Menopause

Menopause experts Andrew M. Kaunitz, MD, and JoAnn E. Manson, MD, DrPH, provide a comprehensive review of various treatments for menopausal symptoms in an article recently published ahead of print in Obstetrics and Gynecology.¹ They discuss hormonal and nonhormonal options to treat vasomotor symptoms, genitourinary syndrome of menopause (GSM), and considerations for the use of hormone therapy in special populations: women with early menopause, women with a history of breast cancer and those who carry the BRCA gene mutation, and women with a history of venous thrombosis.¹

The authors write that, “given the lower rates of adverse events on HT among women close to menopause onset and at lower baseline risk of cardiovascular disease, risk stratification and personalized risk assessment appear to represent a sound strategy for optimizing the benefit–risk profile and safety of HT.”¹ They suggest that instead of stopping systemic HT at age 65 years, the length of treatment be individualized based on a woman’s risk profile and preferences. The authors encourage gynecologists and other clinicians to use benefit–risk profile tools for both hormonal and nonhormonal options to help women make sound decisions on treating menopausal symptoms.¹

Readthe full Clinical Expert Series here.

Menopause experts Andrew M. Kaunitz, MD, and JoAnn E. Manson, MD, DrPH, provide a comprehensive review of various treatments for menopausal symptoms in an article recently published ahead of print in Obstetrics and Gynecology.¹ They discuss hormonal and nonhormonal options to treat vasomotor symptoms, genitourinary syndrome of menopause (GSM), and considerations for the use of hormone therapy in special populations: women with early menopause, women with a history of breast cancer and those who carry the BRCA gene mutation, and women with a history of venous thrombosis.¹

The authors write that, “given the lower rates of adverse events on HT among women close to menopause onset and at lower baseline risk of cardiovascular disease, risk stratification and personalized risk assessment appear to represent a sound strategy for optimizing the benefit–risk profile and safety of HT.”¹ They suggest that instead of stopping systemic HT at age 65 years, the length of treatment be individualized based on a woman’s risk profile and preferences. The authors encourage gynecologists and other clinicians to use benefit–risk profile tools for both hormonal and nonhormonal options to help women make sound decisions on treating menopausal symptoms.¹

Readthe full Clinical Expert Series here.

Menopause experts Andrew M. Kaunitz, MD, and JoAnn E. Manson, MD, DrPH, provide a comprehensive review of various treatments for menopausal symptoms in an article recently published ahead of print in Obstetrics and Gynecology.¹ They discuss hormonal and nonhormonal options to treat vasomotor symptoms, genitourinary syndrome of menopause (GSM), and considerations for the use of hormone therapy in special populations: women with early menopause, women with a history of breast cancer and those who carry the BRCA gene mutation, and women with a history of venous thrombosis.¹

The authors write that, “given the lower rates of adverse events on HT among women close to menopause onset and at lower baseline risk of cardiovascular disease, risk stratification and personalized risk assessment appear to represent a sound strategy for optimizing the benefit–risk profile and safety of HT.”¹ They suggest that instead of stopping systemic HT at age 65 years, the length of treatment be individualized based on a woman’s risk profile and preferences. The authors encourage gynecologists and other clinicians to use benefit–risk profile tools for both hormonal and nonhormonal options to help women make sound decisions on treating menopausal symptoms.¹

Readthe full Clinical Expert Series here.

NEW YORK – Antiandrogen hormones can help stabilize, and even improve, female pattern hair loss.

The pathophysiology of the disorder is unknown, but treatment is based on the assumption that women must be like men, at least when it comes to losing their hair. Intuitively, decreasing androgens should help correct the problem.

R Eko Bintoro/ThinkStockPhotos

The answer, though, is a complicated mix of yes and maybe, Dr. Rochelle Torgerson said at the American Academy of Dermatology summer meeting.

“It used to be assumed that pattern hair loss in women was just the same as it is in men,” said Dr. Torgerson of the Mayo Clinic in Rochester, Minn. “Now there is some evidence that’s not true. In 2010, for example, this was seen in a woman with complete androgen insensitivity syndrome, so in her, androgens were not affecting hair follicles. There must be a place for estrogen.”

Further complicating the picture is the fact that no hormonal medications have FDA approval for hair loss in women, and their use has a history of conflicting data in clinical studies. Still, they remain the cornerstone for treating this physically and emotionally challenging problem.

The initial challenge is simply what to label it at the first visit.

“I have no problem with term ‘androgenetic alopecia,’ since that is what women are seeing when they first look on the Internet for information. But I do try to transition them to ‘female pattern hair loss.’ And I never – ever – use the term ‘male pattern baldness.’ It has a huge impact on women.”

The disease is a progressive miniaturization of the hair follicle over time. The growing cycle slows and the resting phase lengthens. There is progressive thinning over the vertex. Some women may keep most of their frontal hairline, but the vast majority do say it’s thinner than it was.

Spironolactone and oral contraceptives with spironolactone analogues are Dr. Torgerson’s go-to medications for first-line treatment. For spironolactone, she prefers a dose of 100-200 mg/day. Some women experience gastrointestinal upset, dizziness, cramps, breast tenderness, and spotting with these medications.

Her choice for an oral contraceptive is the combination of 20 mcg ethinyl estradiol plus drospirenone, but any oral contraceptive approved for acne may work.

Finasteride and dutasteride are approved for pattern hair loss in men, but not in women. Both inhibit 5 alpha-reductase type II. Dutasteride is more potent that finasteride and also inhibits type 1 alpha-reductase; both of these enzymes convert testosterone into the more potent dihydrotestosterone. The side-effect profile is more moderate than that of spironolactone, but both of the drugs have had mixed results in clinical trials.

One problem with the finasteride trials has been the variation in dosing. The least positive studies used the lowest dose of 1.25 mg. As the dosage increased to 2.5 mg and 5 mg, the benefit increased.

Despite her support for hormonal therapies, Dr. Torgerson doesn’t rely upon them alone – she supports them with the direct action of a 5% minoxidil foam. In addition to prescribing effective therapy, she urges women to actually be patient and to have realistic expectations.

Most women expect dramatic improvement in a short time. “I have no idea where that expectation comes from. This is a slow progressive condition. I agree with them that it’s completely unsexy to have the head of hair they do at that time. But if, in 3 years, they have this same head of hair, that’s going to be an amazing success. And once they have that expectation in their mind, they are usually happy with any other results that they see.”

Dr. Torgerson had no financial conflicts with regard to her presentation.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Antiandrogen hormones can help stabilize, and even improve, female pattern hair loss.

The pathophysiology of the disorder is unknown, but treatment is based on the assumption that women must be like men, at least when it comes to losing their hair. Intuitively, decreasing androgens should help correct the problem.

R Eko Bintoro/ThinkStockPhotos

The answer, though, is a complicated mix of yes and maybe, Dr. Rochelle Torgerson said at the American Academy of Dermatology summer meeting.

“It used to be assumed that pattern hair loss in women was just the same as it is in men,” said Dr. Torgerson of the Mayo Clinic in Rochester, Minn. “Now there is some evidence that’s not true. In 2010, for example, this was seen in a woman with complete androgen insensitivity syndrome, so in her, androgens were not affecting hair follicles. There must be a place for estrogen.”

Further complicating the picture is the fact that no hormonal medications have FDA approval for hair loss in women, and their use has a history of conflicting data in clinical studies. Still, they remain the cornerstone for treating this physically and emotionally challenging problem.

The initial challenge is simply what to label it at the first visit.

“I have no problem with term ‘androgenetic alopecia,’ since that is what women are seeing when they first look on the Internet for information. But I do try to transition them to ‘female pattern hair loss.’ And I never – ever – use the term ‘male pattern baldness.’ It has a huge impact on women.”

The disease is a progressive miniaturization of the hair follicle over time. The growing cycle slows and the resting phase lengthens. There is progressive thinning over the vertex. Some women may keep most of their frontal hairline, but the vast majority do say it’s thinner than it was.

Spironolactone and oral contraceptives with spironolactone analogues are Dr. Torgerson’s go-to medications for first-line treatment. For spironolactone, she prefers a dose of 100-200 mg/day. Some women experience gastrointestinal upset, dizziness, cramps, breast tenderness, and spotting with these medications.

Her choice for an oral contraceptive is the combination of 20 mcg ethinyl estradiol plus drospirenone, but any oral contraceptive approved for acne may work.

Finasteride and dutasteride are approved for pattern hair loss in men, but not in women. Both inhibit 5 alpha-reductase type II. Dutasteride is more potent that finasteride and also inhibits type 1 alpha-reductase; both of these enzymes convert testosterone into the more potent dihydrotestosterone. The side-effect profile is more moderate than that of spironolactone, but both of the drugs have had mixed results in clinical trials.

One problem with the finasteride trials has been the variation in dosing. The least positive studies used the lowest dose of 1.25 mg. As the dosage increased to 2.5 mg and 5 mg, the benefit increased.

Despite her support for hormonal therapies, Dr. Torgerson doesn’t rely upon them alone – she supports them with the direct action of a 5% minoxidil foam. In addition to prescribing effective therapy, she urges women to actually be patient and to have realistic expectations.

Most women expect dramatic improvement in a short time. “I have no idea where that expectation comes from. This is a slow progressive condition. I agree with them that it’s completely unsexy to have the head of hair they do at that time. But if, in 3 years, they have this same head of hair, that’s going to be an amazing success. And once they have that expectation in their mind, they are usually happy with any other results that they see.”

Dr. Torgerson had no financial conflicts with regard to her presentation.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Antiandrogen hormones can help stabilize, and even improve, female pattern hair loss.

The pathophysiology of the disorder is unknown, but treatment is based on the assumption that women must be like men, at least when it comes to losing their hair. Intuitively, decreasing androgens should help correct the problem.

R Eko Bintoro/ThinkStockPhotos

The answer, though, is a complicated mix of yes and maybe, Dr. Rochelle Torgerson said at the American Academy of Dermatology summer meeting.

“It used to be assumed that pattern hair loss in women was just the same as it is in men,” said Dr. Torgerson of the Mayo Clinic in Rochester, Minn. “Now there is some evidence that’s not true. In 2010, for example, this was seen in a woman with complete androgen insensitivity syndrome, so in her, androgens were not affecting hair follicles. There must be a place for estrogen.”

Further complicating the picture is the fact that no hormonal medications have FDA approval for hair loss in women, and their use has a history of conflicting data in clinical studies. Still, they remain the cornerstone for treating this physically and emotionally challenging problem.

The initial challenge is simply what to label it at the first visit.

“I have no problem with term ‘androgenetic alopecia,’ since that is what women are seeing when they first look on the Internet for information. But I do try to transition them to ‘female pattern hair loss.’ And I never – ever – use the term ‘male pattern baldness.’ It has a huge impact on women.”

The disease is a progressive miniaturization of the hair follicle over time. The growing cycle slows and the resting phase lengthens. There is progressive thinning over the vertex. Some women may keep most of their frontal hairline, but the vast majority do say it’s thinner than it was.

Spironolactone and oral contraceptives with spironolactone analogues are Dr. Torgerson’s go-to medications for first-line treatment. For spironolactone, she prefers a dose of 100-200 mg/day. Some women experience gastrointestinal upset, dizziness, cramps, breast tenderness, and spotting with these medications.

Her choice for an oral contraceptive is the combination of 20 mcg ethinyl estradiol plus drospirenone, but any oral contraceptive approved for acne may work.

Finasteride and dutasteride are approved for pattern hair loss in men, but not in women. Both inhibit 5 alpha-reductase type II. Dutasteride is more potent that finasteride and also inhibits type 1 alpha-reductase; both of these enzymes convert testosterone into the more potent dihydrotestosterone. The side-effect profile is more moderate than that of spironolactone, but both of the drugs have had mixed results in clinical trials.

One problem with the finasteride trials has been the variation in dosing. The least positive studies used the lowest dose of 1.25 mg. As the dosage increased to 2.5 mg and 5 mg, the benefit increased.

Despite her support for hormonal therapies, Dr. Torgerson doesn’t rely upon them alone – she supports them with the direct action of a 5% minoxidil foam. In addition to prescribing effective therapy, she urges women to actually be patient and to have realistic expectations.

Most women expect dramatic improvement in a short time. “I have no idea where that expectation comes from. This is a slow progressive condition. I agree with them that it’s completely unsexy to have the head of hair they do at that time. But if, in 3 years, they have this same head of hair, that’s going to be an amazing success. And once they have that expectation in their mind, they are usually happy with any other results that they see.”

Dr. Torgerson had no financial conflicts with regard to her presentation.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Evidence is mounting that early intervention in the menopausal transition could help forestall some of the skin aging associated with estrogen decline.

Estrogen supplementation and collagen stimulation both seem effective in preserving the integrity of a woman’s skin as levels of the hormone decrease, Dr. Diane Madfes said at the American Academy of Dermatology summer meeting.

Type 3 collagen decreases by up to 50% within a few years of menopause, said Dr. Madfes, a dermatologist in New York. This is directly related to a loss of estrogen receptor beta in the dermal matrix, which promotes collagen formation.

“There is a theory – the timing hypothesis – that we have a window of opportunity to intervene. If we can stimulate the collagen before the receptors go down, maybe we can have a beneficial effect on skin.”

Any method of collagen stimulation should work, she said: laser resurfacing, microneedling, or radiofrequency. “We are very good about being able to stimulate collagen. The method doesn’t matter as much as the timing. The important thing is to intervene early. If you see your patients starting to sag, see a loss of elasticity, that is the time to intervene. Get at the collagen while it’s still receptive.”

Estrogen exerts a plethora of antiaging, skin-preserving effects. “We know that a decrease in estrogen is related to telomere shortening. Estrogen protects against oxidative damage. It signals keratinocytes through IGF-1,” she said.

The hormone also protects skin’s water-binding qualities by promoting mucopolysaccharides, sebum production, barrier function, and hyaluronic acid. It may even play a role in protecting against ultraviolet light. Estrogen downregulation affects healing by inhibiting the proliferation of keratinocytes and the proliferation and migration of fibroblasts.

All these add up to rapid skin aging after estrogen levels drop.

“The visible effects of aging on women’s skin are not so much related to her chronological age as to the years after menopause,” Dr. Madfes said – a finding that is particularly illustrated in young women with surgical menopause and those with breast cancer who take tamoxifen. The observation seems to suggest that early intervention with estrogen might help prevent at least some of the signs of aging.

The ongoing KEEPS trial (Kronos Early Estrogen Prevention Study) may shed some light on the issue. KEEPS has randomized 729 women aged 42-58 years to oral or transdermal estrogen; the primary endpoint is rate of atherosclerosis. But an ancillary study is looking at the effect of estrogen on skin wrinkles and skin rigidity.

The substudy is based on positive findings of a 1996 study, which found evidence for facial application of topical estrogen designed for vulvar use. After 6 months, elasticity and firmness significantly improved. Skin moisture increased, as did type 3 collagen and collagen fibers.

Some women do use topical estrogens on their faces. “It seems to promote skin thickening and tightening,“ Dr. Madfes said, although a recent editorial suggested that using the product anywhere but on the genitals can cause estrogen-mediated side effects in both children and pets.

But recommending estrogen is fraught with controversy. Large studies have come to conflicting conclusions about its benefit and safety. And prescribing estrogen is not really within a dermatologist’s purview.

“It’s not for us to suggest that women go on hormone therapy. But we can explain these things and ask if she is taking it, or if she’s talked to her gynecologist about it.”

Dr. Madfes has no financial disclosures to report.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Evidence is mounting that early intervention in the menopausal transition could help forestall some of the skin aging associated with estrogen decline.

Estrogen supplementation and collagen stimulation both seem effective in preserving the integrity of a woman’s skin as levels of the hormone decrease, Dr. Diane Madfes said at the American Academy of Dermatology summer meeting.

Type 3 collagen decreases by up to 50% within a few years of menopause, said Dr. Madfes, a dermatologist in New York. This is directly related to a loss of estrogen receptor beta in the dermal matrix, which promotes collagen formation.

“There is a theory – the timing hypothesis – that we have a window of opportunity to intervene. If we can stimulate the collagen before the receptors go down, maybe we can have a beneficial effect on skin.”

Any method of collagen stimulation should work, she said: laser resurfacing, microneedling, or radiofrequency. “We are very good about being able to stimulate collagen. The method doesn’t matter as much as the timing. The important thing is to intervene early. If you see your patients starting to sag, see a loss of elasticity, that is the time to intervene. Get at the collagen while it’s still receptive.”

Estrogen exerts a plethora of antiaging, skin-preserving effects. “We know that a decrease in estrogen is related to telomere shortening. Estrogen protects against oxidative damage. It signals keratinocytes through IGF-1,” she said.

The hormone also protects skin’s water-binding qualities by promoting mucopolysaccharides, sebum production, barrier function, and hyaluronic acid. It may even play a role in protecting against ultraviolet light. Estrogen downregulation affects healing by inhibiting the proliferation of keratinocytes and the proliferation and migration of fibroblasts.

All these add up to rapid skin aging after estrogen levels drop.

“The visible effects of aging on women’s skin are not so much related to her chronological age as to the years after menopause,” Dr. Madfes said – a finding that is particularly illustrated in young women with surgical menopause and those with breast cancer who take tamoxifen. The observation seems to suggest that early intervention with estrogen might help prevent at least some of the signs of aging.

The ongoing KEEPS trial (Kronos Early Estrogen Prevention Study) may shed some light on the issue. KEEPS has randomized 729 women aged 42-58 years to oral or transdermal estrogen; the primary endpoint is rate of atherosclerosis. But an ancillary study is looking at the effect of estrogen on skin wrinkles and skin rigidity.

The substudy is based on positive findings of a 1996 study, which found evidence for facial application of topical estrogen designed for vulvar use. After 6 months, elasticity and firmness significantly improved. Skin moisture increased, as did type 3 collagen and collagen fibers.

Some women do use topical estrogens on their faces. “It seems to promote skin thickening and tightening,“ Dr. Madfes said, although a recent editorial suggested that using the product anywhere but on the genitals can cause estrogen-mediated side effects in both children and pets.

But recommending estrogen is fraught with controversy. Large studies have come to conflicting conclusions about its benefit and safety. And prescribing estrogen is not really within a dermatologist’s purview.

“It’s not for us to suggest that women go on hormone therapy. But we can explain these things and ask if she is taking it, or if she’s talked to her gynecologist about it.”

Dr. Madfes has no financial disclosures to report.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Evidence is mounting that early intervention in the menopausal transition could help forestall some of the skin aging associated with estrogen decline.

Estrogen supplementation and collagen stimulation both seem effective in preserving the integrity of a woman’s skin as levels of the hormone decrease, Dr. Diane Madfes said at the American Academy of Dermatology summer meeting.

Type 3 collagen decreases by up to 50% within a few years of menopause, said Dr. Madfes, a dermatologist in New York. This is directly related to a loss of estrogen receptor beta in the dermal matrix, which promotes collagen formation.

“There is a theory – the timing hypothesis – that we have a window of opportunity to intervene. If we can stimulate the collagen before the receptors go down, maybe we can have a beneficial effect on skin.”

Any method of collagen stimulation should work, she said: laser resurfacing, microneedling, or radiofrequency. “We are very good about being able to stimulate collagen. The method doesn’t matter as much as the timing. The important thing is to intervene early. If you see your patients starting to sag, see a loss of elasticity, that is the time to intervene. Get at the collagen while it’s still receptive.”

Estrogen exerts a plethora of antiaging, skin-preserving effects. “We know that a decrease in estrogen is related to telomere shortening. Estrogen protects against oxidative damage. It signals keratinocytes through IGF-1,” she said.

The hormone also protects skin’s water-binding qualities by promoting mucopolysaccharides, sebum production, barrier function, and hyaluronic acid. It may even play a role in protecting against ultraviolet light. Estrogen downregulation affects healing by inhibiting the proliferation of keratinocytes and the proliferation and migration of fibroblasts.

All these add up to rapid skin aging after estrogen levels drop.

“The visible effects of aging on women’s skin are not so much related to her chronological age as to the years after menopause,” Dr. Madfes said – a finding that is particularly illustrated in young women with surgical menopause and those with breast cancer who take tamoxifen. The observation seems to suggest that early intervention with estrogen might help prevent at least some of the signs of aging.

The ongoing KEEPS trial (Kronos Early Estrogen Prevention Study) may shed some light on the issue. KEEPS has randomized 729 women aged 42-58 years to oral or transdermal estrogen; the primary endpoint is rate of atherosclerosis. But an ancillary study is looking at the effect of estrogen on skin wrinkles and skin rigidity.

The substudy is based on positive findings of a 1996 study, which found evidence for facial application of topical estrogen designed for vulvar use. After 6 months, elasticity and firmness significantly improved. Skin moisture increased, as did type 3 collagen and collagen fibers.

Some women do use topical estrogens on their faces. “It seems to promote skin thickening and tightening,“ Dr. Madfes said, although a recent editorial suggested that using the product anywhere but on the genitals can cause estrogen-mediated side effects in both children and pets.

But recommending estrogen is fraught with controversy. Large studies have come to conflicting conclusions about its benefit and safety. And prescribing estrogen is not really within a dermatologist’s purview.

“It’s not for us to suggest that women go on hormone therapy. But we can explain these things and ask if she is taking it, or if she’s talked to her gynecologist about it.”

Dr. Madfes has no financial disclosures to report.

[email protected]

On Twitter @Alz_Gal

Among adults aged 65 years and over, women were 4.4 times as likely as men to have osteoporosis, and Mexican Americans were 2.4 times more likely than were blacks to have osteoporosis from 2005 to 2010, the National Center for Health Statistics reported.

So where does leave those who are both women and Mexican American?

First, a little background: The age-adjusted prevalence of osteoporosis measured at either the lumbar spine or femur neck among adults aged 65 years and over was 24.8% for women and 5.6% for men, for an overall prevalence of 16.2%. Adults aged 65-79 years had an unadjusted prevalence of 12.8%, compared with 25.7% for those aged 80 years and over, according to data from the 2005-2010 National Health and Nutrition Examination Survey.

Age-adjusted prevalence over that time period for Mexican Americans aged 65 years and older was 24.9%, compared with 15.7% for non-Hispanic whites and 10.3% for non-Hispanic blacks.

Mexican American women, who find themselves at the intersection of these two trends, had an adjusted osteoporosis rate of 36.8%, the NCHS reported.

Osteoporosis was defined as a bone mineral density value that was more than 2.5 standard deviations below the mean value for young, non-Hispanic white females.

[email protected]

Among adults aged 65 years and over, women were 4.4 times as likely as men to have osteoporosis, and Mexican Americans were 2.4 times more likely than were blacks to have osteoporosis from 2005 to 2010, the National Center for Health Statistics reported.

So where does leave those who are both women and Mexican American?

First, a little background: The age-adjusted prevalence of osteoporosis measured at either the lumbar spine or femur neck among adults aged 65 years and over was 24.8% for women and 5.6% for men, for an overall prevalence of 16.2%. Adults aged 65-79 years had an unadjusted prevalence of 12.8%, compared with 25.7% for those aged 80 years and over, according to data from the 2005-2010 National Health and Nutrition Examination Survey.

Age-adjusted prevalence over that time period for Mexican Americans aged 65 years and older was 24.9%, compared with 15.7% for non-Hispanic whites and 10.3% for non-Hispanic blacks.

Mexican American women, who find themselves at the intersection of these two trends, had an adjusted osteoporosis rate of 36.8%, the NCHS reported.

Osteoporosis was defined as a bone mineral density value that was more than 2.5 standard deviations below the mean value for young, non-Hispanic white females.

[email protected]

Among adults aged 65 years and over, women were 4.4 times as likely as men to have osteoporosis, and Mexican Americans were 2.4 times more likely than were blacks to have osteoporosis from 2005 to 2010, the National Center for Health Statistics reported.

So where does leave those who are both women and Mexican American?

First, a little background: The age-adjusted prevalence of osteoporosis measured at either the lumbar spine or femur neck among adults aged 65 years and over was 24.8% for women and 5.6% for men, for an overall prevalence of 16.2%. Adults aged 65-79 years had an unadjusted prevalence of 12.8%, compared with 25.7% for those aged 80 years and over, according to data from the 2005-2010 National Health and Nutrition Examination Survey.

Age-adjusted prevalence over that time period for Mexican Americans aged 65 years and older was 24.9%, compared with 15.7% for non-Hispanic whites and 10.3% for non-Hispanic blacks.

Mexican American women, who find themselves at the intersection of these two trends, had an adjusted osteoporosis rate of 36.8%, the NCHS reported.

Osteoporosis was defined as a bone mineral density value that was more than 2.5 standard deviations below the mean value for young, non-Hispanic white females.

[email protected]

Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.

Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.

Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.

Genitourinary syndrome of menopause (GSM) is the new terminology to describe symptoms occurring secondary to vulvovaginal atrophy.¹ The recent change in terminology originated with a consensus panel comprising the board of directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the board of trustees of the North American Menopause Society (NAMS). At a terminology consensus conference in May 2013, these groups determined that the term GSM is medically more accurate and all encompassing than vulvovaginal atrophy. It is also more publicly acceptable.

The symptoms of GSM derive from the hypoestrogenic state most commonly associated with menopause and its effects on the genitourinary tract.² Vaginal symptoms associated with GSM include vaginal or vulvar dryness, discharge, itching, and dyspareunia.³ Histologically, a loss of superficial epithelial cells in the genitourinary tract leads to thinning of the tissue. There is then a loss of vaginal rugae and elasticity, leading to narrowing and shortening of the vagina.

In addition, the vaginal epithelium becomes much more fragile, which can lead to tears, bleeding, and fissures. There is also a loss of the subcutaneous fat of the labia majora, a change that can result in narrowing of the introitus, fusion of the labia majora, and shrinkage of the clitoral prepuce and urethra. The vaginal pH level becomes more alkaline, which may alter vaginal flora and increase the risk of urogenital infections—specifically, urinary tract infection (UTI). Vaginal secretions, largely transudate, from the vaginal vasculature also decrease over time. These changes lead to significant dyspareunia and impairment of sexual function.

In this article, we survey the therapies available for GSM, focusing first on proven treatments such as local estrogen administration and use of ospemifene (Osphena), and then describing an emerging treatment involving the use of fractional CO₂ laser.

How prevalent is GSM?
Approximately half of all postmenopausal women in the United States report atrophy-related symptoms and a significant negative effect on quality of life.^4–6 Few women with these symptoms seek medical attention.

The Vaginal Health: Insights, Views, and Attitudes (VIVA) survey found that 80% of women with genital atrophy considered its impact on their lives to be negative, 75% reported negative consequences in their sexual life, 68% reported that it made them feel less sexual, 33% reported negative effects on their marriage or relationship, and 26% reported a negative impact on their self-esteem.⁷

Another review of the impact of this condition by Nappi and Palacios estimated that, by the year 2025, there will be 1.1 billion women worldwide older than age 50 with specific needs related to GSM.⁸ Nappi and Palacios cite 4 recent surveys that suggest that health care providers need to be more proactive in helping patients disclose their symptoms. The same can be said of other symptoms of the urinary tract, such as urinary frequency, urgency, and incontinence, as well as pelvic floor relaxation.

A recently published international survey on vaginal atrophy not only depicts the extremely high prevalence of the condition but also describes fairly significant differences in attitudes toward symptoms between countries in Europe and North America.⁹ Overall, 77% of respondents, who included more than 4,000 menopausal women, believed that women were uncomfortable discussing symptoms of vaginal atrophy.⁹

Pastore and colleagues, using data from the Women’s Health Initiative (WHI), found the most prevalent urogenital symptoms to be vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%).⁴ Unlike vasomotor symptoms of menopause, which tend to decrease over time, GSM does not spontaneously remit and commonly recurs when hormone therapy—the dominant treatment—is withdrawn.

What can we offer our patients?
Vaginal estrogen
The most common therapy used to manage GSM is estrogen. Most recommendations state that if the primary menopausal symptoms are related to vaginal atrophy, then local estrogen administration should be the primary mode of therapy. The Society of Gynecologic Surgeons Systematic Review Group recently concluded that all commercially available vaginal estrogens effectively can relieve common vulvovaginal atrophy−related symptoms and have additional utility in women with urinary urgency, frequency, stress incontinence, urge incontinence, and recurrent UTIs.¹⁰ Although their meta-­analysis clearly demonstrated that estrogen therapy improves the symptoms of GSM, investigators acknowledged that a clearer understanding is needed of the exact risk to the endometrium with sustained use of vaginal estrogen, as well as a more precise assessment of changes in serum estradiol levels.¹⁰

A recent Cochrane review concluded that all forms of local estrogen appear to be equally effective for symptoms of vaginal atrophy.¹¹ One trial cited in the review found significant adverse effects following administration of cream, compared with tablets, causing uterine bleeding, breast pain, and perineal pain.¹¹

Another trial cited in the Cochrane review found significant endometrial overstimulation following use of cream, compared with the vaginal ring. As a treatment of choice, women appeared to favor the estradiol-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.¹¹

After the release of the WHI data, the US Food and Drug Administration (FDA) released a “black box” warning on postmenopausal hormone use in women, which has significantly reduced the use of both local and systemic estrogen in eligible women. NAMS has recommended that the FDA revisit this warning, calling specifically for an independent commission to scrutinize every major WHI paper to determine whether the data justify the conclusions drawn.¹²

Most data back local estrogen as treatment for GSM
In 2013, the North American Menopause Society (NAMS) issued a position statement noting that the choice of therapy for genitourinary syndrome of menopause (GSM) depends on the severity of symptoms, the efficacy and safety of therapy for the individual patient, and patient preference.¹

To date, estrogen therapy is the most effective treatment for moderate to severe GSM, although a direct comparison of estrogen and ospemifene is lacking. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestin is not indicated for women without a uterus—and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. Data are insufficient to confirm the safety of local estrogen in women with breast cancer.

Future research on the use of the fractional CO₂ laser, which seems to be a promising emerging therapy, may provide clinicians with another option to treat the common and distressing problem of GSM.

Reference
1. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888–902.

Ospemifene
This estrogen agonist and antagonist selectively stimulates or inhibits estrogen receptors of different target tissues, making it a selective estrogen receptor modulator (SERM). In a study involving 826 postmenopausal women randomly allocated to 30 mg or 60 mg of ospemifene, the 60-mg dose proved to be more effective for improving vulvovaginal atrophy.¹³ Long-term safety studies revealed that ospemifene 60 mg given daily for 52 weeks was well tolerated and not associated with any endometrial- or breast-related safety issues.^13,14 Common adverse effects of ospemifene reported during clinical trials included hot flashes, vaginal discharge, muscle spasms, general discharge, and excessive sweating.¹²

Vaginal lubricants and moisturizers
Nonestrogen water- or silicone-based vaginal lubricants and moisturizers may alleviate vaginal symptoms related to menopause. These products may be particularly helpful for women who do not wish to use hormone therapies.

Vaginal lubricants are intended to relieve friction and dyspareunia related to vaginal dryness during intercourse, with the ultimate goal of trapping moisture and providing long-term relief of vaginal dryness.

Although data are limited on the efficacy of these products, prospective studies have demonstrated that vaginal moisturizers improve vaginal dryness, pH balance, and elasticity and reduce vaginal itching, irritation, and dyspareunia.

Data are insufficient to support the use of herbal remedies or soy products for the treatment of vaginal symptoms.

An emerging therapy: fractional CO₂ laser
In September 2014, the FDA cleared for use the SmartXide² CO₂ laser system (DEKA Medical) for “incision, excision, vaporization and coagulation of body soft tissues” in medical specialties that include gynecology and genitourinary surgery.¹⁵ The system, also marketed by Cynosure as the MonaLisa Touch treatment, was not approved specifically for treatment of GSM—and it is important to note that the path to device clearance by the FDA is much less cumbersome than the route to drug approval. As NAMS notes in an article about the fractional CO₂ laser, “Device clearance does not require the large, double-blind, randomized, placebo-controlled trials with established efficacy and safety endpoints required for the approval of new drugs.”¹⁶ Nevertheless, this laser system appears to be poised to become a new treatment for the symptoms of GSM. 

This laser supplies energy with a specific pulse to the vaginal wall to rapidly and superficially ablate the epithelial component of atrophic mucosa, which is characterized by low water content. Ablation is followed by tissue coagulation, stimulated by laser energy penetrating into deeper tissues, triggering the synthesis of new collagen and other components of the ground substance of the matrix.

The supraphysiologic level of heat generated by the CO₂ laser induces a rapid and transient heat-shock response that temporarily alters cellular metabolism and activates a small family of proteins referred to as the “heat shock proteins” (HSPs). HSP 70, which is overexpressed following laser treatment, stimulates transforming growth­factor‑beta, triggering an inflammatory response that stimulates fibroblasts, which produce new collagen and extracellular matrix.

The laser has emissions characteristics aligned for the transfer of the energy load to the mucosa while avoiding excessive localized damage. This aspect of its design allows for restoration of the permeability of the connective tissue, enabling the physiologic transfer of various nutrients from capillaries to tissues. When there is a loss of estrogen, as during menopause, vaginal atrophy develops, with the epithelium deteriorating and thinning. The fractional CO₂ laser therapy improves the state of the epithelium by restoring epithelial cell trophism.

The vaginal dryness that occurs with atrophy is due to poor blood flow, as well as reduced activity of the fibroblasts in the deeper tissue. The increased lubrication that occurs after treatment is usually a vaginal transudate from blood outflow through the capillaries that supply blood to the vaginal epithelium. The high presence of water molecules increases permeability, allowing easier transport of metabolites and nutrients from capillaries to tissue, as well as the drainage of waste products from tissues to blood and lymph vessels.

With atrophy, the glycogen in the epithelial cells decreases. Because lactobacilli need glycogen to thrive and are responsible for maintaining the acidity of the vagina, the pH level increases. With the restoration of trophism, glycogen levels increase, furthering colonization of vaginal lactobacilli as well as vaginal acidity, reducing the pH level. This effect also may protect against the development of recurrent UTIs.

A look at the data
To date, more than 2,000 women in Italy and more than 10,000 women worldwide with GSM have been treated with fractional CO₂ laser therapy, and several peer-reviewed publications have documented its efficacy and safety.^17–21

In published studies, however, the populations have been small and the investigations have been mostly short term  (12 weeks).^17–21

A pilot study reported that a treatment cycle of 3 laser applications significantly improved the most bothersome symptoms of vulvovaginal atrophy and improved scores of vaginal health at 12 weeks’ follow-up in 50 women who had not responded to or were unsatisfied with local estrogen therapy.¹⁷ This investigation was followed by 2 additional studies involving another 92 women that specifically addressed the impact of fractional CO₂ laser therapy on dyspareunia and female sexual function.^19,20 Both studies showed statistically significant improvement in dyspareunia as well as Female Sexual Function Index (FSFI) scores. All women in these studies were treated in an office setting with no pretreatment anesthesia. No adverse events were reported.

Recently published histology data highlight significant changes 1 month after fractional CO₂ laser treatment that included a much thicker epithelium with wide columns of large epithelial cells rich in glycogen.²¹ Also noted was a significant reorganization of connective tissue, both in the lamina propria and the core of the papillae (FIGURES 1 and 2).

FIGURE 1: Early-stage vaginal atrophy    This histologic preparation of vaginal mucosa sections reveals untreated early-stage vaginal atrophy (A), with thinning epithelium and the presence of papillae, and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

FIGURE 2: Atrophic vaginitis    This histologic preparation of vaginal mucosa sections shows untreated atrophic vaginitis (A) and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

Caveats
No International Classification of Diseases (ICD) 9 or 10 code has been assigned to the procedure to date, and the cost to the patient ranges from $600 to $1,000 per procedure.¹⁶

NAMS position. A review of the technology by NAMS noted the need for large, long-term, randomized, sham-controlled studies “to further evaluate the safety and efficacy of this procedure.”¹⁶

NAMS also notes that “lasers have become a very costly option for the treatment of symptomatic [GSM], without a single trial comparing active laser treatment to sham laser treatment and no information on long-term safety. In all published trials to date, only several hundred women have been studied and most studies are only 12 weeks in duration.”¹⁶

Not a new concept. The concept of treating skin with a microablative CO₂ laser is not new. This laser has been safely used on the skin of the face, neck, and chest to produce new collagen and elastin fibers with remodeling of tissue.^22,23

Preliminary data on the use of a fractionated CO₂ microablative laser to treat symptoms associated with GSM suggest that the therapy is feasible, effective, and safe in the short term. If these findings are confirmed by larger, longer-term, well-controlled studies, this laser will be an additional safe and effective treatment for this very common and distressing disorder.

Fractional CO₂ laser: A study in progress
Two authors (Mickey Karram, MD, and Eric Sokol, MD) are performing a study of the fractional CO₂ laser for treatment of genitourinary syndrome of menopause (GSM) in the United States. To date, 30 women with GSM have been treated with 3 cycles and followed for 3 months. Preliminary data show significant improvement in all symptoms, with all patients treated in an office setting with no pretreatment or posttreatment analgesia required.

The laser settings for treatment included a power of 30 W, a dwell time of 1,000 µs, spacing between 2 adjacent treated spots of 1,000 µs, and a stack parameter for pulses from 1 to 3. 

Laser energy is delivered through a specially designed scanner and a vaginal probe. The probe is slowly inserted to the top of the vaginal canal and then gradually withdrawn, treating the vaginal epithelium at increments of almost 1 cm (FIGURE 3). The laser beam projects onto a 45° mirror placed at the tip of the probe, which reflects it at 90°, thereby ensuring that only the vaginal wall is treated, and not the uterine cervix.

A treatment cycle included 3 laser treatments at 6-week intervals. Each treatment lasted 3 to 5 minutes. Initial improvement was noted in most patients, including increased lubrication within 1 week after the first treatment, with further improvement after each session. To date, the positive results have persisted, and all women in the trial now have been followed for 3 months—all have noted improvement in symptoms. They will continue periodic assessment, with a final subjective and objective evaluation 1 year after their first treatment.

Bottom line
Although preliminary studies of the fractional CO₂ laser as a treatment for GSM are promising, local estrogen is backed by a large body of reliable data. Ospemifene also has FDA approval for treatment of this disorder.

For women who cannot or will not use a hormone-based therapy, vaginal lubricants and moisturizer may offer at least some relief.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Genitourinary syndrome of menopause (GSM) is the new terminology to describe symptoms occurring secondary to vulvovaginal atrophy.¹ The recent change in terminology originated with a consensus panel comprising the board of directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the board of trustees of the North American Menopause Society (NAMS). At a terminology consensus conference in May 2013, these groups determined that the term GSM is medically more accurate and all encompassing than vulvovaginal atrophy. It is also more publicly acceptable.

The symptoms of GSM derive from the hypoestrogenic state most commonly associated with menopause and its effects on the genitourinary tract.² Vaginal symptoms associated with GSM include vaginal or vulvar dryness, discharge, itching, and dyspareunia.³ Histologically, a loss of superficial epithelial cells in the genitourinary tract leads to thinning of the tissue. There is then a loss of vaginal rugae and elasticity, leading to narrowing and shortening of the vagina.

In addition, the vaginal epithelium becomes much more fragile, which can lead to tears, bleeding, and fissures. There is also a loss of the subcutaneous fat of the labia majora, a change that can result in narrowing of the introitus, fusion of the labia majora, and shrinkage of the clitoral prepuce and urethra. The vaginal pH level becomes more alkaline, which may alter vaginal flora and increase the risk of urogenital infections—specifically, urinary tract infection (UTI). Vaginal secretions, largely transudate, from the vaginal vasculature also decrease over time. These changes lead to significant dyspareunia and impairment of sexual function.

In this article, we survey the therapies available for GSM, focusing first on proven treatments such as local estrogen administration and use of ospemifene (Osphena), and then describing an emerging treatment involving the use of fractional CO₂ laser.

How prevalent is GSM?
Approximately half of all postmenopausal women in the United States report atrophy-related symptoms and a significant negative effect on quality of life.^4–6 Few women with these symptoms seek medical attention.

The Vaginal Health: Insights, Views, and Attitudes (VIVA) survey found that 80% of women with genital atrophy considered its impact on their lives to be negative, 75% reported negative consequences in their sexual life, 68% reported that it made them feel less sexual, 33% reported negative effects on their marriage or relationship, and 26% reported a negative impact on their self-esteem.⁷

Another review of the impact of this condition by Nappi and Palacios estimated that, by the year 2025, there will be 1.1 billion women worldwide older than age 50 with specific needs related to GSM.⁸ Nappi and Palacios cite 4 recent surveys that suggest that health care providers need to be more proactive in helping patients disclose their symptoms. The same can be said of other symptoms of the urinary tract, such as urinary frequency, urgency, and incontinence, as well as pelvic floor relaxation.

A recently published international survey on vaginal atrophy not only depicts the extremely high prevalence of the condition but also describes fairly significant differences in attitudes toward symptoms between countries in Europe and North America.⁹ Overall, 77% of respondents, who included more than 4,000 menopausal women, believed that women were uncomfortable discussing symptoms of vaginal atrophy.⁹

Pastore and colleagues, using data from the Women’s Health Initiative (WHI), found the most prevalent urogenital symptoms to be vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%).⁴ Unlike vasomotor symptoms of menopause, which tend to decrease over time, GSM does not spontaneously remit and commonly recurs when hormone therapy—the dominant treatment—is withdrawn.

What can we offer our patients?
Vaginal estrogen
The most common therapy used to manage GSM is estrogen. Most recommendations state that if the primary menopausal symptoms are related to vaginal atrophy, then local estrogen administration should be the primary mode of therapy. The Society of Gynecologic Surgeons Systematic Review Group recently concluded that all commercially available vaginal estrogens effectively can relieve common vulvovaginal atrophy−related symptoms and have additional utility in women with urinary urgency, frequency, stress incontinence, urge incontinence, and recurrent UTIs.¹⁰ Although their meta-­analysis clearly demonstrated that estrogen therapy improves the symptoms of GSM, investigators acknowledged that a clearer understanding is needed of the exact risk to the endometrium with sustained use of vaginal estrogen, as well as a more precise assessment of changes in serum estradiol levels.¹⁰

A recent Cochrane review concluded that all forms of local estrogen appear to be equally effective for symptoms of vaginal atrophy.¹¹ One trial cited in the review found significant adverse effects following administration of cream, compared with tablets, causing uterine bleeding, breast pain, and perineal pain.¹¹

Another trial cited in the Cochrane review found significant endometrial overstimulation following use of cream, compared with the vaginal ring. As a treatment of choice, women appeared to favor the estradiol-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.¹¹

After the release of the WHI data, the US Food and Drug Administration (FDA) released a “black box” warning on postmenopausal hormone use in women, which has significantly reduced the use of both local and systemic estrogen in eligible women. NAMS has recommended that the FDA revisit this warning, calling specifically for an independent commission to scrutinize every major WHI paper to determine whether the data justify the conclusions drawn.¹²

Most data back local estrogen as treatment for GSM
In 2013, the North American Menopause Society (NAMS) issued a position statement noting that the choice of therapy for genitourinary syndrome of menopause (GSM) depends on the severity of symptoms, the efficacy and safety of therapy for the individual patient, and patient preference.¹

To date, estrogen therapy is the most effective treatment for moderate to severe GSM, although a direct comparison of estrogen and ospemifene is lacking. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestin is not indicated for women without a uterus—and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. Data are insufficient to confirm the safety of local estrogen in women with breast cancer.

Future research on the use of the fractional CO₂ laser, which seems to be a promising emerging therapy, may provide clinicians with another option to treat the common and distressing problem of GSM.

Reference
1. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888–902.

Ospemifene
This estrogen agonist and antagonist selectively stimulates or inhibits estrogen receptors of different target tissues, making it a selective estrogen receptor modulator (SERM). In a study involving 826 postmenopausal women randomly allocated to 30 mg or 60 mg of ospemifene, the 60-mg dose proved to be more effective for improving vulvovaginal atrophy.¹³ Long-term safety studies revealed that ospemifene 60 mg given daily for 52 weeks was well tolerated and not associated with any endometrial- or breast-related safety issues.^13,14 Common adverse effects of ospemifene reported during clinical trials included hot flashes, vaginal discharge, muscle spasms, general discharge, and excessive sweating.¹²

Vaginal lubricants and moisturizers
Nonestrogen water- or silicone-based vaginal lubricants and moisturizers may alleviate vaginal symptoms related to menopause. These products may be particularly helpful for women who do not wish to use hormone therapies.

Vaginal lubricants are intended to relieve friction and dyspareunia related to vaginal dryness during intercourse, with the ultimate goal of trapping moisture and providing long-term relief of vaginal dryness.

Although data are limited on the efficacy of these products, prospective studies have demonstrated that vaginal moisturizers improve vaginal dryness, pH balance, and elasticity and reduce vaginal itching, irritation, and dyspareunia.

Data are insufficient to support the use of herbal remedies or soy products for the treatment of vaginal symptoms.

An emerging therapy: fractional CO₂ laser
In September 2014, the FDA cleared for use the SmartXide² CO₂ laser system (DEKA Medical) for “incision, excision, vaporization and coagulation of body soft tissues” in medical specialties that include gynecology and genitourinary surgery.¹⁵ The system, also marketed by Cynosure as the MonaLisa Touch treatment, was not approved specifically for treatment of GSM—and it is important to note that the path to device clearance by the FDA is much less cumbersome than the route to drug approval. As NAMS notes in an article about the fractional CO₂ laser, “Device clearance does not require the large, double-blind, randomized, placebo-controlled trials with established efficacy and safety endpoints required for the approval of new drugs.”¹⁶ Nevertheless, this laser system appears to be poised to become a new treatment for the symptoms of GSM. 

This laser supplies energy with a specific pulse to the vaginal wall to rapidly and superficially ablate the epithelial component of atrophic mucosa, which is characterized by low water content. Ablation is followed by tissue coagulation, stimulated by laser energy penetrating into deeper tissues, triggering the synthesis of new collagen and other components of the ground substance of the matrix.

The supraphysiologic level of heat generated by the CO₂ laser induces a rapid and transient heat-shock response that temporarily alters cellular metabolism and activates a small family of proteins referred to as the “heat shock proteins” (HSPs). HSP 70, which is overexpressed following laser treatment, stimulates transforming growth­factor‑beta, triggering an inflammatory response that stimulates fibroblasts, which produce new collagen and extracellular matrix.

The laser has emissions characteristics aligned for the transfer of the energy load to the mucosa while avoiding excessive localized damage. This aspect of its design allows for restoration of the permeability of the connective tissue, enabling the physiologic transfer of various nutrients from capillaries to tissues. When there is a loss of estrogen, as during menopause, vaginal atrophy develops, with the epithelium deteriorating and thinning. The fractional CO₂ laser therapy improves the state of the epithelium by restoring epithelial cell trophism.

The vaginal dryness that occurs with atrophy is due to poor blood flow, as well as reduced activity of the fibroblasts in the deeper tissue. The increased lubrication that occurs after treatment is usually a vaginal transudate from blood outflow through the capillaries that supply blood to the vaginal epithelium. The high presence of water molecules increases permeability, allowing easier transport of metabolites and nutrients from capillaries to tissue, as well as the drainage of waste products from tissues to blood and lymph vessels.

With atrophy, the glycogen in the epithelial cells decreases. Because lactobacilli need glycogen to thrive and are responsible for maintaining the acidity of the vagina, the pH level increases. With the restoration of trophism, glycogen levels increase, furthering colonization of vaginal lactobacilli as well as vaginal acidity, reducing the pH level. This effect also may protect against the development of recurrent UTIs.

A look at the data
To date, more than 2,000 women in Italy and more than 10,000 women worldwide with GSM have been treated with fractional CO₂ laser therapy, and several peer-reviewed publications have documented its efficacy and safety.^17–21

In published studies, however, the populations have been small and the investigations have been mostly short term  (12 weeks).^17–21

A pilot study reported that a treatment cycle of 3 laser applications significantly improved the most bothersome symptoms of vulvovaginal atrophy and improved scores of vaginal health at 12 weeks’ follow-up in 50 women who had not responded to or were unsatisfied with local estrogen therapy.¹⁷ This investigation was followed by 2 additional studies involving another 92 women that specifically addressed the impact of fractional CO₂ laser therapy on dyspareunia and female sexual function.^19,20 Both studies showed statistically significant improvement in dyspareunia as well as Female Sexual Function Index (FSFI) scores. All women in these studies were treated in an office setting with no pretreatment anesthesia. No adverse events were reported.

Recently published histology data highlight significant changes 1 month after fractional CO₂ laser treatment that included a much thicker epithelium with wide columns of large epithelial cells rich in glycogen.²¹ Also noted was a significant reorganization of connective tissue, both in the lamina propria and the core of the papillae (FIGURES 1 and 2).

FIGURE 1: Early-stage vaginal atrophy    This histologic preparation of vaginal mucosa sections reveals untreated early-stage vaginal atrophy (A), with thinning epithelium and the presence of papillae, and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

FIGURE 2: Atrophic vaginitis    This histologic preparation of vaginal mucosa sections shows untreated atrophic vaginitis (A) and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

Caveats
No International Classification of Diseases (ICD) 9 or 10 code has been assigned to the procedure to date, and the cost to the patient ranges from $600 to $1,000 per procedure.¹⁶

NAMS position. A review of the technology by NAMS noted the need for large, long-term, randomized, sham-controlled studies “to further evaluate the safety and efficacy of this procedure.”¹⁶

NAMS also notes that “lasers have become a very costly option for the treatment of symptomatic [GSM], without a single trial comparing active laser treatment to sham laser treatment and no information on long-term safety. In all published trials to date, only several hundred women have been studied and most studies are only 12 weeks in duration.”¹⁶

Not a new concept. The concept of treating skin with a microablative CO₂ laser is not new. This laser has been safely used on the skin of the face, neck, and chest to produce new collagen and elastin fibers with remodeling of tissue.^22,23

Preliminary data on the use of a fractionated CO₂ microablative laser to treat symptoms associated with GSM suggest that the therapy is feasible, effective, and safe in the short term. If these findings are confirmed by larger, longer-term, well-controlled studies, this laser will be an additional safe and effective treatment for this very common and distressing disorder.

Fractional CO₂ laser: A study in progress
Two authors (Mickey Karram, MD, and Eric Sokol, MD) are performing a study of the fractional CO₂ laser for treatment of genitourinary syndrome of menopause (GSM) in the United States. To date, 30 women with GSM have been treated with 3 cycles and followed for 3 months. Preliminary data show significant improvement in all symptoms, with all patients treated in an office setting with no pretreatment or posttreatment analgesia required.

The laser settings for treatment included a power of 30 W, a dwell time of 1,000 µs, spacing between 2 adjacent treated spots of 1,000 µs, and a stack parameter for pulses from 1 to 3. 

Laser energy is delivered through a specially designed scanner and a vaginal probe. The probe is slowly inserted to the top of the vaginal canal and then gradually withdrawn, treating the vaginal epithelium at increments of almost 1 cm (FIGURE 3). The laser beam projects onto a 45° mirror placed at the tip of the probe, which reflects it at 90°, thereby ensuring that only the vaginal wall is treated, and not the uterine cervix.

A treatment cycle included 3 laser treatments at 6-week intervals. Each treatment lasted 3 to 5 minutes. Initial improvement was noted in most patients, including increased lubrication within 1 week after the first treatment, with further improvement after each session. To date, the positive results have persisted, and all women in the trial now have been followed for 3 months—all have noted improvement in symptoms. They will continue periodic assessment, with a final subjective and objective evaluation 1 year after their first treatment.

Bottom line
Although preliminary studies of the fractional CO₂ laser as a treatment for GSM are promising, local estrogen is backed by a large body of reliable data. Ospemifene also has FDA approval for treatment of this disorder.

For women who cannot or will not use a hormone-based therapy, vaginal lubricants and moisturizer may offer at least some relief.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Genitourinary syndrome of menopause (GSM) is the new terminology to describe symptoms occurring secondary to vulvovaginal atrophy.¹ The recent change in terminology originated with a consensus panel comprising the board of directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the board of trustees of the North American Menopause Society (NAMS). At a terminology consensus conference in May 2013, these groups determined that the term GSM is medically more accurate and all encompassing than vulvovaginal atrophy. It is also more publicly acceptable.

The symptoms of GSM derive from the hypoestrogenic state most commonly associated with menopause and its effects on the genitourinary tract.² Vaginal symptoms associated with GSM include vaginal or vulvar dryness, discharge, itching, and dyspareunia.³ Histologically, a loss of superficial epithelial cells in the genitourinary tract leads to thinning of the tissue. There is then a loss of vaginal rugae and elasticity, leading to narrowing and shortening of the vagina.

In addition, the vaginal epithelium becomes much more fragile, which can lead to tears, bleeding, and fissures. There is also a loss of the subcutaneous fat of the labia majora, a change that can result in narrowing of the introitus, fusion of the labia majora, and shrinkage of the clitoral prepuce and urethra. The vaginal pH level becomes more alkaline, which may alter vaginal flora and increase the risk of urogenital infections—specifically, urinary tract infection (UTI). Vaginal secretions, largely transudate, from the vaginal vasculature also decrease over time. These changes lead to significant dyspareunia and impairment of sexual function.

In this article, we survey the therapies available for GSM, focusing first on proven treatments such as local estrogen administration and use of ospemifene (Osphena), and then describing an emerging treatment involving the use of fractional CO₂ laser.

How prevalent is GSM?
Approximately half of all postmenopausal women in the United States report atrophy-related symptoms and a significant negative effect on quality of life.^4–6 Few women with these symptoms seek medical attention.

The Vaginal Health: Insights, Views, and Attitudes (VIVA) survey found that 80% of women with genital atrophy considered its impact on their lives to be negative, 75% reported negative consequences in their sexual life, 68% reported that it made them feel less sexual, 33% reported negative effects on their marriage or relationship, and 26% reported a negative impact on their self-esteem.⁷

Another review of the impact of this condition by Nappi and Palacios estimated that, by the year 2025, there will be 1.1 billion women worldwide older than age 50 with specific needs related to GSM.⁸ Nappi and Palacios cite 4 recent surveys that suggest that health care providers need to be more proactive in helping patients disclose their symptoms. The same can be said of other symptoms of the urinary tract, such as urinary frequency, urgency, and incontinence, as well as pelvic floor relaxation.

A recently published international survey on vaginal atrophy not only depicts the extremely high prevalence of the condition but also describes fairly significant differences in attitudes toward symptoms between countries in Europe and North America.⁹ Overall, 77% of respondents, who included more than 4,000 menopausal women, believed that women were uncomfortable discussing symptoms of vaginal atrophy.⁹

Pastore and colleagues, using data from the Women’s Health Initiative (WHI), found the most prevalent urogenital symptoms to be vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%).⁴ Unlike vasomotor symptoms of menopause, which tend to decrease over time, GSM does not spontaneously remit and commonly recurs when hormone therapy—the dominant treatment—is withdrawn.

What can we offer our patients?
Vaginal estrogen
The most common therapy used to manage GSM is estrogen. Most recommendations state that if the primary menopausal symptoms are related to vaginal atrophy, then local estrogen administration should be the primary mode of therapy. The Society of Gynecologic Surgeons Systematic Review Group recently concluded that all commercially available vaginal estrogens effectively can relieve common vulvovaginal atrophy−related symptoms and have additional utility in women with urinary urgency, frequency, stress incontinence, urge incontinence, and recurrent UTIs.¹⁰ Although their meta-­analysis clearly demonstrated that estrogen therapy improves the symptoms of GSM, investigators acknowledged that a clearer understanding is needed of the exact risk to the endometrium with sustained use of vaginal estrogen, as well as a more precise assessment of changes in serum estradiol levels.¹⁰

A recent Cochrane review concluded that all forms of local estrogen appear to be equally effective for symptoms of vaginal atrophy.¹¹ One trial cited in the review found significant adverse effects following administration of cream, compared with tablets, causing uterine bleeding, breast pain, and perineal pain.¹¹

Another trial cited in the Cochrane review found significant endometrial overstimulation following use of cream, compared with the vaginal ring. As a treatment of choice, women appeared to favor the estradiol-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.¹¹

After the release of the WHI data, the US Food and Drug Administration (FDA) released a “black box” warning on postmenopausal hormone use in women, which has significantly reduced the use of both local and systemic estrogen in eligible women. NAMS has recommended that the FDA revisit this warning, calling specifically for an independent commission to scrutinize every major WHI paper to determine whether the data justify the conclusions drawn.¹²

Most data back local estrogen as treatment for GSM
In 2013, the North American Menopause Society (NAMS) issued a position statement noting that the choice of therapy for genitourinary syndrome of menopause (GSM) depends on the severity of symptoms, the efficacy and safety of therapy for the individual patient, and patient preference.¹

To date, estrogen therapy is the most effective treatment for moderate to severe GSM, although a direct comparison of estrogen and ospemifene is lacking. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestin is not indicated for women without a uterus—and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. Data are insufficient to confirm the safety of local estrogen in women with breast cancer.

Future research on the use of the fractional CO₂ laser, which seems to be a promising emerging therapy, may provide clinicians with another option to treat the common and distressing problem of GSM.

Reference
1. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888–902.

Ospemifene
This estrogen agonist and antagonist selectively stimulates or inhibits estrogen receptors of different target tissues, making it a selective estrogen receptor modulator (SERM). In a study involving 826 postmenopausal women randomly allocated to 30 mg or 60 mg of ospemifene, the 60-mg dose proved to be more effective for improving vulvovaginal atrophy.¹³ Long-term safety studies revealed that ospemifene 60 mg given daily for 52 weeks was well tolerated and not associated with any endometrial- or breast-related safety issues.^13,14 Common adverse effects of ospemifene reported during clinical trials included hot flashes, vaginal discharge, muscle spasms, general discharge, and excessive sweating.¹²

Vaginal lubricants and moisturizers
Nonestrogen water- or silicone-based vaginal lubricants and moisturizers may alleviate vaginal symptoms related to menopause. These products may be particularly helpful for women who do not wish to use hormone therapies.

Vaginal lubricants are intended to relieve friction and dyspareunia related to vaginal dryness during intercourse, with the ultimate goal of trapping moisture and providing long-term relief of vaginal dryness.

Although data are limited on the efficacy of these products, prospective studies have demonstrated that vaginal moisturizers improve vaginal dryness, pH balance, and elasticity and reduce vaginal itching, irritation, and dyspareunia.

Data are insufficient to support the use of herbal remedies or soy products for the treatment of vaginal symptoms.

An emerging therapy: fractional CO₂ laser
In September 2014, the FDA cleared for use the SmartXide² CO₂ laser system (DEKA Medical) for “incision, excision, vaporization and coagulation of body soft tissues” in medical specialties that include gynecology and genitourinary surgery.¹⁵ The system, also marketed by Cynosure as the MonaLisa Touch treatment, was not approved specifically for treatment of GSM—and it is important to note that the path to device clearance by the FDA is much less cumbersome than the route to drug approval. As NAMS notes in an article about the fractional CO₂ laser, “Device clearance does not require the large, double-blind, randomized, placebo-controlled trials with established efficacy and safety endpoints required for the approval of new drugs.”¹⁶ Nevertheless, this laser system appears to be poised to become a new treatment for the symptoms of GSM. 

This laser supplies energy with a specific pulse to the vaginal wall to rapidly and superficially ablate the epithelial component of atrophic mucosa, which is characterized by low water content. Ablation is followed by tissue coagulation, stimulated by laser energy penetrating into deeper tissues, triggering the synthesis of new collagen and other components of the ground substance of the matrix.

The supraphysiologic level of heat generated by the CO₂ laser induces a rapid and transient heat-shock response that temporarily alters cellular metabolism and activates a small family of proteins referred to as the “heat shock proteins” (HSPs). HSP 70, which is overexpressed following laser treatment, stimulates transforming growth­factor‑beta, triggering an inflammatory response that stimulates fibroblasts, which produce new collagen and extracellular matrix.

The laser has emissions characteristics aligned for the transfer of the energy load to the mucosa while avoiding excessive localized damage. This aspect of its design allows for restoration of the permeability of the connective tissue, enabling the physiologic transfer of various nutrients from capillaries to tissues. When there is a loss of estrogen, as during menopause, vaginal atrophy develops, with the epithelium deteriorating and thinning. The fractional CO₂ laser therapy improves the state of the epithelium by restoring epithelial cell trophism.

The vaginal dryness that occurs with atrophy is due to poor blood flow, as well as reduced activity of the fibroblasts in the deeper tissue. The increased lubrication that occurs after treatment is usually a vaginal transudate from blood outflow through the capillaries that supply blood to the vaginal epithelium. The high presence of water molecules increases permeability, allowing easier transport of metabolites and nutrients from capillaries to tissue, as well as the drainage of waste products from tissues to blood and lymph vessels.

With atrophy, the glycogen in the epithelial cells decreases. Because lactobacilli need glycogen to thrive and are responsible for maintaining the acidity of the vagina, the pH level increases. With the restoration of trophism, glycogen levels increase, furthering colonization of vaginal lactobacilli as well as vaginal acidity, reducing the pH level. This effect also may protect against the development of recurrent UTIs.

A look at the data
To date, more than 2,000 women in Italy and more than 10,000 women worldwide with GSM have been treated with fractional CO₂ laser therapy, and several peer-reviewed publications have documented its efficacy and safety.^17–21

In published studies, however, the populations have been small and the investigations have been mostly short term  (12 weeks).^17–21

A pilot study reported that a treatment cycle of 3 laser applications significantly improved the most bothersome symptoms of vulvovaginal atrophy and improved scores of vaginal health at 12 weeks’ follow-up in 50 women who had not responded to or were unsatisfied with local estrogen therapy.¹⁷ This investigation was followed by 2 additional studies involving another 92 women that specifically addressed the impact of fractional CO₂ laser therapy on dyspareunia and female sexual function.^19,20 Both studies showed statistically significant improvement in dyspareunia as well as Female Sexual Function Index (FSFI) scores. All women in these studies were treated in an office setting with no pretreatment anesthesia. No adverse events were reported.

Recently published histology data highlight significant changes 1 month after fractional CO₂ laser treatment that included a much thicker epithelium with wide columns of large epithelial cells rich in glycogen.²¹ Also noted was a significant reorganization of connective tissue, both in the lamina propria and the core of the papillae (FIGURES 1 and 2).

FIGURE 1: Early-stage vaginal atrophy    This histologic preparation of vaginal mucosa sections reveals untreated early-stage vaginal atrophy (A), with thinning epithelium and the presence of papillae, and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

FIGURE 2: Atrophic vaginitis    This histologic preparation of vaginal mucosa sections shows untreated atrophic vaginitis (A) and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

Caveats
No International Classification of Diseases (ICD) 9 or 10 code has been assigned to the procedure to date, and the cost to the patient ranges from $600 to $1,000 per procedure.¹⁶

NAMS position. A review of the technology by NAMS noted the need for large, long-term, randomized, sham-controlled studies “to further evaluate the safety and efficacy of this procedure.”¹⁶

NAMS also notes that “lasers have become a very costly option for the treatment of symptomatic [GSM], without a single trial comparing active laser treatment to sham laser treatment and no information on long-term safety. In all published trials to date, only several hundred women have been studied and most studies are only 12 weeks in duration.”¹⁶

Not a new concept. The concept of treating skin with a microablative CO₂ laser is not new. This laser has been safely used on the skin of the face, neck, and chest to produce new collagen and elastin fibers with remodeling of tissue.^22,23

Preliminary data on the use of a fractionated CO₂ microablative laser to treat symptoms associated with GSM suggest that the therapy is feasible, effective, and safe in the short term. If these findings are confirmed by larger, longer-term, well-controlled studies, this laser will be an additional safe and effective treatment for this very common and distressing disorder.

Fractional CO₂ laser: A study in progress
Two authors (Mickey Karram, MD, and Eric Sokol, MD) are performing a study of the fractional CO₂ laser for treatment of genitourinary syndrome of menopause (GSM) in the United States. To date, 30 women with GSM have been treated with 3 cycles and followed for 3 months. Preliminary data show significant improvement in all symptoms, with all patients treated in an office setting with no pretreatment or posttreatment analgesia required.

The laser settings for treatment included a power of 30 W, a dwell time of 1,000 µs, spacing between 2 adjacent treated spots of 1,000 µs, and a stack parameter for pulses from 1 to 3. 

Laser energy is delivered through a specially designed scanner and a vaginal probe. The probe is slowly inserted to the top of the vaginal canal and then gradually withdrawn, treating the vaginal epithelium at increments of almost 1 cm (FIGURE 3). The laser beam projects onto a 45° mirror placed at the tip of the probe, which reflects it at 90°, thereby ensuring that only the vaginal wall is treated, and not the uterine cervix.

A treatment cycle included 3 laser treatments at 6-week intervals. Each treatment lasted 3 to 5 minutes. Initial improvement was noted in most patients, including increased lubrication within 1 week after the first treatment, with further improvement after each session. To date, the positive results have persisted, and all women in the trial now have been followed for 3 months—all have noted improvement in symptoms. They will continue periodic assessment, with a final subjective and objective evaluation 1 year after their first treatment.

Bottom line
Although preliminary studies of the fractional CO₂ laser as a treatment for GSM are promising, local estrogen is backed by a large body of reliable data. Ospemifene also has FDA approval for treatment of this disorder.

For women who cannot or will not use a hormone-based therapy, vaginal lubricants and moisturizer may offer at least some relief.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Case: Disabling vasomotor symptoms in a BRCA1 mutation carrier
Christine is a 39-year-old mother of 2 who underwent risk-reducing, minimally invasive bilateral salpingo-oophorectomy with hysterectomy 4 months ago for a BRCA1 mutation (with benign findings on pathology). Eighteen months before that surgery, she had risk-reducing bilateral mastectomy with reconstruction (implants) and was advised by her surgeon that she no longer needs breast imaging.

Today she reports disabling hot flashes, insomnia, vaginal dryness, and painful sex. Her previous ObGyn, who performed the hysterectomy, was unwilling to prescribe hormone therapy (HT) due to safety concerns. Christine tried venlafaxine at 37 to 75 mg but noted little relief of her vasomotor symptoms.

In discussing her symptoms with you during this initial visit, Christine, a practicing accountant, also reveals that she does not feel as intellectually “sharp” as she did before her gynecologic surgery.

What can you offer for relief of her symptoms?

More BRCA mutation carriers are being identified and choosing to undergo risk-reducing salpingo-oophorectomy and bilateral mastectomy. Accordingly, clinicians are likely to face more questions about the use of systemic HT in this population. Because mutation carriers may worry about the safety of HT, given their BRCA status, some may delay or avoid salpingo-oophorectomy—a surgery that not only reduces the risk of ovarian, fallopian tube, and peritoneal cancer by 80% but also decreases the risk of breast cancer by 48%.¹

Surgically menopausal women in their 30s or 40s who are not treated with HT appear to have an elevated risk for dementia and Parkinsonism.² In addition, vasomotor symptoms are often more severe, and the risks for osteoporosis and, likely, cardiovascular disease are elevated in women with early menopause who are not treated with HT. For these reasons, systemic HT is recommended for women with early menopause, and generally should be continued at least until the normal age of menopause unless specific contraindications are present.³

Because Christine not only has had risk-reducing gynecologic surgery but also risk-reducing bilateral mastectomy, her current risk for breast cancer is very low whether or not she uses HT. Because she does not have a uterus, her symptoms can effectively and safely be treated with systemic estrogen-only therapy.

Among clinicians with special expertise in the management of BRCA mutation carriers, the use of systemic HT would be considered appropriate—and not controversial—in this setting.⁴

Angelina Jolie details her surgeries
In March 2015, 39-year-old Oscar-winning actress and filmmaker Angelina Jolie Pitt published an opinion piece in the New York Times detailing her recent laparoscopic salpingo-oophorectomy and initiation of HT.⁵ Ms. Jolie Pitt, who carries the BRCA1 mutation, lost her mother, grandmother, and aunt to hereditary breast/ovarian cancer. Two years earlier, Ms. Jolie Pitt made news by describing her decision to move ahead with risk-reducing bilateral mastectomy.

Following her risk-reducing salpingo-oophorectomy, she initiated systemic HT using transdermal estradiol and off-label use of a levonorgestrel-releasing intrauterine system for endometrial protection.

Her courageous decision to publicly describe her surgery and subsequent initiation of systemic HT will likely encourage women with ominous family histories to seek out genetic counseling and testing. Her decision to “go public” regarding surgery should help mutation carriers without a history of cancer (known in the BRCA community as “previvors”) who have completed their families to move forward with risk-reducing gynecologic surgery and, when appropriate, use of systemic HT.⁶

The outlook for previvors with intact breasts
Three studies address the risk of breast cancer with use of systemic HT among previvors with intact breasts. A 2005 study followed a cohort of BRCA1 and BRCA2 carriers with intact breasts, 155 of whom had undergone risk-reducing salpingo-oophorectomy, for a mean of 3.6 years. Of these women, 60% and 7%, respectively, of those who had and had not undergone salpingo-oophorectomy used HT. The authors noted that bilateral salpingo-oophorectomy reduced the risk of breast cancer by some 60%, whether or not women used HT.⁷

A 2008 case-control study focused on 472 menopausal BRCA1 carriers, half of whom had been diagnosed with breast cancer (cases); the other half had not received this diagnosis (controls). A 43% reduction in the risk of breast cancer was associated with prior use of HT.⁸

A 2011 presentation described a cohort study in which 1,299 BRCA1 and BRCA2 carriers with intact breasts who had undergone salpingo-oophorectomy were followed for a mean of 5.4 years postoperatively. In this population, use of HT was not associated with an increased risk of breast cancer. Among women with BRCA1 mutations, use of systemic HT was associated with a reduced risk of breast cancer.⁹

Viewed in aggregate, these studies reassure us that short-term use of systemic HT does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations and intact breasts.

Dr. Simon
Nevertheless, I think it is important to point out that a properly powered study to assess actual risk in this setting is not available in the literature.

When a patient refuses HT
Dr. Pinkerton
Some BRCA mutation carriers may refuse HT despite reassurance that it is safe. Nonhormonal therapies are not as effective at relieving severe menopausal symptoms. Almost all selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be offered, although only low-dose paroxetine salt is approved for treatment of postmenopausal hot flashes.^10,11 Gabapentin also has shown efficacy in relieving hot flashes.

For genitourinary syndrome of menopause (GSM; formerly known as vulvovaginal atrophy), lubricants and moisturizers may provide some benefit, but they don’t improve the vaginal superficial cells and, therefore, are not as effective as hormonal options. There is now a selective estrogen receptor modulator (SERM) approved to treat GSM—ospemifene. However, in clinical trials, ospemifene has been shown to increase hot flashes, so it would not be a good option for our patient.¹²

Case: Continued
Christine follows up 3 months after initiating estrogen therapy (oral estradiol 2 mg daily). She reports significant improvement in her hot flashes, with improved sleep and fewer sleep disruptions. In addition, she feels that her “mental sharpness” has returned.

Dr. Pinkerton
What if this patient had an intact uterus? Then she would not be a candidate for estrogen-only therapy because she would need continued endometrial protection. Options then would include low-dose continuous or cyclic progestogen therapy, often starting with micronized progesterone, as the E3N Study suggested it has a less negative effect on the uterus.¹³ Or she could use a levonorgestrel-releasing intrauterine system off label, as Ms. Jolie Pitt elected to do.

Another option would be combining estrogen with a SERM. The only estrogen/SERM combination currently approved by the US Food and Drug Administration (FDA) is conjugated estrogen/bazedoxefine, which showed no increase in breast tenderness, breast density, or bleeding rates, compared with placebo, in multiple trials up to 5 years in duration.¹⁴

Case: Resolved
Christine says she would like to continue HT, although she still experiences dryness and discomfort when sexually active with her husband, despite use of a vaginal lubricant. A pelvic examination is consistent with early changes of GSM.¹⁵

You discuss GSM with Christine and suggest that she consider 1 of 2 strategies:

Christine chooses Option 2. When she returns 6 months later for her well-woman visit, she reports that all of her menopausal symptoms have resolved, and a pelvic examination no longer reveals changes of GSM.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Case: Disabling vasomotor symptoms in a BRCA1 mutation carrier
Christine is a 39-year-old mother of 2 who underwent risk-reducing, minimally invasive bilateral salpingo-oophorectomy with hysterectomy 4 months ago for a BRCA1 mutation (with benign findings on pathology). Eighteen months before that surgery, she had risk-reducing bilateral mastectomy with reconstruction (implants) and was advised by her surgeon that she no longer needs breast imaging.

Today she reports disabling hot flashes, insomnia, vaginal dryness, and painful sex. Her previous ObGyn, who performed the hysterectomy, was unwilling to prescribe hormone therapy (HT) due to safety concerns. Christine tried venlafaxine at 37 to 75 mg but noted little relief of her vasomotor symptoms.

In discussing her symptoms with you during this initial visit, Christine, a practicing accountant, also reveals that she does not feel as intellectually “sharp” as she did before her gynecologic surgery.

What can you offer for relief of her symptoms?

More BRCA mutation carriers are being identified and choosing to undergo risk-reducing salpingo-oophorectomy and bilateral mastectomy. Accordingly, clinicians are likely to face more questions about the use of systemic HT in this population. Because mutation carriers may worry about the safety of HT, given their BRCA status, some may delay or avoid salpingo-oophorectomy—a surgery that not only reduces the risk of ovarian, fallopian tube, and peritoneal cancer by 80% but also decreases the risk of breast cancer by 48%.¹

Surgically menopausal women in their 30s or 40s who are not treated with HT appear to have an elevated risk for dementia and Parkinsonism.² In addition, vasomotor symptoms are often more severe, and the risks for osteoporosis and, likely, cardiovascular disease are elevated in women with early menopause who are not treated with HT. For these reasons, systemic HT is recommended for women with early menopause, and generally should be continued at least until the normal age of menopause unless specific contraindications are present.³

Because Christine not only has had risk-reducing gynecologic surgery but also risk-reducing bilateral mastectomy, her current risk for breast cancer is very low whether or not she uses HT. Because she does not have a uterus, her symptoms can effectively and safely be treated with systemic estrogen-only therapy.

Among clinicians with special expertise in the management of BRCA mutation carriers, the use of systemic HT would be considered appropriate—and not controversial—in this setting.⁴

Angelina Jolie details her surgeries
In March 2015, 39-year-old Oscar-winning actress and filmmaker Angelina Jolie Pitt published an opinion piece in the New York Times detailing her recent laparoscopic salpingo-oophorectomy and initiation of HT.⁵ Ms. Jolie Pitt, who carries the BRCA1 mutation, lost her mother, grandmother, and aunt to hereditary breast/ovarian cancer. Two years earlier, Ms. Jolie Pitt made news by describing her decision to move ahead with risk-reducing bilateral mastectomy.

Following her risk-reducing salpingo-oophorectomy, she initiated systemic HT using transdermal estradiol and off-label use of a levonorgestrel-releasing intrauterine system for endometrial protection.

Her courageous decision to publicly describe her surgery and subsequent initiation of systemic HT will likely encourage women with ominous family histories to seek out genetic counseling and testing. Her decision to “go public” regarding surgery should help mutation carriers without a history of cancer (known in the BRCA community as “previvors”) who have completed their families to move forward with risk-reducing gynecologic surgery and, when appropriate, use of systemic HT.⁶

The outlook for previvors with intact breasts
Three studies address the risk of breast cancer with use of systemic HT among previvors with intact breasts. A 2005 study followed a cohort of BRCA1 and BRCA2 carriers with intact breasts, 155 of whom had undergone risk-reducing salpingo-oophorectomy, for a mean of 3.6 years. Of these women, 60% and 7%, respectively, of those who had and had not undergone salpingo-oophorectomy used HT. The authors noted that bilateral salpingo-oophorectomy reduced the risk of breast cancer by some 60%, whether or not women used HT.⁷

A 2008 case-control study focused on 472 menopausal BRCA1 carriers, half of whom had been diagnosed with breast cancer (cases); the other half had not received this diagnosis (controls). A 43% reduction in the risk of breast cancer was associated with prior use of HT.⁸

A 2011 presentation described a cohort study in which 1,299 BRCA1 and BRCA2 carriers with intact breasts who had undergone salpingo-oophorectomy were followed for a mean of 5.4 years postoperatively. In this population, use of HT was not associated with an increased risk of breast cancer. Among women with BRCA1 mutations, use of systemic HT was associated with a reduced risk of breast cancer.⁹

Viewed in aggregate, these studies reassure us that short-term use of systemic HT does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations and intact breasts.

Dr. Simon
Nevertheless, I think it is important to point out that a properly powered study to assess actual risk in this setting is not available in the literature.

When a patient refuses HT
Dr. Pinkerton
Some BRCA mutation carriers may refuse HT despite reassurance that it is safe. Nonhormonal therapies are not as effective at relieving severe menopausal symptoms. Almost all selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be offered, although only low-dose paroxetine salt is approved for treatment of postmenopausal hot flashes.^10,11 Gabapentin also has shown efficacy in relieving hot flashes.

For genitourinary syndrome of menopause (GSM; formerly known as vulvovaginal atrophy), lubricants and moisturizers may provide some benefit, but they don’t improve the vaginal superficial cells and, therefore, are not as effective as hormonal options. There is now a selective estrogen receptor modulator (SERM) approved to treat GSM—ospemifene. However, in clinical trials, ospemifene has been shown to increase hot flashes, so it would not be a good option for our patient.¹²

Case: Continued
Christine follows up 3 months after initiating estrogen therapy (oral estradiol 2 mg daily). She reports significant improvement in her hot flashes, with improved sleep and fewer sleep disruptions. In addition, she feels that her “mental sharpness” has returned.

Dr. Pinkerton
What if this patient had an intact uterus? Then she would not be a candidate for estrogen-only therapy because she would need continued endometrial protection. Options then would include low-dose continuous or cyclic progestogen therapy, often starting with micronized progesterone, as the E3N Study suggested it has a less negative effect on the uterus.¹³ Or she could use a levonorgestrel-releasing intrauterine system off label, as Ms. Jolie Pitt elected to do.

Another option would be combining estrogen with a SERM. The only estrogen/SERM combination currently approved by the US Food and Drug Administration (FDA) is conjugated estrogen/bazedoxefine, which showed no increase in breast tenderness, breast density, or bleeding rates, compared with placebo, in multiple trials up to 5 years in duration.¹⁴

Case: Resolved
Christine says she would like to continue HT, although she still experiences dryness and discomfort when sexually active with her husband, despite use of a vaginal lubricant. A pelvic examination is consistent with early changes of GSM.¹⁵

You discuss GSM with Christine and suggest that she consider 1 of 2 strategies:

Christine chooses Option 2. When she returns 6 months later for her well-woman visit, she reports that all of her menopausal symptoms have resolved, and a pelvic examination no longer reveals changes of GSM.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Case: Disabling vasomotor symptoms in a BRCA1 mutation carrier
Christine is a 39-year-old mother of 2 who underwent risk-reducing, minimally invasive bilateral salpingo-oophorectomy with hysterectomy 4 months ago for a BRCA1 mutation (with benign findings on pathology). Eighteen months before that surgery, she had risk-reducing bilateral mastectomy with reconstruction (implants) and was advised by her surgeon that she no longer needs breast imaging.

Today she reports disabling hot flashes, insomnia, vaginal dryness, and painful sex. Her previous ObGyn, who performed the hysterectomy, was unwilling to prescribe hormone therapy (HT) due to safety concerns. Christine tried venlafaxine at 37 to 75 mg but noted little relief of her vasomotor symptoms.

In discussing her symptoms with you during this initial visit, Christine, a practicing accountant, also reveals that she does not feel as intellectually “sharp” as she did before her gynecologic surgery.

What can you offer for relief of her symptoms?

More BRCA mutation carriers are being identified and choosing to undergo risk-reducing salpingo-oophorectomy and bilateral mastectomy. Accordingly, clinicians are likely to face more questions about the use of systemic HT in this population. Because mutation carriers may worry about the safety of HT, given their BRCA status, some may delay or avoid salpingo-oophorectomy—a surgery that not only reduces the risk of ovarian, fallopian tube, and peritoneal cancer by 80% but also decreases the risk of breast cancer by 48%.¹

Surgically menopausal women in their 30s or 40s who are not treated with HT appear to have an elevated risk for dementia and Parkinsonism.² In addition, vasomotor symptoms are often more severe, and the risks for osteoporosis and, likely, cardiovascular disease are elevated in women with early menopause who are not treated with HT. For these reasons, systemic HT is recommended for women with early menopause, and generally should be continued at least until the normal age of menopause unless specific contraindications are present.³

Because Christine not only has had risk-reducing gynecologic surgery but also risk-reducing bilateral mastectomy, her current risk for breast cancer is very low whether or not she uses HT. Because she does not have a uterus, her symptoms can effectively and safely be treated with systemic estrogen-only therapy.

Among clinicians with special expertise in the management of BRCA mutation carriers, the use of systemic HT would be considered appropriate—and not controversial—in this setting.⁴

Angelina Jolie details her surgeries
In March 2015, 39-year-old Oscar-winning actress and filmmaker Angelina Jolie Pitt published an opinion piece in the New York Times detailing her recent laparoscopic salpingo-oophorectomy and initiation of HT.⁵ Ms. Jolie Pitt, who carries the BRCA1 mutation, lost her mother, grandmother, and aunt to hereditary breast/ovarian cancer. Two years earlier, Ms. Jolie Pitt made news by describing her decision to move ahead with risk-reducing bilateral mastectomy.

Following her risk-reducing salpingo-oophorectomy, she initiated systemic HT using transdermal estradiol and off-label use of a levonorgestrel-releasing intrauterine system for endometrial protection.

Her courageous decision to publicly describe her surgery and subsequent initiation of systemic HT will likely encourage women with ominous family histories to seek out genetic counseling and testing. Her decision to “go public” regarding surgery should help mutation carriers without a history of cancer (known in the BRCA community as “previvors”) who have completed their families to move forward with risk-reducing gynecologic surgery and, when appropriate, use of systemic HT.⁶

The outlook for previvors with intact breasts
Three studies address the risk of breast cancer with use of systemic HT among previvors with intact breasts. A 2005 study followed a cohort of BRCA1 and BRCA2 carriers with intact breasts, 155 of whom had undergone risk-reducing salpingo-oophorectomy, for a mean of 3.6 years. Of these women, 60% and 7%, respectively, of those who had and had not undergone salpingo-oophorectomy used HT. The authors noted that bilateral salpingo-oophorectomy reduced the risk of breast cancer by some 60%, whether or not women used HT.⁷

A 2008 case-control study focused on 472 menopausal BRCA1 carriers, half of whom had been diagnosed with breast cancer (cases); the other half had not received this diagnosis (controls). A 43% reduction in the risk of breast cancer was associated with prior use of HT.⁸

A 2011 presentation described a cohort study in which 1,299 BRCA1 and BRCA2 carriers with intact breasts who had undergone salpingo-oophorectomy were followed for a mean of 5.4 years postoperatively. In this population, use of HT was not associated with an increased risk of breast cancer. Among women with BRCA1 mutations, use of systemic HT was associated with a reduced risk of breast cancer.⁹

Viewed in aggregate, these studies reassure us that short-term use of systemic HT does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations and intact breasts.

Dr. Simon
Nevertheless, I think it is important to point out that a properly powered study to assess actual risk in this setting is not available in the literature.

When a patient refuses HT
Dr. Pinkerton
Some BRCA mutation carriers may refuse HT despite reassurance that it is safe. Nonhormonal therapies are not as effective at relieving severe menopausal symptoms. Almost all selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be offered, although only low-dose paroxetine salt is approved for treatment of postmenopausal hot flashes.^10,11 Gabapentin also has shown efficacy in relieving hot flashes.

For genitourinary syndrome of menopause (GSM; formerly known as vulvovaginal atrophy), lubricants and moisturizers may provide some benefit, but they don’t improve the vaginal superficial cells and, therefore, are not as effective as hormonal options. There is now a selective estrogen receptor modulator (SERM) approved to treat GSM—ospemifene. However, in clinical trials, ospemifene has been shown to increase hot flashes, so it would not be a good option for our patient.¹²

Case: Continued
Christine follows up 3 months after initiating estrogen therapy (oral estradiol 2 mg daily). She reports significant improvement in her hot flashes, with improved sleep and fewer sleep disruptions. In addition, she feels that her “mental sharpness” has returned.

Dr. Pinkerton
What if this patient had an intact uterus? Then she would not be a candidate for estrogen-only therapy because she would need continued endometrial protection. Options then would include low-dose continuous or cyclic progestogen therapy, often starting with micronized progesterone, as the E3N Study suggested it has a less negative effect on the uterus.¹³ Or she could use a levonorgestrel-releasing intrauterine system off label, as Ms. Jolie Pitt elected to do.

Another option would be combining estrogen with a SERM. The only estrogen/SERM combination currently approved by the US Food and Drug Administration (FDA) is conjugated estrogen/bazedoxefine, which showed no increase in breast tenderness, breast density, or bleeding rates, compared with placebo, in multiple trials up to 5 years in duration.¹⁴

Case: Resolved
Christine says she would like to continue HT, although she still experiences dryness and discomfort when sexually active with her husband, despite use of a vaginal lubricant. A pelvic examination is consistent with early changes of GSM.¹⁵

You discuss GSM with Christine and suggest that she consider 1 of 2 strategies:

Christine chooses Option 2. When she returns 6 months later for her well-woman visit, she reports that all of her menopausal symptoms have resolved, and a pelvic examination no longer reveals changes of GSM.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

WASHINGTON – Women with type 2 diabetes who take estrogen therapy showed lower total gray matter volume, with atrophy particularly evident in the hippocampus.

A new analysis of the Women’s Health Initiative Memory study suggested that these hormone therapy–related decrements in brain volume seem to stabilize in the years after treatment ends. However, said Christina E. Hugenschmidt, Ph.D., the findings also suggested caution when considering a prescription for estrogen therapy for a woman with emerging or frank diabetes.

“The concern is that prescribing estrogen to a woman with diabetes could increase her risk of brain atrophy,” she said at the Alzheimer’s Association International Conference 2015.

Dr. Hugenschmidt of Wake Forest University, Winston-Salem, N.C., reviewed data from the Women’s Health Initiate Memory Study–MRI (WHIMS-MRI).

©Judith Flacke/Thinkstockphotos.com

The parallel placebo-controlled trial randomized women aged 65 years and older to placebo, or 0.625 mg conjugated equine estrogen with or without 2.5 mg progesterone. They were all free of cognitive decline at baseline.

Dr. Hugenschmidt focused on 1,400 women who underwent two magnetic resonance imaging brain scans: one 2.5 years after beginning the study and another about 5 years after that. The primary outcomes were total brain volume, including any ischemic lesions, total gray matter, total white matter, frontal lobe and hippocampal volume, and ischemic white matter lesion load.

At enrollment, the women were a mean age of 70 years old; 124 had type 2 diabetes. About 42% had long-standing disease of 10 years or longer. Not surprisingly, there were some significant differences between the diabetic and nondiabetic groups: Body mass index, waist girth, and waist/hip ratio were all significantly larger in the women with diabetes.

At the first scan, women with diabetes who had been randomized to estrogen therapy had about 18 cc less total brain volume than those without diabetes. The brain volumes of women with diabetes who were taking placebo were nearly identical to those of the nondiabetic women, regardless of what treatment they were taking.

The difference seemed to be driven by a loss of gray matter, Dr. Hugenschmidt said. There was no significant effect on white matter. The hippocampus appeared to have a similar amount of shrinkage. However, she added, there were no differences in cognitive scores on the Mini Mental State Exam.

Insulin use didn’t appear to ameliorate the findings of smaller brain volume among those with diabetes. Atrophy didn’t progress, however; findings at the same scan were similar.

The findings may be linked to the suppression of a natural process that occurs during the perimenopausal transition, Dr. Hugenschmidt said. Estrogen is crucial in maintaining the brain’s energy metabolism. It works by increasing glucose transport and aerobic glycolysis. But during this time of life, as estrogen wanes, it becomes uncoupled from the glucose metabolism pathway. The female brain then begins to use ketone bodies as its primary source of energy. Intact estrogen levels normally downregulate the use of alternative energy sources before menopause; supplementing them seems to prevent this transition from occurring.

“Among older women with diabetes for whom the glucose-based energy metabolism promoted by estrogen is already compromised, this downregulation of alternative energy sources may lead to increased atrophy of gray matter, which has a greater metabolic demand relative to white matter,” Dr. Hugenschmidt and her colleagues wrote in a paper published in Neurology (2015 July 10 [doi:10.1212/WNL.0000000000001816]).

Dr. Hugenschmidt reported having no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

WASHINGTON – Women with type 2 diabetes who take estrogen therapy showed lower total gray matter volume, with atrophy particularly evident in the hippocampus.

A new analysis of the Women’s Health Initiative Memory study suggested that these hormone therapy–related decrements in brain volume seem to stabilize in the years after treatment ends. However, said Christina E. Hugenschmidt, Ph.D., the findings also suggested caution when considering a prescription for estrogen therapy for a woman with emerging or frank diabetes.

“The concern is that prescribing estrogen to a woman with diabetes could increase her risk of brain atrophy,” she said at the Alzheimer’s Association International Conference 2015.

Dr. Hugenschmidt of Wake Forest University, Winston-Salem, N.C., reviewed data from the Women’s Health Initiate Memory Study–MRI (WHIMS-MRI).

©Judith Flacke/Thinkstockphotos.com

The parallel placebo-controlled trial randomized women aged 65 years and older to placebo, or 0.625 mg conjugated equine estrogen with or without 2.5 mg progesterone. They were all free of cognitive decline at baseline.

Dr. Hugenschmidt focused on 1,400 women who underwent two magnetic resonance imaging brain scans: one 2.5 years after beginning the study and another about 5 years after that. The primary outcomes were total brain volume, including any ischemic lesions, total gray matter, total white matter, frontal lobe and hippocampal volume, and ischemic white matter lesion load.

At enrollment, the women were a mean age of 70 years old; 124 had type 2 diabetes. About 42% had long-standing disease of 10 years or longer. Not surprisingly, there were some significant differences between the diabetic and nondiabetic groups: Body mass index, waist girth, and waist/hip ratio were all significantly larger in the women with diabetes.

At the first scan, women with diabetes who had been randomized to estrogen therapy had about 18 cc less total brain volume than those without diabetes. The brain volumes of women with diabetes who were taking placebo were nearly identical to those of the nondiabetic women, regardless of what treatment they were taking.

The difference seemed to be driven by a loss of gray matter, Dr. Hugenschmidt said. There was no significant effect on white matter. The hippocampus appeared to have a similar amount of shrinkage. However, she added, there were no differences in cognitive scores on the Mini Mental State Exam.

Insulin use didn’t appear to ameliorate the findings of smaller brain volume among those with diabetes. Atrophy didn’t progress, however; findings at the same scan were similar.

The findings may be linked to the suppression of a natural process that occurs during the perimenopausal transition, Dr. Hugenschmidt said. Estrogen is crucial in maintaining the brain’s energy metabolism. It works by increasing glucose transport and aerobic glycolysis. But during this time of life, as estrogen wanes, it becomes uncoupled from the glucose metabolism pathway. The female brain then begins to use ketone bodies as its primary source of energy. Intact estrogen levels normally downregulate the use of alternative energy sources before menopause; supplementing them seems to prevent this transition from occurring.

“Among older women with diabetes for whom the glucose-based energy metabolism promoted by estrogen is already compromised, this downregulation of alternative energy sources may lead to increased atrophy of gray matter, which has a greater metabolic demand relative to white matter,” Dr. Hugenschmidt and her colleagues wrote in a paper published in Neurology (2015 July 10 [doi:10.1212/WNL.0000000000001816]).

Dr. Hugenschmidt reported having no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

WASHINGTON – Women with type 2 diabetes who take estrogen therapy showed lower total gray matter volume, with atrophy particularly evident in the hippocampus.

A new analysis of the Women’s Health Initiative Memory study suggested that these hormone therapy–related decrements in brain volume seem to stabilize in the years after treatment ends. However, said Christina E. Hugenschmidt, Ph.D., the findings also suggested caution when considering a prescription for estrogen therapy for a woman with emerging or frank diabetes.

“The concern is that prescribing estrogen to a woman with diabetes could increase her risk of brain atrophy,” she said at the Alzheimer’s Association International Conference 2015.

Dr. Hugenschmidt of Wake Forest University, Winston-Salem, N.C., reviewed data from the Women’s Health Initiate Memory Study–MRI (WHIMS-MRI).

©Judith Flacke/Thinkstockphotos.com

The parallel placebo-controlled trial randomized women aged 65 years and older to placebo, or 0.625 mg conjugated equine estrogen with or without 2.5 mg progesterone. They were all free of cognitive decline at baseline.

Dr. Hugenschmidt focused on 1,400 women who underwent two magnetic resonance imaging brain scans: one 2.5 years after beginning the study and another about 5 years after that. The primary outcomes were total brain volume, including any ischemic lesions, total gray matter, total white matter, frontal lobe and hippocampal volume, and ischemic white matter lesion load.

At enrollment, the women were a mean age of 70 years old; 124 had type 2 diabetes. About 42% had long-standing disease of 10 years or longer. Not surprisingly, there were some significant differences between the diabetic and nondiabetic groups: Body mass index, waist girth, and waist/hip ratio were all significantly larger in the women with diabetes.

At the first scan, women with diabetes who had been randomized to estrogen therapy had about 18 cc less total brain volume than those without diabetes. The brain volumes of women with diabetes who were taking placebo were nearly identical to those of the nondiabetic women, regardless of what treatment they were taking.

The difference seemed to be driven by a loss of gray matter, Dr. Hugenschmidt said. There was no significant effect on white matter. The hippocampus appeared to have a similar amount of shrinkage. However, she added, there were no differences in cognitive scores on the Mini Mental State Exam.

Insulin use didn’t appear to ameliorate the findings of smaller brain volume among those with diabetes. Atrophy didn’t progress, however; findings at the same scan were similar.

The findings may be linked to the suppression of a natural process that occurs during the perimenopausal transition, Dr. Hugenschmidt said. Estrogen is crucial in maintaining the brain’s energy metabolism. It works by increasing glucose transport and aerobic glycolysis. But during this time of life, as estrogen wanes, it becomes uncoupled from the glucose metabolism pathway. The female brain then begins to use ketone bodies as its primary source of energy. Intact estrogen levels normally downregulate the use of alternative energy sources before menopause; supplementing them seems to prevent this transition from occurring.

“Among older women with diabetes for whom the glucose-based energy metabolism promoted by estrogen is already compromised, this downregulation of alternative energy sources may lead to increased atrophy of gray matter, which has a greater metabolic demand relative to white matter,” Dr. Hugenschmidt and her colleagues wrote in a paper published in Neurology (2015 July 10 [doi:10.1212/WNL.0000000000001816]).

Dr. Hugenschmidt reported having no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

Without the option of recommending physician certification as a condition for flibanserin approval, the Food and Drug Administration advisory panel vote might have shifted against approval of the drug for treating hypoactive sexual desire disorder in premenopausal women.

At a joint meeting of two FDA advisory panels in June, members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented. If approved by the FDA, flibanserin would be the first drug approved for treating HSDD.

Assurance that prescribers would be fully apprised of the serious risks of hypotension and syncope associated with the drug, exacerbation of those side effects when combined with alcohol or a CYP3A4 inhibitor – and the modest effects over placebo – was cited by several of the panelists who voted in favor of approval.

All of those voting in favor of approval chose the option of supporting approval “only if certain risk management options beyond labeling are implemented.” None of the panelists voted for the option of supporting approval with “labeling alone to manage the risks.”

The conditions include a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy.

The risks of hypotension and syncope, and central nervous system depression are also exacerbated by moderate or strong CYP3A4 inhibitors, but the interaction with alcohol was raised as a particularly serious issue because of the high rate of alcohol use and binge drinking among women who would likely be treated with flibanserin, according to FDA reviewers.

Courtesy of Sprout Pharmaceuticals

The risk of drug interactions can be mitigated with drug interaction screening programs used in health care systems, such as in electronic medical records and pharmacies, while alcohol use is a patient-dependent behavior, is common among women, and therefore more difficult to control, Kimberly Lehrfeld, Pharm.D., a team leader in the division of risk management in the FDA’s office of medication error prevention and analysis, said at the meeting. Several panelists recommended that alcohol use be a contraindication.

Physician certification is among the Elements to Assure Safe Use or ETASU, which along with a medication guide and a communication plan for health care providers, are components of a Risk Evaluation and Mitigation Strategy (REMS), a way to help manage the risks of a drug or biologic while still making it available to patients who need it.

Physician certification is part of the REMS for drugs such as mifepristone (Mifeprex), thalidomide (Thalomid), and natalizumab (Tysabri).

“A risk strategy that gets physicians the information they need to use it properly is going to be key,” said Dr. Robert Silbergleit, who voted for approval.”A REMS strategy is going to be very important because I think that the most likely risks … are going to come from physicians who don’t use the drug properly because they’re not properly educated.”

Dr. Silbergleit, a professor in the department of emergency medicine at the University of Michigan, Ann Arbor, said he was also concerned about the marketing of the drug. “Clinicians may be in the situation where they have to counter direct-to-consumer marketing that could lead to misuse of the drug,” he said at the meeting.

Also voting for approval, Marjorie Shaw Phillips, R.Ph., pharmacy coordinator at Georgia Regents Medical Center in Augusta, said that everyone needs to be aware of the potential safety concerns. But while she does not think pharmacy registration would be beneficial, there is a role for the pharmacist to confirm that it’s an educated provider prescribing the drug and that they’ve discussed the risks with the patient.

She added that it will be important for physicians to set realistic expectations for patients.

“It’s not a magical little pink pill, and there are going to be a whole lot of women with sexual dysfunction for whom there’s no evidence that it’s going to benefit them,” she said at the meeting.

The panel did not specifically recommend pharmacy certification, but pharmacists would have to verify that the prescribing physicians are certified, if the drug is approved, an FDA official said at the meeting.

A decision from the FDA is expected in August. The FDA panelists reported having no relevant financial disclosures.

Sprout Pharmaceuticals, flibanserin’s manufacturer, said in a statement that the company looks forward “to continuing our work with the FDA as it completes its review of our new drug application, including the discussion of a Risks Evaluation and Mitigation Strategy.” If approved, the company plans to market flibanserin as “Addyi.”

[email protected]

Without the option of recommending physician certification as a condition for flibanserin approval, the Food and Drug Administration advisory panel vote might have shifted against approval of the drug for treating hypoactive sexual desire disorder in premenopausal women.

At a joint meeting of two FDA advisory panels in June, members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented. If approved by the FDA, flibanserin would be the first drug approved for treating HSDD.

Assurance that prescribers would be fully apprised of the serious risks of hypotension and syncope associated with the drug, exacerbation of those side effects when combined with alcohol or a CYP3A4 inhibitor – and the modest effects over placebo – was cited by several of the panelists who voted in favor of approval.

All of those voting in favor of approval chose the option of supporting approval “only if certain risk management options beyond labeling are implemented.” None of the panelists voted for the option of supporting approval with “labeling alone to manage the risks.”

The conditions include a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy.

The risks of hypotension and syncope, and central nervous system depression are also exacerbated by moderate or strong CYP3A4 inhibitors, but the interaction with alcohol was raised as a particularly serious issue because of the high rate of alcohol use and binge drinking among women who would likely be treated with flibanserin, according to FDA reviewers.

Courtesy of Sprout Pharmaceuticals

The risk of drug interactions can be mitigated with drug interaction screening programs used in health care systems, such as in electronic medical records and pharmacies, while alcohol use is a patient-dependent behavior, is common among women, and therefore more difficult to control, Kimberly Lehrfeld, Pharm.D., a team leader in the division of risk management in the FDA’s office of medication error prevention and analysis, said at the meeting. Several panelists recommended that alcohol use be a contraindication.

Physician certification is among the Elements to Assure Safe Use or ETASU, which along with a medication guide and a communication plan for health care providers, are components of a Risk Evaluation and Mitigation Strategy (REMS), a way to help manage the risks of a drug or biologic while still making it available to patients who need it.

Physician certification is part of the REMS for drugs such as mifepristone (Mifeprex), thalidomide (Thalomid), and natalizumab (Tysabri).

“A risk strategy that gets physicians the information they need to use it properly is going to be key,” said Dr. Robert Silbergleit, who voted for approval.”A REMS strategy is going to be very important because I think that the most likely risks … are going to come from physicians who don’t use the drug properly because they’re not properly educated.”

Dr. Silbergleit, a professor in the department of emergency medicine at the University of Michigan, Ann Arbor, said he was also concerned about the marketing of the drug. “Clinicians may be in the situation where they have to counter direct-to-consumer marketing that could lead to misuse of the drug,” he said at the meeting.

Also voting for approval, Marjorie Shaw Phillips, R.Ph., pharmacy coordinator at Georgia Regents Medical Center in Augusta, said that everyone needs to be aware of the potential safety concerns. But while she does not think pharmacy registration would be beneficial, there is a role for the pharmacist to confirm that it’s an educated provider prescribing the drug and that they’ve discussed the risks with the patient.

She added that it will be important for physicians to set realistic expectations for patients.

“It’s not a magical little pink pill, and there are going to be a whole lot of women with sexual dysfunction for whom there’s no evidence that it’s going to benefit them,” she said at the meeting.

The panel did not specifically recommend pharmacy certification, but pharmacists would have to verify that the prescribing physicians are certified, if the drug is approved, an FDA official said at the meeting.

A decision from the FDA is expected in August. The FDA panelists reported having no relevant financial disclosures.

Sprout Pharmaceuticals, flibanserin’s manufacturer, said in a statement that the company looks forward “to continuing our work with the FDA as it completes its review of our new drug application, including the discussion of a Risks Evaluation and Mitigation Strategy.” If approved, the company plans to market flibanserin as “Addyi.”

[email protected]

Without the option of recommending physician certification as a condition for flibanserin approval, the Food and Drug Administration advisory panel vote might have shifted against approval of the drug for treating hypoactive sexual desire disorder in premenopausal women.

At a joint meeting of two FDA advisory panels in June, members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented. If approved by the FDA, flibanserin would be the first drug approved for treating HSDD.

Assurance that prescribers would be fully apprised of the serious risks of hypotension and syncope associated with the drug, exacerbation of those side effects when combined with alcohol or a CYP3A4 inhibitor – and the modest effects over placebo – was cited by several of the panelists who voted in favor of approval.

All of those voting in favor of approval chose the option of supporting approval “only if certain risk management options beyond labeling are implemented.” None of the panelists voted for the option of supporting approval with “labeling alone to manage the risks.”

The conditions include a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy.

The risks of hypotension and syncope, and central nervous system depression are also exacerbated by moderate or strong CYP3A4 inhibitors, but the interaction with alcohol was raised as a particularly serious issue because of the high rate of alcohol use and binge drinking among women who would likely be treated with flibanserin, according to FDA reviewers.

Courtesy of Sprout Pharmaceuticals

The risk of drug interactions can be mitigated with drug interaction screening programs used in health care systems, such as in electronic medical records and pharmacies, while alcohol use is a patient-dependent behavior, is common among women, and therefore more difficult to control, Kimberly Lehrfeld, Pharm.D., a team leader in the division of risk management in the FDA’s office of medication error prevention and analysis, said at the meeting. Several panelists recommended that alcohol use be a contraindication.

Physician certification is among the Elements to Assure Safe Use or ETASU, which along with a medication guide and a communication plan for health care providers, are components of a Risk Evaluation and Mitigation Strategy (REMS), a way to help manage the risks of a drug or biologic while still making it available to patients who need it.

Physician certification is part of the REMS for drugs such as mifepristone (Mifeprex), thalidomide (Thalomid), and natalizumab (Tysabri).

“A risk strategy that gets physicians the information they need to use it properly is going to be key,” said Dr. Robert Silbergleit, who voted for approval.”A REMS strategy is going to be very important because I think that the most likely risks … are going to come from physicians who don’t use the drug properly because they’re not properly educated.”

Dr. Silbergleit, a professor in the department of emergency medicine at the University of Michigan, Ann Arbor, said he was also concerned about the marketing of the drug. “Clinicians may be in the situation where they have to counter direct-to-consumer marketing that could lead to misuse of the drug,” he said at the meeting.

Also voting for approval, Marjorie Shaw Phillips, R.Ph., pharmacy coordinator at Georgia Regents Medical Center in Augusta, said that everyone needs to be aware of the potential safety concerns. But while she does not think pharmacy registration would be beneficial, there is a role for the pharmacist to confirm that it’s an educated provider prescribing the drug and that they’ve discussed the risks with the patient.

She added that it will be important for physicians to set realistic expectations for patients.

“It’s not a magical little pink pill, and there are going to be a whole lot of women with sexual dysfunction for whom there’s no evidence that it’s going to benefit them,” she said at the meeting.

The panel did not specifically recommend pharmacy certification, but pharmacists would have to verify that the prescribing physicians are certified, if the drug is approved, an FDA official said at the meeting.

A decision from the FDA is expected in August. The FDA panelists reported having no relevant financial disclosures.

Sprout Pharmaceuticals, flibanserin’s manufacturer, said in a statement that the company looks forward “to continuing our work with the FDA as it completes its review of our new drug application, including the discussion of a Risks Evaluation and Mitigation Strategy.” If approved, the company plans to market flibanserin as “Addyi.”

[email protected]

INDIANAPOLIS – About 50% of women with multiple sclerosis are postmenopausal, but objective data about the impact of menopause on the course of multiple sclerosis are lacking.

“We don’t know anything about the impact of menopause on the MS course; there is wide variability in patient-reported outcomes, but nothing written about comorbidities or symptom management,” Dr. Riley Bove, a neurologist at Brigham and Women’s Hospital, Boston, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We’ve been working on this. A lot of it is unknown.”

She described menopause is “an opportunity for providers to tackle symptoms and improve well-being and discuss meaningful quality of life and priorities with patients. It can be a good time to talk about these things.”

In a study that Dr. Bove conducted with the online patient-powered research platform PatientsLikeMe, female MS patients were asked to describe the impact of menopause on their disease. Among the themes that emerged were an occasional perimenopausal onset of MS (“menopause and MS symptoms were pretty much simultaneous,” one 58-year-old respondent said); the effect of hot flashes on MS symptoms (“I confused the two, especially hot flashes,” said a 53-year-old woman); and worsening of MS-related disability after menopause, particularly surgical (“Before I stopped taking birth control pills I was working and able to walk and house clean , etc.,” a 53-year-old respondent said. “I had the surgery, and I started to progress toward being completely wheelchair bound.”)

When it comes to solid recommendations for how to manage MS symptoms that overlap with menopause, “we’re in an evidence-free zone,” Dr. Bove said. “Symptoms in MS are kind of like dominoes: You have difficulty sleeping and then your day is off, fatigue is up and your mood is off, and everything can spiral. In the clinic, perimenopausal women often say things like, ‘I feel like I’m falling apart’ or ‘something has to give’ or ‘I need a change.’ ”

Common overlapping symptoms include vasomotor manifestations such as hot flashes, cold flashes, vascular instability, and rapid heartbeat. “The leading mechanistic explanation for the vasomotor symptoms is that abrupt hormone deprivation will result in the loss of negative feedback over hypothalamic NA [noradrenaline] synthesis,” Dr. Bove explained. “The proximity of the hypothalamic thermoregulatory center to luteinizing hormone–releasing hormone-producing areas may also be involved.”

Sleep disturbances and insomnia in menopausal MS patients can impact fatigue and mood. Also, hot flashes can directly exacerbate the MS symptoms, fluctuating over the day or the week.

According to recommendations from the North American Menopause Society, estradiol is the most effective therapy for treating vasomotor symptoms. Other options include selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs). “Probably the best studied SNRI is venlafaxine,” Dr. Bove said. “It seems to have modest effects on sleep quality and insomnia perimenopausally, as well as on hot flashes.”

Other alternatives include clonidine and gabapentin.

“If a patient wants to use [hormone therapy] for menopausal symptoms, it has to be an individualized approach,” Dr. Bove said. “You have to communicate with the primary care physician to understand what else is going on in this woman’s medical history. The current recommendations are to treat the symptoms with as low a dose as possible for as short a duration as possible. Our MS patients are also at risk for neurodegeneration, for brain volume loss, for cognitive decline, and for worsening function over time.”

With respect to cognition, observational studies have demonstrated that during a certain window of opportunity – defined as within 5 years of the last menstrual period – hormone therapy (HT) may have protective effects against Alzheimer’s disease and against cognitive decline in general. “Beyond this window of time, perhaps due to estrogen receptor down regulation, HT can be harmful, with an increased risk of stroke and dementia reported later on,” she said.

Against this, the Women’s Health Initiative Memory Study (WHIMS) looked at unopposed estrogen, and estrogen and progestin combination, compared with placebo. It found that in women who initiated HT at the age of 65 or older faced an increased risk of dementia from any cause, and of cognitive decline. “This study really put the kibosh on HT as a form of neuroprotection,” Dr. Bove said. “But perhaps it’s unfair to the many patients who are at risk for cognitive decline and neurodegeneration, because the WHIMS did not find an increased risk of adverse cognitive events in women in whom HT was started perimenopausally. Longitudinal, placebo-controlled trials of the effects of HT within the window of opportunity are required to either prove or refute the observational studies that already exist that suggest HT may be neuroprotective. This is an important point to discuss with patients.”

The impact of perimenopausal sleep disturbance on MS symptoms also is unknown. A practical approach to managing sleep disturbance in perimenopausal MS patients is to identify and assess the triggers. “If the bladder symptoms are the major trigger versus mood disturbances such as depression and anxiety, the intervention will be different,” she said. “Consider counseling and/or consultation with a sleep specialist.” Some patients may benefit from pharmacologic treatment to “get them over the hump and get them sleeping better for a little while, versus longer term management if they have a life history of insomnia,” she said. “If the problem is sleep management, you’ll need a drug with a longer half-life. Consider other comorbidities such as anxiety and restless leg syndrome.” Classes of medications to consider include benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, SSRIs and SNRIs.

Mood symptoms commonly overlap in menopausal patients with MS, especially those related to depression and anxiety. “They may be underdiagnosed and undertreated,” Dr. Bove said. “It’s been shown that depression influences the perceived severity of other MS symptoms. Depression is a strong predictor of cognitive and sexual dysfunction, so our perimenopausal MS women have a vulnerability to more severe mood symptoms.” Managing mood symptoms “needs to be multifaceted” and may include psychotherapy to optimize coping abilities, antidepressants, support groups, fatigue and sleep optimization, and social work “to see how employment or financial stressors may be playing a role in a person’s mood.”

In addition, menopausal women may report changes in attention, executive function, multitasking, word finding difficulties, and memory problems, especially in the first year after the final menstrual period. “It’s known that about half of MS patients experience some degree of cognitive impairment,” she said. “Neurocognitive testing may help to identify particular areas of dysfunction that would be amenable to some kind of cognitive rehabilitation.”

Bladder symptoms also can impact postmenopausal patients, especially increasing bladder irritability and incontinence (stress and urge). In MS, “the baseline bladder dysfunction may be magnified,” Dr. Bove said. “If you’re trying to tease out whether the postmenopausal bladder symptoms are from menopause or MS, the MS relapses tend to have more urgency, frequency, and urge incontinence, and the presentation will be more acute. Urodynamic testing can be used to tease this out. The big lifestyle piece that urologists like to hone in on is that people in America drink too much fluid. A practical guideline is that after 3 p.m. just drink for thirst; don’t worry that everything will fall apart if you don’t get your eight glasses of water per day in. If you’re not thirsty, you probably don’t need it.”

While postmenopausal women face an increased risk for osteoporosis, that risk is magnified for MS patients because of the cumulative effect of steroid use – particularly for those who were diagnosed in the pre–disease-modifying-therapy era – being sedentary, and being deconditioned. “Other MS issues such as balance, vision problems, strength or cognitive impairments may all impact gait and compound the risk of falls,” Dr. Bove said. “Osteoporosis prevention and screening should be encouraged in these patients.”

Dr. Bove concluded her presentation by noting that in general, women with disabilities are less likely to be up to date on Pap tests, mammograms, and other important preventive screening tests. “The magnitude of disparities is greater for women with complex limitations,” she said. “Women with MS may have a lower cancer risk, but a larger tumor size at diagnosis.” For example, “is this because the patient is uncomfortable getting on an exam table to get a Pap smear, or is the physician not thinking about other aspects of the person’s life because the focus is on the MS?”

Dr. Bove disclosed that she has received funding from the National Multiple Sclerosis Society, the National Institutes of Health, and from the Harvard Clinical Investigator Training Program.

[email protected]

On Twitter @dougbrunk

INDIANAPOLIS – About 50% of women with multiple sclerosis are postmenopausal, but objective data about the impact of menopause on the course of multiple sclerosis are lacking.

“We don’t know anything about the impact of menopause on the MS course; there is wide variability in patient-reported outcomes, but nothing written about comorbidities or symptom management,” Dr. Riley Bove, a neurologist at Brigham and Women’s Hospital, Boston, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We’ve been working on this. A lot of it is unknown.”

She described menopause is “an opportunity for providers to tackle symptoms and improve well-being and discuss meaningful quality of life and priorities with patients. It can be a good time to talk about these things.”

In a study that Dr. Bove conducted with the online patient-powered research platform PatientsLikeMe, female MS patients were asked to describe the impact of menopause on their disease. Among the themes that emerged were an occasional perimenopausal onset of MS (“menopause and MS symptoms were pretty much simultaneous,” one 58-year-old respondent said); the effect of hot flashes on MS symptoms (“I confused the two, especially hot flashes,” said a 53-year-old woman); and worsening of MS-related disability after menopause, particularly surgical (“Before I stopped taking birth control pills I was working and able to walk and house clean , etc.,” a 53-year-old respondent said. “I had the surgery, and I started to progress toward being completely wheelchair bound.”)

When it comes to solid recommendations for how to manage MS symptoms that overlap with menopause, “we’re in an evidence-free zone,” Dr. Bove said. “Symptoms in MS are kind of like dominoes: You have difficulty sleeping and then your day is off, fatigue is up and your mood is off, and everything can spiral. In the clinic, perimenopausal women often say things like, ‘I feel like I’m falling apart’ or ‘something has to give’ or ‘I need a change.’ ”

Common overlapping symptoms include vasomotor manifestations such as hot flashes, cold flashes, vascular instability, and rapid heartbeat. “The leading mechanistic explanation for the vasomotor symptoms is that abrupt hormone deprivation will result in the loss of negative feedback over hypothalamic NA [noradrenaline] synthesis,” Dr. Bove explained. “The proximity of the hypothalamic thermoregulatory center to luteinizing hormone–releasing hormone-producing areas may also be involved.”

Sleep disturbances and insomnia in menopausal MS patients can impact fatigue and mood. Also, hot flashes can directly exacerbate the MS symptoms, fluctuating over the day or the week.

According to recommendations from the North American Menopause Society, estradiol is the most effective therapy for treating vasomotor symptoms. Other options include selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs). “Probably the best studied SNRI is venlafaxine,” Dr. Bove said. “It seems to have modest effects on sleep quality and insomnia perimenopausally, as well as on hot flashes.”

Other alternatives include clonidine and gabapentin.

“If a patient wants to use [hormone therapy] for menopausal symptoms, it has to be an individualized approach,” Dr. Bove said. “You have to communicate with the primary care physician to understand what else is going on in this woman’s medical history. The current recommendations are to treat the symptoms with as low a dose as possible for as short a duration as possible. Our MS patients are also at risk for neurodegeneration, for brain volume loss, for cognitive decline, and for worsening function over time.”

With respect to cognition, observational studies have demonstrated that during a certain window of opportunity – defined as within 5 years of the last menstrual period – hormone therapy (HT) may have protective effects against Alzheimer’s disease and against cognitive decline in general. “Beyond this window of time, perhaps due to estrogen receptor down regulation, HT can be harmful, with an increased risk of stroke and dementia reported later on,” she said.

Against this, the Women’s Health Initiative Memory Study (WHIMS) looked at unopposed estrogen, and estrogen and progestin combination, compared with placebo. It found that in women who initiated HT at the age of 65 or older faced an increased risk of dementia from any cause, and of cognitive decline. “This study really put the kibosh on HT as a form of neuroprotection,” Dr. Bove said. “But perhaps it’s unfair to the many patients who are at risk for cognitive decline and neurodegeneration, because the WHIMS did not find an increased risk of adverse cognitive events in women in whom HT was started perimenopausally. Longitudinal, placebo-controlled trials of the effects of HT within the window of opportunity are required to either prove or refute the observational studies that already exist that suggest HT may be neuroprotective. This is an important point to discuss with patients.”

The impact of perimenopausal sleep disturbance on MS symptoms also is unknown. A practical approach to managing sleep disturbance in perimenopausal MS patients is to identify and assess the triggers. “If the bladder symptoms are the major trigger versus mood disturbances such as depression and anxiety, the intervention will be different,” she said. “Consider counseling and/or consultation with a sleep specialist.” Some patients may benefit from pharmacologic treatment to “get them over the hump and get them sleeping better for a little while, versus longer term management if they have a life history of insomnia,” she said. “If the problem is sleep management, you’ll need a drug with a longer half-life. Consider other comorbidities such as anxiety and restless leg syndrome.” Classes of medications to consider include benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, SSRIs and SNRIs.

Mood symptoms commonly overlap in menopausal patients with MS, especially those related to depression and anxiety. “They may be underdiagnosed and undertreated,” Dr. Bove said. “It’s been shown that depression influences the perceived severity of other MS symptoms. Depression is a strong predictor of cognitive and sexual dysfunction, so our perimenopausal MS women have a vulnerability to more severe mood symptoms.” Managing mood symptoms “needs to be multifaceted” and may include psychotherapy to optimize coping abilities, antidepressants, support groups, fatigue and sleep optimization, and social work “to see how employment or financial stressors may be playing a role in a person’s mood.”

In addition, menopausal women may report changes in attention, executive function, multitasking, word finding difficulties, and memory problems, especially in the first year after the final menstrual period. “It’s known that about half of MS patients experience some degree of cognitive impairment,” she said. “Neurocognitive testing may help to identify particular areas of dysfunction that would be amenable to some kind of cognitive rehabilitation.”

Bladder symptoms also can impact postmenopausal patients, especially increasing bladder irritability and incontinence (stress and urge). In MS, “the baseline bladder dysfunction may be magnified,” Dr. Bove said. “If you’re trying to tease out whether the postmenopausal bladder symptoms are from menopause or MS, the MS relapses tend to have more urgency, frequency, and urge incontinence, and the presentation will be more acute. Urodynamic testing can be used to tease this out. The big lifestyle piece that urologists like to hone in on is that people in America drink too much fluid. A practical guideline is that after 3 p.m. just drink for thirst; don’t worry that everything will fall apart if you don’t get your eight glasses of water per day in. If you’re not thirsty, you probably don’t need it.”

While postmenopausal women face an increased risk for osteoporosis, that risk is magnified for MS patients because of the cumulative effect of steroid use – particularly for those who were diagnosed in the pre–disease-modifying-therapy era – being sedentary, and being deconditioned. “Other MS issues such as balance, vision problems, strength or cognitive impairments may all impact gait and compound the risk of falls,” Dr. Bove said. “Osteoporosis prevention and screening should be encouraged in these patients.”

Dr. Bove concluded her presentation by noting that in general, women with disabilities are less likely to be up to date on Pap tests, mammograms, and other important preventive screening tests. “The magnitude of disparities is greater for women with complex limitations,” she said. “Women with MS may have a lower cancer risk, but a larger tumor size at diagnosis.” For example, “is this because the patient is uncomfortable getting on an exam table to get a Pap smear, or is the physician not thinking about other aspects of the person’s life because the focus is on the MS?”

Dr. Bove disclosed that she has received funding from the National Multiple Sclerosis Society, the National Institutes of Health, and from the Harvard Clinical Investigator Training Program.

[email protected]

On Twitter @dougbrunk

INDIANAPOLIS – About 50% of women with multiple sclerosis are postmenopausal, but objective data about the impact of menopause on the course of multiple sclerosis are lacking.

“We don’t know anything about the impact of menopause on the MS course; there is wide variability in patient-reported outcomes, but nothing written about comorbidities or symptom management,” Dr. Riley Bove, a neurologist at Brigham and Women’s Hospital, Boston, said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “We’ve been working on this. A lot of it is unknown.”

She described menopause is “an opportunity for providers to tackle symptoms and improve well-being and discuss meaningful quality of life and priorities with patients. It can be a good time to talk about these things.”

In a study that Dr. Bove conducted with the online patient-powered research platform PatientsLikeMe, female MS patients were asked to describe the impact of menopause on their disease. Among the themes that emerged were an occasional perimenopausal onset of MS (“menopause and MS symptoms were pretty much simultaneous,” one 58-year-old respondent said); the effect of hot flashes on MS symptoms (“I confused the two, especially hot flashes,” said a 53-year-old woman); and worsening of MS-related disability after menopause, particularly surgical (“Before I stopped taking birth control pills I was working and able to walk and house clean , etc.,” a 53-year-old respondent said. “I had the surgery, and I started to progress toward being completely wheelchair bound.”)

When it comes to solid recommendations for how to manage MS symptoms that overlap with menopause, “we’re in an evidence-free zone,” Dr. Bove said. “Symptoms in MS are kind of like dominoes: You have difficulty sleeping and then your day is off, fatigue is up and your mood is off, and everything can spiral. In the clinic, perimenopausal women often say things like, ‘I feel like I’m falling apart’ or ‘something has to give’ or ‘I need a change.’ ”

Common overlapping symptoms include vasomotor manifestations such as hot flashes, cold flashes, vascular instability, and rapid heartbeat. “The leading mechanistic explanation for the vasomotor symptoms is that abrupt hormone deprivation will result in the loss of negative feedback over hypothalamic NA [noradrenaline] synthesis,” Dr. Bove explained. “The proximity of the hypothalamic thermoregulatory center to luteinizing hormone–releasing hormone-producing areas may also be involved.”

Sleep disturbances and insomnia in menopausal MS patients can impact fatigue and mood. Also, hot flashes can directly exacerbate the MS symptoms, fluctuating over the day or the week.

According to recommendations from the North American Menopause Society, estradiol is the most effective therapy for treating vasomotor symptoms. Other options include selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs). “Probably the best studied SNRI is venlafaxine,” Dr. Bove said. “It seems to have modest effects on sleep quality and insomnia perimenopausally, as well as on hot flashes.”

Other alternatives include clonidine and gabapentin.

“If a patient wants to use [hormone therapy] for menopausal symptoms, it has to be an individualized approach,” Dr. Bove said. “You have to communicate with the primary care physician to understand what else is going on in this woman’s medical history. The current recommendations are to treat the symptoms with as low a dose as possible for as short a duration as possible. Our MS patients are also at risk for neurodegeneration, for brain volume loss, for cognitive decline, and for worsening function over time.”

With respect to cognition, observational studies have demonstrated that during a certain window of opportunity – defined as within 5 years of the last menstrual period – hormone therapy (HT) may have protective effects against Alzheimer’s disease and against cognitive decline in general. “Beyond this window of time, perhaps due to estrogen receptor down regulation, HT can be harmful, with an increased risk of stroke and dementia reported later on,” she said.

Against this, the Women’s Health Initiative Memory Study (WHIMS) looked at unopposed estrogen, and estrogen and progestin combination, compared with placebo. It found that in women who initiated HT at the age of 65 or older faced an increased risk of dementia from any cause, and of cognitive decline. “This study really put the kibosh on HT as a form of neuroprotection,” Dr. Bove said. “But perhaps it’s unfair to the many patients who are at risk for cognitive decline and neurodegeneration, because the WHIMS did not find an increased risk of adverse cognitive events in women in whom HT was started perimenopausally. Longitudinal, placebo-controlled trials of the effects of HT within the window of opportunity are required to either prove or refute the observational studies that already exist that suggest HT may be neuroprotective. This is an important point to discuss with patients.”

The impact of perimenopausal sleep disturbance on MS symptoms also is unknown. A practical approach to managing sleep disturbance in perimenopausal MS patients is to identify and assess the triggers. “If the bladder symptoms are the major trigger versus mood disturbances such as depression and anxiety, the intervention will be different,” she said. “Consider counseling and/or consultation with a sleep specialist.” Some patients may benefit from pharmacologic treatment to “get them over the hump and get them sleeping better for a little while, versus longer term management if they have a life history of insomnia,” she said. “If the problem is sleep management, you’ll need a drug with a longer half-life. Consider other comorbidities such as anxiety and restless leg syndrome.” Classes of medications to consider include benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, SSRIs and SNRIs.

Mood symptoms commonly overlap in menopausal patients with MS, especially those related to depression and anxiety. “They may be underdiagnosed and undertreated,” Dr. Bove said. “It’s been shown that depression influences the perceived severity of other MS symptoms. Depression is a strong predictor of cognitive and sexual dysfunction, so our perimenopausal MS women have a vulnerability to more severe mood symptoms.” Managing mood symptoms “needs to be multifaceted” and may include psychotherapy to optimize coping abilities, antidepressants, support groups, fatigue and sleep optimization, and social work “to see how employment or financial stressors may be playing a role in a person’s mood.”

In addition, menopausal women may report changes in attention, executive function, multitasking, word finding difficulties, and memory problems, especially in the first year after the final menstrual period. “It’s known that about half of MS patients experience some degree of cognitive impairment,” she said. “Neurocognitive testing may help to identify particular areas of dysfunction that would be amenable to some kind of cognitive rehabilitation.”

Bladder symptoms also can impact postmenopausal patients, especially increasing bladder irritability and incontinence (stress and urge). In MS, “the baseline bladder dysfunction may be magnified,” Dr. Bove said. “If you’re trying to tease out whether the postmenopausal bladder symptoms are from menopause or MS, the MS relapses tend to have more urgency, frequency, and urge incontinence, and the presentation will be more acute. Urodynamic testing can be used to tease this out. The big lifestyle piece that urologists like to hone in on is that people in America drink too much fluid. A practical guideline is that after 3 p.m. just drink for thirst; don’t worry that everything will fall apart if you don’t get your eight glasses of water per day in. If you’re not thirsty, you probably don’t need it.”

While postmenopausal women face an increased risk for osteoporosis, that risk is magnified for MS patients because of the cumulative effect of steroid use – particularly for those who were diagnosed in the pre–disease-modifying-therapy era – being sedentary, and being deconditioned. “Other MS issues such as balance, vision problems, strength or cognitive impairments may all impact gait and compound the risk of falls,” Dr. Bove said. “Osteoporosis prevention and screening should be encouraged in these patients.”

Dr. Bove concluded her presentation by noting that in general, women with disabilities are less likely to be up to date on Pap tests, mammograms, and other important preventive screening tests. “The magnitude of disparities is greater for women with complex limitations,” she said. “Women with MS may have a lower cancer risk, but a larger tumor size at diagnosis.” For example, “is this because the patient is uncomfortable getting on an exam table to get a Pap smear, or is the physician not thinking about other aspects of the person’s life because the focus is on the MS?”

Dr. Bove disclosed that she has received funding from the National Multiple Sclerosis Society, the National Institutes of Health, and from the Harvard Clinical Investigator Training Program.

[email protected]

On Twitter @dougbrunk