A recent systematic review «» (47 RCTs, 35 912 participants) and meta-analysis (34 RCTs, 15 079 participants) also updates the Cochrane review from 2013. Data are given as standardized mean difference [SMD] and 95% confidence intervals (CI). According to this meta-analysis the effect of any MHT on sexual function in postmenopausal women is between no effect and small benefit (ET [0.16, 0.02-0.29, I2 59%, 16 studies, 2925 participants], EPT [0.11,-0.0-0.29; I2 65%, 7 studies, 2432 participants], tibolone [0.18, 0.06-0.30, I2 0%, 4 studies, 1058 participants]). Sensitivity analysis found large harm to small benefit of EPT on sexual function score (SMD, -0.57, -1.40-0.27), but this finding was based on one study with 23 participants. All studies were assessed being at high risk of bias. This meta-analysis also differentiated between different forms of administration and no significant difference between the effect of systemic (0.21, 0.02-0.41, I2 56%, 6 studies, 1095 participants) and vaginal therapy (0.12, -0.07-0.31, I2 63%, 10 studies, 1830 participants) for all outcomes of all comparisons was detected. 33/47 studies were deemed at high risk of bias and over all the confidence intervals were wide and effect sizes small.
Comment: Different vaginal estrogen regimens varying from ultra low-dose estriol to high-dose estradiol may yield very different effects and analyses should to take this into account. Same applies for systemic MTH, where lower doses (conjugated estrogen 0.45mg, estradiol 1mg) are often preferred and a dose-dependent effect should be explored.
The Kronos Early Estrogen Prevention Study (KEEPS) «» was a 4-year, double-blinded, placebo-controlled RCT of MHT in healthy, recently menopausal women. In an ancillary study on 670 women (mean 52.7 years years, ≤36 months postmenopausal were randomized to either 0.45 mg/d oral conjugated estrogens, 50 µg/d transdermal estradiol patch, or matching placebo. Sequential oral micronized progesterone (200mg, if randomized to estrogen) or placebo for 12 days each month were given for endometrial protection. Sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain, score 0-36) were assessed with the Female Sexual Function Inventory (FSFI) questionnaire. An FSFI score <26.55 indicated low sexual function (LSF) and at baseline LSF was present in 71 to 74% of women. Data were gathered via questionnaires at baseline and a 1.5, 3, and 4 years.
Across all time points, treatment with transdermal estradiol increased the FSFI overall score by 7.2% over placebo (mean efficacy, 2.6, 95% CI 1.11-4.10), whereas treatment with oral conjugated estrogen did not (mean efficacy, 1.4, 95% CI -0.1-2.8). Scores with sustained improvements compared with placebo during the 4 years includelubrication (0.61, 95% CI 0.25-0.97) and pain (0.67; 95% CI 0.25-1.09). Oral conjugated estrogen significantly increased SHBG-levels and conferred only temporary increase in FSFI at three years compared with placebo. The overall effect on FSFI in women with LSF at baseline (mean efficacy 3.7, 95% CI 2.0-5.4) was significant compared with placebo, whereas for women without LSF (mean efficacy -0.2, 95% CI -3.0-2.6) it was not (p for interaction 0.02).
Comment: The KEEPS trial is the largest placebo-controlled RCT that assessed the effect of MHT on sexual function. Distress associated with sexual function or different estrogen doses were not assessed. Differential effects of route of administration on FSFI warrant attention. Larger doses of estrogens may yield different results and additional improvement in FSFI could be attained with simultaneous vaginal treatment of GSM.
General comment: Current data on the effect of menopausal hormone therapy (MHT) on sexual function carry several biases and large heterogeneity limiting the interpretation of these results. Furthermore, data are scarce on the effect of MHT on sexual function in women who have sex with women, or in women who do not engage in penetrative sex.