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. 2023 May 10;30(6):659–671. doi: 10.1097/GME.0000000000002185

Hormone therapy for sexual function in perimenopausal and postmenopausal women: a systematic review and meta-analysis update

Nadia Meziou 1,2, Clare Scholfield 3, Caroline A Taylor 3, Heather L Armstrong 1,3
PMCID: PMC10227948  PMID: 37159867

Estrogen therapy, estrogen plus progestogen therapy, tibolone, and selective estrogen receptor modulators, compared with control, may slightly improve sexual function. This should be considered when discussing treatment options for other menopausal symptoms.

Key Words: Hormone therapy, Menopause, Meta-analysis, Sexual function

Abstract

Importance

Distressing sexual problems are a common complaint of menopausal women. In 2013, a Cochrane review assessed the effect of hormone therapy on sexual function in menopausal women; however, new evidence has since been published, which should be considered.

Objective

This systematic review and meta-analysis aims to update the evidence synthesis on the effect of hormone therapy, compared with control, on sexual function in perimenopausal and postmenopausal women.

Evidence Review

Thirteen databases and clinical trial registries (Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Literatura Latino-Americana e do Caribe em Ciéncias da Saúde, Database of Abstracts of Reviews of Effects, ClinicalTrials.gov, International Clinical Trials Registry Platform, Iranian Registry of Clinical Trials, Chinese Clinical Trial Registry, ISRCTN) were searched from December 2012 to March 30, 2022. Backward reference searching on all retrieved full texts was also performed. Study quality was assessed using the Cochrane ROB.2 tool. Data were pooled in random-effect model meta-analyses, which included all studies identified in the present search and all studies previously included in the 2013 Cochrane review.

Findings

Forty-seven randomized controlled trials (35,912 participants) were included in the systematic review, and 34 randomized controlled trials (15,079 participants) were included in the meta-analysis. The meta-analysis revealed that, in comparison to control, estrogen therapy (standardized mean difference [SMD], 0.16; 95% confidence interval [CI], 0.02 to 0.29; I2 = 59%; 2,925 participants, 16 studies), estrogen plus progestogen therapy (SMD, 0.11; 95% CI, −0.07 to 0.29; I2 = 65%; 2,432 participants, 7 studies), tibolone (SMD, 0.15; 95% CI, 0.02 to 0.28; I2 = 0%; 916 participants, 2 studies), and selective estrogen receptor modulators (SMD, 0.18; 95% CI, 0.06 to 0.30; I2 = 0%; 1,058 participants, 4 studies) may result in no effect to small benefit on sexual function composite score.

Conclusion and Relevance

Hormone therapy may slightly improve sexual functioning. This potential small benefit should be considered when discussing treatment options for other menopausal symptoms.


Key points

  • Question: What is the effect of hormone therapy (HT) on sexual function in perimenopausal and postmenopausal women?

  • Findings: Forty-seven randomized controlled trials (35,912 participants) evaluating the effect of HT were included. Estrogen therapy, estrogen plus progestogen therapy, tibolone, and selective estrogen receptor modulators, compared with control, may result in no effect to small benefit on sexual function in perimenopausal and postmenopausal women. Heterogeneity of effects across studies was low to high.

  • Meaning: HT may slightly improve sexual function. The effect of HT on sexual function should be considered when discussing treatment options for other menopausal symptoms.

With 71% to 76% of middle-aged women stating that sexual activity is an important aspect of their lives,1,2 sexual well-being during menopause is a necessary concern. Sexual function is often described in opposition to female sexual dysfunction (FSD), which is a clinically significant disturbance in a person's ability to respond sexually, or to experience sexual pleasure, that causes distress.3 Distressing sexual problems peak among middle-aged women, whereas sexual problems without accompanying distress tend to increase with age.4 The International Menopause Society recommends a biopsychosocial approach of sexual function accounting for fluctuations in health status, neurochemical balance, psychological issues, interpersonal concerns, and sociocultural beliefs and values.5

Hormone therapy (HT) is the first-line treatment for moderate to severe genitourinary symptoms of menopause.6-8 The genitourinary syndrome of menopause (GSM), affecting half of postmenopausal women, results in lack of lubrication, discomfort, and pain during sexual activity.9 Postmenopausal sexually active women with FSD are nearly four times more likely to have GSM than those without FSD.10 Therefore, HT might improve sexual function in menopause by decreasing genitourinary symptoms.5 In addition, HT may also improve sexual function by decreasing sleep disturbance in women with vasomotor symptoms.11-13

In 2013, a Cochrane systematic review found that HT, compared with placebo or no intervention, slightly improved sexual function in perimenopausal and recently postmenopausal women.14 Since the publication of this review, new clinical trials have been conducted. This systematic review aimed to update the evidence synthesis on the effect of estrogen therapy, estrogen plus progestogen therapy, tibolone, and selective estrogen receptor modulators (SERM) on sexual function in perimenopausal and postmenopausal women.

METHODS

Protocol and registration

The review protocol was registered on PROSPERO on March 30, 2022 (CRD42022320302).

Criteria for study inclusion

Types of studies

Published and unpublished randomized controlled trials (RCTs) were included. Crossover trials were considered, but only data from the first phase were included because urogenital symptoms often reoccur after HT is stopped.15 Studies including only a subset of eligible participants were considered for inclusion when data were reported for the subset of interest.

Types of participants

Perimenopausal or postmenopausal women were included. Perimenopausal women were defined as women who had their last menstrual period (LMP) within the last 12 months before inclusion.16 Postmenopausal women were defined as women with menopause induced by a medical intervention or with natural menopause defined as 12 consecutive months of spontaneous amenorrhea.16 Recently postmenopausal women had their LMP within the last 5 years.16 Symptomatic menopausal women are women with any menopausal symptom described in Monteleone et al,17 including vulvovaginal atrophy, vasomotor symptoms, and sexual dysfunction.

Types of interventions

The intervention of interest is HT compared with control. All HT therapies included in Nastri et al14 were considered: estrogen therapy, estrogen plus progestogen therapy, tibolone, and SERM. This review did not include dehydroepiandrosterone and testosterone because their effect on sexual function has already been investigated elsewhere.18,19 Only trials in which the interval between the onset of the intervention and the assessment of outcomes was at least 1 month were included. For studies with multiple assessments, only the assessment closest to 6 months after starting the intervention was considered. Indeed, tolerability should be assessed 3 months after beginning treatment15; therefore, a 6-moth time point is conservative.

Types of outcome measures

All outcomes reported by Nastri et al14 were considered for inclusion, as were any other relevant aspect of sexual function. The primary outcome of this review is sexual function composite score. Secondary outcomes are desire, arousal, lubrication, orgasm, pain, and sexual satisfaction. Only outcomes measured and scored by validated questionnaires were included. Because this is an update of Nastri et al,14 adverse events related to HT were not an outcome of this review.

Search methods for identification of studies

In Nastri et al,14 the last search was performed on December 12, 2012. When the searching interface allowed date limitation by month, the search was restricted from December 2012 to present. Otherwise, the search was restricted from 2013 to 2022 with good faith that any missed article between December 13 and December 31, 2012, would be found by citation tracking. The search strategy was inspired from previous reviews.14,20-22 Most electronic databases used in Nastri et al14 were searched including the following: Cochrane Central Register of Controlled Trials through the Cochrane Library, EMBASE, Medical Literature Analysis and Retrieval System Online (MEDLINE), PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Literatura Latino-Americana e do Caribe em Ciéncias da Saúde, and Database of Abstracts of Reviews of Effects (DARE). To increase specificity, validated RCT filters were added to the MEDLINE,23 EMBASE,24 and CINAHL25 search strategies. Protocols of ongoing trials on all registers used in Nastri et al14 were searched via ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. In addition, the Iranian Registry of Clinical Trials, the Chinese Clinical Trial Registry, and the ISRCTN registry were also searched (Supplemental Digital Content, Appendices A1-10, http://links.lww.com/MENO/B125). Some sources used in Nastri et al14 were unable to be used: The Menstrual Disorders and Subfertility database Specialised Register and Current Controlled-Trials could not be found, and OpenGrey was shut down in 2021. In addition, DARE updates stopped in 2015. Finally, backward reference searching on all retrieved full texts was also performed.

Data collection and analysis

Study selection

Titles and abstracts of all retrieved studies were screened using Rayyan and full texts of all potentially eligible studies were searched. The first author applied the selection criteria to determine included articles in consultation with the final author if eligibility was unclear. When a full text could not be retrieved, authors were contacted if possible. The entire selection process is documented using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram26 (Fig. 1).

FIG. 1.

FIG. 1

PRISMA flow diagram. PRISMA, Systematic Reviews and Meta-Analyses.

Data extraction and management

Data extraction and checking was performed by the first author in consultation with the final author. For studies with multiple publications, the main trial report was used as the reference, and secondary articles were used for additional details. Data were extracted as mean ± SD. Standard errors and 95% confidence intervals (95% CI) were converted to SDs.27 Data reported as median (interquartile range) was converted with formulas assuming a normal distribution of the data.28

Assessment of risk of bias in included studies

Risk-of-bias assessment was performed by the first author, in consultation with the final author, using the ROB.2 tool developed by the Cochrane Collaboration.29 Bias arising from randomization process (domain 1) was assessed at study level, whereas all other domains were assessed at outcome level. Every domain was rated as “low,” “some concerns,” or “high” risk of bias. If all five domains were rated “low,” the overall risk of bias was “low.” If one to three domains were rated “some concerns,” with all other domains rated “low,” the overall risk of bias was “some concerns.” If four or more domains were rated “some concerns,” or one or more domain was rated “high,” the overall risk of bias was “high.” Regarding bias due to missing outcome data (domain 3), data were considered available for all or nearly all participants when at least 95% of randomized participants had outcome data. Proportions of missing data were considered to differ between groups when the difference was at least 5%. For bias in measurement of the outcome (domain 4), all outcomes were considered subjective.

Measures of treatment effect

All outcomes were reported as continuous. Standardized mean differences (SMDs) are reported as different scales were used. When a meta-analysis was possible, effect sizes were pooled along with those previously published in Nastri et al.14 An inverse variance random-effect model was used because studies were not expected to measure the same true value as trial contexts varied (Table 1).54 RevMan was used to pool the data.

TABLE 1.

Characteristics of included studies

Study Country Center(s) Population Menopause status Follow-up Scale
Archer et al30 United States Multicenter GSM with vaginal dryness as MBS at baseline Postmenopausal 12 wk FSFI
Bosak et al31 Iran Single center GSM with dyspareunia at baseline Postmenopausal 12 wk LSSQ
Bumphenkiatikul et al32 Thailand Single center GSM and female sexual dysfunction at baseline Postmenopausal 12 wk FSFI
Carmignani et al33 Brazil Multicenter Urogenital symptoms at baseline. Postmenopausal 16 wk MRS
Caruso et al34 Italy Single center Significant vaginal bulging caused by pelvic organ prolapse and GSM at baseline Postmenopausal 25 wk PISQ-12
Constantine et al35 United States Multicenter GSM at baseline: with dyspareunia (n = 605) or vaginal dryness (n = 314) as MBS Postmenopausal 12 wk FSFI
Cruz et al36 Brazil Single center GSM at baseline Postmenopausal 20 wk FSFI
Davison et al37 Australia Single center Healthy postmenopausal women Recently postmenopausal 6 mo MENQOL
Ferrante et al38 United States Multicenter ≥3/2 documented urinary tract infections in the past year/6 mo before enrollment Postmenopausal 6 mo FSFI
Hirschberg et al39 Spain
Sweden
Multicenter Hormone receptor positive early breast cancer treated with aromatase inhibitors for at least 6 mo and severe to moderate vaginal dryness at baseline Perimenopausal and postmenopausal 12 wk FSFI
Taylor et al40 (KEEPS-sexual) United States Multicenter Symptomatic or asymptomatic menopausal women Perimenopausal or recently postmenopausal 48 mo FSFI
Lillemon et al41 United States Single center Postmenopausal women Postmenopausal 12 wk FSFI
Mac Bride42 United States Single center GSM at baseline Postmenopausal 12 wk MENQOL, FSFI
Reed et al43 and Caan et al44 United States Multicenter Vasomotor symptoms at baseline Perimenopausal or recently postmenopausal 8 wk FSFI
Diem et al,45 Mitchell et al,46 Jensen,47 and
Gibson et al48
United States Multicenter GSM at baseline Postmenopausal 12 wk FSFI
Olmez et al49 Turkey Single center Cervical cancer survivors with radiotherapy treatment at least 6 mo before enrollment in the trial Postmenopausal 6 mo FSFI
Kingsberg et al50
(REJOICE)
United States
Canada
Multicenter GSM with dyspareunia as MBS at baseline Postmenopausal 12 wk FSFI
Sun et al51 China Single center Women with severe uterine and anterior vaginal wall prolapse at baseline referred for transvaginal pelvic reconstructive surgery with mesh Postmenopausal 12 mo PISQ-12
Tanmahasamut et al52 Thailand Single center GSM at baseline Perimenopausal and postmenopausal 8 wk FSFI
Verghese et al47 United-Kingdom Multicenter Women with pelvic organ prolapse at baseline having pelvic organ prolapse surgery without use of vaginal mesh Postmenopausal 12 mo PISQ-12
Study Arm N Intervention/Control Posology Authors' conclusion
Archer et al30 I 313 Oral ospemifene 60 mg once daily for 12 wk Women in the ospemifene group reported significantly higher FSFI total scores than women in the placebo group at week 12.
C 314 Placebo
Bosak et al31 I 32 CE vaginal cream 1 g once daily for 2 wk, then twice weekly for 10 wk There is a significant difference in sexual satisfaction between estrogen and placebo groups.
C 32 Placebo
Bumphenkiatikul et al32 I 34 CE vaginal tablet 0.625 mg once daily for 3 wk, then twice weekly for 9 wk The 12-wk study with vaginal administration of CE tablet had no demonstrable effects on the changes in the FSFI.
C 33 Placebo
Carmignani et al33 I 20 E2 and norethisterone acetate tablet 1 mg of E2 and 0.5 mg of norethisterone acetate once daily for 16 wk Sexual symptoms did not change with treatment.
C 20 Placebo
Caruso et al34 I [1] 19 [2] 19 0.005% E2 vaginal cream [1] 1 g once daily for 3 wk, then twice weekly for 9 wk, then 1 wk with no treatment, then once daily for 3 wk, then twice weekly for 9 wk
[2] 1 g once daily for 3 wk, then twice weekly for 9 wk
The improvement in the no-intervention group was lower than that in E2 vaginal gel before and after surgery (25 wk) group, and similar to that in E2 vaginal gel before surgery only group (12 wk).
C 37 No intervention
Constantine et al35 I 463 Oral ospemifene 60 mg once daily for 12 wk Treatment with ospemifene significantly improved the total FSFI score and FSFI domain scores.
C 456 Placebo
Cruz et al36 I 15 E2 vaginal cream 1 mg three times a week for 20 wk CO2 laser + E2 vaginal cream and CO2 laser + placebo arms were not compared in this trial.
C 15 Placebo
Davison et al37 I 12 E2 and drospirenone oral tablet 1 mg of E2 and 2 mg of drospirenone once daily for 26 wk At 26 wk, there was a significant difference between treatment groups in the MENQOL sexual function score adjusted for age and baseline, indicating E2 and drospirenone treatment benefit.
C 11 Placebo
Ferrante et al38 I 17 Vaginal CE cream or E2 ring 0.5 g (=0.312 mg of CE) twice weekly for 6 mo or 2 mg ring every 3 mo CE vaginal cream and placebo were not compared in this trial.
C 17 Placebo
Hirschberg et al39 I 50 E3 vaginal gel 1 g (=50 mg of E3) once daily for 3 wk, then 1 g (=50 mg of E3) twice weekly for 9 wk The pairwise comparison did not reveal significant differences between active and placebo groups regarding the total FSFI score and the scores of each domain.
C 11 Placebo
Taylor et al40 (KEEPS, sexual) I [1] 230
[2] 222
[1] CEE oral pill and progesterone oral capsule
[2] 17ß-E2 transdermal patch and progesterone oral capsule
[1] 0.45 mg of CEE daily and 200 mg of progesterone for 12 d a month
[2] 50 μg E2 daily and 200 mg of progesterone for 12 d a month
Compared with placebo, the E2 group showed significant improvements in desire, arousal, orgasm, and satisfaction scores at 18 mo. Treatment with CEE demonstrated fewer significant improvements relative to placebo.
C 275 Placebo
Lillemon et al41 I 20 E2 vaginal ring 2 mg E2 ring for 12 wk There were no significant changes in FSFI scores.
C 19 Placebo
Mac Bride42 I [1] 19
[2] 18
[1] E2 vaginal cream
[2] E3 vaginal cream
[1] 0.5 g (=10 μg of E2) once daily for 2 wk, then twice weekly for 10 wk There was not a statistically significant difference in sexual function composite score either between the 3 groups or between the 2 active treatment groups and the placebo group.
C 19 Placebo [2] 0.5 g (=10 μg of E3) once daily for 2 wk, then twice weekly for 10 wk
MsFLASH VMS Reed et al,43 Caan et al44 I 97 Oral 17ß-E2 0.5 mg daily for 8 wk In an adjusted linear regression model, 8-wk treatment with E2 compared with placebo did not affect composite FSFI among the women who were sexually active at baseline.
C 146 Placebo
MsFLASH VHT Diem et al,45 Mitchell et al,46 Jensen,47 and Gibson et al48 I 102 E2 vaginal tablet 10 μg once daily for 2 wk, then twice weekly for 10 wk Change in FSFI did not significantly vary between treatment groups, either total score or any of the 6 domains.
C 100 Placebo
Olmez et al49 I [1] 16
[2] 16
[1] Tibolone
[2] E2 and MPA
[1] 2.5 mg daily
[2] 0.625 mg of E2 and 5 mg of MPA daily
HT and placebo arms FSFI scores were not compared. Only before and after treatment FSFI scores in each arm were compared.
C 17 Placebo
Kingsberg et al50 (REJOICE) I [1] 191 [2] 191
[3] 190
17ß-E2 vaginal soft-gel capsule [1] 4 μg once daily for 2 wk, then twice a week for 10 wk
[2] 10 μg once daily for 2 wk, then twice a week for 10 wk
[3] 25 μg once daily for 2 wk, then twice a week for 10 wk
17ß-E2 vaginal soft-gel capsule improved FSFI scores in a dose-dependent manner.
C 192 Placebo
Sun et al51 I 93 Promestriene vaginal cream 0.5 g twice weekly for 6 wk There was no significant difference in PISQ-12 decrease from baseline to month 12 among women receiving and not receiving vaginal estrogen therapy.
C 93 No intervention
Tanmahasamut et al52 I 40 17ß-E2 vaginal gel 2 mL (=25 μg of E2) once daily for 2 wk, then twice weekly for 6 wk The mean FSFI summary score was significantly increased at week 8 in the E2 group, but they were not significantly different in the control group. At week 8, the E2 group had statistically significant improvement in lubrication, orgasm, and pain.
C 40 Placebo
Verghese et al53 I 50 E2 vaginal pessaries 10 μg once daily for 2 wk, then twice weekly for 4 wk, then 6 wk with no treatment after surgery, then twice weekly for 20 wk The majority of women in both trial groups reported improvement in their sexual function.
C 50 No intervention

C, control; CE, conjugated estrogen; CEE, conjugated equine estrogen; E2, Estradiol; E3, Estriol; FSFI, Female Sexual Function Index; GSM, genitourinary syndrome of menopause; HT, hormone therapy; I, Intervention; LSSQ, Larson Sexual Satisfaction Questionnaire; MBS, most bothersome symptom; MENQOL, Menopause Quality of Life questionnaire; MPA, medroxyprogesterone acetate; MRS, Menopause Rating Scale; N, Number of participants randomized; PISQ-12, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12.

For consistency of results interpretation with Nastri et al,14 an SMD between −0.49 and −0.20 was considered small harm, between −0.19 and 0.19 was considered no effect, between 0.20 and 0.49 was considered small benefit, between 0.50 and 0.79 was considered moderate benefit, and at least 0.80 was considered large benefit.55

Unit of analysis issues

When reported, the intention-to-treat (ITT) or modified ITT (mITT) data were used. ITT data were prioritized over mITT data.

Missing data

In case of missing trial information, authors of included articles were contacted and sent a personalized data request form.

Assessment of heterogeneity

To explore clinical heterogeneity, the overall population was divided into two subgroups as defined in Nastri et al14: (1) perimenopausal, recently postmenopausal, and symptomatic women, and (2) asymptomatic postmenopausal women with more than 5 years since their LMP. Indeed, Nastri et al14 showed that different results were to be expected in these populations. Likewise, because different routes of administration have different indications and different safety profiles,50 a subgroup analysis comparing systemic HT with vaginal HT was run. Statistical heterogeneity was assessed using the I2 statistic. Statistical heterogeneity was considered high when I2 ≥ 70%, moderate when 50% ≤ I2 < 70%, and low when I2 ≤ 50%.15 Because thresholds for the interpretation of the I2 statistic can be misleading,27 a sensitivity analysis excluding studies at high risk of bias, however, was performed.

Assessment of nonreporting bias

To minimize language bias, English, French, or Spanish language studies were considered. To avoid selective nonreporting bias, authors were contacted when outcomes relevant to the review and presented in the protocol or the Methods section were absent from the final report. When more than 10 studies were included in an analysis, a funnel plot was examined. Symmetry was assessed visually, and if asymmetric, all potential causes of small study effect, including publication bias, were considered. Likewise, in such situation, a fixed-effect meta-analysis giving less weight to small studies was performed to investigate a potential shift of the random-effect meta-analysis estimate toward the result of small studies.27

RESULTS

Description of studies

Search results and study design

From the original search performed on December 2012 in Nastri et al,14 27 studies were included in the systematic review, of which 19 were included in the current meta-analysis (Fig. 1). In this systematic review update, database and clinical trial registry searches were performed on March 30, 2022. A total of 5,062 records were retrieved (Fig. 1), and 20 studies from 33 records were identified for inclusion (Table 1). From these, 15 were included in the meta-analysis. All were parallel-arm RCTs. Six studies reported funding by the pharmaceutical industry.30,35,37,39,40,50 One study is an unpublished master's thesis.42 Further definition of “studies,” “records,” and “reports” is provided in Page et al.26

Participants

The 20 studies included 4,358 participants: 2,489 in the HT arms and 1,869 in the placebo or no-intervention arms. Two studies included perimenopausal and recently postmenopausal women, one included recently postmenopausal women only, and all other studies included postmenopausal women (Table 1). Ten studies included sexually active women.30-32,34,40,50-52,57-62 Of these, three studies defined sexual activity as penetrative sex30,32,50; four studies included penetrative sex, nonpenetrative sex, and masturbation34,40,57-62; and the remaining studies did not report any information on the definition of sexual activity. Two studies included participants who reported sexual activity with a female partner.57-62

Interventions

Among the 20 studies published since December 2012, 14 studies evaluated estrogen therapy.31,32,34,36,38,39,41,42,50-52,57-62 Four studies evaluated estrogen plus progestogen therapy.33,37,40,49 One study evaluated tibolone.43 Two studies evaluated the SERM ospemifene.30,35 The intervention was delivered vaginally in 14 studies. Other studies reported oral30,35,37,40,61,62 or transdermal administration.40 The route of administration was unclear in one study.33 When studies had several groups using the same drug with different route of administration, dose, or treatment duration, these groups were merged in the meta-analysis.40,42,50 In three studies, the control was no intervention.34,51,53 All other studies used matching placebos.

Outcomes

Sexual functioning was assessed using different measures including the following: Female Sexual Function Index (FSFI),63 Larson Sexual Satisfaction Questionnaire,64,65 Menopause Quality of Life questionnaire,66 Menopause Rating Scale,67 Day-to-Day Impact of Vaginal Aging questionnaire,68 and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-1269 (Table 1). When sexual function was measured on different scales, data from the FSFI were used if reported. Sexual function composite score was measured in all studies except one that only measured sexual satisfaction.31 One study measured sexual function composite score in the overall population and in sexually active participants only.61,62 Only data from the sexually active participants were included in the evidence synthesis because the FSFI is only validated in sexually active women.70 Four studies reported adjusted effect estimates.30,40,57-62

Risk of bias in included studies

Overall risk of bias was assessed to be low for 1 study, of some concern for 4 studies, and high for 15 studies (Table 2). The main source of high risk of bias was missing outcome data. Regarding bias due to deviation from intended intervention (domain 2), one study measured sexual function using the FSFI without excluding sexually inactive participants from the analysis.40 Therefore, the method of analyzing the data was judged inappropriate to estimate the effect of assignment to the intervention because it could lead to an underestimation of the FSFI score.70 For bias in measurement of the outcome (domain 4), in two studies,38,52 the overall FSFI mean score in one of the groups fell outside of the possible range of 2 to 36, indicating that sexual function was incorrectly scored.63,70 Thus, the method of measurement of the outcome was judged inappropriate, and both studies were excluded from the meta-analysis.

TABLE 2.

Risk of bias of included studiesa

Study Bias arising from the randomization process
(domain 1)
Bias due to deviation from intended intervention (domain 2) Bias due to missing outcome data (domain 3) Bias in measurement of the outcome (domain 4) Bias in selection of reported results (domain 5) Overall risk of bias
Estrogen therapy vs control
 Bosak et al31 Some concerns Low High Low Some concerns High
 Bumphenkiatikul et al32 Low Low Some concerns Low Some concerns Some concerns
 Caruso et al34 Some concerns Some concerns High Some concerns Some concerns High
 Cruz et al36 Low Low High Low Some concerns High
 Ferrante et al38 Low Low High High Some concerns High
 Hirschberg et al39 Low Low High Low Some concerns High
 Lillemon et al41 Some concerns Some concerns Some concerns Low Some concerns High
 Mac Bride42 Some concerns Low Some concerns Low High High
 MsFLASH VHT Diem et al,45  Mitchell et al,46 Jensen,47 and  Gibson et al48 Low Low Low Low Low Low
 MsFLASH VMS Reed et al,43  Caan et al44 Low Low High Low Some concerns High
 Kingsberg et al50 (REJOICE) Some concerns Some concerns Some concerns Low Some concerns High
 Sun et al51 Low Some concerns High Some concerns Some concerns High
 Tanmahasamut et al52 Low Low High High Some concerns High
 Verghese et al53 Low Some concerns High Some concerns Low High
Estrogen plus progestogen therapy vs control
 Carmignani et al33 Low Low Low Low Some concerns Some concerns
 Davison et al37 Low Low Some concerns Low Some concerns Some concerns
 Hirschberg et al39 Some concerns High High Low Low High
 Taylor et al40 (KEEPS, sexual) Some concerns Low High Low Some concerns High
Tibolone vs control
 Olmez et al49 Some concerns Low High Low Some concerns High
SERM vs control
 Archer et al30 Low Low High Low Low High
 Constantine et al35 Some concerns Low Some concerns Low Some concerns Some concerns

aFor the outcome sexual function composite score for all studies except Bosak et al (outcome sexual satisfaction).

Meta-analyses

The studies described previously were pooled as appropriate with the effect sizes previously published in Nastri et al.14 As such, 47 RCTs (35,912 participants) were included in the systematic review, and 34 RCTs (15,079 participants) were included in the meta-analysis.

Estrogen therapy versus control

In symptomatic or recently postmenopausal women, estrogen therapy had no effect to small benefit on sexual function composite score with moderate heterogeneity (SMD, 0.17; 95% CI, 0.01 to 0.32; I2 = 63%; 2,447 participants, 13 studies32,36,39,41,42,50,51,53,57-62,71-73; Fig. 2). In unselected postmenopausal women, HT had no effect to small benefit on sexual function composite score with low heterogeneity (SMD, 0.11; 95% CI, −0.18 to 0.41; I2 = 47%; 478 participants, 3 studies74-76). Any difference between the two groups is likely due to chance (P = 0.76). Among all participants of included studies, estrogen therapy had no effect to small benefit on sexual function composite score with moderate heterogeneity (SMD, 0.16; 95% CI, 0.02 to 0.29, I2 = 59%; 2,925 participants, 16 studies). The sensitivity analysis led to the same conclusion (SMD, 0.25; 95% CI, 0.07 to 0.43; I2 = 48%; 1,006 participants, 5 studies). No concerning asymmetry was observed on the funnel plot (Supplemental Digital Content, Appendix B, http://links.lww.com/MENO/B126).

FIG. 2.

FIG. 2

Forest plots showing the comparison of hormone therapy and control for sexual function composite score for estrogen therapy (A), estrogen plus progestogen therapy (B), tibolone (C), and SERM (D). SERM, selective estrogen receptor modulators.

Estrogen plus progestogen therapy versus control

In symptomatic or recently postmenopausal women, estrogen plus progestogen therapy had small harm to small benefit on sexual function composite score with high heterogeneity (SMD, 0.04; 95% CI, −0.31 to 0.39; I2 = 76%; 1,118 participants, 4 studies37,40,49,78; Fig. 2). In unselected postmenopausal women, estrogen plus progestogen therapy had no effect to small benefit on sexual function composite score with moderate heterogeneity (SMD, 0.09; 95% CI, −0.19 to 0.37; I2 = 54%; 1,314 participants, 3 studies78-80). Any difference between the two groups is likely due to chance (P = 0.82). Among all participants of included studies, estrogen plus progestogen therapy had no effect to small benefit on sexual function composite score with moderate heterogeneity (SMD, 0.11; 95% CI, −0.07 to 0.29; I2 = 65%; 2,432 participants, 7 studies). The sensitivity analysis found large harm to small benefit of estrogen plus progestogen therapy on sexual function composite score (SMD, −0.57; 95% CI, −1.40 to 0.27; 23 participants, 1 study). This result, however, is limited because of the small number of participants included in the analysis (Supplemental Digital Content, Appendix B, http://links.lww.com/MENO/B126).

Tibolone versus control

In symptomatic or recently postmenopausal women, tibolone had no effect to small benefit on sexual function composite score with low heterogeneity (SMD, 0.15; 95% CI, 0.02 to 0.28; I2 = 0%; 916 participants, 2 studies49,81; Fig. 2). In unselected postmenopausal women, tibolone had no effect to moderate benefit on sexual function composite score with low heterogeneity (SMD, 0.38; 95% CI, 0.04 to 0.71; I2 = 0%; 142 participants, 2 studies79,82). Any difference between the two groups is likely due to chance (P = 0.21). Among all participants of included studies, tibolone had no effect to small benefit on sexual function composite score with low heterogeneity (SMD, 0.18; 95% CI, 0.06 to 0.30; I2 = 0%; 1,058 participants, 4 studies). No sensitivity analysis could be run as all studies were assessed at high risk of bias.

SERM versus control

In symptomatic or recently postmenopausal women, SERM had no effect to small benefit on sexual function composite score with low heterogeneity (SMD, 0.18; 95% CI, 0.05 to 0.32; I2 = 0%, 842 participants, 2 studies30,83; Fig. 2). In unselected postmenopausal women, SERM had small harm to small benefit on sexual function composite score with low heterogeneity (SMD, 0; 95% CI, −0.24 to 0.24; I2 = 0%; 283 participants, 1 study76). Any difference between the two groups is likely due to chance (P = 0.20). Among all participants of included studies, SERM had no effect to small benefit on sexual function composite score with low heterogeneity (SMD, 0.14; 95% CI, 0.02 to 0.26; I2 = 0%; 1,125 participants, 3 studies). The sensitivity analysis led to the same conclusion (SMD, 0.11; 95% CI, −0.12 to 0.34; I2 = 36%; 498 participants, 2 studies; Supplemental Digital Content, Appendix B, http://links.lww.com/MENO/B126).

Systemic HT versus vaginal HT

For all outcomes of all comparisons, there was no significant difference between the subgroups systemic HT and vaginal HT (Supplemental Digital Content, Appendix B, http://links.lww.com/MENO/B126).

DISCUSSION

Summary of main results

This systematic review includes 47 RCTs (35,912 participants). The meta-analysis revealed that, compared with control, estrogen therapy, estrogen plus progestogen therapy, tibolone, and SERM may result in no effect to small benefit on sexual function composite score in perimenopausal and postmenopausal women. No significant difference in effect was noted between perimenopausal, recently postmenopausal, or symptomatic women versus unselected postmenopausal women. Although adverse events related to HT were not included in this review, other systematic reviews have investigated the safety profile of HT.22,84-89

Overall completeness and applicability of evidence

Population

Among the 20 studies published since December 2012, 10 included sexually active women and 1 included both sexually inactive and sexually active women. Because most trials measured sexual function using the FSFI,63 it is likely that studies that did not specify included sexually active women, even though missuses of the scale are common.70 Because low sexual function may lead to sexual inactivity, future researchers could use a scale validated for nonsexually active women,66 although these also have limitations. Moreover, only two newer studies reported the inclusion of women who have sex with women, and mixed evidence exists regarding the prevalence and intensity of genitopelvic pain in women who have sex with women compared with women who have sex with men.90 Nevertheless, previous research has suggested that better communication between lesbian women, compared with heterosexual and bisexual women, is likely to diminish the impact of genitopelvic pain by allowing for variations in sexual activities.91 Indeed, women who have sex with women tend to rely more on relationship dynamics and partner support, as they have described healthcare providers' advice unhelpful for their sexual problems.92 Future research should actively recruit and focus on better understanding sexual function among women who have sex with women.

Intervention

In Nastri et al,14 most interventions were administered orally, whereas vaginal administration was more common in newer studies. The meta-analysis did not reveal any difference in the effect of HT on sexual function when comparing routes of administration. Results from this analysis, however, are limited because it was not prespecified in the protocol.

Outcomes

The scales included in this review were designed to measure sexual functioning. None, however, can be used to diagnosis FSD because they do not include measures of distress.3 Only two newer studies measured sexual distress using a single item from the revised Female Sexual Distress Scale (FSDS-R).57,58,60-62 Future clinical trials investigating sexual function should also measure sexual distress which may help reduce stigma around low sexual functioning during the menopausal transition.93,94 Because the revised Female Sexual Distress Scale needs further validation in this population, these results, however, were not included in the current review.95 Traditionally, an FSFI score lower than 26.55 has been used to indicated clinical levels of sexual dysfunction96; however, new evidence suggests that a cutoff score lower than 21 is associated with greater sexual distress.97 In addition, different scales can lead to different prevalence estimates within the same population,98 which can influence the estimated clinical effect of the intervention and may also explain some of the observed heterogeneity. Furthermore, using the FSFI with sexually inactive women could lead to an underestimation of the overall effect of HT on sexual function composite score.70

Study quality

Seventeen of the 20 studies published since December 2012 might suffer from attrition bias given the high amount of missing data. Nevertheless, the effect of HT on sexual function did not change when excluding studies at high risk of bias. Among these trials, missingness for sexual function was usually higher than other outcomes. As discussed, proper use of the FSFI could reduce the amount of missing data.70 In addition, measuring sexual function over a 6-month period rather than 4 weeks could reduce the number of participants excluded after randomization; this has been previously suggested99 and is validated in women who have sex with women.100 Similarly, missing data could also be reduced by rephrasing the FSFI to include all forms of vaginal penetration100,101 or using a measure such as the Day-to-Day Impact of Vaginal Aging questionnaire,68 which considers nonpenetrative sexual activity. Furthermore, nearly all studies that investigated sexual satisfaction used the FSFI satisfaction domain; however, one question cannot be answered by unpartnered women, and high rates of missing data for this question were reported in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) trials.102 Therefore, restricting inclusion to women who have a partner or using a scale that does not require the responder to have a partner could reduce the amount of missing data. Finally, clinical trial participants may be uncomfortable discussing sexuality as compared with other health-related topics, so future RCTs could add willingness to answer sexuality questionnaires as an inclusion criterion. Practitioners should also start open conversations about sex with their patients to normalize discussing sexual health in medical settings. Indeed, in the Real Women's Views of Treatment Options for Menopausal Vaginal Changes (REVIVE) survey, only 19% of women reported that their healthcare provider asked about their sexual health, whereas 40% expected that their healthcare provider would start the conversation about vulvovaginal symptoms.103

Potential biases in the review process

This review has limitations. Screening, data extraction, and risk-of-bias assessment were performed primarily by the first author, in consultation with the final author in case of doubt. Ideally, these would have been performed by two reviewers blinded from each other, with a third investigator resolving potential conflicts.27 When a full-text publication could not be found, authors were contacted, but none responded. Finally, this review might suffer from language bias because only reports in English, French, or Spanish were considered for inclusion. Only one record in another language, however, was found, and records in English reporting the same study were also retrieved.

Genitourinary syndrome of menopause

Results of this review do not invalidate the use of topical HT for the treatment of GSM or the need to diagnose GSM. Evidence shows that only 14% of women who discuss their genitourinary symptoms with a healthcare provider receive a GSM diagnosis, resulting in underdiagnosis of the condition.103 With almost half of postmenopausal women judging their symptoms as a natural part of aging or not bothersome enough to mention,103 it is essential that healthcare providers investigate genitourinary symptoms among their patients, as effective treatments exist. The International Menopause Society strongly recommends that practitioners initiate a conversation on female sexual well-being at the beginning of menopause.5 Furthermore, cross-cultural studies reveal that more distressing symptoms are noted in cultures where menopause is taboo104 and more negative attitudes toward menopause are associated with increased symptom reporting.105 Healthcare providers should open the dialogue on menopausal transition before the onset of perimenopause to set realistic expectations about symptoms and offer knowledge on available treatment options, empowering women to encourage positive reappraisal and reduce the stigma around menopause.

Implications for research

Summary effects of this review are accompanied by wide CIs, and 33 of 47 studies were assessed at high risk of bias, lowering the level of confidence in the results. Any potential benefit of HT on sexual function, however, is expected to be small, and HT is already recommended in the treatment of GSM-related dyspareunia. Therefore, it can be concluded that the effect of HT on sexual function in perimenopausal and postmenopausal women is well understood and unlikely to change in the future. Expert consensus statements tend toward a biopsychosocial understanding of FSD with treatment strategies including both pharmacological and psychological interventions.106,107 Future clinical trials may wish to evaluate their synergic effect in menopausal women with distressing sexual problems. A more holistic appraisal of sexuality would lead to more pragmatic patient-relevant research embracing the World Health Organization's definition of sexual health as “a state of physical, emotional, mental and social well-being in relation to sexuality [that] is not merely the absence of disease, dysfunction or infirmity.”108

CONCLUSIONS

This systematic review and meta-analysis found that HT may slightly improve sexual functioning. This potential small benefit should be considered when discussing treatment options for other menopausal symptoms. Future research should consider the role of HT as one component of a more holistic approach to managing low sexual functioning in perimenopausal and postmenopausal women.

Supplementary Material

meno-30-659-s001.docx (212.3KB, docx)

Footnotes

Funding/support: N.M. was supported by Programme de bourses Mobilité Internationale en Master (MIRES).

Financial disclosure/conflicts of interest: C.A.T. does occasional lectures for pharmaceutical companies (Gedeon Richter, Mylan, Bayer) for which she receives a fee. The remaining authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s Website (www.menopause.org).

Contributor Information

Nadia Meziou, Email: nadia.meziou@etu.u-paris.fr.

Clare Scholfield, Email: clare.scholfield@solent.nhs.uk.

Caroline A. Taylor, Email: Caroline.Taylor2@solent.nhs.uk.

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