their mid-40s to mid-50s, those with high serum levels of per- and polyfluoroalkyl substances (PFAS) were likely to enter menopause 2 years earlier than those with low levels of these chemicals.

That is, the median age of natural menopause was 52.8 years versus 50.8 years in women with high versus low serum levels of these chemicals in an analysis of data from more than 1,100 women in the Study of Women’s Health Across the Nation (SWAN) Multi-Pollutant Study, which excluded women with premature menopause (before age 40) or early menopause (before age 45).

“This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life,” Ning Ding, PhD, MPH, University of Michigan, Ann Arbor, and colleagues concluded in their article, published online June 3 in the Journal of Clinical Endocrinology & Metabolism.

“Even menopause a few years earlier than usual could have a significant impact on cardiovascular and bone health, quality of life, and overall health in general among women,” senior author Sung Kyun Park, ScD, MPH, from the same institution, added in a statement.

PFAS don’t break down in the body, build up with time

PFAS have been widely used in many consumer and industrial products such as nonstick cookware, stain-repellent carpets, waterproof rain gear, microwave popcorn bags, and firefighting foam, the authors explained.

These have been dubbed “forever chemicals” because they do not degrade. Household water for an estimated 110 million Americans (one in three) may be contaminated with these chemicals, according to an Endocrine Society press release.

“PFAS are everywhere. Once they enter the body, they don’t break down and [they] build up over time,” said Dr. Ding. “Because of their persistence in humans and potentially detrimental effects on ovarian function, it is important to raise awareness of this issue and reduce exposure to these chemicals.”

Environmental exposure and accelerated ovarian aging

Earlier menopause has been associated with an increased risk of cardiovascular disease, osteoporosis, and earlier cardiovascular and overall mortality, and environmental exposure may accelerate ovarian aging, the authors wrote.

PFAS, especially the most studied types – perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) – are plausible endocrine-disrupting chemicals, but findings so far have been inconsistent.

A study of people in Ohio exposed to contaminated water found that women with earlier natural menopause had higher serum PFOA and PFOS levels (J Clin Endocriniol Metab. 2011;96:1747-53).

But in research based on National Health and Nutrition Survey Examination data, higher PFOA, PFOS, or perfluorononanoic acid (PFNA) levels were not linked to earlier menopause, although higher levels of perfluorohexane sulfonic acid (PFHxS) were (Environ Health Perspect. 2014;122:145-50).

There may have been reverse causation, where postmenopausal women had higher PFAS levels because they were not excreting these chemicals in menstrual blood.

In a third study, PFOA exposure was not linked with age at menopause onset, but this was based on recall from 10 years earlier (Environ Res. 2016;146:323-30).

The current analysis examined data from 1,120 premenopausal women who were aged 45-56 years from 1999 to 2000.

The women were seen at five sites (Boston; Detroit; Los Angeles; Oakland, Calif.; and Pittsburgh) and were ethnically diverse (577 white, 235 black, 142 Chinese, and 166 Japanese).

Baseline serum PFAS levels were measured using high performance liquid chromatography-mass spectrometry. The women were followed up to 2017 and incident menopause (12 consecutive months with no menstruation) was determined from annual interviews.

Of the 1,120 women and 5,466 person-years of follow-up, 578 women had a known date of natural incident menopause and were included in the analysis. The remaining 542 women were excluded mainly because their date of final menstruation was unknown because of hormone therapy (451) or they had a hysterectomy, or did not enter menopause during the study.

Compared with women in the lowest tertile of PFOS levels, women in the highest tertile had a significant 26%-27% greater risk of incident menopause – after adjusting for age, body mass index, and prior hormone use, race/ethnicity, study site, education, physical activity, smoking status, and parity.

Higher PFOA and PFNA levels but not higher PFHxS levels were also associated with increased risk.

Compared with women with a low overall PFAS level, those with a high level had a 63% increased risk of incident menopause (hazard ratio, 1.63; 95% confidence interval, 1.08-2.45), equivalent to having menopause a median of 2 years earlier.

Although production and use of some types of PFAS in the United States are declining, Dr. Ding and colleagues wrote, exposure continues, along with associated potential hazards to human reproductive health.

“Due to PFAS widespread use and environmental persistence, their potential adverse effects remain a public health concern,” they concluded.

SWAN was supported by the National Institutes of Health, Department of Health & Human Services through the National Institute on Aging, National Institute of Nursing Research, NIH Office of Research on Women’s Health, and the SWAN repository. The current article was supported by the National Center for Research Resources and National Center for Advancing Translational Sciences, NIH, National Institute of Environmental Health Sciences, and Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The authors have reported no relevant financial relationships.

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