Menopause

EXPERT COMMENTARY

GSM encompasses a constellation of symptoms involving the vulva, vagina, urethra, and bladder, and it can affect quality of life in more than half of women by 3 years past menopause.^1,2 Local estrogen creams, tablets, and rings are considered the gold standard treatment for GSM.³ The rising cost of many of these pharmacologic treatments has created headlines and concerns over price gouging for drugs used to treat female sexual dysfunction.⁴ Recent alternatives to local estrogens include vaginal moisturizers and lubricants, vaginal dehydroepiandrosterone (DHEA) suppositories, oral ospemifene, and vaginal laser therapy.

Laser treatment (with fractionated CO2, erbium, and hybrid lasers) activates heat shock proteins and tissue growth factors to stimulateneocollagenesis and neovascularization within the vaginal epithelium,but it is expensive and not covered by insurance because it is considered a cosmetic procedure.⁵Most evidence on laser therapy for GSM comes from prospective case series with small numbers and short-term follow-up with no comparison arms.^6,7 A recent trial by Cruz and colleagues, however, is notable because it is one of the first published studies that compared vaginal laser with vaginal estrogen alone and with a combination laser plus estrogen arm. We need level 1 comparative data from studies such as this to help us counsel the millions of US women with GSM.

Details of the study

In this single-site randomized, double-blind, placebo-controlled trial conducted in Brazil, postmenopausal women were assigned to 1 of 3 treatment groups (15 per group):

• CO2 laser (MonaLisa Touch, SmartXide 2 system; DEKA Laser; Florence, Italy): 2 treatments total, 1 month apart, plus placebo cream (laser arm)
• estriol cream (1 mg estriol 3 times per week for 20 weeks) plus sham laser (estriol arm)
• CO2 laser plus estriol cream 3 times per week (laser plus estriol combination arm).

The primary outcome included a change in visual analog scale (VAS) score for symptoms related to vulvovaginal atrophy (VVA), including dyspareunia, dryness, and burning (0–10 scale with 0 = no symptoms and 10 = most severe symptoms), and change in the objective Vaginal Health Index (VHI). Assessments were made at baseline and at 8 and 20 weeks. Participants were included if they were menopausal for at least 2 years and had at least 1 moderately bothersome VVA symptom (based on a VAS score of 4 or greater).

Secondary outcomes included the objective FSFI questionnaire evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain. FSFI scores can range from 2 (severe dysfunction) to 36 (no dysfunction). A total FSFI score less than 26 was deemed equivalent to dysfunction. Cytologic smear evaluation using a vaginal maturation index was included in all 3 treatment arms. Sample size calculation of 45 patients (15 per arm) for this trial was based on a 3-point difference in the VHI.

The baseline characteristics for participants in each treatment arm were similar, except that participants in the vaginal estriol group were less symptomatic at baseline. This group had less burning at baseline based on the FSFI and less dyspareunia based on the VAS.

Laser treatment improved dryness, burning, and dyspareunia but caused more pain

All 3 treatment groups showed statistically significant improvement in vaginal dryness at 20 weeks, but only the laser-alone arm and the laser plus estriol arms showed improvement in dyspareunia and burning. The total FSFI scores improved significantly only in the laser plus estriol arm (TABLE). No difference in the vaginal maturation index was noted between groups; however, improved numbers of parabasal cells were found in participants in the laser treatment arms.

While participants in the laser treatment arms (alone and in combination with estriol) showed significant improvement in the VAS domains of dyspareunia and burning compared with those treated with estriol alone, there was a contradictory finding of more pain in both laser arms at 20 weeks compared with the estriol-alone group, based on the FSFI. The FSFI is a validated, objective quality-of-life questionnaire, and the finding of more pain with laser treatment is a concern.

Study strengths and weaknesses

This study is one of the first of its kind to compare laser therapy alone and in combination with local estriol to vaginal estriol alone for the treatment of GSM. The trial’s strength is in its design as a double-blind, placebo-controlled block randomized trial, which adds to the prospective cohort trials that generally show favorable outcomes for fractionated laser for the treatment of GSM.

The study’s weaknesses include its small sample size, single trial site, and short-term follow-up. Findings from this trial should be considered preliminary and not generalizable. Other weaknesses are the 3 of 45 participants lost to follow-up and the significant baseline differences among the women, with lower bothersome baseline VAS scores in the estriol arm.

Furthermore, this study was not powered for multiple comparisons, and conclusions favoring laser therapy cannot be overinflated. Lasers such as CO2 target the chromophore water, and indiscriminate use in severely dry vaginal epithelium may cause more pain or scarring. Longer-term follow-up is needed.

More research also is needed to develop guidelines related to pre-laser treatment to achieve optimal vaginal pH and ideal vaginal maturation, including, for example, vaginal priming with estrogen, DHEA, or other moisturizers.

This study also suggests the use of vaginal laser therapy as a drug delivery mechanism for combination therapy. Many vaginal estrogen treatments are expensive (despite prescription drug coverage), and laser treatments are very expensive (and not covered by insurance), so research to optimize outcomes and minimize patient expense is needed.

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.

EXPERT COMMENTARY

GSM encompasses a constellation of symptoms involving the vulva, vagina, urethra, and bladder, and it can affect quality of life in more than half of women by 3 years past menopause.^1,2 Local estrogen creams, tablets, and rings are considered the gold standard treatment for GSM.³ The rising cost of many of these pharmacologic treatments has created headlines and concerns over price gouging for drugs used to treat female sexual dysfunction.⁴ Recent alternatives to local estrogens include vaginal moisturizers and lubricants, vaginal dehydroepiandrosterone (DHEA) suppositories, oral ospemifene, and vaginal laser therapy.

Laser treatment (with fractionated CO2, erbium, and hybrid lasers) activates heat shock proteins and tissue growth factors to stimulateneocollagenesis and neovascularization within the vaginal epithelium,but it is expensive and not covered by insurance because it is considered a cosmetic procedure.⁵Most evidence on laser therapy for GSM comes from prospective case series with small numbers and short-term follow-up with no comparison arms.^6,7 A recent trial by Cruz and colleagues, however, is notable because it is one of the first published studies that compared vaginal laser with vaginal estrogen alone and with a combination laser plus estrogen arm. We need level 1 comparative data from studies such as this to help us counsel the millions of US women with GSM.

Details of the study

In this single-site randomized, double-blind, placebo-controlled trial conducted in Brazil, postmenopausal women were assigned to 1 of 3 treatment groups (15 per group):

• CO2 laser (MonaLisa Touch, SmartXide 2 system; DEKA Laser; Florence, Italy): 2 treatments total, 1 month apart, plus placebo cream (laser arm)
• estriol cream (1 mg estriol 3 times per week for 20 weeks) plus sham laser (estriol arm)
• CO2 laser plus estriol cream 3 times per week (laser plus estriol combination arm).

The primary outcome included a change in visual analog scale (VAS) score for symptoms related to vulvovaginal atrophy (VVA), including dyspareunia, dryness, and burning (0–10 scale with 0 = no symptoms and 10 = most severe symptoms), and change in the objective Vaginal Health Index (VHI). Assessments were made at baseline and at 8 and 20 weeks. Participants were included if they were menopausal for at least 2 years and had at least 1 moderately bothersome VVA symptom (based on a VAS score of 4 or greater).

Secondary outcomes included the objective FSFI questionnaire evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain. FSFI scores can range from 2 (severe dysfunction) to 36 (no dysfunction). A total FSFI score less than 26 was deemed equivalent to dysfunction. Cytologic smear evaluation using a vaginal maturation index was included in all 3 treatment arms. Sample size calculation of 45 patients (15 per arm) for this trial was based on a 3-point difference in the VHI.

The baseline characteristics for participants in each treatment arm were similar, except that participants in the vaginal estriol group were less symptomatic at baseline. This group had less burning at baseline based on the FSFI and less dyspareunia based on the VAS.

Laser treatment improved dryness, burning, and dyspareunia but caused more pain

All 3 treatment groups showed statistically significant improvement in vaginal dryness at 20 weeks, but only the laser-alone arm and the laser plus estriol arms showed improvement in dyspareunia and burning. The total FSFI scores improved significantly only in the laser plus estriol arm (TABLE). No difference in the vaginal maturation index was noted between groups; however, improved numbers of parabasal cells were found in participants in the laser treatment arms.

While participants in the laser treatment arms (alone and in combination with estriol) showed significant improvement in the VAS domains of dyspareunia and burning compared with those treated with estriol alone, there was a contradictory finding of more pain in both laser arms at 20 weeks compared with the estriol-alone group, based on the FSFI. The FSFI is a validated, objective quality-of-life questionnaire, and the finding of more pain with laser treatment is a concern.

Study strengths and weaknesses

This study is one of the first of its kind to compare laser therapy alone and in combination with local estriol to vaginal estriol alone for the treatment of GSM. The trial’s strength is in its design as a double-blind, placebo-controlled block randomized trial, which adds to the prospective cohort trials that generally show favorable outcomes for fractionated laser for the treatment of GSM.

The study’s weaknesses include its small sample size, single trial site, and short-term follow-up. Findings from this trial should be considered preliminary and not generalizable. Other weaknesses are the 3 of 45 participants lost to follow-up and the significant baseline differences among the women, with lower bothersome baseline VAS scores in the estriol arm.

Furthermore, this study was not powered for multiple comparisons, and conclusions favoring laser therapy cannot be overinflated. Lasers such as CO2 target the chromophore water, and indiscriminate use in severely dry vaginal epithelium may cause more pain or scarring. Longer-term follow-up is needed.

More research also is needed to develop guidelines related to pre-laser treatment to achieve optimal vaginal pH and ideal vaginal maturation, including, for example, vaginal priming with estrogen, DHEA, or other moisturizers.

This study also suggests the use of vaginal laser therapy as a drug delivery mechanism for combination therapy. Many vaginal estrogen treatments are expensive (despite prescription drug coverage), and laser treatments are very expensive (and not covered by insurance), so research to optimize outcomes and minimize patient expense is needed.

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.

EXPERT COMMENTARY

GSM encompasses a constellation of symptoms involving the vulva, vagina, urethra, and bladder, and it can affect quality of life in more than half of women by 3 years past menopause.^1,2 Local estrogen creams, tablets, and rings are considered the gold standard treatment for GSM.³ The rising cost of many of these pharmacologic treatments has created headlines and concerns over price gouging for drugs used to treat female sexual dysfunction.⁴ Recent alternatives to local estrogens include vaginal moisturizers and lubricants, vaginal dehydroepiandrosterone (DHEA) suppositories, oral ospemifene, and vaginal laser therapy.

Laser treatment (with fractionated CO2, erbium, and hybrid lasers) activates heat shock proteins and tissue growth factors to stimulateneocollagenesis and neovascularization within the vaginal epithelium,but it is expensive and not covered by insurance because it is considered a cosmetic procedure.⁵Most evidence on laser therapy for GSM comes from prospective case series with small numbers and short-term follow-up with no comparison arms.^6,7 A recent trial by Cruz and colleagues, however, is notable because it is one of the first published studies that compared vaginal laser with vaginal estrogen alone and with a combination laser plus estrogen arm. We need level 1 comparative data from studies such as this to help us counsel the millions of US women with GSM.

Details of the study

In this single-site randomized, double-blind, placebo-controlled trial conducted in Brazil, postmenopausal women were assigned to 1 of 3 treatment groups (15 per group):

• CO2 laser (MonaLisa Touch, SmartXide 2 system; DEKA Laser; Florence, Italy): 2 treatments total, 1 month apart, plus placebo cream (laser arm)
• estriol cream (1 mg estriol 3 times per week for 20 weeks) plus sham laser (estriol arm)
• CO2 laser plus estriol cream 3 times per week (laser plus estriol combination arm).

The primary outcome included a change in visual analog scale (VAS) score for symptoms related to vulvovaginal atrophy (VVA), including dyspareunia, dryness, and burning (0–10 scale with 0 = no symptoms and 10 = most severe symptoms), and change in the objective Vaginal Health Index (VHI). Assessments were made at baseline and at 8 and 20 weeks. Participants were included if they were menopausal for at least 2 years and had at least 1 moderately bothersome VVA symptom (based on a VAS score of 4 or greater).

Secondary outcomes included the objective FSFI questionnaire evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain. FSFI scores can range from 2 (severe dysfunction) to 36 (no dysfunction). A total FSFI score less than 26 was deemed equivalent to dysfunction. Cytologic smear evaluation using a vaginal maturation index was included in all 3 treatment arms. Sample size calculation of 45 patients (15 per arm) for this trial was based on a 3-point difference in the VHI.

The baseline characteristics for participants in each treatment arm were similar, except that participants in the vaginal estriol group were less symptomatic at baseline. This group had less burning at baseline based on the FSFI and less dyspareunia based on the VAS.

Laser treatment improved dryness, burning, and dyspareunia but caused more pain

All 3 treatment groups showed statistically significant improvement in vaginal dryness at 20 weeks, but only the laser-alone arm and the laser plus estriol arms showed improvement in dyspareunia and burning. The total FSFI scores improved significantly only in the laser plus estriol arm (TABLE). No difference in the vaginal maturation index was noted between groups; however, improved numbers of parabasal cells were found in participants in the laser treatment arms.

While participants in the laser treatment arms (alone and in combination with estriol) showed significant improvement in the VAS domains of dyspareunia and burning compared with those treated with estriol alone, there was a contradictory finding of more pain in both laser arms at 20 weeks compared with the estriol-alone group, based on the FSFI. The FSFI is a validated, objective quality-of-life questionnaire, and the finding of more pain with laser treatment is a concern.

Study strengths and weaknesses

This study is one of the first of its kind to compare laser therapy alone and in combination with local estriol to vaginal estriol alone for the treatment of GSM. The trial’s strength is in its design as a double-blind, placebo-controlled block randomized trial, which adds to the prospective cohort trials that generally show favorable outcomes for fractionated laser for the treatment of GSM.

The study’s weaknesses include its small sample size, single trial site, and short-term follow-up. Findings from this trial should be considered preliminary and not generalizable. Other weaknesses are the 3 of 45 participants lost to follow-up and the significant baseline differences among the women, with lower bothersome baseline VAS scores in the estriol arm.

Furthermore, this study was not powered for multiple comparisons, and conclusions favoring laser therapy cannot be overinflated. Lasers such as CO2 target the chromophore water, and indiscriminate use in severely dry vaginal epithelium may cause more pain or scarring. Longer-term follow-up is needed.

More research also is needed to develop guidelines related to pre-laser treatment to achieve optimal vaginal pH and ideal vaginal maturation, including, for example, vaginal priming with estrogen, DHEA, or other moisturizers.

This study also suggests the use of vaginal laser therapy as a drug delivery mechanism for combination therapy. Many vaginal estrogen treatments are expensive (despite prescription drug coverage), and laser treatments are very expensive (and not covered by insurance), so research to optimize outcomes and minimize patient expense is needed.

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.

SAN FRANCISCO – What can women with migraine expect during the menopausal transition?

About 60% will experience a change in their headache pattern. And for 60% of that group, it’s a change for the worse, Yu-Chen Cheng, MD, reported at the annual meeting of the American Headache Society.

She presented a retrospective longitudinal study of 60 women with a preexisting history of migraine who were followed through the menopausal transition. All had long-term medical records available, including brain imaging results and hormonal laboratory data.

The impetus for the study was the fact that even though three-quarters of America’s estimated 38 million migraineurs are women, all of whom will eventually undergo menopause, the question of what happens to them headache-wise as they go through this process of permanent cessation of ovarian function has received little research attention.

©Eraxion/thinkstockphotos.com

[email protected]

SOURCE: Cheng Y-C and Maleki N. Headache. 2018;58:71. Abstract OR16.

SAN FRANCISCO – What can women with migraine expect during the menopausal transition?

About 60% will experience a change in their headache pattern. And for 60% of that group, it’s a change for the worse, Yu-Chen Cheng, MD, reported at the annual meeting of the American Headache Society.

She presented a retrospective longitudinal study of 60 women with a preexisting history of migraine who were followed through the menopausal transition. All had long-term medical records available, including brain imaging results and hormonal laboratory data.

The impetus for the study was the fact that even though three-quarters of America’s estimated 38 million migraineurs are women, all of whom will eventually undergo menopause, the question of what happens to them headache-wise as they go through this process of permanent cessation of ovarian function has received little research attention.

©Eraxion/thinkstockphotos.com

[email protected]

SOURCE: Cheng Y-C and Maleki N. Headache. 2018;58:71. Abstract OR16.

SAN FRANCISCO – What can women with migraine expect during the menopausal transition?

About 60% will experience a change in their headache pattern. And for 60% of that group, it’s a change for the worse, Yu-Chen Cheng, MD, reported at the annual meeting of the American Headache Society.

She presented a retrospective longitudinal study of 60 women with a preexisting history of migraine who were followed through the menopausal transition. All had long-term medical records available, including brain imaging results and hormonal laboratory data.

The impetus for the study was the fact that even though three-quarters of America’s estimated 38 million migraineurs are women, all of whom will eventually undergo menopause, the question of what happens to them headache-wise as they go through this process of permanent cessation of ovarian function has received little research attention.

©Eraxion/thinkstockphotos.com

[email protected]

SOURCE: Cheng Y-C and Maleki N. Headache. 2018;58:71. Abstract OR16.

Use of oral estrogens declined by half during 2007-2015 in women aged 50 years and older, but trends have varied for other forms of estrogen, according to a commercial database with prescription claims for more than 12 million women.

The prevalence of prescriptions for noncontraceptive oral estrogen dropped from 83 per 1,000 women in 2007 to 42 per 1,000 in 2015 for women aged 50 years and older, Joel L. Weissfeld, MD, MPH, of the Office of Surveillance and Epidemiology at the Center for Drug Evaluation and Research at the Food and Drug Administration, and his associates reported based on data from IQVIA Real World Data Adjudicated Claims – U.S. Database.

[email protected]

SOURCE: Weissfeld JL et al. Menopause. 2018;25(6):611-14.

Use of oral estrogens declined by half during 2007-2015 in women aged 50 years and older, but trends have varied for other forms of estrogen, according to a commercial database with prescription claims for more than 12 million women.

The prevalence of prescriptions for noncontraceptive oral estrogen dropped from 83 per 1,000 women in 2007 to 42 per 1,000 in 2015 for women aged 50 years and older, Joel L. Weissfeld, MD, MPH, of the Office of Surveillance and Epidemiology at the Center for Drug Evaluation and Research at the Food and Drug Administration, and his associates reported based on data from IQVIA Real World Data Adjudicated Claims – U.S. Database.

[email protected]

SOURCE: Weissfeld JL et al. Menopause. 2018;25(6):611-14.

Use of oral estrogens declined by half during 2007-2015 in women aged 50 years and older, but trends have varied for other forms of estrogen, according to a commercial database with prescription claims for more than 12 million women.

The prevalence of prescriptions for noncontraceptive oral estrogen dropped from 83 per 1,000 women in 2007 to 42 per 1,000 in 2015 for women aged 50 years and older, Joel L. Weissfeld, MD, MPH, of the Office of Surveillance and Epidemiology at the Center for Drug Evaluation and Research at the Food and Drug Administration, and his associates reported based on data from IQVIA Real World Data Adjudicated Claims – U.S. Database.

[email protected]

SOURCE: Weissfeld JL et al. Menopause. 2018;25(6):611-14.

A capsule containing a combination of 17-beta-estradiol and progesterone significantly improved vasomotor symptoms in menopausal women without causing a single case of endometrial hyperplasia.

The results of the 12-week REPLENISH study suggested that this preparation effectively treats vasomotor symptoms and could be a safe alternative to the popular, but unstudied, compounded bioidentical hormones that millions of women turned to after the Women’s Health Initiative study cast doubt on the safety of hormone therapy, Rogerio A. Lobo, MD, and his colleagues wrote in Obstetrics and Gynecology.

“17-beta-estradiol–progesterone may represent a new option, using natural hormones, for postmenopausal women, including the estimated millions currently using inadequately studied, non–FDA approved, compounded [hormone therapy],” wrote Dr. Lobo of Columbia University, New York.

REPLENISH randomized 1,845 postmenopausal women (mean age 55 years) to placebo or one of four active, daily, oral estradiol-progesterone doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The primary safety outcome was endometrial hyperplasia. There were two primary efficacy endpoints: mean changes in frequency and severity of moderate to severe vasomotor symptoms from baseline at weeks 4 and 12.

There were no cases of endometrial hyperplasia with any estradiol-progesterone dose, nor were there any endometrial cancers. The rates of endometrial proliferation and endometrial polyps were low (about 3% each).

The frequency of vasomotor symptoms decreased significantly, compared with placebo, in all active groups. The severity of vasomotor symptoms also decreased significantly and in a dose-dependent manner. Onset of action was similarly dose-dependent, with the 1 mg/100 mg group experiencing a clinically meaningful benefit by week 3 and the 0.5 mg/50 mg group by week 6.

Adverse events were mild-moderate and included breast tenderness, headache, nausea, pelvic pain, vaginal bleeding, and vaginal discharge. Serious adverse events included acute pancreatitis, deep vein thrombosis (in a woman with prior left femoral popliteal bypass surgery and a family history of deep vein thrombosis), chronic obstructive pulmonary disease, infective cholecystitis, and breast cancer.

TherapeuticsMD sponsored the study; Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant for the company and several others. Some coauthors report additional research support from and consulting with TherapeuticsMD and other companies, and three coauthors are stock-holding employees of TherapeuticsMD.

[email protected]

SOURCE: Lobo RA et al. Obstet Gynecol. 2018 Jan;132(1):161-70.

A capsule containing a combination of 17-beta-estradiol and progesterone significantly improved vasomotor symptoms in menopausal women without causing a single case of endometrial hyperplasia.

The results of the 12-week REPLENISH study suggested that this preparation effectively treats vasomotor symptoms and could be a safe alternative to the popular, but unstudied, compounded bioidentical hormones that millions of women turned to after the Women’s Health Initiative study cast doubt on the safety of hormone therapy, Rogerio A. Lobo, MD, and his colleagues wrote in Obstetrics and Gynecology.

“17-beta-estradiol–progesterone may represent a new option, using natural hormones, for postmenopausal women, including the estimated millions currently using inadequately studied, non–FDA approved, compounded [hormone therapy],” wrote Dr. Lobo of Columbia University, New York.

REPLENISH randomized 1,845 postmenopausal women (mean age 55 years) to placebo or one of four active, daily, oral estradiol-progesterone doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The primary safety outcome was endometrial hyperplasia. There were two primary efficacy endpoints: mean changes in frequency and severity of moderate to severe vasomotor symptoms from baseline at weeks 4 and 12.

There were no cases of endometrial hyperplasia with any estradiol-progesterone dose, nor were there any endometrial cancers. The rates of endometrial proliferation and endometrial polyps were low (about 3% each).

The frequency of vasomotor symptoms decreased significantly, compared with placebo, in all active groups. The severity of vasomotor symptoms also decreased significantly and in a dose-dependent manner. Onset of action was similarly dose-dependent, with the 1 mg/100 mg group experiencing a clinically meaningful benefit by week 3 and the 0.5 mg/50 mg group by week 6.

Adverse events were mild-moderate and included breast tenderness, headache, nausea, pelvic pain, vaginal bleeding, and vaginal discharge. Serious adverse events included acute pancreatitis, deep vein thrombosis (in a woman with prior left femoral popliteal bypass surgery and a family history of deep vein thrombosis), chronic obstructive pulmonary disease, infective cholecystitis, and breast cancer.

TherapeuticsMD sponsored the study; Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant for the company and several others. Some coauthors report additional research support from and consulting with TherapeuticsMD and other companies, and three coauthors are stock-holding employees of TherapeuticsMD.

[email protected]

SOURCE: Lobo RA et al. Obstet Gynecol. 2018 Jan;132(1):161-70.

A capsule containing a combination of 17-beta-estradiol and progesterone significantly improved vasomotor symptoms in menopausal women without causing a single case of endometrial hyperplasia.

The results of the 12-week REPLENISH study suggested that this preparation effectively treats vasomotor symptoms and could be a safe alternative to the popular, but unstudied, compounded bioidentical hormones that millions of women turned to after the Women’s Health Initiative study cast doubt on the safety of hormone therapy, Rogerio A. Lobo, MD, and his colleagues wrote in Obstetrics and Gynecology.

“17-beta-estradiol–progesterone may represent a new option, using natural hormones, for postmenopausal women, including the estimated millions currently using inadequately studied, non–FDA approved, compounded [hormone therapy],” wrote Dr. Lobo of Columbia University, New York.

REPLENISH randomized 1,845 postmenopausal women (mean age 55 years) to placebo or one of four active, daily, oral estradiol-progesterone doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, or 0.25 mg/50 mg). The primary safety outcome was endometrial hyperplasia. There were two primary efficacy endpoints: mean changes in frequency and severity of moderate to severe vasomotor symptoms from baseline at weeks 4 and 12.

There were no cases of endometrial hyperplasia with any estradiol-progesterone dose, nor were there any endometrial cancers. The rates of endometrial proliferation and endometrial polyps were low (about 3% each).

The frequency of vasomotor symptoms decreased significantly, compared with placebo, in all active groups. The severity of vasomotor symptoms also decreased significantly and in a dose-dependent manner. Onset of action was similarly dose-dependent, with the 1 mg/100 mg group experiencing a clinically meaningful benefit by week 3 and the 0.5 mg/50 mg group by week 6.

Adverse events were mild-moderate and included breast tenderness, headache, nausea, pelvic pain, vaginal bleeding, and vaginal discharge. Serious adverse events included acute pancreatitis, deep vein thrombosis (in a woman with prior left femoral popliteal bypass surgery and a family history of deep vein thrombosis), chronic obstructive pulmonary disease, infective cholecystitis, and breast cancer.

TherapeuticsMD sponsored the study; Dr. Lobo has received research grants from TherapeuticsMD and has served as a consultant for the company and several others. Some coauthors report additional research support from and consulting with TherapeuticsMD and other companies, and three coauthors are stock-holding employees of TherapeuticsMD.

[email protected]

SOURCE: Lobo RA et al. Obstet Gynecol. 2018 Jan;132(1):161-70.

In postmenopausal women, a higher level of testosterone in comparison to estrogen may increase the cardiovascular disease risk later in life, results of a recent analysis suggest.

A higher ratio of testosterone to estradiol was associated with the development of cardiovascular disease, coronary heart disease, and heart failure in postmenopausal women, according to results from an analysis based on 2,834 postmenopausal women in MESA (Multi-Ethnic Study of Atherosclerosis).

In addition, total testosterone levels were associated with increased cardiovascular disease and coronary heart disease, while estradiol is associated with a reduced risk of coronary heart disease and heart failure with reduced ejection fraction, investigators reported in the Journal of the American College of Cardiology.

Without any interventional studies as guidance, it’s not clear what the “best strategy” would be to modify sex hormone levels and reduce cardiovascular disease risk, wrote investigator Di Zhao, PhD, of the department of epidemiology at Johns Hopkins University Bloomberg School of Public Health, Baltimore, and her study coauthors.

“Nonetheless, a more androgenic sex hormone profile may identify a woman at higher risk for cardiovascular disease who may benefit from other risk-reducing strategies,” Dr. Zhao and her colleagues wrote in their report.

The postmenopausal women included in this analysis all had baseline measurements of testosterone, estradiol, dehydroepiandrosterone, and sex hormone–binding globulin levels between 2000 and 2002, according to the report.

After more than 12 years of follow-up, investigators found that a higher total testosterone to estradiol ratio was independently associated with an increased risk of incident cardiovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.40), coronary heart disease (HR, 1.45; 95% CI, 1.19-1.78), and heart failure (HR, 1.31; 95% CI, 1.01-1.70).

Investigators also reported a statistically significant association between total testosterone levels and risk of cardiovascular disease and coronary heart disease but not risk of heart failure.

In a subgroup analysis of postmenopausal women with heart failure, investigators found a significant positive association with the testosterone to estradiol ratio (HR, 1.65; 95% CI, 1.07-2.54) and inverse associations for estradiol (HR, 0.60; 95% CI, 0.39-0.93) and for dehydroepiandrosterone (HR, 0.59; 95% CI, 0.44-0.78).

On their own, estradiol levels had no association with cardiovascular disease events overall, but they were associated with lower coronary heart disease risk, according to investigators. Estradiol also was associated with a lower heart failure risk, though the trend did not reach statistical significance.

The study was partially funded by the American Heart Association’s Go Red for Women Research Network. Study authors reported disclosures related to Cordex Systems, Siemens Diagnostics, and other entities.

SOURCE: Zhao D et al. J Am Coll Cardiol. 2018 Jun 5; 71:2555-66.

In postmenopausal women, a higher level of testosterone in comparison to estrogen may increase the cardiovascular disease risk later in life, results of a recent analysis suggest.

A higher ratio of testosterone to estradiol was associated with the development of cardiovascular disease, coronary heart disease, and heart failure in postmenopausal women, according to results from an analysis based on 2,834 postmenopausal women in MESA (Multi-Ethnic Study of Atherosclerosis).

In addition, total testosterone levels were associated with increased cardiovascular disease and coronary heart disease, while estradiol is associated with a reduced risk of coronary heart disease and heart failure with reduced ejection fraction, investigators reported in the Journal of the American College of Cardiology.

Without any interventional studies as guidance, it’s not clear what the “best strategy” would be to modify sex hormone levels and reduce cardiovascular disease risk, wrote investigator Di Zhao, PhD, of the department of epidemiology at Johns Hopkins University Bloomberg School of Public Health, Baltimore, and her study coauthors.

“Nonetheless, a more androgenic sex hormone profile may identify a woman at higher risk for cardiovascular disease who may benefit from other risk-reducing strategies,” Dr. Zhao and her colleagues wrote in their report.

The postmenopausal women included in this analysis all had baseline measurements of testosterone, estradiol, dehydroepiandrosterone, and sex hormone–binding globulin levels between 2000 and 2002, according to the report.

After more than 12 years of follow-up, investigators found that a higher total testosterone to estradiol ratio was independently associated with an increased risk of incident cardiovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.40), coronary heart disease (HR, 1.45; 95% CI, 1.19-1.78), and heart failure (HR, 1.31; 95% CI, 1.01-1.70).

Investigators also reported a statistically significant association between total testosterone levels and risk of cardiovascular disease and coronary heart disease but not risk of heart failure.

In a subgroup analysis of postmenopausal women with heart failure, investigators found a significant positive association with the testosterone to estradiol ratio (HR, 1.65; 95% CI, 1.07-2.54) and inverse associations for estradiol (HR, 0.60; 95% CI, 0.39-0.93) and for dehydroepiandrosterone (HR, 0.59; 95% CI, 0.44-0.78).

On their own, estradiol levels had no association with cardiovascular disease events overall, but they were associated with lower coronary heart disease risk, according to investigators. Estradiol also was associated with a lower heart failure risk, though the trend did not reach statistical significance.

The study was partially funded by the American Heart Association’s Go Red for Women Research Network. Study authors reported disclosures related to Cordex Systems, Siemens Diagnostics, and other entities.

SOURCE: Zhao D et al. J Am Coll Cardiol. 2018 Jun 5; 71:2555-66.

In postmenopausal women, a higher level of testosterone in comparison to estrogen may increase the cardiovascular disease risk later in life, results of a recent analysis suggest.

A higher ratio of testosterone to estradiol was associated with the development of cardiovascular disease, coronary heart disease, and heart failure in postmenopausal women, according to results from an analysis based on 2,834 postmenopausal women in MESA (Multi-Ethnic Study of Atherosclerosis).

In addition, total testosterone levels were associated with increased cardiovascular disease and coronary heart disease, while estradiol is associated with a reduced risk of coronary heart disease and heart failure with reduced ejection fraction, investigators reported in the Journal of the American College of Cardiology.

Without any interventional studies as guidance, it’s not clear what the “best strategy” would be to modify sex hormone levels and reduce cardiovascular disease risk, wrote investigator Di Zhao, PhD, of the department of epidemiology at Johns Hopkins University Bloomberg School of Public Health, Baltimore, and her study coauthors.

“Nonetheless, a more androgenic sex hormone profile may identify a woman at higher risk for cardiovascular disease who may benefit from other risk-reducing strategies,” Dr. Zhao and her colleagues wrote in their report.

The postmenopausal women included in this analysis all had baseline measurements of testosterone, estradiol, dehydroepiandrosterone, and sex hormone–binding globulin levels between 2000 and 2002, according to the report.

After more than 12 years of follow-up, investigators found that a higher total testosterone to estradiol ratio was independently associated with an increased risk of incident cardiovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.02-1.40), coronary heart disease (HR, 1.45; 95% CI, 1.19-1.78), and heart failure (HR, 1.31; 95% CI, 1.01-1.70).

Investigators also reported a statistically significant association between total testosterone levels and risk of cardiovascular disease and coronary heart disease but not risk of heart failure.

In a subgroup analysis of postmenopausal women with heart failure, investigators found a significant positive association with the testosterone to estradiol ratio (HR, 1.65; 95% CI, 1.07-2.54) and inverse associations for estradiol (HR, 0.60; 95% CI, 0.39-0.93) and for dehydroepiandrosterone (HR, 0.59; 95% CI, 0.44-0.78).

On their own, estradiol levels had no association with cardiovascular disease events overall, but they were associated with lower coronary heart disease risk, according to investigators. Estradiol also was associated with a lower heart failure risk, though the trend did not reach statistical significance.

The study was partially funded by the American Heart Association’s Go Red for Women Research Network. Study authors reported disclosures related to Cordex Systems, Siemens Diagnostics, and other entities.

SOURCE: Zhao D et al. J Am Coll Cardiol. 2018 Jun 5; 71:2555-66.

Our knowledge regarding the benefits and risks of systemic menopausal hormone therapy (HT) has continued to evolve since the 2002 publication of the initial findings of the Women’s Health Initiative (WHI). In late 2017, the US Preventive Services Task Force (USPSTF) issued its recommendation against the use of menopausal HT for the prevention of chronic conditions. In this Menopause Update, Dr. JoAnn Manson, Dr. JoAnn Pinkerton, and I detail why we do not support the Task Force’s recommendation. In a sidebar discussion, Dr. Manson also reviews the results of 2 WHI HT trials, published in September 2017, that analyzed mortality in trial participants over an 18-year follow-up.

In addition, I summarize an observational study that assessed the association of HT and Alzheimer disease (AD) as well as a clinical trial that compared the impact of oral versus transdermal estrogen on sexuality in recently menopausal women.

What's the impact of long-term use of systemic HT on Alzheimer disease risk?

Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology. 2017;88(11):1062-1068.

Data from the WHI HT randomized trials have clarified that initiation of oral HT among women aged 65 and older increases the risk of cognitive decline. By contrast, an analysis of younger WHI participants found that oral HT had no impact on cognitive function. Recently, Imtiaz and colleagues conducted a prospective cohort study of postmenopausal HT and AD in women residing in a Finnish county, with 25 years of follow-up. A diagnosis of AD was based on administrative health records and use of medications prescribed specifically to treat dementia. Use of systemic HT was identified via self-report. Overall, among more than 8,000 women followed, 227 cases of AD (mean age, 72 years) were identified.

In an analysis that controlled for factors including age, body mass index, alcohol use, smoking, physical activity, occupation status, and parity, up to 5 years of HT use was not associated with a risk of being diagnosed with AD. Five to 10 years of HT use was associated with a hazard ratio (HR) of 0.89, an 11% risk reduction that did not achieve statistical significance. By contrast, more than 10 years' use of systemic HT was associated with an HR of 0.53, a statistically significant 47% reduction in risk of AD.¹

Other studies found conflicting results

Three large randomized trials found that HT initiated early in menopause and continued for less than 7 years had no impact on cognitive function.^2-4 The Cache County (Utah) long-term prospective cohort study, however, found that HT started early in menopause and continued for 10 years or longer was associated with a significant reduction in risk of AD.⁵

Of note are results from the 2017 report of 18-year cumulative mortality among WHI participants (see the box on page 30). In that study, mortality from AD and other dementia was lower among participants who were randomly assigned to treatment with estrogen alone versus placebo (HR, 0.74; 95% confidence interval [CI], 0.59-0.94). With estrogen-progestin therapy, the HR was 0.93 (95% CI, 0.77-1.11), and the pooled HR for the 2 trials was 0.85 (95% CI, 0.74-0.98).⁶

NAMS guidance

The North American Menopause Society (NAMS) HT position statement recommends that prevention of dementia should not be considered an indication for HT use since definitive data are not available.⁷ The statement indicates also that estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause and taken until the average age of menopause to prevent health risks seen with early loss of hormones.

Read Dr. Manson’s discussion of 18 years of follow-up data on menopause.

Read how the route of HT may affect sexuality outcomes.

Oral vs transdermal estrogen therapy: Is one preferable regarding sexuality?

Taylor HS, Tal A, Pal L, et al. Effects of oral vs transdermal estrogen therapy on sexual function in early post menopause: ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017;177(10):1471-1479.

If route of administration of systemic HT influences sexuality outcomes in menopausal women, this would inform how we counsel our patients regarding HT.

Recently, Taylor and colleagues conducted a randomized clinical trial to examine the effects of HT's route of administration on sexual function.⁸ The 4-year Kronos Early Estrogen Prevention Study (KEEPS) ancillary sexual study randomly assigned 670 recently menopausal women to 0.45 mg of oral conjugated equine estrogens (CEE), an 0.05-mg estradiol transdermal patch, or placebo (with oral micronized progesterone for those on active treatment). The participants were aged 42 to 58 years and were within 36 months from their last menstrual period.

Participants were evaluated using the Female Sexual Function Inventory (FSFI) questionnaire, which assessed desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI is scored using a point range of 0 to 36. A higher FSFI score indicates better sexual function. An FSFI score less than 26.55 depicts low sexual function (LSF). 

Transdermal estrogen improved sexual function scores

Treatment with oral CEE was associated with no significant change in FSFI score compared with placebo, although benefits were seen for lubrication. By contrast, estrogen patch use improved the FSFI score (mean improvement, 2.6). Although improvement in FSFI score with transdermal estrogen was limited to participants with baseline LSF, most participants in fact had LSF at baseline.

Read about the authors’ concern over new USPSTF guidance.

The USPSTF recommendation against menopausal HT use for prevention of chronic conditions: Guidance that may confuse--and mislead

US Preventive Services Task Force; Grossman DC, CurrySJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA. 2017;318(22):2224-2233.

In late 2017, the USPSTF issued its recommendation against the use of menopausal HT for prevention of chronic conditions.⁹ We are concerned that this recommendation will be misconstrued as suggesting that the use of HT is not appropriate for any indication, including treatment of bothersome menopausal symptoms.

Although the Task Force's report briefly indicated that the guidance does not refer to HT use for treatment of symptoms, this important disclaimer likely will be overlooked or ignored by many readers. The result may be increased uncertainty and anxiety in decision making regarding HT use. Thus, we might see a further decline in the proportion of menopausal women who are prescribed appropriate treatment for symptoms that impair quality of life.

HT use improves menopausal symptoms

According to the 2017 NAMS Position Statement, for symptomatic women in early menopause (that is, younger than age 60 or within 10 years of menopause onset) and free of contraindications to treatment, use of systemic HT is appropriate.⁷ Currently, clinicians are reluctant to prescribe HT, and women are apprehensive regarding its use.¹⁰ Unfortunately, the USPSTF guidance may further discourage appropriate treatment of menopausal symptoms.

Findings from randomized clinical trials, as well as preclinical, clinical, and epidemiologic studies, clarify the favorable benefit-risk profile for HT use by recently menopausal women with bothersome vasomotor and related menopausal symptoms.^7,10-12

Notably, the USPSTF guidance does not address women with premature or early menopause, those with persistent (long-duration) vasomotor symptoms, or women at increased risk for osteoporosis and related fractures. Furthermore, the prevalent and undertreated condition, genitourinary syndrome of menopause, deserves but does not receive attention.

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.

Our knowledge regarding the benefits and risks of systemic menopausal hormone therapy (HT) has continued to evolve since the 2002 publication of the initial findings of the Women’s Health Initiative (WHI). In late 2017, the US Preventive Services Task Force (USPSTF) issued its recommendation against the use of menopausal HT for the prevention of chronic conditions. In this Menopause Update, Dr. JoAnn Manson, Dr. JoAnn Pinkerton, and I detail why we do not support the Task Force’s recommendation. In a sidebar discussion, Dr. Manson also reviews the results of 2 WHI HT trials, published in September 2017, that analyzed mortality in trial participants over an 18-year follow-up.

In addition, I summarize an observational study that assessed the association of HT and Alzheimer disease (AD) as well as a clinical trial that compared the impact of oral versus transdermal estrogen on sexuality in recently menopausal women.

What's the impact of long-term use of systemic HT on Alzheimer disease risk?

Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology. 2017;88(11):1062-1068.

Data from the WHI HT randomized trials have clarified that initiation of oral HT among women aged 65 and older increases the risk of cognitive decline. By contrast, an analysis of younger WHI participants found that oral HT had no impact on cognitive function. Recently, Imtiaz and colleagues conducted a prospective cohort study of postmenopausal HT and AD in women residing in a Finnish county, with 25 years of follow-up. A diagnosis of AD was based on administrative health records and use of medications prescribed specifically to treat dementia. Use of systemic HT was identified via self-report. Overall, among more than 8,000 women followed, 227 cases of AD (mean age, 72 years) were identified.

In an analysis that controlled for factors including age, body mass index, alcohol use, smoking, physical activity, occupation status, and parity, up to 5 years of HT use was not associated with a risk of being diagnosed with AD. Five to 10 years of HT use was associated with a hazard ratio (HR) of 0.89, an 11% risk reduction that did not achieve statistical significance. By contrast, more than 10 years' use of systemic HT was associated with an HR of 0.53, a statistically significant 47% reduction in risk of AD.¹

Other studies found conflicting results

Three large randomized trials found that HT initiated early in menopause and continued for less than 7 years had no impact on cognitive function.^2-4 The Cache County (Utah) long-term prospective cohort study, however, found that HT started early in menopause and continued for 10 years or longer was associated with a significant reduction in risk of AD.⁵

Of note are results from the 2017 report of 18-year cumulative mortality among WHI participants (see the box on page 30). In that study, mortality from AD and other dementia was lower among participants who were randomly assigned to treatment with estrogen alone versus placebo (HR, 0.74; 95% confidence interval [CI], 0.59-0.94). With estrogen-progestin therapy, the HR was 0.93 (95% CI, 0.77-1.11), and the pooled HR for the 2 trials was 0.85 (95% CI, 0.74-0.98).⁶

NAMS guidance

The North American Menopause Society (NAMS) HT position statement recommends that prevention of dementia should not be considered an indication for HT use since definitive data are not available.⁷ The statement indicates also that estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause and taken until the average age of menopause to prevent health risks seen with early loss of hormones.

Read Dr. Manson’s discussion of 18 years of follow-up data on menopause.

Read how the route of HT may affect sexuality outcomes.

Oral vs transdermal estrogen therapy: Is one preferable regarding sexuality?

Taylor HS, Tal A, Pal L, et al. Effects of oral vs transdermal estrogen therapy on sexual function in early post menopause: ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017;177(10):1471-1479.

If route of administration of systemic HT influences sexuality outcomes in menopausal women, this would inform how we counsel our patients regarding HT.

Recently, Taylor and colleagues conducted a randomized clinical trial to examine the effects of HT's route of administration on sexual function.⁸ The 4-year Kronos Early Estrogen Prevention Study (KEEPS) ancillary sexual study randomly assigned 670 recently menopausal women to 0.45 mg of oral conjugated equine estrogens (CEE), an 0.05-mg estradiol transdermal patch, or placebo (with oral micronized progesterone for those on active treatment). The participants were aged 42 to 58 years and were within 36 months from their last menstrual period.

Participants were evaluated using the Female Sexual Function Inventory (FSFI) questionnaire, which assessed desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI is scored using a point range of 0 to 36. A higher FSFI score indicates better sexual function. An FSFI score less than 26.55 depicts low sexual function (LSF). 

Transdermal estrogen improved sexual function scores

Treatment with oral CEE was associated with no significant change in FSFI score compared with placebo, although benefits were seen for lubrication. By contrast, estrogen patch use improved the FSFI score (mean improvement, 2.6). Although improvement in FSFI score with transdermal estrogen was limited to participants with baseline LSF, most participants in fact had LSF at baseline.

Read about the authors’ concern over new USPSTF guidance.

The USPSTF recommendation against menopausal HT use for prevention of chronic conditions: Guidance that may confuse--and mislead

US Preventive Services Task Force; Grossman DC, CurrySJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA. 2017;318(22):2224-2233.

In late 2017, the USPSTF issued its recommendation against the use of menopausal HT for prevention of chronic conditions.⁹ We are concerned that this recommendation will be misconstrued as suggesting that the use of HT is not appropriate for any indication, including treatment of bothersome menopausal symptoms.

Although the Task Force's report briefly indicated that the guidance does not refer to HT use for treatment of symptoms, this important disclaimer likely will be overlooked or ignored by many readers. The result may be increased uncertainty and anxiety in decision making regarding HT use. Thus, we might see a further decline in the proportion of menopausal women who are prescribed appropriate treatment for symptoms that impair quality of life.

HT use improves menopausal symptoms

According to the 2017 NAMS Position Statement, for symptomatic women in early menopause (that is, younger than age 60 or within 10 years of menopause onset) and free of contraindications to treatment, use of systemic HT is appropriate.⁷ Currently, clinicians are reluctant to prescribe HT, and women are apprehensive regarding its use.¹⁰ Unfortunately, the USPSTF guidance may further discourage appropriate treatment of menopausal symptoms.

Findings from randomized clinical trials, as well as preclinical, clinical, and epidemiologic studies, clarify the favorable benefit-risk profile for HT use by recently menopausal women with bothersome vasomotor and related menopausal symptoms.^7,10-12

Notably, the USPSTF guidance does not address women with premature or early menopause, those with persistent (long-duration) vasomotor symptoms, or women at increased risk for osteoporosis and related fractures. Furthermore, the prevalent and undertreated condition, genitourinary syndrome of menopause, deserves but does not receive attention.

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.

Our knowledge regarding the benefits and risks of systemic menopausal hormone therapy (HT) has continued to evolve since the 2002 publication of the initial findings of the Women’s Health Initiative (WHI). In late 2017, the US Preventive Services Task Force (USPSTF) issued its recommendation against the use of menopausal HT for the prevention of chronic conditions. In this Menopause Update, Dr. JoAnn Manson, Dr. JoAnn Pinkerton, and I detail why we do not support the Task Force’s recommendation. In a sidebar discussion, Dr. Manson also reviews the results of 2 WHI HT trials, published in September 2017, that analyzed mortality in trial participants over an 18-year follow-up.

In addition, I summarize an observational study that assessed the association of HT and Alzheimer disease (AD) as well as a clinical trial that compared the impact of oral versus transdermal estrogen on sexuality in recently menopausal women.

What's the impact of long-term use of systemic HT on Alzheimer disease risk?

Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology. 2017;88(11):1062-1068.

Data from the WHI HT randomized trials have clarified that initiation of oral HT among women aged 65 and older increases the risk of cognitive decline. By contrast, an analysis of younger WHI participants found that oral HT had no impact on cognitive function. Recently, Imtiaz and colleagues conducted a prospective cohort study of postmenopausal HT and AD in women residing in a Finnish county, with 25 years of follow-up. A diagnosis of AD was based on administrative health records and use of medications prescribed specifically to treat dementia. Use of systemic HT was identified via self-report. Overall, among more than 8,000 women followed, 227 cases of AD (mean age, 72 years) were identified.

In an analysis that controlled for factors including age, body mass index, alcohol use, smoking, physical activity, occupation status, and parity, up to 5 years of HT use was not associated with a risk of being diagnosed with AD. Five to 10 years of HT use was associated with a hazard ratio (HR) of 0.89, an 11% risk reduction that did not achieve statistical significance. By contrast, more than 10 years' use of systemic HT was associated with an HR of 0.53, a statistically significant 47% reduction in risk of AD.¹

Other studies found conflicting results

Three large randomized trials found that HT initiated early in menopause and continued for less than 7 years had no impact on cognitive function.^2-4 The Cache County (Utah) long-term prospective cohort study, however, found that HT started early in menopause and continued for 10 years or longer was associated with a significant reduction in risk of AD.⁵

Of note are results from the 2017 report of 18-year cumulative mortality among WHI participants (see the box on page 30). In that study, mortality from AD and other dementia was lower among participants who were randomly assigned to treatment with estrogen alone versus placebo (HR, 0.74; 95% confidence interval [CI], 0.59-0.94). With estrogen-progestin therapy, the HR was 0.93 (95% CI, 0.77-1.11), and the pooled HR for the 2 trials was 0.85 (95% CI, 0.74-0.98).⁶

NAMS guidance

The North American Menopause Society (NAMS) HT position statement recommends that prevention of dementia should not be considered an indication for HT use since definitive data are not available.⁷ The statement indicates also that estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause and taken until the average age of menopause to prevent health risks seen with early loss of hormones.

Read Dr. Manson’s discussion of 18 years of follow-up data on menopause.

Read how the route of HT may affect sexuality outcomes.

Oral vs transdermal estrogen therapy: Is one preferable regarding sexuality?

Taylor HS, Tal A, Pal L, et al. Effects of oral vs transdermal estrogen therapy on sexual function in early post menopause: ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017;177(10):1471-1479.

If route of administration of systemic HT influences sexuality outcomes in menopausal women, this would inform how we counsel our patients regarding HT.

Recently, Taylor and colleagues conducted a randomized clinical trial to examine the effects of HT's route of administration on sexual function.⁸ The 4-year Kronos Early Estrogen Prevention Study (KEEPS) ancillary sexual study randomly assigned 670 recently menopausal women to 0.45 mg of oral conjugated equine estrogens (CEE), an 0.05-mg estradiol transdermal patch, or placebo (with oral micronized progesterone for those on active treatment). The participants were aged 42 to 58 years and were within 36 months from their last menstrual period.

Participants were evaluated using the Female Sexual Function Inventory (FSFI) questionnaire, which assessed desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI is scored using a point range of 0 to 36. A higher FSFI score indicates better sexual function. An FSFI score less than 26.55 depicts low sexual function (LSF). 

Transdermal estrogen improved sexual function scores

Treatment with oral CEE was associated with no significant change in FSFI score compared with placebo, although benefits were seen for lubrication. By contrast, estrogen patch use improved the FSFI score (mean improvement, 2.6). Although improvement in FSFI score with transdermal estrogen was limited to participants with baseline LSF, most participants in fact had LSF at baseline.

Read about the authors’ concern over new USPSTF guidance.

The USPSTF recommendation against menopausal HT use for prevention of chronic conditions: Guidance that may confuse--and mislead

US Preventive Services Task Force; Grossman DC, CurrySJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA. 2017;318(22):2224-2233.

In late 2017, the USPSTF issued its recommendation against the use of menopausal HT for prevention of chronic conditions.⁹ We are concerned that this recommendation will be misconstrued as suggesting that the use of HT is not appropriate for any indication, including treatment of bothersome menopausal symptoms.

Although the Task Force's report briefly indicated that the guidance does not refer to HT use for treatment of symptoms, this important disclaimer likely will be overlooked or ignored by many readers. The result may be increased uncertainty and anxiety in decision making regarding HT use. Thus, we might see a further decline in the proportion of menopausal women who are prescribed appropriate treatment for symptoms that impair quality of life.

HT use improves menopausal symptoms

According to the 2017 NAMS Position Statement, for symptomatic women in early menopause (that is, younger than age 60 or within 10 years of menopause onset) and free of contraindications to treatment, use of systemic HT is appropriate.⁷ Currently, clinicians are reluctant to prescribe HT, and women are apprehensive regarding its use.¹⁰ Unfortunately, the USPSTF guidance may further discourage appropriate treatment of menopausal symptoms.

Findings from randomized clinical trials, as well as preclinical, clinical, and epidemiologic studies, clarify the favorable benefit-risk profile for HT use by recently menopausal women with bothersome vasomotor and related menopausal symptoms.^7,10-12

Notably, the USPSTF guidance does not address women with premature or early menopause, those with persistent (long-duration) vasomotor symptoms, or women at increased risk for osteoporosis and related fractures. Furthermore, the prevalent and undertreated condition, genitourinary syndrome of menopause, deserves but does not receive attention.

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.

CHICAGO – Two women in their 30s resumed menstruation about 7 months after one of their ovaries was injected with human mesenchymal stem cells obtained from their hips.

Neither of the women had menstruated for about 5 years; both were in premature menopause and wanted desperately to start a family. Estrogen levels began increasing soon after treatment, and night sweats and other symptoms of menopause almost disappeared. After a year, the treated ovary was almost the size of a normal premenopausal ovary. There weren’t any complications or side effects, and both women are now pursuing pregnancy.

The results are “very exciting, very encouraging,” said senior investigator Ayman Al-Hendy, MD, PhD, a gynecology professor at the University of Illinois at Chicago.

Robert Lodge/MDEdge News

[email protected]

SOURCE: Al-Hendy A et al. ENDO 2018, Abstract OR33-6.

CHICAGO – Two women in their 30s resumed menstruation about 7 months after one of their ovaries was injected with human mesenchymal stem cells obtained from their hips.

Neither of the women had menstruated for about 5 years; both were in premature menopause and wanted desperately to start a family. Estrogen levels began increasing soon after treatment, and night sweats and other symptoms of menopause almost disappeared. After a year, the treated ovary was almost the size of a normal premenopausal ovary. There weren’t any complications or side effects, and both women are now pursuing pregnancy.

The results are “very exciting, very encouraging,” said senior investigator Ayman Al-Hendy, MD, PhD, a gynecology professor at the University of Illinois at Chicago.

Robert Lodge/MDEdge News

[email protected]

SOURCE: Al-Hendy A et al. ENDO 2018, Abstract OR33-6.

CHICAGO – Two women in their 30s resumed menstruation about 7 months after one of their ovaries was injected with human mesenchymal stem cells obtained from their hips.

Neither of the women had menstruated for about 5 years; both were in premature menopause and wanted desperately to start a family. Estrogen levels began increasing soon after treatment, and night sweats and other symptoms of menopause almost disappeared. After a year, the treated ovary was almost the size of a normal premenopausal ovary. There weren’t any complications or side effects, and both women are now pursuing pregnancy.

The results are “very exciting, very encouraging,” said senior investigator Ayman Al-Hendy, MD, PhD, a gynecology professor at the University of Illinois at Chicago.

Robert Lodge/MDEdge News

[email protected]

SOURCE: Al-Hendy A et al. ENDO 2018, Abstract OR33-6.

Rheumatoid arthritis gets worse after menopause, likely because of lower hormone levels, according to a review of 8,189 women in the National Data Bank for Rheumatic Diseases, published recently in Rheumatology.

The investigators compared scores on the Health Assessment Questionnaire (HAQ) between 2,005 premenopausal women with a mean age of 39.7 years; 611 women transitioning through menopause with a mean age of 50.7 years, and 5,573 postmenopausal women with a mean age of 62.3 years. As participants in the data bank, the women completed a questionnaire at regular intervals that included the HAQ, which is a 3-point measure of functional status, with 0 meaning no disability and 3 severe disability. They had all been diagnosed with rheumatoid arthritis prior to menopause.

Devonyu/Thinkstock

[email protected]

SOURCE: Mollard E et. al. Rheumatology. 2018 Jan 29. doi: 10.1093/rheumatology/kex526

Rheumatoid arthritis gets worse after menopause, likely because of lower hormone levels, according to a review of 8,189 women in the National Data Bank for Rheumatic Diseases, published recently in Rheumatology.

The investigators compared scores on the Health Assessment Questionnaire (HAQ) between 2,005 premenopausal women with a mean age of 39.7 years; 611 women transitioning through menopause with a mean age of 50.7 years, and 5,573 postmenopausal women with a mean age of 62.3 years. As participants in the data bank, the women completed a questionnaire at regular intervals that included the HAQ, which is a 3-point measure of functional status, with 0 meaning no disability and 3 severe disability. They had all been diagnosed with rheumatoid arthritis prior to menopause.

Devonyu/Thinkstock

[email protected]

SOURCE: Mollard E et. al. Rheumatology. 2018 Jan 29. doi: 10.1093/rheumatology/kex526

Rheumatoid arthritis gets worse after menopause, likely because of lower hormone levels, according to a review of 8,189 women in the National Data Bank for Rheumatic Diseases, published recently in Rheumatology.

The investigators compared scores on the Health Assessment Questionnaire (HAQ) between 2,005 premenopausal women with a mean age of 39.7 years; 611 women transitioning through menopause with a mean age of 50.7 years, and 5,573 postmenopausal women with a mean age of 62.3 years. As participants in the data bank, the women completed a questionnaire at regular intervals that included the HAQ, which is a 3-point measure of functional status, with 0 meaning no disability and 3 severe disability. They had all been diagnosed with rheumatoid arthritis prior to menopause.

Devonyu/Thinkstock

[email protected]

SOURCE: Mollard E et. al. Rheumatology. 2018 Jan 29. doi: 10.1093/rheumatology/kex526

Hormone therapy may reduce the likelihood of depressive symptoms during early menopause, according to data from a placebo-controlled study published online Jan. 10 in JAMA Psychiatry.

Researchers randomized 172 medically healthy women who were perimenopausal or early postmenopausal to either patches of 0.1 mg of 17 beta-estradiol or placebo patches for 12 months, as well as oral micronized progesterone or placebo every 2-3 months.

Women in the placebo arm were more than twice as likely to score at least 16 on the Center for Epidemiologic Studies–Depression Scale (CES-D) at least once during the study, compared with women in the hormone therapy arm (32.3% vs. 17.3%; odds ratio, 2.5; 95% confidence interval, 1.1-5.7; P = .03). They also scored at least 16 on the scale during more visits than did women in the intervention arm (P = .002).

Women who received placebo had a significantly higher mean CES-D score over the course of the 12-month study, compared with those in the intervention arm. At 6 months, mean unadjusted CES-D scores were 5.6 in the placebo group and 4.2 in the intervention group. At 12 months, the scores were 5.7 and 4 respectively.

“Importantly, these results were significant despite statistically adjusting for change in vasomotor symptom bother, suggesting that TE+IMP [transdermal estradiol + intermittent micronized progesterone] has direct prophylactic mood benefits that are independent from its beneficial effects on menopausal symptoms, as previously observed in women with major depressive disorder treated with TE+IMP,” wrote Jennifer L. Gordon, PhD, of the psychology department at the University of Regina, Saskatchewan, and her associates.

The effect of hormone therapy on depression scores changed significantly depending on the women’s stage of menopause. Women in the early menopause transition experienced significant mood benefits, but women in the late menopause transition and those who were postmenopausal did not.

Treatment effects also were influenced by stress, as women who reported experiencing more stressful life events in the 6 months before enrolling in the study showed greater mood benefits than did those with fewer stressful life events.

However, baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not significantly change the effects of treatment.

Women who received the hormone therapy reported significantly more spotting and bleeding, compared with the placebo group, and one woman in the treatment group experienced acute deep vein thrombosis that led her to stop treatment and receive medical care. Two cases of major depressive disorder were noted in the placebo group.

Dr. Gordon and her associates cited several limitations. For example, they said, the active and placebo patches used in the study were not identical. “However, our findings remain significant when adjusting for participants’ beliefs about their treatment condition,” they wrote.

The study was supported by the National Institutes of Health, and one author was supported by a fellowship of the Fonds de la Recherche du Québec–Santé. No conflicts of interest were declared.

[email protected]

SOURCE: Gordon JL et al. JAMA Psychiatry. 2018 Jan 10. doi: 1010/jamapsychiatry.2018.3998.

Hormone therapy may reduce the likelihood of depressive symptoms during early menopause, according to data from a placebo-controlled study published online Jan. 10 in JAMA Psychiatry.

Researchers randomized 172 medically healthy women who were perimenopausal or early postmenopausal to either patches of 0.1 mg of 17 beta-estradiol or placebo patches for 12 months, as well as oral micronized progesterone or placebo every 2-3 months.

Women in the placebo arm were more than twice as likely to score at least 16 on the Center for Epidemiologic Studies–Depression Scale (CES-D) at least once during the study, compared with women in the hormone therapy arm (32.3% vs. 17.3%; odds ratio, 2.5; 95% confidence interval, 1.1-5.7; P = .03). They also scored at least 16 on the scale during more visits than did women in the intervention arm (P = .002).

Women who received placebo had a significantly higher mean CES-D score over the course of the 12-month study, compared with those in the intervention arm. At 6 months, mean unadjusted CES-D scores were 5.6 in the placebo group and 4.2 in the intervention group. At 12 months, the scores were 5.7 and 4 respectively.

“Importantly, these results were significant despite statistically adjusting for change in vasomotor symptom bother, suggesting that TE+IMP [transdermal estradiol + intermittent micronized progesterone] has direct prophylactic mood benefits that are independent from its beneficial effects on menopausal symptoms, as previously observed in women with major depressive disorder treated with TE+IMP,” wrote Jennifer L. Gordon, PhD, of the psychology department at the University of Regina, Saskatchewan, and her associates.

The effect of hormone therapy on depression scores changed significantly depending on the women’s stage of menopause. Women in the early menopause transition experienced significant mood benefits, but women in the late menopause transition and those who were postmenopausal did not.

Treatment effects also were influenced by stress, as women who reported experiencing more stressful life events in the 6 months before enrolling in the study showed greater mood benefits than did those with fewer stressful life events.

However, baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not significantly change the effects of treatment.

Women who received the hormone therapy reported significantly more spotting and bleeding, compared with the placebo group, and one woman in the treatment group experienced acute deep vein thrombosis that led her to stop treatment and receive medical care. Two cases of major depressive disorder were noted in the placebo group.

Dr. Gordon and her associates cited several limitations. For example, they said, the active and placebo patches used in the study were not identical. “However, our findings remain significant when adjusting for participants’ beliefs about their treatment condition,” they wrote.

The study was supported by the National Institutes of Health, and one author was supported by a fellowship of the Fonds de la Recherche du Québec–Santé. No conflicts of interest were declared.

[email protected]

SOURCE: Gordon JL et al. JAMA Psychiatry. 2018 Jan 10. doi: 1010/jamapsychiatry.2018.3998.

Hormone therapy may reduce the likelihood of depressive symptoms during early menopause, according to data from a placebo-controlled study published online Jan. 10 in JAMA Psychiatry.

Researchers randomized 172 medically healthy women who were perimenopausal or early postmenopausal to either patches of 0.1 mg of 17 beta-estradiol or placebo patches for 12 months, as well as oral micronized progesterone or placebo every 2-3 months.

Women in the placebo arm were more than twice as likely to score at least 16 on the Center for Epidemiologic Studies–Depression Scale (CES-D) at least once during the study, compared with women in the hormone therapy arm (32.3% vs. 17.3%; odds ratio, 2.5; 95% confidence interval, 1.1-5.7; P = .03). They also scored at least 16 on the scale during more visits than did women in the intervention arm (P = .002).

Women who received placebo had a significantly higher mean CES-D score over the course of the 12-month study, compared with those in the intervention arm. At 6 months, mean unadjusted CES-D scores were 5.6 in the placebo group and 4.2 in the intervention group. At 12 months, the scores were 5.7 and 4 respectively.

“Importantly, these results were significant despite statistically adjusting for change in vasomotor symptom bother, suggesting that TE+IMP [transdermal estradiol + intermittent micronized progesterone] has direct prophylactic mood benefits that are independent from its beneficial effects on menopausal symptoms, as previously observed in women with major depressive disorder treated with TE+IMP,” wrote Jennifer L. Gordon, PhD, of the psychology department at the University of Regina, Saskatchewan, and her associates.

The effect of hormone therapy on depression scores changed significantly depending on the women’s stage of menopause. Women in the early menopause transition experienced significant mood benefits, but women in the late menopause transition and those who were postmenopausal did not.

Treatment effects also were influenced by stress, as women who reported experiencing more stressful life events in the 6 months before enrolling in the study showed greater mood benefits than did those with fewer stressful life events.

However, baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not significantly change the effects of treatment.

Women who received the hormone therapy reported significantly more spotting and bleeding, compared with the placebo group, and one woman in the treatment group experienced acute deep vein thrombosis that led her to stop treatment and receive medical care. Two cases of major depressive disorder were noted in the placebo group.

Dr. Gordon and her associates cited several limitations. For example, they said, the active and placebo patches used in the study were not identical. “However, our findings remain significant when adjusting for participants’ beliefs about their treatment condition,” they wrote.

The study was supported by the National Institutes of Health, and one author was supported by a fellowship of the Fonds de la Recherche du Québec–Santé. No conflicts of interest were declared.

[email protected]

SOURCE: Gordon JL et al. JAMA Psychiatry. 2018 Jan 10. doi: 1010/jamapsychiatry.2018.3998.