By Jeffrey T. Jensen, MD, MPH, Editor
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he receives grant/research support from and is a consultant for ObstetRx, Bayer, Merck, and Sebela Pharma; is a consultant for AbbVie, Mithra, and Daré Bioscience; and receives grant/research support from CooperSurgical and the Population Council.
SYNOPSIS: A post-hoc analysis of data from a 12-week randomized study that compared vaginal estradiol to vaginal moisturizers found no increase in sexual frequency or decrease in pain associated with either treatment, compared to placebo.
SOURCE: Mitchell CM, Guthrie KA, Larson J, et al. Sexual frequency and pain in a randomized clinical trial of vaginal estradiol tablets, moisturizer, and placebo in postmenopausal women. Menopause 2019;26:816-822.
In this paper, Mitchell and colleagues report results from a secondary post-hoc analysis of data from a previously published double-blind placebo-controlled trial. That study randomized postmenopausal women with moderate to severe genitourinary discomfort to vaginal treatment with a vaginal estradiol tablet, vaginal moisturizer, or placebo.1 Women used the vaginal tablet daily for two weeks, and then twice weekly for 10 weeks; they used the gel every third day throughout the trial (total 12 weeks of therapy). The treatment groups included an active vaginal estrogen tablet (Vagifem, 10 mcg estradiol) plus a placebo (hydroxy-methylcellulose) gel, a placebo tablet plus an approved vaginal moisturizer (Replens; contains purified water, glycerin, mineral oil, polycarbophil, carbomer homopolymer type B, hydrogenated palm oil glyceride, sorbic acid, and sodium hydroxide), or dual placebo (tablet and gel).
The primary outcome of the original randomized study was a change in severity of the most bothersome symptom (MBS) between enrollment and weeks four and 12. The MBS was defined by the participant at trial enrollment as either vulvovaginal itching, pain, dryness, irritation, or pain with penetration, with severity rated as none, mild, moderate, or severe on a 0 to 3 scale. The investigators found similar mean reductions in MBS severity over 12 weeks with both active treatments and placebo.
This new secondary analysis was intended to evaluate the effect of treatment on the frequency of sexual activity and on the pain severity with sexual activity. The study population of 302 women (102 received the estradiol tablet, 100 received the active gel, and 100 received placebo) had 80% power to detect a 22% difference in these outcomes with a 5% alpha error. The mean age of participants was 61 years; most were white (88%), college-educated (66%), and most reported sexual activity in the month before enrollment (81%).
After 12 weeks of therapy, similar proportions of women in the vaginal estrogen (49.5%, [95% confidence interval, 39.1, 59.8]), vaginal gel (35.2% [25.2, 45.2]), and dual placebo (39.8 [29.7, 49.9]) groups reported sexual activity in the past week. The mean pain scores with sexual activity at 12 weeks also did not differ between groups. Based on these results, the authors concluded that a 12-week treatment course of low-dose vaginal estradiol or commercial vaginal moisturizer treatment did not result in a significant improvement in the frequency of sexual activity or the pain scores in postmenopausal women.
Another published study found no benefit of hormonal therapy on sexual function in postmenopausal women - or did it?
While it is well-established that vulvovaginal atrophy accompanies the increase in sexual discomfort associated with postmenopausal hypoestrogenism, and that hormonal therapy (HT) improves symptoms of genital atrophy, the impact of postmenopausal hormonal therapy on sexual function remains an area of ongoing controversy. Much of the problem comes from study design and the difficulty of assessing the right outcomes. We must critically assess the limitations of studies evaluating sexual health to better serve the needs of postmenopausal patients.
Recently I reported on an analysis of data from the Women’s Health Initiative Study (WHI) that evaluated sexual activity following discontinuation of therapy.2 This study found no difference in the prevalence of sexual activity postintervention between former participants randomized to hormonal therapy (36%) and placebo (34%, P = 0.37). However, women in the study who had received active hormonal treatment during the intervention period were significantly more likely (20%) to report a decreased frequency of intercourse postintervention than the group formerly randomized to placebo (9%), and also were more likely to report decreases in desire (17% vs. 6%), arousal (17% vs. 7%), ability to orgasm (19% vs. 7%), and satisfaction with sexual activity (17% vs. 8%), as well as increases in the tightness of the vagina (12% vs. 3%) and discomfort with intercourse (15% vs. 3%). Furthermore, sexual activity reported by former hormonal therapy users following discontinuation was 5.6% higher than sexual activity reported by placebo users (27.6% vs. 22.0%; P < 0.001). The results suggest that changes in sexual function occur over time in postmenopausal women, with hormonal therapy associated with modest protection.
It is also possible that women accommodate vaginal symptoms by avoiding intercourse. Compared to women randomized to estrogen, significantly fewer
former placebo users (37% vs. 44%) reported having had sex after the WHI, and those who did reported a significant decrease in the frequency of sex with a partner postintervention.
The Mitchell papers provide similar hints that estrogen makes a difference. Significantly more women randomized to vaginal estradiol reported penetrative sex in the past week (43.5%; 33.2, 53.8) compared to the vaginal gel (33.0%; 23.1, 42.8). While the comparison with the dual placebo did not quite reach statistical significance (34.8% [24.9, 44.7]), the trend is the same. Women who received estrogen also showed improvement in vaginal maturation scores and a lowering of vaginal pH. While the overall comparison did not suggest that estrogen treatment resulted in a decrease in pain, the overall pain scores reported by women were low in all groups. Of great interest is the fact that many women did not report a score for sexual pain, presumably because they were not engaging in penetrative sex. Once again, we see a single efficacy with hormonal therapy; compared to placebo, more women who received estrogen reported a score for pain with sexual activity.
To be fair, a strength of the Mitchell paper is the use of patient-centered outcomes. However, we need to really consider if 12 weeks of therapy reflect reality. Treatment of vaginal symptoms also may require an emphasis on prevention; starting vaginal therapy a decade after menopause (the mean age of participants in this study was 61 years) simply may be too late.
- Mitchell CM, Reed SD, Diem S, et al. Efficacy of vaginal estradiol or vaginal moisturizer vs placebo for treating postmenopausal vulvovaginal symptoms: A randomized clinical trial. JAMA Intern Med 2018;178:681-690.
- Gass M, Larson J, Cochrane B, et al. Sexual activity and vaginal symptoms in the postintervention phase of the Women’s Health Initiative hormone therapy trials. Menopause 2018;25:252-264.