Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology,
Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for and receives grant/research support from Bayer, Merck, ContraMed, and FHI360; receives grant/research support from Abbvie, HRA Pharma, Medicines 360, and CONRAD; and is a consultant for the Population Council.
SYNOPSIS: Women who discontinued systemic postmenopausal hormonal therapy following participation in the Women’s Health Initiative studies experienced an increase in vaginal and sexual symptoms.
SOURCE: 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.
Although it is well-established that hormonal therapy (HT) improves symptoms of genital atrophy, the effect of postmenopausal HT on sexual function remains controversial. Gass and colleagues analyzed data from the postintervention phase of the Women’s Health Initiative (WHI) study to determine the effect of HT discontinuation on sexual function.
The WHI studies randomized 27,347 postmenopausal women aged 50 to 79 years to receive either combined hormonal therapy (daily oral conjugated equine estrogens [CEE] 0.625 mg plus oral 2.5 mg medroxyprogesterone acetate) or, if hysterectomized, estrogen-only (CEE 0.625 mg) or placebo. Although the study excluded women symptomatic with vasomotor symptoms, genital symptoms were not specified as exclusion criteria. All participants completed extensive questionnaires at baseline that included sexual history. Both studies were discontinued prematurely, and women received notification of their randomization group, breaking the blind. After this notification, subjects were invited to participate in a postintervention follow-up survey. Investigators added questions to these postintervention surveys regarding sexual function, which included seven key clinical characteristics of sexual activity: frequency of intercourse, discomfort with intercourse, desire, arousal, ability to climax, vaginal tightness, and satisfaction with sexual activity. The response options differed slightly between the estrogen-progestin therapy (EPT; compared current symptoms with symptoms while on treatment) and estrogen therapy (ET; asked about current symptom frequency only) studies.
A total of 13,902 women (9,450 in the EPT trial; 4,452 in the ET trial) responded to postintervention questionnaires, representing response rates of 93% and 90%, respectively. The majority (92%) of responses to these surveys were received between eight and 13 months after each trial stopped. There was no difference in the response rate or baseline characteristics between subjects randomized to active treatment or placebo. Overall, women with medical conditions (e.g., cancer, myocardial infarction, congestive heart failure, diabetes mellitus, hyperlipidemia, hypertension, arthritis, and depression) reported significantly lower levels of sexual activity than healthy women. Although the survey asked questions about sexual activity with and without a partner, about half of the women reported no sexual activity since discontinuing HT, and the main explanation for this was lack of a partner. Sexual activity also declined with age, from 46% among women younger than 60 years of age to only 9% among women older than 80 years of age.
The change in function following discontinuation of HT represents the primary results of interest. Here, we see a mixed effect. The prevalence of sexual activity postintervention was not significantly different between former EPT (36%) and placebo (34%, P = 0.37). However, women in the EPT study who had received active 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 more likely to report a decrease in desire (17% vs. 6%), arousal (17% vs. 7%), ability to climax (19% vs. 7%), and satisfaction with sexual activity (17% vs. 8%); an increase in tightness of vagina (12% vs. 3%); and discomfort with intercourse (15% vs. 3%).
Sexual activity reported by former ET users following discontinuation was 5.6% higher than placebo users (27.6% vs. 22.0%; P < 0.001). Only two of the sexual function items yielded statistically significant differences by intervention arm in the ET trial: Women formerly assigned to placebo reported both desire and arousal to be “rarely” or “not at all” present more frequently than those who had discontinued active treatment.
These results suggest that changes in sexual function occur over time in postmenopausal women, with HT associated with modest protection that declines following discontinuation.
The WHI continues to provide opportunity for investigators seeking to understand the benefits and risks of HT. Although the large sample size and randomized design are enormous strengths, representativeness remains a major criticism of the study, as the population enrolled was asymptomatic and approximately 10 years postmenopausal — a decade older than the age at which women commonly start HT. The older age and exclusion of women with vasomotor symptoms affects generalizability to healthy younger menopausal women. The exclusion of women with vasomotor symptoms also likely excluded many women with comorbid symptoms of vulvovaginal atrophy. This conclusion is reinforced by supplemental material presented by Gass et al; only 13% of sexually active women in the original WHI population reported vaginal dryness at enrollment.
So, can we learn anything from studying the sexual health of this population following discontinuation of HT? After notification of randomization that “broke the blind,” was this effectively turning the WHI into a cohort study? A fundamental weakness is that the researchers asked subjects to recall sexual outcomes while on treatment (or placebo) and compare these to postintervention status. We do know that HT improved vaginal dryness after one year of treatment, decreasing to 8% among women assigned to HT while staying essentially the same among women randomized to placebo (12%). We also see a postintervention climb back to baseline (14%) among those formerly assigned to HT but a decrease to 8% among those who received placebo. Although this supports a rapid reversal of the treatment effect of HT, we can’t ignore the fact that unblinding occurred. The decrease among placebo users suggests that women find other means of accommodating dryness over time, perhaps through the use of lubricants. The authors of a recently published study in JAMA Internal Medicine suggested that lubricants work just as well as vaginal estrogen, but the length of treatment and dose of estrogen may not have made this a fair comparison.1 An alternative hypothesis is that some women simply avoid sex, for a myriad of reasons. While the proportion of women reporting sex with a partner postintervention did not differ between women randomized to active treatment and placebo in the EPT study, when the question was asked differently in the ET study (e.g., over the past three months), significantly fewer former placebo users (37% vs. 44%) reported having had sex. Also, as noted above, women in the EPT group reported a significant decrease in the frequency of sex with a partner postintervention. The study did not provide any comparison of absolute frequency between the groups. Other studies have shown that intercourse frequency may be driven by male partners and is not associated with satisfying sex for women.
Although flawed, this postintervention follow-up study provides limited insight into the effects of discontinuation of HT on sexual symptoms. In the early 2000s, I saw a busy referral practice of women with vulvodynia and sexual pain disorders. Following the publicity of the initial findings of the WHI, I noticed a steep increase in new complaints of dyspareunia and a return of symptoms in many women with prior successful treatments for vulvar dermatoses. Many cases were associated with discontinuation of HT. Although a number of local hormonal and nonhormonal options will improve vulvovaginal symptoms, for many women the convenience of systemic HT will make sense, particularly when bone protection is considered. As clinicians, we need to bring sexual health into the conversation around menopausal HT.
- 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; March 19. doi:10.1001/jamainternmed.2018.0116. [Epub ahead of print].