Clinicians strive to individualize menopausal therapies. Commonly, shared decision-making takes into account a woman's concerns for quality-of-life outcomes such as sexual function when choosing treatment. Libido, lubrication, orgasm, and penetration pain may be adversely altered during menopause1–5 and medications to treat other menopausal symptoms can potentially worsen or improve sexual function.
Although postmenopausal estrogen therapy is approved by the U.S. Food and Drug Administration for treatment of moderate to severe hot flushes and genital atrophy, only ospemifene is U.S. Food and Drug Administration-approved for improving menopausal dyspareunia. Relatively few postmenopausal hormone therapy trials have examined sexual function6; the majority evaluated transdermal estrogen.7–10 Oral estrogen can increase sex hormone-binding globulin and decrease circulating free testosterone,11 theoretically diminishing desire and arousal. Women continue to choose oral hormone formulations to manage menopausal symptoms12; further study of sexual function is warranted.
Although many women manage hot flushes with hormone therapy, increasing numbers are considering nonhormonal options,13 including selective norepinephrine reuptake inhibitors, like venlafaxine. However, decreased sexual function with serotonergic medications used in depressed populations has been observed,14 specifically diminished libido,14–18 arousal,14,17,18 and orgasm14,16–18 with venlafaxine. Sexual dysfunction with selective norepinephrine reuptake inhibitors appears dose-related19; doses recommended for depression are higher than those recommended for hot flushes. Few venlafaxine studies in nondepressed populations exist,20–22 but limited menopausal trial data suggest no sexual function changes.20–22
We prospectively evaluated self-reported sexual function among nondepressed midlife women with bothersome hot flushes in a double-blind randomized trial of oral low-dose estradiol or venlafaxine (compared with a placebo).
MATERIALS AND METHODS
Details regarding study design and methodology are published23 as well as the primary study results on hot flushes.23,24 The study was a multisite, randomized, placebo-controlled, double-blind clinical trial and was approved by the institutional review boards at participating sites. Participants provided written informed consent.
The trial was conducted at Menopause Strategies: Finding Lasting Answers for Symptoms and Health network sites in Boston, Philadelphia, and Seattle. Participants were recruited by mail (November 2011 to October 2012). Eligible midlife women were perimenopausal or postmenopausal aged 40–62 years. Women had at least 14 hot flushes or night sweats per week for 2 weeks (4 or more days or nights each week rated bothersome or severe). Hot flush diaries over a third week ensured that hot flush frequency did not decline more than 50% from the 2-week baseline. Women were excluded if they used psychotropic, hot flush therapies, or hormonally mediated therapies (low-dose vaginal estrogen three times or less per week allowed). Women were excluded for a major depression episode or addiction problems (past year), suicide attempt (past 3 years), bipolar disorder or psychosis, or any major preexisting health problem, including contraindication to study medications. There were no eligibility criteria specifically related to sexual function and both sexually active and inactive women were enrolled.
Eligible participants were screened by phone and had at least three in-person visits. Stratified randomization of eligible women to 0.5 mg oral estradiol per day, 75 mg venlafaxine per day, or a matching placebo pill occurred at the second visit using a dynamic randomization algorithm (2:2:3) to ensure comparability between treatment groups with respect to site and to increase power to detect differences. Women randomized to venlafaxine started on 37.5 mg and increased to 75 mg on day 8.
Women received a phone call 1 and 4 weeks after randomization to assess adverse events and adherence. They were mailed questionnaires to complete during week 4.
Sexual function was measured at baseline and 4 and 8 weeks using the Female Sexual Function Index (see Appendices 1 and 2, available online at http://links.lww.com/AOG/A538).25 The composite score is a sum of the six domain scores (desire, arousal, lubrication, orgasm, satisfaction, pain) and ranges from 2 (not sexually active and no desire) to 36. Women were classified as sexually inactive at baseline if they reported “no sexual activity” over the past 4 weeks with a partner or self (not restricted to vaginal penetration).
To determine how bothered or distressed women were by their levels of sexual function, we adapted two questions (nos. 1 and 13) from the Female Sexual Distress Scale, “In the past 4 weeks, how often did you feel distressed or bothered about your sex life?”26 Scoring was: 0=never, 1=rarely, 2=occasionally, 3=frequently, or 4=always and was analyzed as a binary outcome with 0, 1, and 2 defined as “not or minimally” and 3 and 4 defined as “frequently or always” distressed.
All analyses were based on the intention-to-treat principle and included all randomized participants with follow-up Female Sexual Function Index measurements irrespective of study medication adherence. Baseline characteristics and possible correlates of sexual function (eg, urinary incontinence, vaginal dryness) were compared pairwise across two treatment groups (active, placebo) using t tests or χ2 tests. Our primary aims were to compare the change in sexual function from baseline to 8 weeks among 1) all randomized women; and 2) participants who were sexually active at baseline. The primary analysis consisted of the treatment group-estimated contrast from a linear regression model summarizing composite Female Sexual Function Index score at 4 and 8 weeks as a function of group, clinical site, time point, and baseline Female Sexual Function Index. Subgroup analyses were performed to assess effect modification among women who were postmenopausal, had anxiety, or poor sleep.
Our secondary aims were to compare, across treatment group, the changes from baseline to week 8 in: 1) the frequency of all women reporting distress or bother in sexual function; and 2) Female Sexual Function Index sexual domain scores among sexually active women. The first of these aims was analyzed using logistic regression models summarizing the prevalence of distress at week 8 as a function of treatment assignment and baseline distress, and the second was analyzed using methods described as in aim 1. Among sexual domains that showed significant differences in change from baseline (active compared with placebo), we compared the proportions of women (active compared with placebo) with at least 2-point decreases or increases in any given domain through χ2 tests. A priori, 2-point change differences were considered clinically significant.26 We also assessed differences in the proportions of women with change from baseline in anorgasmia (orgasm never or almost never), urinary incontinence (3-Incontinence Question Index),27 and vaginal dryness (single item, Menopause Quality of Life questionnaire)28 using logistic regression models summarizing the prevalence of the outcome at week 8 as a function of treatment assignment and baseline prevalence.
Adverse sexual experiences were not specified in a symptom checklist recorded at baseline and 8 weeks; rather, newly emergent events related to sexual function were captured in a write-in “other” category.
The sample size of the trial was determined by the primary trial endpoint (hot flush frequency).29 Post hoc analysis showed 88% power to detect an effect size of 0.5 standard deviation between each active group and placebo with two-sided P<.05 or a 3-point difference between groups in change from baseline to week 8 in composite Female Sexual Function Index. No adjustments in sexual function analyses were made for multiple comparisons. Analyses were conducted using SAS 9.3 with two-sided P<.05 considered statistically significant.
The study included 335 women (Fig. 1) after excluding four women without any sexual function question responses at baseline. Treatment adherence was 94–95% for all groups. One hundred seventy-five women reported sexual activity with male partners; five with female partners; and 105 reported self-stimulation (not mutually exclusive). Sexual preference did not vary by group. Among women who reported being married or in an intimate relationship, the average relationship duration was 24 years (range 0.5–45 years). There were no statistically significant differences in baseline characteristics between treatment groups with the exception of decreased alcohol use in the venlafaxine group as compared with placebo (Table 1).
Median composite baseline Female Sexual Function Index score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. At baseline, 67% of women on estradiol, 63% on venlafaxine, and 72% on placebo were sexually active (n=228). The distribution of baseline composite sexual function scores was bimodal for all women but displayed a single mode among those who were sexually active at baseline. Baseline scores did not vary by group (Table 2).
A total of 230 participants were available for analysis of composite Female Sexual Function Index change from baseline to week 8. Composite mean Female Sexual Function Index score change from baseline to week 8 was 1.4 (95% confidence interval [CI] −0.4 to 3.2) for estradiol, 1.1 (95% CI −0.5 to 2.7) for venlafaxine, and −0.3 (95% CI −1.6 to 1.0) for placebo. In an adjusted linear regression model, 8-week treatment with either estradiol or venlafaxine (compared with placebo) did not affect composite Female Sexual Function Index (P=.38, P=.79, respectively; Fig. 2). The same analysis was repeated among the women who were sexually active at baseline with similar results (Table 2). The same analysis repeated in three subgroups of women—postmenopausal, moderately anxious, or with moderate sleep disturbances—revealed no differences (data not shown).
Sixty-five of 335 participants (estradiol n=22, venlafaxine n=21, placebo, n=22) reported sexually related personal distress at baseline (distress score=3 or 4). Treatment with either estradiol or venlafaxine (both compared with placebo) for 8 weeks did not significantly alter the prevalence of sexually related distress among all women (P=.30, P=.48, respectively) or the sexually active women (P=.51, P=.19, respectively).
Changes in specific Female Sexual Function Index domain scores (week 8 minus baseline) were compared by treatment group among women sexually active at baseline (Table 3). Among women randomized to estradiol compared with placebo, there was improvement in the desire score (P=.04). Women randomized to venlafaxine, as compared with placebo, had worsened orgasm (P=.04) but improvement in penetration pain scores (P=.04). All differences from placebo were small; the greatest difference observed was score improvement of 0.9 out of 6 for penetration pain with venlafaxine.
There were 209 sexually active women (62%) who answered questions about orgasm at baseline and follow-up. The proportion of women randomized to estradiol and placebo who reported anorgasmia at baseline was 9.4% and 12.5%, respectively, and decreased to 8.3% and 11.2%, respectively, at 8 weeks (change from baseline, estradiol compared with placebo, P=.10). In contrast, the proportion of women randomized to venlafaxine who reported anorgasmia at baseline was 11.9% but increased to 20.8% at 8 weeks, although this change in proportions was not statistically different from the change observed in the placebo group (P=.07). A greater proportion of women in the venlafaxine (61%) as compared with the placebo-assigned (39%) groups reported at least a 2-point decrease on the orgasm domain over the 8-week intervention (P=.03).
No statistically significant differences (active compared with placebo) in the change in proportions of women reporting at least a 2-point change over the 8-week intervention were observed in the other Female Sexual Function Index domains that showed statistically significant change from baseline, ie, for desire (estradiol compared with placebo) and for penetration pain (venlafaxine compared with placebo).
Proportions of women reporting either stress or urge incontinence at baseline were high among all groups (62.1% estradiol, 64.6% venlafaxine, 54.9% placebo). Although proportions were diminished in all groups by 8 weeks, the change in the proportions did not statistically vary between groups (46.2% estradiol, 40.7% venlafaxine, 41.6% placebo).
Women randomized to venlafaxine reported the greatest improvement in vaginal dryness during intercourse. At baseline, 37.9%, 37.5%, and 41.7% of women in the estradiol, venlafaxine, and placebo groups, respectively, reported vaginal dryness. At 8 weeks, this decreased to 26.4%, 18.2%, and 35.6%, respectively. Only the venlafaxine group had statistically significant improvement in the proportion of women reporting vaginal dryness compared with the placebo (P=.006).
There were no newly emergent adverse events related to sexual function reported in any group and no women discontinued the study as a result of sexual adverse events.
Among nondepressed midlife women with bothersome hot flushes, neither low-dose oral estradiol nor low-dose venlafaxine (75 mg per day) over 8 weeks significantly altered sexual function as measured with a validated composite sexual function questionnaire, the Female Sexual Function Index.25 Results did not vary when only those women who were sexually active at baseline were included in the analysis. However, subtle domain differences were observed among sexually active women. Desire domain scores improved in women randomized to estradiol (compared with placebo); no differences in arousal, orgasm, lubrication, or penetration pain were observed. Orgasm domain scores slightly worsened but pain improved in women randomized to venlafaxine (compared with placebo); no differences in other sexual function domains were found. Compared with baseline, the proportion of women randomized to venlafaxine who reported never having orgasms, or almost never, doubled at 8 weeks but was not significantly different from placebo.
A plethora of trials have examined low-dose oral estradiol effects on bone, endometrium, and hot flushes, but little data on sexual function exist. One 16-week study found no improvement in sexual function with oral conjugated estrogen.30 Similarly, an open-label study of low-dose oral estrogen found sexual function was not statistically different from baseline at 12 weeks.31 Studies of longer duration have found improvement,4 including preliminary analyses from the 4-year Kronos Early Estrogen Prevention Study (KEEPS). Both oral conjugated estrogens and transdermal estradiol improved lubrication and reduced pain; transdermal, but not oral, estradiol improved desire, arousal, and orgasm.32
Diminished orgasm with venlafaxine observed in our study was anticipated as similar findings have been observed in depressed populations evaluating venlafaxine,14,16–18 sertraline, paroxetine,14,16–18 and escitalopram.26 Selective norepinephrine reuptake inhibitors act by increasing availability of serotonin and norepinephrine at synapses, which can then inhibit dopamine centrally, potentially decreasing arousal and orgasm. However, in a review of 16 studies of selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors for hot flushes, sexual function side effects were not increased above placebo.33 Other studies concur with these findings,20–22,34–39 but validated sexual function measures were not used consistently and many were small studies.
Our findings of diminished pain and dryness with venlafaxine were not anticipated, although there is evidence of biologic plausibility for both. Venlafaxine is not uncommonly prescribed for treatment of pain syndromes40,41 and increased serotonin may up- or downregulate serotonin receptors, over 90% of which are present peripherally, thus modulating pain, arteriole vasodilation, vasoconstriction, or a combination of these mechanisms are likely important for improved dryness. All of these affects appear variable woman to woman, as supported by our findings.42
Female sexual physiology is complex and although sexual desire, orgasmic response, and sexual activity frequency decrease with age in women,3,4 sexual distress also decreases. Clearly, the changes that occur in midlife women are poorly understood. “Normal” Female Sexual Function Index scores in midlife women from the Penn Ovarian Aging cohort (ages 40–54 years)5 and from the first Menopause Strategies: Finding Lasting Answers for Symptoms and Health trial (ages 40–62 years)26 suggest assigning a “new normal” cut point of sexual function at a composite score of 20 may be most appropriate for midlife women based on observed bimodal distributions.26 The Female Sexual Function Index scores and distributions in this trial were comparable to those prior studies.5,26 This is in contradistinction to scores observed among younger women, mean age 36.2 years (range 18–74 years), in which a cut point of 26.5 or greater was used to assign normal female sexual function based on a bimodal distribution.43
Strengths of this study include detailed sexual function information obtained with validated questionnaires, including an assessment of sexually related distress, 25% nonwhite participants, high adherence to therapy, and a low dropout rate. This study has limitations. Although this was a community-based sample, the volunteer participants may be a select group who were motivated to seek treatment. An 8-week treatment interval may have been too brief. There were missing data, but data completeness did not vary by group and at week 8, 89% of women provided data on approximately 90% of sexual function questions. Detecting differences between groups in our primary outcome smaller than 3 points would have required a greater sample size; the clinical relevance of this magnitude is unknown. Finally, secondary analyses were considered exploratory and should be interpreted with caution.
These findings are important because the use of serotoninergic agents for hot flushes is likely to increase, because a low-dose formulation of paroxetine was recently approved by the U.S. Food and Drug Administration, representing the first nonhormonal agent indicated for the treatment of vasomotor symptoms.44 A full understanding of the differences in sexual function among women taking oral estradiol or a serotoninergic agent for menopausal symptoms is important for clinical discussions between patients and their health care providers.
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