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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