Hormone therapy for sexual function in perimenopausal and postmenopausal women

  • Review
  • Intervention

Authors

  • Carolina O Nastri,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    2. Ultrasonography and Retraining Medical School of Ribeirao Preto (EURP), Ribeirao Preto, Sao Paulo, Brazil
    Search for more papers by this author
  • Lucia A Lara,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    Search for more papers by this author
  • Rui A Ferriani,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    Search for more papers by this author
  • Ana Carolina JS Rosa-e-Silva,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    Search for more papers by this author
  • Jaqueline BP Figueiredo,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    2. Ultrasonography and Retraining Medical School of Ribeirao Preto (EURP), Ribeirao Preto, Sao Paulo, Brazil
    Search for more papers by this author
  • Wellington P Martins

    Corresponding author
    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    2. Ultrasonography and Retraining Medical School of Ribeirao Preto (EURP), Ribeirao Preto, Sao Paulo, Brazil
    • Wellington P Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clinicas da FMRP-USP, 8 andar, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, 14048-900, Brazil. wpmartins@gmail.com.

    Search for more papers by this author

Abstract

Background

The perimenopausal and postmenopausal periods are associated with many symptoms, including sexual complaints.

Objectives

To assess the effect of hormone therapy (HT) on sexual function in perimenopausal and postmenopausal women.

Search methods

We searched for articles in the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, ISI Web of Knowledge and OpenGrey. The last search was performed in December 2012.

Selection criteria

We included randomised controlled trials comparing HT to either placebo or no intervention (control). We considered as HT estrogens alone; estrogens in combination with progestogens; synthetic steroids (for example tibolone); or selective estrogen receptor modulators (SERMs) (for example raloxifene, bazedoxifene). Studies of other drugs possibly used in the relief of menopausal symptoms were excluded. We included studies that evaluated sexual function using any validated assessment tool. The primary outcome was a composite score for sexual function and the scores for individual domains (arousal and sexual interest, orgasm, and pain) were secondary outcomes. Studies were selected by two authors independently.

Data collection and analysis

Data were independently extracted by two authors and checked by a third. Risk of bias assessment was performed independently by two authors. We contacted study investigators as required. Data were analysed using standardized mean difference (SMD) and relative risk (RR). We stratified the analysis by participant characteristics with regard to menopausal symptoms. The overall quality of the evidence for the primary outcome was evaluated using the GRADE criteria.

Main results

The search retrieved 2351 records from which 27 studies (16,393 women) were included. The 'symptomatic or early post-menopausal' subgroup included nine studies: perimenopausal women (one study), up to 36 months postmenopause (one study), up to five years postmenopause (one study), experiencing vasomotor or other menopausal symptoms (five studies), or experiencing hot flushes and sexual dysfunction (one study). The 'unselected postmenopausal women' subgroup included 18 studies, which included women regardless of menopausal symptoms and permitted the inclusion of women with more than five years since the final menstrual period. No studies were restricted to women with sexual dysfunction. Only five studies evaluated sexual function as a primary outcome. Eighteen studies were deemed at high risk of bias, and the other nine studies were at unclear risk of bias. Twenty studies received commercial funding.

Findings for sexual function (measured by composite score):

For estrogens alone versus control, in symptomatic or early postmenopausal women the SMD and 95% CI were compatible with a small to moderate benefit in sexual function for the HT group (SMD 0.38, 95% CI 0.23 to 0.54, P < 0.00001, 3 studies, 699 women, I² = 55%, high-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.16, 95% CI -0.02 to 0.34, P = 0.08, 2 studies, 478 women, I² = 44%, low-quality evidence). The subgroups were not pooled because of considerable heterogeneity.

For estrogens combined with progestogens versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with a small to moderate benefit for sexual function in the HT group (SMD 0.42, 95% CI 0.19 to 0.64, P = 0.0003, 1 study, 335 women, moderate-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.09, 95% CI -0.02 to 0.20, P = 0.10, 3 studies, 1314 women, I² = 0%, moderate-quality evidence). The subgroups were not pooled because of considerable heterogeneity.

For tibolone versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with no effect to a small benefit for sexual function in the HT group (SMD 0.13, 95% CI 0.00 to 0.26, P = 0.05, 1 study, 883 women, low-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit (SMD 0.38, 95% CI 0.04 to 0.71, P = 0.03, 2 studies, 142 women, I² = 0%, low-quality evidence). In the combined analysis, the 95% CI was compatible with no effect to a small benefit (SMD 0.17, 95% CI 0.04 to 0.29, P = 0.008, 3 studies, 1025 women, I² = 20%).

For SERMs versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with no effect to a moderate benefit for sexual function in the HT group (SMD 0.23, 95% CI -0.04 to 0.50, P = 0.09, 1 study, 215 women, low-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with small harm to a small benefit (SMD 0.04, 95% CI -0.20 to 0.29, P = 0.72, 1 study, 283 women, low-quality evidence). In the combined analysis, the 95% CI was compatible with no effect to a small benefit (SMD 0.13, 95% CI -0.05 to 0.31, P = 0.16, 2 studies, 498 women, I² = 2%).

A comparison of SERMs combined with estrogens versus control was only evaluated in symptomatic or early postmenopausal women. The 95% CI was compatible with no effect to a small benefit for sexual function in the HT group (SMD 0.21, 95% CI 0.00 to 0.43, P = 0.05, 1 study, 542 women, moderate-quality evidence).

Authors' conclusions

HT treatment with estrogens alone or in combination with progestogens was associated with a small to moderate improvement in sexual function, particularly in pain, when used in women with menopausal symptoms or in early postmenopause (within five years of amenorrhoea), but not in unselected postmenopausal women. Evidence regarding other HTs (synthetic steroids and SERMs) is of low quality and we are uncertain of their effect on sexual function. The current evidence does not suggest an important effect of tibolone or of SERMs alone or combined with estrogens on sexual function. More studies evaluating the effect of synthetic steroids, SERMS and the association of SERM + estrogens would improve the quality of the evidence for the effect of these treatments on sexual function in peri and postmenopausal women. Future studies should also evaluate the effect of HT solely among women with sexual complaints.

Résumé scientifique

Hormonothérapie dans la fonction sexuelle des femmes en périménopause et postménopause

Contexte

Les périodes de périménopause et postménopause sont liées à de nombreux symptômes, notamment des troubles sexuels.

Objectifs

Évaluer les effets d'une hormonothérapie (HT) sur la fonction sexuelle chez des femmes en périménopause et postménopause.

Stratégie de recherche documentaire

Nous avons recherché des articles dans le registre spécialisé du groupe Cochrane sur les troubles menstruels et de la fertilité (MDSG pour « Menstrual Disorders and Subfertility Group »), CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, ISI Web of Knowledge et OpenGrey. Les dernières recherches ont été réalisées en décembre 2012.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés comparant une HT à un placebo ou à l'absence d'intervention (groupe témoin). Nous avons évalué une HT à base d'œstrogènes seuls ; d'œstrogènes associés à des progestatifs ; de stéroïdes synthétiques (par exemple : la tibolone) ou de modulateurs sélectifs des récepteurs aux œstrogènes (SERM pour « Selective Estrogen Receptor Modulators ») (par exemple : le raloxifène et le bazédoxifène). Les études portant sur d'autres médicaments éventuellement administrés pour soulager les symptômes ménopausiques ont été exclues. Nous avons inclus les études évaluant la fonction sexuelle à l'aide d'un outil d'évaluation validé. Le critère de jugement principal était un score composite de la fonction sexuelle et les critères de jugement secondaires étaient des scores de domaines individuels (excitation et attirance sexuelle, orgasme et douleurs). Deux auteurs ont indépendamment sélectionné des études.

Recueil et analyse des données

Deux auteurs ont indépendamment extrait des données et un troisième les a vérifiées. Deux auteurs ont indépendamment évalué les risques de biais. Nous avons contacté les chercheurs des études, le cas échéant. La différence moyenne standardisée (DMS) et le risque relatif (RR) ont été utilisés pour analyser les données. Nous avons stratifié l'analyse en fonction des caractéristiques des participantes concernant les symptômes ménopausiques. Le critère GRADE a été utilisé pour évaluer la qualité globale des preuves se rapportant au critère de jugement principal.

Résultats principaux

Les recherches ont extrait 2 351 enregistrements dont 27 études (16 393 femmes) ont été incluses. Le sous-groupe « femmes symptomatiques ou en postménopause précoce » se composait de neuf études : des femmes en périménopause (une étude), en postménopause jusqu'à 36 mois (une étude), en postménopause jusqu'à cinq ans (une étude), présentant des symptômes vasomoteurs, d'autres symptômes ménopausiques (cinq études) ou des bouffées de chaleur et une dysfonction sexuelle (une étude). Le sous-groupe « femmes en postménopause non sélectionnées » incluait 18 études composées de femmes quels que soient leurs symptômes ménopausiques et autorisait l'inclusion de femmes dont des dernières menstruations dataient de plus de cinq ans. Aucune étude ne se limitait à des femmes présentant une dysfonction sexuelle. Seules cinq études ont évalué la fonction sexuelle en tant que critère de jugement principal. Les risques de biais de dix-huit études ont été jugés élevés et les risques de biais des neuf autres étaient incertains. Vingt études bénéficiaient d'un financement commercial.

Résultats sur la fonction sexuelle (mesurés par un score composite) :

Pour le groupe prenant des œstrogènes seuls comparé à un groupe témoin, chez les femmes symptomatiques ou en postménopause précoce, la DMS et l'IC à 95 % étaient compatibles avec une efficacité légère à modérée sur la fonction sexuelle pour le groupe suivant une HT (DMS 0,38, IC à 95 % 0,23 à 0,54, P < 0,00001, 3 études, 699 femmes, I² = 55 %, preuves de qualité élevée). Chez les femmes en postménopause non sélectionnées, l'IC à 95 % était compatible avec une efficacité nulle à légère (DMS 0,16, IC à 95 % - 0,02 à 0,34, P = 0,08, 2 études, 478 femmes, I² = 44 %, preuves de qualité médiocre). En raison d'une hétérogénéité importante, les sous-groupes n'ont pas été regroupés.

Pour le groupe prenant des œstrogènes associés à des progestatifs comparé à un groupe témoin, chez les femmes symptomatiques ou en postménopause précoce, l'IC à 95 % était compatible avec une efficacité légère à modérée sur la fonction sexuelle pour le groupe suivant une HT (DMS 0,42, IC à 95 % 0,19 à 0,64, P = 0,0003, 1 étude, 335 femmes, preuves de qualité moyenne). Chez les femmes en postménopause non sélectionnées, l'IC à 95 % était compatible avec une efficacité nulle à légère (DMS 0,09, IC à 95 % - 0,02 à 0,20, P = 0,10, 3 études, 1 314 femmes, I² = 0 %, preuves de qualité moyenne). En raison d'une hétérogénéité importante, les sous-groupes n'ont pas été regroupés.

Pour le groupe prenant de la tibolone comparé à un groupe témoin, chez les femmes symptomatiques ou en postménopause précoce, l'IC à 95 % était compatible avec une efficacité nulle à légère sur la fonction sexuelle pour le groupe suivant une HT (DMS 0,13, IC à 95 % 0,00 à 0,26, P = 0,05, 1 étude, 883 femmes, preuves de qualité médiocre). Chez les femmes en postménopause non sélectionnées, l'IC à 95 % était compatible avec une efficacité nulle à modérée (DMS 0,38, IC à 95 % 0,04 à 0,71, P = 0,03, 2 études, 142 femmes, I² = 0 %, preuves de qualité médiocre). Dans une analyse combinée, l'IC à 95 % était compatible avec une efficacité nulle à légère (DMS 0,17, IC à 95 % 0,04 à 0,29, P = 0,008, 3 études, 1 025 femmes, I² = 20 %).

Pour le groupe prenant des SERM comparé à un groupe témoin, chez les femmes symptomatiques ou en postménopause précoce, l'IC à 95 % était compatible avec une efficacité nulle à modérée sur la fonction sexuelle pour le groupe suivant une HT (DMS 0,23, IC à 95 % - 0,04 à 0,50, P = 0,09, 1 étude, 215 femmes, preuves de qualité médiocre). Chez les femmes en postménopause non sélectionnées, l'IC à 95 % était compatible avec un risque léger et une efficacité légère (DMS 0,04, IC à 95 % - 0,20 à 0,29, P = 0,72, 1 étude, 283 femmes, preuves de qualité médiocre). Dans une analyse combinée, l'IC à 95 % était compatible avec une efficacité nulle à légère (DMS 0,13, IC à 95 % - 0,05 à 0,31, P = 0,16, 2 études, 498 femmes, I² = 2 %).

Une comparaison entre un groupe prenant des SERM combinés à des œstrogènes et un groupe témoin était uniquement réalisée chez les femmes symptomatiques ou en postménopause précoce. L'IC à 95 % était compatible avec une efficacité nulle à légère sur la fonction sexuelle pour le groupe suivant une HT (DMS 0,21, IC à 95 % 0,00 à 0,43, P = 0,05, 1 étude, 542 femmes, preuves de qualité moyenne).

Conclusions des auteurs

Une HT avec des œstrogènes seuls ou associés à des progestatifs était liée à une amélioration légère à modérée de la fonction sexuelle, plus particulièrement les douleurs, lorsqu'elle était administrée à des femmes présentant des symptômes ménopausiques ou en postménopause précoce (jusqu'à cinq années d'aménorrhée), mais pas à des femmes en postménopause non sélectionnées. Les preuves concernant les autres HT (stéroïdes synthétiques et SERM) sont de qualité médiocre et nous ignorons leurs effets sur la fonction sexuelle. Les preuves actuellement disponibles ne suggèrent aucun effet significatif de la tibolone ou des SERM seuls ou associés à des œstrogènes, sur la fonction sexuelle. Plus d’études évaluant les effets des stéroïdes synthétiques, des SERM et de l'association de SERM à des œstrogènes, permettraient uneamélioration de la qualité des preuves concernant les effets de ces traitements sur la fonction sexuelle chez les femmes en périménopause ou postménopause. D'autres études devront également évaluer les effets d'une HT seule chez des femmes présentant des troubles sexuels.

Resumo

Terapia hormonal para função sexual em mulheres na peri e pós-menopausa

Introdução

Os períodos peri-menopausa e pós-menopausa estão associados com vários sintomas, incluindo queixas sexuais.

Objetivos

Para avaliar o efeito da terapia hormonal (TH) sobre a função sexual em mulheres na peri-menopausa e pós-menopausa.

Métodos de busca

Realizamos uma pesquisa por artigos na Cochrane Menstrual Disorders and Subfertility Grupo (MDSG) Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, ISI Web of Knowledge and OpenGrey. A última pesquisa foi realizada em Dezembro de 2012

Critério de seleção

Incluímos ensaios clínicos randomizados comparando TH com placebo ou nenhuma intervenção (controle). Consideramos como TH estrogênios isolados; estrogênios combinados com progestagênios; esteróides sintéticos (por exemplo tibolona); ou moduladores seletivos do receptor de estrogênio (MSREs) (por exemplo raloxifeno, bazedoxifeno). Estudos sobre outras drogas possivelmente usadas para o alívio dos sintomas da menopausa foram excluídos. Incluimos estudos que avaliaram a função sexual usando qualquer ferramenta de avaliação validada. O desfecho primário foi a pontuação total para a função sexual e os escores para domínios individuais (excitação e interesse sexual, orgasmo e dor) foram considerados desfechos secundários. Os estudos foram selecionados por dois autores de forma independente.

Coleta dos dados e análises

Os dados foram extraídos independentemente por dois autores e verificados por um terceiro. Avaliação do risco de viés foi realizado de forma independente por dois autores. Contactamos os autores dos estudos conforme necessário. Os dados foram analisados usando diferença média padronizada (DMP) e risco relativo (RR). Estratificamos a análise por características das participantes no que diz respeito aos sintomas da menopausa. A qualidade global das evidências para o desfecho primário foi avaliada utilizando os critérios GRADE.

Principais resultados

A pesquisa recuperou 2351 registros a partir do qual foram incluídos 27 estudos (16.393 mulheres). O subgrupo "sintomática ou pós-menopausa precoce" incluiu nove estudos: mulheres na peri-menopausa (um estudo), até 36 meses pós-menopausa (um estudo), até cinco anos pós-menopausa (um estudo), com queixa vasomotora ou outros sintomas da menopausa (cinco estudos ), ou fogachos e disfunção sexual (um estudo). O subgrupo das "mulheres na pós-menopausa não selecionadas" incluiu 18 estudos, os quais incluíram mulheres independentemente dos sintomas da menopausa e mulheres com mais de cinco anos do último período menstrual. Nenhum estudo foi restrito a mulheres com disfunção sexual. Apenas cinco estudos avaliaram a função sexual como desfecho primário. Dezoito estudos foram considerados de alto risco de viés, e os outros nove estudos estavam em risco incerto de viés. Vinte estudos receberam financiamento comercial.

Achados para a função sexual (medido pelo escore composto):

Para estrogênio isolado versus controle, em mulheres sintomáticas ou pós-menopausa imediata a DMP e IC 95% eram compatíveis com pequeno benefício na função sexual para o grupo TH a moderada (DMP 0,38, IC 95% 0,23-0,54, P <0,00001, 3 estudos , 699 mulheres, P = 55%, evidência de alta qualidade). Em mulheres pós-menopausadas não selecionadas, o IC 95% foi compatível com nenhum efeito a pequeno benefício (DMP 0,16, IC 95% - 0,02 a 0,34, P = 0,08, dois estudos, 478 mulheres, P = 44%, evidências de baixa qualidade). Os subgrupos não foram agrupados devido a considerável heterogeneidade.

Para estrogênios combinados com progestagênios versus controle, em mulheres sintomáticas ou na pós-menopausa imediata o IC 95% foi compatível com um pequeno a moderado benefício para a função sexual no grupo TH (DMP 0,42, IC 95% 0,19-0,64, P = 0,0003, um estudo, 335 mulheres, evidência de qualidade moderada). Em mulheres pós-menopausadas não selecionadas, o IC 95% foi compatível com nenhum efeito a pequeno benefício (DMP 0,09, IC 95% - 0,02 a 0,20, P = 0,10, três estudos, 1314 mulheres, P = 0%, evidência de qualidade moderada). Os subgrupos não foram agrupados devido a considerável heterogeneidade.

Para a tibolona versus controle, em mulheres sintomáticas ou pós-menopausa imediata o IC 95% foi compatível com nenhum efeito ou um pequeno benefício para a função sexual no grupo TH (DMP 0,13, IC 95% 0,00-0,26, P = 0,05, um estudo, 883 mulheres, evidências de baixa qualidade). Em mulheres pós-menopausadas não selecionadas, o IC de 95% foi compatível com nenhum efeito a benefício moderado (DMP 0,38, IC 95% 0,04-0,71, P = 0,03, dois estudos, 142 mulheres, P = 0%, evidências de baixa qualidade). Na análise conjunta, o IC 95% foi compatível com nenhum efeito a pequeno benefício (DMP 0,17, IC de 95% 0,04-0,29, P = 0,008, três estudos, 1025 mulheres, P = 20%).

Para os MSREs versus controle, em mulheres sintomáticas ou pós-menopausa imediata o IC 95% foi compatível com nenhum efeito a benefício moderado para a função sexual no grupo TH (DMP 0,23, IC 95% - 0,04 a 0,50, P = 0,09, um estudo, 215 mulheres, evidência de baixa qualidade). Em mulheres na pós-menopausa não selecionadas, o IC 95% foi compatível com pequeno dano a um pequeno benefício (DMP 0,04, IC 95% -0,20 a 0,29, P = 0,72, um estudo, 283 mulheres, evidência de baixa qualidade). Na análise conjunta, o IC 95% foi compatível com nenhum efeito a um pequeno benefício (DMP 0,13, IC 95% - 0,05 a 0,31, P = 0,16, dois estudos, 498 mulheres, P = 2%).

A comparação dos MSREs com estrogênios combinados versus controle só foi avaliada em mulheres sintomáticas ou na pós-menopausa imediata. O IC 95% foi compatível com nenhum efeito a pequeno benefício para a função sexual no grupo TH (DMP 0,21, IC 95% 0,00-0,43, P = 0,05, um estudo, 542 mulheres, evidências com qualidade moderada).

Conclusão dos autores

TH com estrogênios isolados ou em combinação com progestagênios foi associada com pequena a moderada melhora na função sexual, particularmente na dor, quando utilizada em mulheres com sintomas da menopausa ou na pós-menopausa imediata (no prazo de cinco anos de amenorreia), mas não em mulheres pós-menopausadas não selecionadas. Evidências sobre outros THs (esteróides sintéticos e MSREs) é de baixa qualidade e não temos certeza do seu efeito sobre a função sexual. A evidência atual não sugere um efeito importante da tibolona ou de MSREs isolados ou combinados com estrogênios sobre a função sexual. Mais estudos avaliando o efeito de esteróides sintéticos, MSREs e a associação de MSREs + estrogênios iria melhorar a qualidade da evidência para o efeito destes tratamentos sobre a função sexual em mulheres na peri e pós-menopausa. Estudos futuros também devem avaliar o efeito da TH apenas entre as mulheres com queixas sexuais.

Notas de tradução

Traduzido por: Lucia alves S Lara, Unidade de Medicina Baseada em Evidências da Unesp, Brazil Contato: portuguese.ebm.unit@gmail.com

Plain language summary

Hormonal therapy for sexual function in menopausal women

We aimed to assess the effect of hormonal therapy (HT), specifically estrogens alone, estrogens in combination with progestogens, synthetic steroids, and SERMs, on sexual function in perimenopausal and postmenopausal women. The time around and after the last menstrual period (menopause) is associated with many symptoms, including a decline of sexual function. HT is a generic term that refers to any type of hormone therapy used during menopause for alleviation of menopause-related symptoms. We carried out an electronic search of medical literature databases, searching for randomised controlled trials (RCTs) comparing hormone therapy (HT) to either no treatment or a placebo treatment. No other type of study was included. The last search was performed in December 2012.

Twenty-seven studies were included; they were conducted in more than 30 countries. Sexual function was assessed in 8802 women in the treatment groups and in 7591 women in the control groups. A single study was responsible for the inclusion of 8462 women, 51.2% of the total number. We grouped the studies by participant characteristics with regard to menopausal symptoms. The symptomatic or early menopausal group was from nine studies in which women were perimenopausal (one study), up to 36 months postmenopause (one study), up to five years postmenopause (one study), experiencing vasomotor or other menopausal symptoms (five studies), or experiencing hot flushes and sexual dysfunction (one study). The unselected postmenopausal women group came from 18 studies. The group included women regardless of menopausal symptoms and allowed inclusion of women with more than five years since their final menstrual period. No studies were restricted to women with sexual dysfunction and only five studies evaluated sexual function as a primary outcome. Eighteen studies were deemed at high risk of bias, and the other nine studies were at unclear risk of bias. Twenty studies received commercial funding.

Findings for sexual function (measured by overall score) were as follows:

In the comparison of estrogens alone versus control, for symptomatic or early postmenopausal women the observed effect was compatible with a small to moderate benefit for sexual function in the HT group (high-quality evidence). For unselected postmenopausal women the observed effect was compatible with no effect to a small benefit, provided by low-quality evidence.

In the comparison of estrogens combined with progestogens versus control, for symptomatic or early postmenopausal women, the observed effect was compatible with a small to moderate benefit for sexual function in the HT group (moderate-quality evidence). For  unselected postmenopausal women, the observed effect was compatible with no effect to a small benefit (moderate-quality evidence).

In the comparison of tibolone versus control, for symptomatic or early postmenopausal women the observed effect was compatible with no effect to a small benefit for sexual function in the HT group (low-quality evidence). For unselected postmenopausal women, the observed effect was compatible with no effect to a moderate benefit (low-quality evidence).

In the comparison of SERMs (raloxifene and bazedoxifene) versus control, for symptomatic or early postmenopausal women the observed effect was compatible with no effect to a moderate benefit for sexual function in the HT group (low-quality evidence). For unselected postmenopausal women, the observed effect was compatible with a small harm to small benefit (low-quality evidence).

Comparing bazedoxifene combined with estrogens to control, for symptomatic or early postmenopausal women the observed effect was compatible with no effect to a small benefit, with moderate-quality evidence. No study was included in the subgroup of unselected postmenopausal women.

The included studies did not allow a comprehensive assessment of harms from these therapies; other systematic reviews must be taken into account to understand the possible harms of HT.

We concluded that HT treatment with estrogens alone or in combination with progestogens is associated with a small to moderate improvement in sexual function when used specifically in women with menopausal symptoms or who were in early postmenopause (within five years after onset of menopause), but not when used for any postmenopausal woman. Evidence regarding other HTs (tibolone, raloxifene, and bazedoxifene) is of low quality. The current evidence does not suggest an important effect of tibolone, raloxifene and bazedoxifene, alone or combined with estrogens, on sexual function.

Résumé simplifié

Hormonothérapie dans la fonction sexuelle des femmes ménopausées

Notre objectif était d'évaluer les effets d'une hormonothérapie (HT), en particulier l'administration d'œstrogènes seuls, d'œstrogènes associés à des progestatifs, de stéroïdes synthétiques et de SERM sur la fonction sexuelle de femmes en périménopause et postménopause. La période précédant et suivant les dernières menstruations (ménopause) est associée à de nombreux symptômes, notamment un déclin de la fonction sexuelle. La HT est un terme générique faisant référence à n'importe quel type d'hormonothérapie prescrit pendant la ménopause afin de soulager les symptômes ménopausiques. Nous avons effectué des recherches électroniques dans les bases de données de la littérature médicale afin d'identifier des essais contrôlés randomisés (ECR) comparant une hormonothérapie (HT) à l'absence de traitement ou à un traitement par placebo. Aucun autre type d'étude n'a été inclus. Les dernières recherches ont été réalisées en décembre 2012.

Vingt-sept études ont été incluses et réalisées dans plus de 30 pays différents. La fonction sexuelle a été évaluée chez 8 802 femmes appartenant aux groupes de traitement et chez 7 591 femmes appartenant aux groupes témoins. Une seule étude a permis d'inclure 8 462 femmes, soit 51,2 % de l'effectif total. Nous avons regroupé les études en fonction des caractéristiques des participantes concernant les symptômes ménopausiques. Le groupe en ménopause symptomatique ou précoce provient de 9 études dans lesquelles des femmes étaient en périménopause (une étude), en postménopause jusqu'à 36 mois (une étude), en postménopause jusqu'à cinq ans (une étude), présentaient des symptômes vasomoteurs, d'autres symptômes ménopausiques (cinq études) ou des bouffées de chaleur et une dysfonction sexuelle (une étude). Le groupe des femmes en postménopause non sélectionnées provient de 18 études. Ce groupe incluait des femmes quels que soient leurs symptômes ménopausiques et autorisait l'inclusion de femmes dont les dernières menstruations dataient de plus de cinq ans. Aucune étude ne se limitait aux femmes présentant une dysfonction sexuelle et seules cinq études ont évalué la fonction sexuelle comme critère de jugement principal. Les risques de biais de dix-huit études ont été jugés élevés et les risques de biais des neuf autres étaient incertains. Vingt études bénéficiaient d'un financement commercial.

Les résultats sur la fonction sexuelle (mesurés par un score global) étaient les suivants :

Dans la comparaison du groupe prenant des œstrogènes seuls à un groupe témoin, chez les femmes symptomatiques et en postménopause précoce, les effets observés étaient compatibles avec une efficacité légère à modérée sur la fonction sexuelle dans le groupe suivant une HT (preuves de qualité élevée). Chez les femmes en postménopause non sélectionnées, les effets observés étaient compatibles avec une efficacité nulle à légère en raison de preuves de qualité médiocre.

Dans la comparaison du groupe prenant des œstrogènes associés à des progestatifs à un groupe témoin, chez les femmes symptomatiques et en postménopause précoce, les effets observés étaient compatibles avec une efficacité légère à modérée sur la fonction sexuelle dans le groupe suivant une HT (preuves de qualité moyenne). Chez les femmes en postménopause non sélectionnées, les effets observés étaient compatibles avec une efficacité nulle à légère (preuves de qualité moyenne).

Dans la comparaison du groupe prenant de la tibolone à un groupe témoin, chez les femmes symptomatiques et en postménopause précoce, les effets observés étaient compatibles avec une efficacité nulle à légère sur la fonction sexuelle dans le groupe suivant une HT (preuves de qualité médiocre). Chez les femmes en postménopause non sélectionnées, les effets observés étaient compatibles avec une efficacité nulle à modérée (preuves de qualité médiocre).

Dans la comparaison du groupe prenant des SERM (raloxifène et bazédoxifène) à un groupe témoin, chez les femmes symptomatiques et en postménopause précoce, les effets observés étaient compatibles avec une efficacité nulle à modérée sur la fonction sexuelle dans le groupe suivant une HT (preuves de qualité médiocre). Chez les femmes en postménopause non sélectionnées, les effets observés étaient compatibles avec un risque léger et une efficacité légère (preuves de qualité médiocre).

En comparant le groupe prenant du bazédoxifène associé à des œstrogènes à un groupe témoin, chez les femmes symptomatiques et en postménopause précoce, les effets observés étaient compatibles avec une efficacité nulle à légère (preuves de qualité moyenne). Aucune étude n'a été incluse dans le sous-groupe composé de femmes en postménopause non sélectionnées.

Les études incluses ne permettaient pas une évaluation exhaustive des risques causés par ces traitements ; d'autres revues systématiques devront être prises en compte pour comprendre les éventuels risques d'une HT.

Nous avons conclu qu'une HT à base d'œstrogènes seuls ou associés à des progestatifs est liée à une amélioration légère à modérée de la fonction sexuelle lorsqu'elle est uniquement prescrite à des femmes présentant des symptômes ménopausiques ou en postménopause précoce (dans un délai de cinq ans après l'apparition de la ménopause), mais pas lorsqu'elle était prescrite à des femmes en postménopause. Les preuves concernant les autres HT (tibolone, raloxifène et bazédoxifène) sont de qualité médiocre. Les preuves actuellement disponibles ne suggèrent aucun effet significatif de la tibolone, du raloxifène et du bazédoxifène, seuls ou associés à des œstrogènes, sur la fonction sexuelle.

Notes de traduction

Traduit par: French Cochrane Centre 16th July, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Resumo para leigos

Terapia hormonal para função sexual em mulheres na menopausa

Objetivamos avaliar o efeito da terapia hormonal (TH), especificamente estrogênio isolado, estrogênio em combinação com progestagênios, esteróides sintéticos e MSREs, na função sexual em mulheres na peri-menopausa e na pós-menopausa. O período próximo e após a última menstruação (menopausa) está associado a muitos sintomas, incluindo o declínio na função sexual. TH é um termo genérico que se refere a qualquer tipo de terapia com hormônios usado durante a menopausa para o alívio de sintomas relacionados à menopausa. Realizamos uma pesquisa eletrônica em bancos de dados da literatura médica, pesquisando por ensaios clínicos randomizados (ECRs) comparando a terapia hormonal (TH) a nenhum tratamento ou tratamento placebo. Nenhum outro tipo de estudo foi incluído. A última pesquisa foi realizada em Dezembro de 2012.

Vinte e sete estudos foram incluídos, eles foram conduzidos em mais de 30 países. A função sexual foi avaliada em 8802 mulheres no grupo de tratamento e em 7591 no grupo controle. Um único estudo contribuiu com a inclusão de 8462 mulheres, 51,2% do número total. Agrupamos os estudos por características das participantes no que diz respeito aos sintomas da menopausa. O grupo menopausa sintomática ou imediata foi de nove estudos, nos quais mulheres estavam na peri-menopausa (um estudo), até 36 meses pós-menopausa (um estudo), até cinco anos pós-menopausa (um estudo), com sintomas vasomotores ou outros sintomas da menopausa (cinco estudos) ou apresentando ondas de calor e disfunção sexual (um estudo). O grupo de mulheres pós-menopausa não selecionadas vieram de 18 estudos. O grupo incluiu mulheres, independente dos sintomas de menopausa, e permitiu a inclusão de mulheres com mais de cinco anos desde o seu último período menstrual. Nenhum estudo foi restringido a mulheres com disfunção sexual e apenas cinco estudos avaliaram a função sexual como desfecho primário. Dezoito estudos foram considerados com alto risco de viés, e os outros nove estudos tiveram risco incerto de viés. Vinte estudos receberam financiamento comercial.

As conclusões para função sexual (avaliada pela contagem total) foram os seguintes:

Na comparação de estrogênio isolado versus controle, para mulheres sintomáticas ou na pós-menopausa imediata o efeito observado foi compatível com pequeno a moderado benefício na função sexual no grupo de TH (evidência de alta qualidade). Para as mulheres na pós-menopausa não selecionadas o efeito observado foi compatível com nenhum a pequeno benefício, fornecido por evidência de baixa qualidade.

Na comparação de estrogenios combinados com progestagênios versus controles para mulheres sintomáticas ou na pós-menopausa imediata, o efeito observado foi compatível com pequeno a moderado benefício na função sexual no grupo de TH (evidência de moderada qualidade). Para as mulheres na pós-menopausa não selecionadas o efeito observado foi compatível com nenhum a pequeno benefício (evidencia de moderada qualidade).

Na comparação entre tibolona versus controle, para mulheres sintomáticas ou na pós-menopausa imediata, o efeito observado foi compatível com nenhum a pequeno efeito na função sexual no grupo em TH (evidência de baixa qualidade). Para as mulheres na pós-menopausa não selecionadas o efeito observado foi compatível com nenhum a pequeno benefício (evidencia de baixa qualidade).

Na comparação dos MSREs (raloxifeno e bazedoxifeno) versus controle, para as mulheres sintomáticas ou na pós-menopausa imediata, o efeito observado foi compatível com nenhum a moderado benefício na função sexual do grupo em TH (evidência de baixa qualidade). Para as mulheres na pós-menopausa não selecionadas, o efeito observado foi compatível com um pequeno prejuízo a um pequeno benefício (evidência de baixa qualidade).

Comparando bazedoxifeno combinado com estrogenios com grupo controle, para mulheres sintomáticas ou na pós-menopausa imediata, o efeito observado foi compatível com nenhum a pequeno benefício, com evidência de moderada qualidade. Nenhum estudo foi incluído no subgrupo de mulheres não selecionados na pós-menopausa.

Os estudos incluídos não permitiram uma avaliação abrangente dos malefícios dessas terapias; outras revisões sistemáticas devem ser considerada para verificar os possíveis danos da TH.

Concluímos que TH com estrogênio isolado ou em combinação com progestagênios está associada com uma pequena a moderada melhoria na função sexual quando utilizada especificamente em mulheres com sintomas ou na menopausa imediata (dentro dos primeiros cinco anos após o início da menopausa), mas não quando utilizado para qualquer mulher na pós-menopausa. Evidências consideradas sobre outras TH (tibolona, ​​raloxifeno, e bazedoxifeno) são de baixa qualidade. A evidência atual não sugere um efeito importante da tibolona, ​​do raloxifeno e do bazedoxifeno, isolados ou combinados com estrogênios sobre a função sexual.

Notas de tradução

Traduzido por: Lucia alves S Lara, Unidade de Medicina Baseada em Evidências da Unesp, Brazil Contato: portuguese.ebm.unit@gmail.com

Summary of findings(Explanation)

Summary of findings for the main comparison. Hormonal therapy compared with no treatment or placebo for sexual function in symptomatic or recently postmenopausal women
  1. 1 Symptomatic or early postmenopausal women: this subgroup included women with any menopause-related symptoms (not only sexual dysfunction) or postmenopausal women with less then 5 years from the last menstrual period.

    2 The only included study was deemed at high risk of attrition bias.

    3 The only included study was deemed at high risk of bias.
    4 The effect size is small and the 95% CI relatively large. Evidence from only one study.

    5Total population size is relatively small, and the 95% CI is very large. Evidence from only one study.

    6The 95% CI is very large. Evidence from only one study.

Hormonal therapy compared with no treatment or placebo for sexual function in symptomatic or recently postmenopausal women

Population: symptomatic or early postmenopausal women1.

Intervention: estrogen alone, estrogen + progestogens, synthetic steroids (tibolone), SERMs, SERMs + estradiol.

Comparison: placebo or no treatment.

Composite sexual function score

Comparison

Corresponding risk (95% CI) - HTNo of Participants
(studies)
Effect of HT Quality of the evidence
(GRADE)
Estrogens alone

The mean score in the estrogens groups was 0.38 standard deviations higher

(0.23 to 0.54 higher)

699
(3 studies)
Small to moderate benefit⊕⊕⊕⊕
high
Estrogens + ProgestogensThe mean composite score in the estrogens + progestogens groups was
0.42 standard deviations higher
(0.19 to 0.64 higher)
335
(1 study)
Small to moderate benefit⊕⊕⊕⊝
moderate2
Synthetic SteroidsThe mean composite score in the synthetic steroids groups was
0.13 standard deviations higher
(0 to 0.26 higher)
883
(1 study)
No effect to small benefit⊕⊕⊝⊝
low3,4
SERMsThe mean composite score in the SERMs groups was
0.23 standard deviations higher
(0.04 lower to 0.5 higher)
215
(1 study)
No effect to moderate benefit⊕⊕⊝⊝
low5
SERMs + Estrogens

The mean composite score in the SERMs + estrogens groups was

0.21 standard deviations higher

(0 to 0.43 higher)

542
(1 study)
No effect to small benefit⊕⊕⊕⊝
moderate6
The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group - expressed as change in standard deviations.
CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Hormonal therapy compared with no treatment or placebo for sexual function in unselected postmenopausal women

Summary of findings 2. Hormonal therapy compared with no treatment or placebo for sexual function in unselected postmenopausal women
  1. 1 Unselected postmenopausal women: postmenopausal women regardless of menopausal symptoms; this studies permitted the inclusion of women with more than 5 years since the final menstrual period.

    .2 2/3 studies were deemed at high risk of bias.

    3 The effect size is small and the 95% CI relatively large.

    4 3/3 studies were deemed at high risk of bias.

    5 2/2 included studies were deemed at high risk of bias.
    6 Total population size is relatively small and the 95% CI large.

    7Total population size is relatively small, the effect size is very small, and the 95% CI large.

Hormonal therapy compared with no treatment or placebo for sexual function in unselected postmenopausal women

Population: unselected postmenopausal women1.

Intervention: estrogen alone, estrogen + progestogens, synthetic steroids (tibolone), SERMs, SERMs + estradiol.

Comparison: placebo or no treatment.

Composite sexual function score

Comparison

Corresponding risk (95% CI) - HTNo of Participants
(studies)
Effect of HTQuality of the evidence
(GRADE)

Estrogens alone

unselected postmenopausal women

The mean composite score in the oestrogens alone groups was 0.16 standard deviations higher
(0.02 lower to 0.34 higher)
478
(3 studies)
No effect to small benefit⊕⊕⊝⊝
low2,3

Estrogens + Progestogens

unselected postmenopausal women

The mean composite score in the Estrogens + Progestogens groups was
0.09 standard deviations higher
(0.02 lower to 0.20 higher)
1314
(3 studies)
No effect to small benefit⊕⊕⊕⊝
moderate4

Synthetic Steroids

unselected postmenopausal women

The mean composite score in the synthetic steroids groups was
0.38 standard deviations higher
(0.04 to 0.71 higher)
142
(2 studies)
No effect to moderate benefit⊕⊕⊝⊝
low5,6

SERMs

unselected postmenopausal women

The mean composite score in the SERMs groups was

0.04 standard deviations higher

(0.20 lower to 0.29 higher)

283
(1 study)
Small harm to small benefit⊕⊕⊝⊝
low7
The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group - expressed as change in standard deviations.
CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Menopause is the permanent end of menstruation and fertility but, even before the true onset of menopause, women may experience menopausal symptoms and changes in their menstrual cycle in a period called perimenopause (NAMS 2012). Natural menopause is defined as occurring after 12 consecutive months of spontaneous amenorrhoea with no obvious pathologic cause. Induced menopause is defined as the permanent cessation of menstruation after either surgical removal of the ovaries or iatrogenic ablation of ovarian function (for example chemotherapy or pelvic radiation therapy) (NAMS 2012). The most common symptoms associated with menopause are hot flushes, night sweats, sleep disturbance, vaginal atrophy, and dyspareunia (NAMS 2012). In order to alleviate these symptoms, some women start using menopausal hormone therapy (HT) (NAMS 2012; Santen 2010).

According to the Diagnostic and Statistical Manual of Mental Disorders, DSM IV (APA 2000), sexual dysfunction is defined by disturbances in sexual desire and by psychophysiological changes that characterize the sexual response cycle, causing marked distress and interpersonal difficulty. Sexual functioning is of great importance for quality of life, as approximately 75% of middle-aged American women consider sexual activity as being of moderate to extreme importance (Cain 2003). Despite its importance, female sexual function is not easy to define or investigate because it depends on several factors such as health and well-being, cultural habits, socioeconomic status, relationship issues, and existence and health of the partner (Davis 2009). Female sexual dysfunction might be evaluated in different domains, including sexual interest and arousal, orgasm and pain (Binik 2010). Although sexual function declines throughout the menopause transition (NAMS 2012; Rosen 2011), it is unclear whether this is caused by the low estrogen levels, aging, or both (da Silva Lara 2009; Nappi 2009a).

Description of the intervention

HT is a generic term that refers to any type of hormone therapy used during menopause for alleviation of menopause-related symptoms (Santen 2010). The use of HT has been studied in various settings. Clinical benefit has been observed when HT is used for the relief of hot flushes and night sweats (Formoso 2012; MacLennan 2004) and for the relief of vaginal atrophy symptoms (Suckling 2006). The most commonly used types of HT are estrogens alone, estrogens in combination with progestogens, synthetic steroids (for example tibolone), and selective estrogen receptor modulators (SERMs) (for example raloxifene). Other substances, such as androgens and phytoestrogens, might be used for the relief of some menopausal-related symptoms; however, we will not evaluate the effect of these drugs in this review because they are not widely accepted as HT.

How the intervention might work

Women with night sweats may find that their subsequent poor sleep patterns lead to tiredness and loss of energy which in addition to vaginal symptoms may affect women’s self esteem, self confidence and sexuality(Graziottin 2005; McKinley 2008). A proportion of peri and postmenopausal women might, at least in theory, benefit from HT in some aspects of this complex net of symptoms since HT improves vulvovaginal atrophy and vasomotor symptoms (NAMS 2012; Santen 2010).

Why it is important to do this review

Sexual function is considered to be a very important factor in women’s health, and medical counselling about HT should balance the benefits and risks (NAMS 2012; Santen 2010). Information regarding how HT can influence sexual function is important when considering the use of these drugs (Wierman 2010). The true effect of HT on sexual function is difficult to comprehend based on the literature published so far; partially because of the different drugs and doses, different tools to evaluate sexual function, and the particular population studied in each trial. That highlights the need for a systematic review of the best available evidence to facilitate evidence-based decisions.

Objectives

To assess the effect of HT, specifically estrogens alone, estrogens in combination with progestogens, synthetic steroids, and SERMs for sexual function in postmenopausal women.

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs) were considered eligible for inclusion. We excluded non-randomised studies (for example studies with evidence of inadequate sequence generation such as alternate days, patient numbers) as they are associated with a high risk of bias. Crossover trials were included but we planned to include in the meta-analysis only data from the first phase, as the crossover is not a valid design in this context. The withdrawal of HT may cause symptoms, being a potential source of bias.

Types of participants

Perimenopausal or postmenopausal women were included. Perimenopausal women were defined as women with menopausal symptoms who had their last menstrual period within the 12 months before inclusion. Postmenopausal women were defined as women with induced menopause (bilateral oophorectomy, as a result of chemotherapy or pelvic radiation therapy) or natural menopause (12 consecutive months of spontaneous amenorrhoea with no obvious pathologic cause).

Types of interventions

Prescription of HT compared with the prescription of placebo or no intervention. We considered as HT, estrogens alone; estrogens in combination with progestogens; synthetic steroids (for example tibolone); and SERMs (for example raloxifene, bazedoxifene). Other drugs possibly used in the relief of menopausal symptoms were not included in this review. We only included trials in which the interval between the onset of the intervention and the assessment of outcomes was greater than or equal to one month. In the studies with multiple assessments, we considered only the assessment closest to six months after starting the intervention.

Types of outcome measures

We evaluated sexual function, measured and scored by validated questionnaires in all aspects: arousal and sexual interest, orgasm, and pain (Binik 2010).

Primary outcomes
Sexual function

1. Composite score

Secondary outcomes
Arousal and sexual interest

2. Frequency of sexual activity

3. Libido, desire or interest in sex

4. Arousal

5. Fantasy

Orgasm

6. Orgasm

7. Number of orgasms

8. Pleasure or enjoyment in sex

9. Satisfaction

Pain

10. Dyspareunia

Adverse events related to HT were not included as outcomes because we only included trials that reported sexual function; therefore, evidence for these topics would be a subset of the overall body of evidence, which could not be representative of the complete current evidence. In order to help weight the benefits and harms of the treatments, we took into account (in the 'Discussion' section) the findings of other systematic reviews that addressed adverse events.

Search methods for identification of studies

We searched for RCTs following a search strategy developed in consultation with the Trials Search Co-ordinator for the Cochrane Menstrual Disorders and Subfertility Group (MDSG).

Electronic searches

The electronic searches were last performed on 12 December 2012.

We searched for RCTs using the following electronic databases, from inception: Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 1); Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Appendix 2); EMBASE (Appendix 3), this search was combined with trial filters developed by Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/methodology/filters.html); Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) (Appendix 4); MDSG Specialised Register (Appendix 5); Medical Literature Analysis and Retrieval System Online (MEDLINE) (Appendix 6), this search was combined with the Cochrane highly sensitive search strategy for identifying randomised trials; and PsycINFO (Appendix 7).
We searched for study protocols and ongoing trials using the following websites: ClinicalTrials.gov (clinicaltrials.gov/ct2/search) (Appendix 8); Current Controlled Trials (www.controlled-trials.com) (Appendix 9); and World Health Organization International Clinical Trials Registry Platform search portal (apps.who.int/trialsearch/Default.aspx) (Appendix 10). We searched for conference abstracts in the ISI Web of Knowledge (Appendix 11) and grey literature in OpenGrey (www.opengrey.eu) (Appendix 12). We searched for similar reviews in the Cochrane Library for Database of Abstracts of Reviews of Effects (DARE) (Appendix 13).

There was no language restriction in these searches.

Searching other resources

We handsearched the reference list of articles retrieved by the search.

Data collection and analysis

Selection of studies

An initial screen of the titles and abstracts retrieved by the search was performed independently by two authors (JBPF and LASL); disagreements were resolved by discussion with another author (WPM). The full texts of all potentially eligible studies were retrieved. Two review authors (CON and LASL) independently examined these full text articles for compliance with the inclusion criteria and selected studies eligible for inclusion in the review. We corresponded with study investigators, as required, to clarify study eligibility. Disagreements as to study eligibility were resolved by discussion with another review author (WPM). The selection process is documented in a 'PRISMA' flow chart.

Data extraction and management

Two review authors (CON and LASL) independently extracted data from eligible studies using a data extraction form designed and pilot-tested by the authors. Any disagreements were resolved by discussion or by a third review author (WPM). Data extracted included study characteristics and outcome data. Where studies had multiple publications, the main trial report was used as the reference and additional details were derived from secondary papers. We corresponded with study investigators for further data on methods or results as required.

Assessment of risk of bias in included studies

Two review authors (CON, and WPM) independently assessed the included studies for risk of bias using the Cochrane risk of bias assessment tool (www.cochrane-handbook.org) to assess: allocation (random sequence generation and allocation concealment); blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data; selective reporting; and other bias. Disagreements were resolved by discussion. We described all judgements fully and presented the conclusions in the 'Risk of bias' table. The consideration of bias risk was incorporated into the interpretation of review findings by means of sensitivity analyses.

When evaluating selective reporting bias, we took care to search for within-trial selective reporting, such as trials failing to report obvious outcomes, or reporting them in insufficient detail to allow inclusion. We sought published protocols and compared the outcomes between the protocol and the final published study.

Measures of treatment effect

For continuous data, measured on different scales across studies, we calculated the standardised mean difference (SMD) using the fixed-effect model inverse variance (IV) method. For dichotomous data, we used the numbers of events in the control and intervention groups of each study to calculate the fixed-effect model Mantel-Haenszel (M-H) risk ratio (RR). Wherever studies presented two groups with the same intervention (for example two different dosages) they were combined to create a single pair-wise comparison to prevent loss of information and avoid results-related choices (Higgins 2011). We reversed the direction of effect of individual studies, if required, to ensure consistency across trials. We treated ordinal data (for example quality of life scores) as continuous data. We presented 95% confidence intervals (CI) for all outcomes. Where data to calculate SMDs or RRs were not available, we utilised the most detailed numerical data available that might facilitate a similar analyses of included studies (for example test statistics, P values). When studies reported sufficient detail to calculate mean difference but gave no information on the associated standard deviation (SD), the outcome was assumed to have an SD equal to the highest SD from other studies using the same assessment scale. We compared the magnitude and direction of effects reported by studies with how they were presented in the review, taking account of legitimate differences. We included both data reported as final mean scores in each group and mean change scores from baseline in each group. Where studies reported both values, we preferentially included mean change scores from baseline.

For the purpose of interpretation, a SMD between 0.2 and 0.5 was considered as a small effect; between 0.5 and 0.8 was considered a moderate effect; and higher than 0.8 was considered a large effect (Cohen 1988).

Unit of analysis issues

The primary analysis was per woman randomised.

Dealing with missing data

The data were analysed on an intention-to-treat basis as far as possible and attempts were made to obtain missing data from the original trialists. If studies reported sufficient detail to calculate mean differences but no information was given on the associated SDs, the outcomes were assumed to have SDs equal to the highest SD from other studies within the same analysis.

Assessment of heterogeneity

We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta-analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity by the I² statistic. An I² value greater than 50% was taken to indicate substantial heterogeneity.

Assessment of reporting biases

In view of the difficulty in detecting and correcting for publication bias and other reporting biases, the authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were 10 or more studies in an analysis, we planned to use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

If the studies were sufficiently similar, we combined the data using a fixed effect model in the following comparisons.

1. Estrogens alone versus placebo or no intervention, stratified by the characteristics of the included participants:

(i) studies that only included women with menopausal symptoms or women with less than five years since the onset of menopause, or both (early postmenopausal);

(ii) studies that included unselected postmenopausal women.

2. Estrogens combined with progestogens versus placebo or no intervention:

(i) studies that only included women with menopausal symptoms or women with less than five years since the onset of menopause, or both (early postmenopausal);

(ii) studies that included unselected postmenopausal women.

3. Synthetic steroids (tibolone) versus placebo or no intervention:

(i) studies that only included women with menopausal symptoms or women with less than five years since the onset of menopause, or both (early postmenopausal);

(ii) studies that included unselected postmenopausal women.

4. SERMs (raloxifene and bazedoxifene) versus placebo or no intervention:

(i) studies that only included women with menopausal symptoms or women with less than five years since the onset of menopause, or both (early postmenopausal);

(ii) studies that included unselected postmenopausal women.

5. SERMs (bazedoxifene) combined with estogens versus placebo or no intervention:

(i) studies that only included women with menopausal symptoms or women with less than five years since the onset of menopause, or both (early postmenopausal);

(ii) studies that included unselected postmenopausal women.

An increase in a particular outcome, which may be beneficial (for example composite score) or detrimental (for example dyspareunia), was displayed graphically in the meta-analysis to the right of the centre-line and a decrease in an outcome to the left of the centre-line. We merged women with menopausal symptoms with early postmenopausal women (STRAW stage +1) (STRAW 2008) because menopausal-related symptoms are common in early postmenopausal women: almost half of the women complains of vasomotor symptoms (Gold 2000). No important heterogeneity was observed when comparing the subgroups used for stratification and we considered the pooled analysis of the studies in both subgroups.

Subgroup analysis and investigation of heterogeneity

Besides the stratification based on the characteristics of the included participants described above (studies that only included women with menopausal symptoms or less than five years since the onset of menopause, or both; and studies that included unselected postmenopausal women), we planned two other subgroup analyses for investigation of heterogeneity: (1) type of menopause, only natural menopause, only induced menopause, only perimenopause, or non-specified; (2) participants' baseline status, only women with sexual dysfunction, only women without sexual dysfunction, unselected women.

When we detected substantial heterogeneity, we explored possible explanations by again checking the data and by sensitivity analyses. If it persisted, we adopted a random-effects model in order to have a more conservative estimate of the effect. We took any statistical heterogeneity into account when interpreting the results, especially if there was a variation in the direction of effect.

Sensitivity analysis

We conducted sensitivity analyses for the primary outcome to determine whether the conclusions would have differed if eligibility was restricted to studies without a high risk of bias.

Overall quality of the body of evidence: 'Summary of findings' (SoF) table

A SoF table was generated using GRADEPRO software. This table evaluated the overall quality of the body of evidence for the primary review outcome using GRADE criteria (study limitations, consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) were justified and incorporated into reporting of the results for the primary outcome.

Results

Description of studies

Results of the search

The last search was performed on 12 December 2012. The search retrieved 2351 records after adjusting for duplicates. A total of 143 records were further assessed for eligibility: 27 studies (from 36 records) were included and data from 23 studies were included in the quantitative synthesis; 95 studies (from 99 records) were excluded; and four studies (from eight records) are waiting classification as the full text articles were not available and authors did not reply to our e-mails. See Figure 1; Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Figure 1.

Study flow diagram.

Included studies

Study design and setting

Twenty-seven studies were included: 25 parallel-group and two crossover trials (Fonseca 2007; Laan 2001). Ten studies were single-centre studies: three were conducted in Brazil (Fonseca 2007; Mameri Filho 2005; Morais-Socorro 2012), one in Italy (Gambacciani 2011), one in Poland (Czarnecka 2000), one in Romania (Hudita 2003), one in Taiwan (Yang 2004), one in the Netherlands (Laan 2001) and one in the USA (Dayal 2005). Eleven studies were multi-centre, performed in only one country: one in Denmark (Nielsen 2006), two in Estonia (Estonian blind trial; Estonian non-blind trial), two in Sweden (Nathorst-Böös 1993; Wiklund 1993), and six in the USA (Huang 2008; Maki 2007; SMART-3; Speroff 2003; Strickler 2000; WHI). Six studies were multi-centre studies conducted in more than one country: one in Brazil and USA (Gast 2009); one in Hong Kong, Malaysia, Philippines, Singapore and Thailand (Haines 2009); one in Australia, New Zealand and UK (WISDOM); two in Canada and USA (Modugno 2003; Simon 2007); and one study was conducted in 31 countries (LIBERATE). In four studies sexual function was evaluated but the reported data were not suitable for meta-analysis. Twenty studies received funding from the studied drug laboratory and only five of them aimed to evaluate sexual function as a primary outcome (Fonseca 2007; Gast 2009; Mameri Filho 2005; Nathorst-Böös 1993; Osmanagaoglu 2006).

Participants

The studies included 16,505 women in the treatment groups and 15,049 in the control groups: sexual function was assessed in 8802 women in the treatment groups and in 7591 women in the control groups. One study (WHI) was responsible for the inclusion of 8462 women, 51.2% of the total. The available trials did not allow the planned subgroup analysis and the subgroups were divided according to the participants' characteristics.

One study included only women in perimenopause (Morais-Socorro 2012); one included only women until 36 months after the onset of menopause (Maki 2007); one included only women until five years after the last menstrual period (Nielsen 2006); five studies included only women with vasomotor or other menopausal symptoms (Gambacciani 2011; Haines 2009; Nathorst-Böös 1993; Speroff 2003; Wiklund 1993); and one study included women with hot flushes and sexual dysfunction (Mameri Filho 2005). All these nine studies were included in the subgroup 'Symptomatic or early postmenopausal'. No study included only women with sexual dysfunction. Only five studies evaluated sexual function as a primary outcome (Fonseca 2007; Gast 2009; Mameri Filho 2005; Nathorst-Böös 1993; Osmanagaoglu 2006).

Eighteen studies included women regardless of menopausal symptoms and permitted the inclusion of women with more than five years since the final menstrual period (Czarnecka 2000; Dayal 2005; Estonian blind trial; Estonian non-blind trial; Fonseca 2007; Gast 2009; Huang 2008; Hudita 2003; Laan 2001; LIBERATE; Modugno 2003; Osmanagaoglu 2006; Simon 2007; SMART-3; Strickler 2000; WHI; WISDOM; Yang 2004). All these 18 studies were included in the subgroup 'unselected postmenopausal women'.

Interventions
  • 10/27 studies compared estrogens alone versus control

  • 12/27 studies compared estrogens combined with progestogens versus control

  • 5/27 studies compared synthetic steroids (tibolone) versus control

  • 3/27 studies compared SERMs (raloxifene and bazedoxifene) versus control

  • 1/27 studies compared SERM combined with estrogens versus control

In 14 studies the follow-up period until the included analysis was three months; in one study the follow-up was four months (Maki 2007); in four studies it was six months (Fonseca 2007; LIBERATE; Osmanagaoglu 2006; Yang 2004); in five studies follow-up was 12 months (Estonian blind trial; Estonian non-blind trial; Strickler 2000; WHI; WISDOM); in two studies follow-up was 24 months (Huang 2008; Nielsen 2006); and in one study follow-up was 36 months (Modugno 2003).

In 24 studies women in the control group used a matching placebo and In three studies women in the control group did not receive any intervention (Czarnecka 2000; Estonian non-blind trial; Osmanagaoglu 2006).

Where studies had more than one group using the same drug, in different doses, those groups were merged (Hudita 2003; Nielsen 2006; Simon 2007; SMART-3; Speroff 2003; Strickler 2000). In four studies sexual function was evaluated but the reported data were not suitable for meta-analysis. Three of them compared estrogens combined with progestogens and placebo (Fonseca 2007; Gambacciani 2011; Gast 2009), and the other compared tibolone with placebo (Hudita 2003).

Most interventions were delivered orally, however some were administered transdermally (Haines 2009; Huang 2008; Wiklund 1993) and vaginally (Gast 2009; Speroff 2003).

Outcomes

The tools used for assessing sexual function were: Arizona Sexual Experiences (ASEX) scale, Menopause-specific Quality of Life (MENQOL), Golombok-Rust Inventory of Sexual Satisfaction (GRISS), Greene Climacteric Scale, simplified and complete McCoy Female Sexuality Questionnaire (MFSQ), Brief Index of Sexual Functioning-Women (BISF-W), Medical Outcomes Study (MOS), Sexual Problems Index, Modified Mini-Mental State Examination (QOL), Rosen’s female sexual function index (FSFI), Subjective Symptoms Assessment Profile (SSA-P), Utian Quality of Life, and Women's Health Questionnaire (WHQ) (see Characteristics of included studies).

Where studies reported composite scores, they evaluated the following domains:

We were able to include 'change from baseline score' from 13 studies (Dayal 2005; Haines 2009; Laan 2001; LIBERATE; Maki 2007; Nathorst-Böös 1993; Nielsen 2006; Simon 2007; Speroff 2003; Strickler 2000; WHI; Wiklund 1993; Yang 2004). From seven studies we could only include the final scores (Czarnecka 2000; Huang 2008; Mameri Filho 2005; Morais-Socorro 2012; Osmanagaoglu 2006; SMART-3; WISDOM). Three studies reported only the percentages of women who improved their scores (Estonian blind trial; Estonian non-blind trial; Modugno 2003).

Four studies reported data that were not usable (Fonseca 2007; Gambacciani 2011; Gast 2009; Hudita 2003).

Excluded studies

Ninety-five studies (from 99 records) were excluded: 83 studies did not evaluate sexual function; seven studies were not randomised or were pseudo-randomised; six studies did not evaluate sexual function by a validated questionnaire; two studies did not have a proper control group, without HT; and in one study women in the study group also received testosterone (Figure 1; Characteristics of excluded studies). Additionally, four more studies (from eight records) are awaiting classification (Characteristics of studies awaiting classification).

Risk of bias in included studies

See Figure 2 and Figure 3 for the graph and summary of review authors' judgements about the risk of bias for included studies.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Sequence generation

Twelve studies were at unclear risk of selection bias as they did not describe the method of randomisation. The other 15 studies reported adequate methods of randomisation and were deemed at low risk of bias.

Allocation concealment

Twenty-two studies did not report the method used for allocation concealment and thus were considered at unclear risk of selection bias. Only five studies reported adequate allocation concealment methods and were deemed at low risk of selection bias.

Blinding

Three studies were open label and the control group did not receive any intervention, thus they were deemed at high risk of performance bias. Four studies did not described the blinding of the participants and were deemed at unclear risk of performance bias whilst 20 studies were deemed at low risk of performance bias. Only five studies described attempts to blind the outcome assessment and were deemed at low risk of detection bias whilst 22 studies were considered at unclear risk of detection bias.

Incomplete outcome data

Nine studies reported important or unbalanced loss of participants and were deemed at high risk of attrition bias (Haines 2009; Huang 2008; Laan 2001; LIBERATE; Modugno 2003; Nielsen 2006; Simon 2007; WHI; WISDOM). Five studies the losses to follow-up were high or not clear; they were deemed at unclear risk of bias (Gambacciani 2011; Hudita 2003; Nathorst-Böös 1993; SMART-3; Yang 2004).

Selective reporting

Four studies applied a validated questionnaire to evaluate sexual function, however the obtained scores were not given (Fonseca 2007; Gambacciani 2011; Gast 2009; Hudita 2003). One study applied three tools to evaluate sexual function but only few domains were chosen to be reported (Maki 2007). Thus all these five studies were deemed at high risk of reporting bias, while the remaining 22 were considered at low risk.

Other potential sources of bias

Three studies were considered at high risk of bias because they had unbalanced groups at baseline and only final scores could be used in the meta-analysis (Czarnecka 2000; Dayal 2005; Osmanagaoglu 2006). The other 23 studies were considered at low risk of other bias.

Effects of interventions

See: Summary of findings for the main comparison Hormonal therapy compared with no treatment or placebo for sexual function in symptomatic or recently postmenopausal women; Summary of findings 2 Hormonal therapy compared with no treatment or placebo for sexual function in unselected postmenopausal women

1. Comparison of estrogens alone versus placebo or no treatment

Primary outcome
1.1 Sexual function - composite score

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with a small to moderate benefit for the HT group (SMD 0.38, 95% CI 0.23 to 0.54, P < 0.00001, 3 studies, 699 women, I² = 55%, high-quality evidence) (Figure 4). When performing the sensitivity analysis (restricting eligibility criteria only to studies judged to not be at high risk of bias), the CI was also compatible with a small to moderate benefit for HT (SMD 0.47, 95% CI 0.29 to 0.64, P < 0.00001, 2 studies, 548 women, I² = 2%).

Figure 4.

Forest plot of comparison: 1 Estrogens alone, outcome: 1.1 Composite score.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.16, 95% CI -0.02 to 0.34, P = 0.08, 2 studies, 478 women, I² = 44%, low-quality evidence) (Figure 4). When performing the sensitivity analysis, the CI was compatible with no effect to a small benefit (SMD 0.10, 95% CI -0.18 to 0.39, P = 0.49, 1 study, 189 women).

Considerable heterogeneity was observed (I² = 70%) when comparing these two subgroups and so pooled analysis was not appropriate.

Secondary outcomes
Arousal and sexual interest
1.2 Frequency of sexual activity

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit for the HT group (SMD 0.30, 95% CI 0.02 to 0.59, P = 0.04, 2 studies, 287 women, I² = 0%) (Analysis 1.2).

No study reported this outcome in the subgroup of unselected postmenopausal women.

1.3 Libido, desire or interest in sex

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with moderate harm to moderate benefit for the HT group (SMD 0.02, 95% CI -0.47 to 0.51, P = 0.92, 1 study, 64 women) (Analysis 1.3).

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with small harm to no effect for the HT group (SMD -0.19, 95% CI -0.40 to 0.01, P = 0.06, 1 study, 366 women) (Analysis 1.3).

No heterogeneity was observed (I² = 0%) when comparing these two subgroups. In the pooled analysis, the 95% CI was compatible with a small harm to no effect for the HT group (SMD -0.16, 95% CI -0.35 to 0.03, P = 0.09, 2 studies, 430 women, I² = 0%) (Analysis 1.3).

1.4 Arousal

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.14, 95% CI -0.12 to 0.40, P = 0.30, 1 study, 223 women) (Analysis 1.4).

No study reported this outcome in the subgroup of unselected postmenopausal women.

1.5 Fantasy

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (SMD 0.40, 95% CI 0.14 to 0.67, P = 0.003, 1 study, 223 women) (Analysis 1.5).

No study reported this outcome in the subgroup of unselected postmenopausal women.

Orgasm
1.6 Orgasm

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with moderate harm to moderate benefit for the HT group (SMD 0.03, 95% CI -0.46 to 0.52, P = 0.91, 1 study, 64 women) (Analysis 1.6).

No study reported this outcome in the subgroup of unselected postmenopausal women.

1.7 Number of orgasms

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.07, 95% CI -0.19 to 0.33, P = 0.60, 1 study, 223 women) (Analysis 1.7).

In the subgroup of unselected postmenopausal women, the 95% CI was wide and compatible with small harm to small benefit (SMD -0.05 95% CI -0.36 to 0.25, P = 0.73, 1 study, 168 women) (Analysis 1.7).

No important heterogeneity was observed (I² = 0%) when comparing these two subgroups. In the pooled result, the 95% CI was compatible with no effect (SMD 0.02, 95% CI -0.18 to 0.22, P = 0.87, 2 studies, 391 women, I² = 0%) (Analysis 1.7).

1.8 Pleasure or enjoyment in sex

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (SMD 0.31, 95% CI 0.05 to 0.58, P = 0.02, 1 study, 223 women) (Analysis 1.8).

No study reported this outcome in the subgroup of unselected postmenopausal women.

1.9 Satisfaction

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.27, 95% CI 0.09 to 0.44, P = 0.003, 3 studies, 510 women, I² = 0%) (Analysis 1.9).

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect (SMD -0.01, 95% CI -0.06 to 0.03, P = 0.62, 2 studies, 7044 women, I² = 0%) (Analysis 1.9).

Considerable heterogeneity was observed (I² = 87.1%) when comparing these two subgroups and a pooled analysis was not considered.

Pain
1.10 Dyspareunia

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with small to moderate benefit for the HT group (SMD -0.48, 95% CI -0.75 to -0.20, P = 0.0007, 3 studies, 771 women, I² = 71%) (Analysis 1.10). Altough the I² was high, all included studies observed a benefit for the HT group (only a different magnitude).

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to small benefit for the HT group (SMD -0.20, 95% CI -0.37 to -0.03, P = 0.02, 2 studies, 571 women, I² = 0%) (Analysis 1.10).

Substantial heterogeneity was observed (I² = 64.7%) when comparing these two subgroups. However all single studies pointed to benefit of HT and, in the pooled analysis, the 95% CI was compatible with a small to moderate benefit (SMD -0.37, 95% CI -0.57 to -0.17, P = 0.0003, 5 studies, 1342 women, I² = 67%) (Analysis 1.10).

2. Comparison of estrogens combined with progestogens versus placebo or no treatment

Primary outcome
2.1 Sexual function - composite score

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with a small to moderate benefit for the HT group (SMD 0.42, 95% CI 0.19 to 0.64, P = 0.0003, 1 study, 335 women, moderate-quality evidence) (Figure 5). The same result was observed in the sensitivity analysis.

Figure 5.

Forest plot of comparison: 2 Estrogens + Progestogens, outcome: 2.1 Composite score.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to small benefit for the HT group (SMD 0.09, 95% CI -0.02 to 0.20, P = 0.10, 3 studies, 1314 women, I² = 0%, moderate-quality evidence) (Figure 5). Sensitivity analysis was not performed because all three included studies were considered to be at a high risk of bias.

Considerable heterogeneity was observed (I² = 84.7%) when comparing these two subgroups and so pooled analysis was not appropriate.

Secondary outcomes
Arousal and sexual interest
2.2 Frequency of sexual activity

No study reported this outcome.

2.3 Libido, desire or interest in sex (continuous data)
In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (SMD 0.44, 95% CI 0.13 to 0.76, P = 0.006, 1 study, 158 women) (Analysis 2.3).

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to moderate benefit (SMD 0.19, 95% CI -0.12 to 0.51, P = 0.24, 2 studies, 155 women) (Analysis 2.3).

No important heterogeneity was observed (I² = 16.5%) when comparing these two subgroups. In the pooled analysis, the 95% CI was compatible with no effect to a moderate benefit for the HT group (SMD 0.32, 95% CI 0.09 to 0.54, P = 0.006, 3 studies, 313 women, I² = 0%) (Analysis 2.3).

2.4 Libido, desire or interest in sex (binary)

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect (RR 1.08, 95% CI 0.98 to 1.18, P = 0.11, 2 studies, 1323 women, I² = 0%) (Analysis 2.4).

2.5 Arousal

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (SMD 0.28, 95% CI -0.10 to 0.67, P = 0.15, 1 study, 104 women) (Analysis 2.5).

2.6 Fantasy

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (SMD 0.41, 95% CI 0.10 to 0.73, P = 0.01, 1 study, 158 women) (Analysis 2.6).

No study reported this outcome in the subgroup of unselected postmenopausal women.

Orgasm
2.7 Orgasm

No study reported this outcome.

2.8 Number of orgasms

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was wide and compatible with small harm to a small benefit for the HT group (SMD 0.03, 95% CI -0.36 to 0.41, P = 0.89, 1 study, 104 women) (Analysis 2.8).

2.9 Pleasure or enjoyment in sex
No study reported this outcome.
2.10 Satisfaction (continuous)

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect (SMD 0.00, 95% CI -0.04 to 0.04, P = 0.54, 2 studies, 11,139 women) (Analysis 2.10).

2.11 Satisfaction (binary)

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was wide and compatible with small harm to moderate benefit for the HT group (RR 1.11, 95% CI 0.74 to 1.67, P = 0.62, 2 studies, 1323 women, I² = 72%) (Analysis 2.11).

Pain
2.12 Dyspareunia (continuous data)

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit for the HT group (SMD -0.39, 95% CI -0.78 to -0.00, P = 0.05, 1 studies, 104 women) (Analysis 2.12).

2.13 Dyspareunia (binary data)

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (RR 0.68, 95% CI 0.46 to 1.02, P = 0.07, 2 studies, 1323 women, I² = 0%) (Analysis 2.13).

3. Comparison of synthetic steroids versus placebo or no treatment

Primary outcome
3.1 Sexual function - composite score

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.13, 95% CI 0.00 to 0.26, P = 0.05, 1 study, 883 women, low-quality evidence) (Figure 6). Sensitivity analysis was not performed because the included study was considered to be at high risk of bias.

Figure 6.

Forest plot of comparison: 3 Synthetic steroids, outcome: 3.1 Composite score.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to moderate benefit (SMD 0.38, 95% CI 0.04 to 0.71, P = 0.03, 2 studies, 142 women, I² = 0%, low-quality evidence) (Figure 6). Sensitivity analysis was not performed because the two included studies were considered to be at high risk of bias.

Moderate heterogeneity was observed (I² = 44.3%) when comparing these two subgroups. Considering the pooled analysis, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.17, 95% CI 0.04 to 0.29, P = 0.008, 3 studies, 1025 women) (Figure 6).

Secondary outcomes
Arousal and sexual interest
3.2 Frequency of sexual activity

No study reported this outcome.

3.3 Libido, desire or interest in sex

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with a moderate to large benefit for the HT group (SMD 1.19, 95% CI 0.62 to 1.75, P < 0.0001, 1 study, 57 women) (Analysis 3.3).

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with a moderate to large benefit (SMD 0.91, 95% CI 0.50 to 1.31, P < 0.0001, 1 study, 105 women) (Analysis 3.3).

No important heterogeneity was observed (I² = 0%) when comparing these two subgroups. In the pooled analysis, the 95% CI was compatible with a moderate to large benefit for the HT group (SMD 1.00, 95% CI 0.67 to 1.33, P < 0.0001, 2 studies, 162 women, I² = 0%) (Analysis 3.3).

3.4 Arousal

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with a moderate to large benefit for the HT group (SMD 0.81, 95% CI 0.41 to 1.21, P < 0.0001, 1 study, 105 women) (Analysis 3.4).

3.5 Fantasy

No study reported this outcome.

Orgasm
3.6 Orgasm

No study reported this outcome.

3.7 Number of orgasms

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit for the HT group (SMD 0.24, 95% CI -0.15 to 0.62, P = 0.23, 1 study, 105 women) (Analysis 3.7).

3.8 Pleasure or enjoyment in sex

No study reported this outcome.

3.9 Satisfaction

No study reported this outcome in the subgroup of symptomatic or early postmenopausal women.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit for the HT group (SMD 0.50, 95% CI 0.11 to 0.89, P = 0.01, 1 study, 105 women) (Analysis 3.9).

Pain
3.10 Dyspareunia

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD -0.16, 95% CI -0.25 to -0.08, P = 0.0001, 1 study, 2144 women) (Analysis 3.10).

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit (SMD -0.38, 95% CI -0.77 to 0.00, P = 0.05, 1 study, 105 women) (Analysis 3.10).

No important heterogeneity was observed (I² = 14.9%) when comparing these two subgroups. In the pooled analysis, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD -0.17, 95% CI -0.26 to -0.09, P < 0.0001, 2 studies, 2249 women, I² = 15%) (Analysis 3.10).

4. Comparison of SERMs versus placebo or no treatment

Primary outcome
4.1 Sexual function - composite score

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to moderate benefit for the HT group (SMD 0.23, 95% CI -0.04 to 0.50, P = 0.09, 1 study, 215 women, low-quality evidence) (Figure 7). The same result was observed in the sensitivity analysis.

Figure 7.

Forest plot of comparison: 4 SERMs, outcome: 4.1 Composite score.

In the subgroup of unselected postmenopausal women, the 95% CI was compatible with small harm to a small benefit (SMD 0.04, 95% CI -0.20 to 0.29, P = 0.72, 1 study, 283 women, low-quality evidence) (Figure 7). The same result was observed in the sensitivity analysis.

No important heterogeneity was observed (I² = 1.7%) when comparing these two subgroups. In the pooled result, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.13, 95% CI -0.05 to 0.31, P = 0.16, 2 studies, 498 women, I² = 2%) (Figure 7).

Secondary outcomes
Arousal and sexual interest
4.2 Frequency of sexual activity

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with small harm to moderate benefit for the HT group (RR 1.06, 95% CI 0.73 to 1.54, P = 0.75, 1 study, 939 women) (Analysis 4.2).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.3 Libido, desire or interest in sex

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with a small harm to small benefit for the HT group (RR 0.98, 95% CI 0.72 to 1.33, P = 0.89, 1 study, 937 women) (Analysis 4.3).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.4 Arousal (continuous data)

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit for the HT group (SMD 0.19, 95% CI -0.07 to 0.46, P = 0.16, 1 study, 215 women) (Analysis 4.4).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.5 Arousal (binary data)

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with a small harm to small benefit for the HT group (RR 0.91, 95% CI 0.61 to 1.36, P = 0.65, 1 study, 337 women) (Analysis 4.5).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.6 Fantasy (continuous)

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.09, 95% CI -0.18 to 0.36, P = 0.52, 1 study, 215 women) (Analysis 4.6).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.7 Fantasy (binary)

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with small harm to small benefit (RR 0.93, 95% CI 0.63 to 1.35, P = 0.69, 1 study, 338 women) (Analysis 4.7).

No study reported this outcome in the subgroup of unselected postmenopausal women.

Orgasm
4.8 Orgasm

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with small harm to moderate benefit (RR 1.18, 95% CI 0.71 to 1.94, P = 0.52, 1 study, 310 women) (Analysis 4.8).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.9 Number of orgasms

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with a small harm to small benefit for the HT group (RR 0.89, 95% CI 0.56 to 1.41, P = 0.62, 1 study, 342 women) (Analysis 4.9).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.10 Pleasure or enjoyment in sex

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with small harm to small benefit for the HT group (RR 0.85, 95% CI 0.52 to 1.38, P = 0.50, 1 study, 342 women) (Analysis 4.10).

No study reported this outcome in the subgroup of unselected postmenopausal women.

4.11 Satisfaction

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with a small harm to small benefit (SMD 0.07, 95% CI -0.20 to 0.34, P = 0.60, 1 study, 215 women) (Analysis 4.11).

No study reported this outcome in the subgroup of unselected postmenopausal women.

Pain
4.12 Dyspareunia

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit for the HT group (RR 0.69, 95% CI 0.46 to 1.03, P = 0.07, 1 study, 343 women) (Analysis 4.12).

No study reported this outcome in the subgroup of unselected postmenopausal women.

5. Comparison of SERMs combined with estrogens versus placebo or no treatment

Primary outcome
5.1 Sexual function - composite score

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.21, 95% CI 0.00 to 0.43, P = 0.05, 1 study, 542 women, moderate-quality evidence) (Figure 8). The same result was observed in the sensitivity analysis.

Figure 8.

Forest plot of comparison: 5 SERMs + estrogens, outcome: 5.1 Composite score.

No study was included in the subgroup of unselected postmenopausal women.

Secondary outcomes
Arousal and sexual interest
5.2 Frequency of sexual activity

No study reported this outcome.

5.3 Libido, desire or interest in sex
No study reported this outcome.
5.4 Arousal

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to small benefit for the HT group (SMD 0.20, 95% CI -0.02 to 0.41, P = 0.07, 1 study, 542 women) (Analysis 5.4).

No study was included in the subgroup of unselected postmenopausal women.

5.5 Fantasy

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was wide and compatible with small harm to small benefit for the HT group (SMD 0.00, 95% CI -0.21 to 0.21, P = 1.00, 1 study, 542 women) (Analysis 5.5).

No study was included in the subgroup of unselected postmenopausal women.

Orgasm
5.6 Orgasm

No study reported this outcome.

5.7 Number of orgasms

No study reported this outcome.

5.8 Pleasure or enjoyment in sex

No study reported this outcome.

5.9 Satisfaction

In the subgroup of symptomatic or early postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit for the HT group (SMD 0.31, 95% CI 0.10 to 0.52, P = 0.005, 1 study, 542 women) (Analysis 5.9).

No study was included in the subgroup of unselected postmenopausal women.

Pain
5.10 Dyspareunia

No study reported this outcome.

We could not perform subgroup analyses as the available trials did not allow such analysis.

We could not use a funnel plot to assess publication bias because no analysis included 10 or more studies.

Discussion

Summary of main results

Examining the results of the included studies, we observed a small to moderate benefit in sexual function when estrogen alone (high-quality evidence) or in combination with progestogens (moderate-quality evidence) was used by women with menopause related symptoms (e.g. hot flushes, night sweat, vaginal dryness) and/or during the early post-menopausal period. When examining the effect of HT on the specific sexual domains (sexual interest/arousal, orgasm and pain), we observed that only the pain domain was consistently improved by HT across studies. Findings for tibolone and SERMs had very wide 95% CIs and the true effect may be somewhere between no effect and moderate benefit. For SERMs combined with estrogens we found moderate-quality evidence of no effect to a small benefit for the HT group (Summary of findings for the main comparison).

For unselected postmenopausal women, no HT showed evidence of effect. Estrogen alone (low-quality evidence) or in combination with progestogens (moderate-quality evidence) had no effect to a small benefit on sexual function. The tibolone effect is somewhere between no effect to a moderate benefit (low-quality evidence) and the effect of SERMs is between a small harm and small benefit (low-quality evidence) (Summary of findings 2).

Women considering the use of HT for other reasons may consider the observed effect on sexual function in the decision-making process. Although we did not evaluate any potential harm of HT, other wider systematic reviews did. Briefly, the conclusions of these systematic reviews are that 1. HT with estrogens alone increases the risk of stroke, venous thromboembolism and gallbladder disease (Gabriel Sanchez 2005; Marjoribanks 2012; Nelson 2012) and may worsen urinary incontinence (Cody 2012); estrogen alone is also contraindicated for women with an intact uterus as it increases the risk of endometrial hyperplasia. 2. HT with estrogens combined with progestogens increases the risk of a coronary event, venous thromboembolism, stroke, breast cancer, gallbladder disease, death from lung cancer, urinary incontinence, and probably dementia (Cody 2012; Gabriel Sanchez 2005; Hogervorst 2009; Lethaby 2008; Marjoribanks 2012; Nelson 2012); 3. HT with tibolone increases the risk of stroke and breast cancer recurrence (Formoso 2012); and 4. data regarding the safety of HT with SERMs to relieve menopausal symptoms are still scarce. Currently, short-term HT is recommended to alleviate menopausal symptoms and rarely for other indications.

Overall completeness and applicability of evidence

Twenty-six included studies evaluated postmenopausal women with at least six months of amenorrhoea and elevated follicle stimulating hormone (FSH), and only one study included perimenopausal women (Morais-Socorro 2012). So the conclusions are mostly based on postmenopausal women. Although the most important question in this review would be the effect of HT on women with sexual dysfunction, we were not able to answer that question as no trial included only women with sexual complaints. The studies differed in type of participants, drugs, dosages, administration routes, and the tools used to assess sexual function, which can explain the observed heterogeneity.

The review included 27 studies but four did not have data suitable for meta-analysis.Three of them compared estradiol + progestogens with placebo, one evaluated symptomatic postmenopausal women (Gambacciani 2011) and two unselected postmenopausal women (Fonseca 2007; Gast 2009); and one compared tibolone with placebo in unselected postmenopausal women (Hudita 2003). In all four studies the authors stated that women had improved sexual function but the data were not reported in detail; the four studies were deemed at high risk of selective reporting bias.

The review did not provide sufficient evidence to provide clinicians with a firm indication as to the best route of administration of HT for treating women with sexual dysfunction. It has been suggested that some clinicians may prefer to recommend vaginal HT for this indication, given that other routes of administration have recognised risks. More evidence is needed in this area.

Quality of the evidence

Eighteen of 27 studies included in this review were deemed at high risk of bias. This issue was responsible for our downgrading of the quality of evidence for many comparisons. Many included studies were supported by the pharmaceutical industry, in most cases the manufacturer of the studied drug (see Characteristics of included studies). The quality of the evidence for specific comparisons was as follows.

Symptomatic and early postmenopausal women - composite score of sexual function

(see Summary of findings for the main comparison)

The evidence on the effect of estradiol only was considered to be of high quality.

The evidence on the effect of estradiol combined with progestogens was considered to be of moderate quality; it was downgraded because the total population size was relatively small. For continuous outcomes, it would be important to evaluate at least 400 participants to have enough precision in the evaluation of a small effect.

The evidence on the effect of a synthetic steroid (tibolone) was considered to be of low quality. It was downgraded because of the quality of the studies; the only included study was deemed to be at high risk of bias, and because of imprecision the 95% CI was wide.

The evidence on the effect of SERMS was considered to be of low quality. It was downgraded because of very serious imprecision, the total population size was relatively small and the 95% CI was very wide.

The evidence on the effect of SERMS combined with estrogens was considered to be of moderate quality. It was downgraded for serious imprecision as the 95% CI was very wide.

Unselected postmenopausal women - composite score of sexual function

(see Summary of findings 2)

The evidence on the effect of estradiol only was considered to be of low quality. It was downgraded because of study quality, two-thirds of the included studies were deemed to be at high risk of bias, and because of imprecision the 95% CI was wide.

The evidence on the effect of estradiol combined with progestogens was considered to be of moderate quality. It was downgraded because of study quality, all three included studies were deemed at high risk of bias.

The evidence on the effect of synthetic steroids (tibolone) was considered to be of low quality. It was downgraded because of study quality, both included studies were deemed at high risk of bias, and because of imprecision as the population size was relatively small and the 95% CI was wide.

The evidence on the effect of SERMS was considered to be of low quality because of very serious imprecision, the population size was relatively small and the 95% CI was wide.

Potential biases in the review process

We made an extensive electronic and manual search and carefully evaluated the study reports for eligibility. Sexual function was assessed as a secondary outcome in some trials, which could impair the identification of all relevant trials. During data extraction, many arbitrary decisions were made. Each decision was reasoned among the authors, and we tried to assume the most conservative decision. We contacted the authors of the majority of the included studies, but authors from only two studies provided additional data.

Agreements and disagreements with other studies or reviews

Systematic reviews and scientific institutions' statements are controversial regarding the use of estrogen to improve sexual function. Some reviews conclude that some types of estrogen therapy could improve some domains of sexual function (Kotz 2004; Nappi 2009b) and some conclude they do not (NAMS 2012; Santen 2010). We observed a small to moderate benefit of HT with estrogens, combined or not with progestogens, on the composite scores for sexual function. Regarding the specific domains, too few studies could be pooled for each domain making it difficult to obtain a conclusion. Regarding synthetic steroids, other reviews agree that evidence of an effect of tibolone on sexual function is scarce (Kenemans 2005; Santen 2010).

Authors' conclusions

Implications for practice

HT treatment with estrogens alone or in combination with progestogens is associated with a small to moderate improvement in sexual function, particularly in pain, when used by women with menopausal symptoms or in early postmenopause (within five years of amenorrhoea), but not when used for unselected postmenopausal women. Evidence regarding other HTs (synthetic steroids and SERMs) is of low quality and we are uncertain of their effect on sexual function. The current evidence does not suggest an important effect of tibolone or of SERMs, alone or combined with estrogens, on sexual function.

Implications for research

More studies evaluating the effect of synthetic steroids, SERMS, and SERM + estrogens are necessary to improve the quality of the evidence on the effect of these treatments on sexual function in peri or postmenopausal women. Future studies should also evaluate the effect of HT when used specifically by women with sexual complaints.

Acknowledgements

We acknowledge Marian Showell - Trials Search Coordinator from the Cochrane Menstrual Disorders and Subfertility Group - for her valuable help in the search strategy.

Data and analyses

Download statistical data

Comparison 1. Estrogens alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Composite score6 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.2 Symptomatic or early post-menopausal3699Std. Mean Difference (IV, Fixed, 95% CI)0.38 [0.23, 0.54]
1.3 Unselected post-menopausal women3478Std. Mean Difference (IV, Fixed, 95% CI)0.16 [-0.02, 0.34]
2 Frequency of sexual activity2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 Symptomatic or early post-menopausal2287Mean Difference (IV, Fixed, 95% CI)0.30 [0.02, 0.59]
2.2 Unselected post-menopausal women00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Libido, desire or interest in sex2430Std. Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.35, 0.03]
3.1 Symptomatic or early post-menopausal164Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.47, 0.51]
3.2 Unselected post-menopausal women1366Std. Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.40, 0.01]
4 Arousal1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Fantasy1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Orgasm1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Number of orgasms2391Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.18, 0.22]
7.1 Symptomatic or early post-menopausal1223Std. Mean Difference (IV, Fixed, 95% CI)0.07 [-0.19, 0.33]
7.2 Unselected post-menopausal women1168Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.36, 0.25]
8 Pleasure or enjoyment of sex1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Satisfaction5 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
9.1 Symptomatic or early post-menopausal3510Std. Mean Difference (IV, Fixed, 95% CI)0.27 [0.09, 0.44]
9.2 Unselected post-menopausal women27044Std. Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.06, 0.03]
10 Dyspareunia51342Std. Mean Difference (IV, Random, 95% CI)-0.37 [-0.57, -0.17]
10.1 Symptomatic or early post-menopausal3771Std. Mean Difference (IV, Random, 95% CI)-0.48 [-0.75, -0.20]
10.2 Unselected post-menopausal women2571Std. Mean Difference (IV, Random, 95% CI)-0.20 [-0.37, -0.03]
Analysis 1.1.

Comparison 1 Estrogens alone, Outcome 1 Composite score.

Analysis 1.2.

Comparison 1 Estrogens alone, Outcome 2 Frequency of sexual activity.

Analysis 1.3.

Comparison 1 Estrogens alone, Outcome 3 Libido, desire or interest in sex.

Analysis 1.4.

Comparison 1 Estrogens alone, Outcome 4 Arousal.

Analysis 1.5.

Comparison 1 Estrogens alone, Outcome 5 Fantasy.

Analysis 1.6.

Comparison 1 Estrogens alone, Outcome 6 Orgasm.

Analysis 1.7.

Comparison 1 Estrogens alone, Outcome 7 Number of orgasms.

Analysis 1.8.

Comparison 1 Estrogens alone, Outcome 8 Pleasure or enjoyment of sex.

Analysis 1.9.

Comparison 1 Estrogens alone, Outcome 9 Satisfaction.

Analysis 1.10.

Comparison 1 Estrogens alone, Outcome 10 Dyspareunia.

Comparison 2. Estrogens + progestogens
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Composite score4 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Symptomatic or early post-menopausal1335Std. Mean Difference (IV, Fixed, 95% CI)0.42 [0.19, 0.64]
1.2 Unselected post-menopausal women31314Std. Mean Difference (IV, Fixed, 95% CI)0.09 [-0.02, 0.20]
3 Libido, desire or interest in sex3313Std. Mean Difference (IV, Fixed, 95% CI)0.32 [0.09, 0.54]
3.1 Symptomatic or early post-menopausal1158Std. Mean Difference (IV, Fixed, 95% CI)0.44 [0.13, 0.76]
3.2 Unselected post-menopausal women2155Std. Mean Difference (IV, Fixed, 95% CI)0.19 [-0.12, 0.51]
4 Libido, desire or interest in sex2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Symptomatic or early post-menopausal00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Unselected post-menopausal women21323Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.98, 1.18]
5 Arousal1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Symptomatic or early post-menopausal0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Unselected post-menopausal women1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Fantasy1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Number of orgasms1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Symptomatic or early post-menopausal0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 Unselected post-menopausal women1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Satisfaction2 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
10.1 Symptomatic or early post-menopausal00Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10.2 Unselected post-menopausal women211139Std. Mean Difference (IV, Fixed, 95% CI)0.00 [-0.04, 0.04]
11 Satisfaction2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 Symptomatic or early post-menopausal00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
11.2 Unselected post-menopausal women21323Risk Ratio (M-H, Random, 95% CI)1.11 [0.74, 1.67]
12 Dyspareunia1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
12.1 Symptomatic or early post-menopausal0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12.2 Unselected post-menopausal women1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Dyspareunia2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 Symptomatic or early post-menopausal00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.2 Unselected post-menopausal women21323Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.46, 1.02]
Analysis 2.1.

Comparison 2 Estrogens + progestogens, Outcome 1 Composite score.

Analysis 2.3.

Comparison 2 Estrogens + progestogens, Outcome 3 Libido, desire or interest in sex.

Analysis 2.4.

Comparison 2 Estrogens + progestogens, Outcome 4 Libido, desire or interest in sex.

Analysis 2.5.

Comparison 2 Estrogens + progestogens, Outcome 5 Arousal.

Analysis 2.6.

Comparison 2 Estrogens + progestogens, Outcome 6 Fantasy.

Analysis 2.8.

Comparison 2 Estrogens + progestogens, Outcome 8 Number of orgasms.

Analysis 2.10.

Comparison 2 Estrogens + progestogens, Outcome 10 Satisfaction.

Analysis 2.11.

Comparison 2 Estrogens + progestogens, Outcome 11 Satisfaction.

Analysis 2.12.

Comparison 2 Estrogens + progestogens, Outcome 12 Dyspareunia.

Analysis 2.13.

Comparison 2 Estrogens + progestogens, Outcome 13 Dyspareunia.

Comparison 3. Synthetic steroids
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Composite score31025Std. Mean Difference (IV, Fixed, 95% CI)0.17 [0.04, 0.29]
1.1 Symptomatic or early post-menopausal1883Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-1.01, 0.26]
1.2 Unselected post-menopausal women2142Std. Mean Difference (IV, Fixed, 95% CI)0.38 [0.04, 0.71]
3 Libido, desire or interest in sex2162Std. Mean Difference (IV, Fixed, 95% CI)1.00 [0.67, 1.33]
3.1 Symptomatic or early post-menopausal157Std. Mean Difference (IV, Fixed, 95% CI)1.19 [0.62, 1.75]
3.2 Unselected post-menopausal women1105Std. Mean Difference (IV, Fixed, 95% CI)0.91 [0.50, 1.31]
4 Arousal1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Symptomatic or early post-menopausal0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Unselected post-menopausal women1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Number of orgasms1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Symptomatic or early post-menopausal0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 Unselected post-menopausal women1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Satisfaction1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 Symptomatic or early post-menopausal0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9.2 Unselected post-menopausal women1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Dyspareunia22249Std. Mean Difference (IV, Fixed, 95% CI)-0.17 [-0.26, -0.09]
10.1 Symptomatic or early post-menopausal12144Std. Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.25, -0.08]
10.2 Unselected post-menopausal women1105Std. Mean Difference (IV, Fixed, 95% CI)-0.38 [-0.77, 0.00]
Analysis 3.1.

Comparison 3 Synthetic steroids, Outcome 1 Composite score.

Analysis 3.3.

Comparison 3 Synthetic steroids, Outcome 3 Libido, desire or interest in sex.

Analysis 3.4.

Comparison 3 Synthetic steroids, Outcome 4 Arousal.

Analysis 3.7.

Comparison 3 Synthetic steroids, Outcome 7 Number of orgasms.

Analysis 3.9.

Comparison 3 Synthetic steroids, Outcome 9 Satisfaction.

Analysis 3.10.

Comparison 3 Synthetic steroids, Outcome 10 Dyspareunia.

Comparison 4. SERMs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Composite score2498Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.05, 0.31]
1.1 Symptomatic or early post-menopausal1215Std. Mean Difference (IV, Fixed, 95% CI)0.23 [-0.04, 0.50]
1.2 Unselected post-menopausal women1283Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.20, 0.29]
2 Frequency of sexual activity1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Libido, desire or interest in sex1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Arousal1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Arousal1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Fantasy1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Fantasy1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
7.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Orgasm1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Number of orgasms1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Pleasure or enjoyment of sex1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Satisfaction1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
11.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
11.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Dyspareunia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
12.1 Symptomatic or early post-menopausal0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12.2 Unselected post-menopausal women1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 SERMs, Outcome 1 Composite score.

Analysis 4.2.

Comparison 4 SERMs, Outcome 2 Frequency of sexual activity.

Analysis 4.3.

Comparison 4 SERMs, Outcome 3 Libido, desire or interest in sex.

Analysis 4.4.

Comparison 4 SERMs, Outcome 4 Arousal.

Analysis 4.5.

Comparison 4 SERMs, Outcome 5 Arousal.

Analysis 4.6.

Comparison 4 SERMs, Outcome 6 Fantasy.

Analysis 4.7.

Comparison 4 SERMs, Outcome 7 Fantasy.

Analysis 4.8.

Comparison 4 SERMs, Outcome 8 Orgasm.

Analysis 4.9.

Comparison 4 SERMs, Outcome 9 Number of orgasms.

Analysis 4.10.

Comparison 4 SERMs, Outcome 10 Pleasure or enjoyment of sex.

Analysis 4.11.

Comparison 4 SERMs, Outcome 11 Satisfaction.

Analysis 4.12.

Comparison 4 SERMs, Outcome 12 Dyspareunia.

Comparison 5. SERMs + estrogens
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Composite score1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Arousal1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Fantasy1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Satisfaction1 Std. Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 Symptomatic or early post-menopausal1 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9.2 Unselected post-menopausal women0 Std. Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 SERMs + estrogens, Outcome 1 Composite score.

Analysis 5.4.

Comparison 5 SERMs + estrogens, Outcome 4 Arousal.

Analysis 5.5.

Comparison 5 SERMs + estrogens, Outcome 5 Fantasy.

Analysis 5.9.

Comparison 5 SERMs + estrogens, Outcome 9 Satisfaction.

Appendices

Appendix 1. CENTRAL search strategy

Database: EBM Reviews - Cochrane Central Register of Controlled Trials
Search Strategy (Feb-10-2012):
--------------------------------------------------------------------------------
1 exp climacteric/ or exp menopause/ or exp menopause, premature/ or exp perimenopause/ or exp postmenopause/ (5129)
2 climacter$.tw. (578)
3 menopaus$.tw. (3505)
4 perimenopaus$.tw. (314)
5 post?menopaus$.tw. (7324)
6 or/1-5 (10559)
7 exp hormone replacement therapy/ or exp oestrogen replacement therapy/ (2445)
8 HRT.tw. (1114)
9 exp oestrogens/ or exp epimestrol/ or exp estradiol/ or exp oestrogenic steroids, alkylated/ or exp "oestrogens, conjugated (usp)"/ or exp "oestrogens, esterified (usp)"/ or exp estrone/ or exp ethinyl estradiol/ or exp mestranol/ or exp quinestrol/ (5632)
10 (oestrogen$ or oestrogen$).tw. (5785)
11 estradiol$.tw. (3728)
12 oestradiol$.tw. (925)
13 CEE.tw. (276)
14 (estrone$ or estriol$).tw. (536)
15 exp Dienestrol/ (4)
16 Dienestrol$.tw. (2)
17 exp estriol/ or exp estetrol/ or exp ethinyl estradiol-norgestrel combination/ (253)
18 (estriol or estetrol).tw. (172)
19 premarin.tw. (145)
20 prempro.tw. (9)
21 exp selective oestrogen receptor modulators/ or exp clomiphene/ or exp raloxifene/ or exp tamoxifen/ or exp toremifene/ (1969)
22 SERMS.tw. (19)
23 selective oestrogen receptor modulator$.tw. (170)
24 (clomiphene or clomid).tw. (630)
25 (clomifene or clomifert).tw. (12)
26 serophene.tw. (1)
27 raloxifene.tw. (479)
28 keoxifene.tw. (0)
29 ly?139481.tw. (1)
30 ly?156758.tw. (0)
31 evista.tw. (28)
32 tamoxifen.tw. (2528)
33 dimethylamine$.tw. (13)
34 novaldex.tw. (3)
35 tomaxithen.tw. (0)
36 soltamox.tw. (0)
37 zitazonium.tw. (1)
38 menerba.tw. (0)
39 MF?101.tw. (1)
40 femarelle.tw. (2)
41 DT56a.tw. (2)
42 LY?117018.tw. (0)
43 toremifene.tw. (99)
44 serm.tw. (54)
45 bazedoxifene.tw. (24)
46 or/7-45 (13449)
47 6 and 46 (6297)
48 exp sexual dysfunction, physiological/ or exp dyspareunia/ (1150)
49 exp Sexual Dysfunctions, Psychological/ (1081)
50 sex$.tw. (16984)
51 dyspareunia.tw. (182)
52 (vagina$ adj2 atroph$).tw. (82)
53 (vagina$ adj2 dry$).tw. (116)
54 orgasm.tw. (130)
55 libido.tw. (234)
56 orgasmic.tw. (83)
57 frigid$.tw. (16)
58 arousal.tw. (1668)
59 HSDD.tw. (14)
60 (hypoactive adj2 desire).tw. (38)
61 exp Libido/ (229)
62 psychosexual$.tw. (52)
63 or/48-62 (19268)
64 47 and 63 (611)

Database: EBM Reviews - Cochrane Central Register of Controlled Trials
Search Strategy (Dec-12-2012):
--------------------------------------------------------------------------------
1 exp climacteric/ or exp menopause/ or exp menopause, premature/ or exp perimenopause/ or exp postmenopause/ (5205)
2 climacter$.tw. (585)
3 menopaus$.tw. (3555)
4 perimenopaus$.tw. (323)
5 post?menopaus$.tw. (7429)
6 or/1-5 (10702)
7 exp hormone replacement therapy/ or exp oestrogen replacement therapy/ (2466)
8 HRT.tw. (1116)
9 exp oestrogens/ or exp epimestrol/ or exp estradiol/ or exp oestrogenic steroids, alkylated/ or exp "oestrogens, conjugated (usp)"/ or exp "oestrogens, esterified (usp)"/ or exp estrone/ or exp ethinyl estradiol/ or exp mestranol/ or exp quinestrol/ (5693)
10 (oestrogen$ or oestrogen$).tw. (5837)
11 estradiol$.tw. (3759)
12 oestradiol$.tw. (930)
13 CEE.tw. (279)
14 (estrone$ or estriol$).tw. (538)
15 exp Dienestrol/ (4)
16 Dienestrol$.tw. (2)
17 exp estriol/ or exp estetrol/ or exp ethinyl estradiol-norgestrel combination/ (254)
18 (estriol or estetrol).tw. (173)
19 premarin.tw. (145)
20 prempro.tw. (9)
21 exp selective oestrogen receptor modulators/ or exp clomiphene/ or exp raloxifene/ or exp tamoxifen/ or exp toremifene/ (1989)
22 SERMS.tw. (19)
23 selective oestrogen receptor modulator$.tw. (171)
24 (clomiphene or clomid).tw. (637)
25 (clomifene or clomifert).tw. (13)
26 serophene.tw. (1)
27 raloxifene.tw. (484)
28 keoxifene.tw. (0)
29 ly?139481.tw. (1)
30 ly?156758.tw. (0)
31 evista.tw. (28)
32 tamoxifen.tw. (2542)
33 dimethylamine$.tw. (13)
34 novaldex.tw. (3)
35 tomaxithen.tw. (0)
36 soltamox.tw. (0)
37 zitazonium.tw. (1)
38 menerba.tw. (0)
39 MF?101.tw. (1)
40 femarelle.tw. (2)
41 DT56a.tw. (2)
42 LY?117018.tw. (0)
43 toremifene.tw. (100)
44 serm.tw. (54)
45 bazedoxifene.tw. (26)
46 tibolone.tw. (381)
47 or/7-46 (13688)
48 6 and 47 (6434)
49 exp sexual dysfunction, physiological/ or exp dyspareunia/ (1169)
50 exp Sexual Dysfunctions, Psychological/ (1101)
51 sex$.tw. (17282)
52 dyspareunia.tw. (187)
53 (vagina$ adj2 atroph$).tw. (84)
54 (vagina$ adj2 dry$).tw. (118)
55 orgasm.tw. (133)
56 libido.tw. (232)
57 orgasmic.tw. (83)
58 frigid$.tw. (16)
59 arousal.tw. (1694)
60 HSDD.tw. (18)
61 (hypoactive adj2 desire).tw. (42)
62 exp Libido/ (236)
63 psychosexual$.tw. (52)
64 or/49-63 (19596)
65 48 and 64 (626)
66 limit 65 to yr="2012 -Current" (1)

CENTRAL (Dec-12-2012): Total combining the searches and excluding duplicates = 618 records

Appendix 2. CINAHL search strategy

Search strategy (Dec-12-2012)

(menopaus*) AND (sexual) AND ((trial) OR (random*))

CINAHL (Dec-12-2012) = 51 records

Appendix 3. EMBASE search strategy

Database: Embase <1980 to 2012 Week 05>
Search Strategy (Feb-10-2012):
--------------------------------------------------------------------------------
1 exp climacterium/ (5534)
2 exp menopause/ or exp early menopause/ or exp menopause related disorder/ or exp "menopause and climacterium"/ (80560)
3 exp postmenopause/ (35369)
4 climacter$.tw. (4081)
5 menopaus$.tw. (39257)
6 perimenopaus$.tw. (3372)
7 post?menopaus$.tw. (43057)
8 or/1-7 (100043)
9 exp hormone substitution/ or exp hormonal therapy/ or exp substitution therapy/ or exp oestrogen therapy/ (180718)
10 (hormone adj2 therap$).tw. (24219)
11 HRT.tw. (9442)
12 exp oestrogen/ (191124)
13 exp estradiol/ or exp drospirenone plus estradiol/ or estradiol valerate/ or exp desogestrel plus estradiol/ or estradiol valerate plus medroxyprogesterone acetate/ or exp cyproterone acetate plus estradiol valerate/ or exp dydrogesterone plus estradiol/ or exp 17alpha estradiol/ or exp dienogest plus estradiol valerate/ (85882)
14 exp conjugated oestrogen/ (8464)
15 (oestrogen$ or oestrogen$).tw. (122637)
16 estradiol$.tw. (63931)
17 oestradiol$.tw. (11333)
18 CEE.tw. (979)
19 (estrone$ or estriol$).tw. (9388)
20 exp dienestrol/ (440)
21 Dienestrol$.tw. (163)
22 exp estriol/ (6931)
23 exp estetrol/ (98)
24 exp ethinylestradiol/ (14071)
25 (estriol or estetrol).tw. (3369)
26 premarin.tw. (2672)
27 prempro.tw. (340)
28 exp selective oestrogen receptor modulator/ (5151)
29 exp clomifene/ (4963)
30 exp raloxifene/ (7915)
31 exp tamoxifen/ (39125)
32 exp toremifene/ (1603)
33 (SERMS or SERM).tw. (1775)
34 selective oestrogen receptor modulator$.tw. (2266)
35 (clomiphene or clomid).tw. (4939)
36 (clomifene or clomifert).tw. (160)
37 serophene.tw. (177)
38 raloxifene.tw. (2934)
39 keoxifene.tw. (55)
40 ly?139481.tw. (12)
41 ly?156758.tw. (32)
42 evista.tw. (876)
43 (tamoxifen or toremifene).tw. (19437)
44 dimethylamine$.tw. (1233)
45 novaldex.tw. (111)
46 tomaxithen.tw. (0)
47 soltamox.tw. (7)
48 zitazonium.tw. (27)
49 menerba.tw. (2)
50 MF?101.tw. (11)
51 femarelle.tw. (13)
52 DT56a.tw. (16)
53 LY?117018.tw. (88)
54 bazedoxifene.tw. (172)
55 or/9-54 (425090)
56 exp sexual dysfunction/ (48943)
57 exp dyspareunia/ or exp female sexual dysfunction/ or exp pain/ (638015)
58 dyspareunia.tw. (2847)
59 sexual$.tw. (155950)
60 (vagina$ adj2 atroph$).tw. (411)
61 (vagina$ adj2 dry$).tw. (784)
62 orgasm.tw. (2470)
63 libido.tw. (3413)
64 orgasmic.tw. (902)
65 exp libido disorder/ or exp libido/ (8803)
66 frigid$.tw. (536)
67 arousal.tw. (18842)
68 HSDD.tw. (257)
69 exp hypoactive sexual desire disorder/ or exp psychosexual disorder/ (17691)
70 psychosexual$.tw. (1763)
71 (hypoactive adj2 desire).tw. (503)
72 or/56-71 (833932)
73 Clinical Trial/ (823866)
74 Randomized Controlled Trial/ (296765)
75 exp randomization/ (55652)
76 Single Blind Procedure/ (14775)
77 Double Blind Procedure/ (102866)
78 Crossover Procedure/ (31796)
79 Placebo/ (192025)
80 Randomi?ed controlled trial$.tw. (68479)
81 Rct.tw. (8444)
82 random allocation.tw. (1087)
83 randomly allocated.tw. (16170)
84 allocated randomly.tw. (1729)
85 (allocated adj2 random).tw. (691)
86 Single blind$.tw. (11499)
87 Double blind$.tw. (121111)
88 ((treble or triple) adj blind$).tw. (256)
89 placebo$.tw. (164757)
90 prospective study/ (181795)
91 or/73-90 (1172999)
92 case study/ (14614)
93 case report.tw. (213535)
94 abstract report/ or letter/ (806942)
95 or/92-94 (1030873)
96 91 not 95 (1139147)
97 8 and 55 and 72 and 96 (3060)
98 (2011$ or 2012$).em. (1460691)
99 97 and 98 (257)

Database: Embase <1980 to 2012 Week 49>
Search Strategy (Dec-12-2012):
--------------------------------------------------------------------------------
1 exp climacterium/ (6705)
2 exp menopause/ or exp early menopause/ or exp menopause related disorder/ or exp "menopause and climacterium"/ (90343)
3 exp postmenopause/ (39779)
4 climacter$.tw. (4572)
5 menopaus$.tw. (44463)
6 perimenopaus$.tw. (3861)
7 post?menopaus$.tw. (48798)
8 or/1-7 (112189)
9 exp hormone substitution/ or exp hormonal therapy/ or exp substitution therapy/ or exp oestrogen therapy/ (198437)
10 (hormone adj2 therap$).tw. (27140)
11 HRT.tw. (10421)
12 exp oestrogen/ (203527)
13 exp estradiol/ or exp drospirenone plus estradiol/ or estradiol valerate/ or exp desogestrel plus estradiol/ or estradiol valerate plus medroxyprogesterone acetate/ or exp cyproterone acetate plus estradiol valerate/ or exp dydrogesterone plus estradiol/ or exp 17alpha estradiol/ or exp dienogest plus estradiol valerate/ (91843)
14 exp conjugated oestrogen/ (8862)
15 (oestrogen$ or oestrogen$).tw. (134593)
16 estradiol$.tw. (68968)
17 oestradiol$.tw. (11736)
18 CEE.tw. (1104)
19 (estrone$ or estriol$).tw. (9956)
20 exp dienestrol/ (445)
21 Dienestrol$.tw. (168)
22 exp estriol/ (7219)
23 exp estetrol/ (104)
24 exp ethinylestradiol/ (14692)
25 (estriol or estetrol).tw. (3528)
26 premarin.tw. (2726)
27 prempro.tw. (352)
28 exp selective oestrogen receptor modulator/ (5793)
29 exp clomifene/ (5133)
30 exp raloxifene/ (8515)
31 exp tamoxifen/ (42352)
32 exp toremifene/ (1687)
33 (SERMS or SERM).tw. (2000)
34 selective oestrogen receptor modulator$.tw. (2557)
35 (clomiphene or clomid).tw. (5172)
36 (clomifene or clomifert).tw. (183)
37 serophene.tw. (180)
38 raloxifene.tw. (3320)
39 keoxifene.tw. (56)
40 ly?139481.tw. (12)
41 ly?156758.tw. (32)
42 evista.tw. (920)
43 (tamoxifen or toremifene).tw. (21615)
44 dimethylamine$.tw. (1325)
45 novaldex.tw. (115)
46 tomaxithen.tw. (0)
47 soltamox.tw. (9)
48 zitazonium.tw. (28)
49 menerba.tw. (5)
50 MF?101.tw. (15)
51 femarelle.tw. (16)
52 DT56a.tw. (21)
53 LY?117018.tw. (90)
54 bazedoxifene.tw. (234)
55 tibolone.tw. (1177)
56 or/9-55 (462350)
57 exp sexual dysfunction/ (53308)
58 exp dyspareunia/ or exp female sexual dysfunction/ or exp pain/ (706511)
59 dyspareunia.tw. (3375)
60 sexual$.tw. (171463)
61 (vagina$ adj2 atroph$).tw. (500)
62 (vagina$ adj2 dry$).tw. (945)
63 orgasm.tw. (2745)
64 libido.tw. (3746)
65 orgasmic.tw. (994)
66 exp libido disorder/ or exp libido/ (9473)
67 frigid$.tw. (564)
68 arousal.tw. (20708)
69 HSDD.tw. (308)
70 exp hypoactive sexual desire disorder/ or exp psychosexual disorder/ (19099)
71 psychosexual$.tw. (1916)
72 (hypoactive adj2 desire).tw. (579)
73 or/57-72 (920650)
74 Clinical Trial/ (874957)
75 Randomized Controlled Trial/ (333721)
76 exp randomization/ (60141)
77 Single Blind Procedure/ (16726)
78 Double Blind Procedure/ (112171)
79 Crossover Procedure/ (35690)
80 Placebo/ (209677)
81 Randomi?ed controlled trial$.tw. (81591)
82 Rct.tw. (10539)
83 random allocation.tw. (1190)
84 randomly allocated.tw. (18016)
85 allocated randomly.tw. (1851)
86 (allocated adj2 random).tw. (713)
87 Single blind$.tw. (12838)
88 Double blind$.tw. (132548)
89 ((treble or triple) adj blind$).tw. (290)
90 placebo$.tw. (182396)
91 prospective study/ (220551)
92 or/74-91 (1294010)
93 case study/ (17958)
94 case report.tw. (235659)
95 abstract report/ or letter/ (852092)
96 or/93-95 (1100856)
97 92 not 96 (1258346)
98 8 and 56 and 73 and 97 (3288)
99 2012$.em. (1232383)
100 98 and 99 (209)

MDSG (Dec-12-2012): Total combining the searches and excluding duplicates = 467 records

Appendix 4. LILACS search strategy

Search strategy (Dec-12-2012)

(menopaus$) AND (sexual) AND ((trial) OR (random$))

LILACS (Dec-12-2012) = 6 records

Appendix 5. MDSG Specialised Register search strategy

Menstrual disorders and subfertility (MDSG) database search for LA1380 12.12.12

Keywords CONTAINS "menopausal" or "*Menopause" or "perimenopausal" or "perimenopause" or "Postmenopausal" or "postmenopause" or "climacteric " or “vasomotor” or Title CONTAINS"menopausal" or "*Menopause" or "perimenopausal" or "perimenopause" or "Postmenopausal" or "postmenopause" or "climacteric " or “vasomotor”

AND

Keywords CONTAINS "Hormone Replacement Therapy" or "*Hormone Substitution" or "hormone therapy" or "hormone therapy oestrogen" or "estraderm" or "estradiol" or "Estriol-" or "estrofen" or "oestrogen" or "oestrogen-progestogen" or "*oestrogens" or "Estrone" or "estroprogestin" or "ethinyl-estradiol" or "ethinyl estradiol-cyproterone acetate" or "ethinyl estradiol + drospirenone" or "oestrodiol" or "oestrogen" or "conjugated equine " or "conjugated oestrogen" or "conjugated oestrogens" or "CEE" or "HRT" or "HT " or "premarin" or "Prempro" or "SERM"or"selective oestrogen receptor modulator"or "*Clomiphene"or"raloxifene"or "toremifen"or"toremifene"or "bazedoxifene acetate"or "Evista"or"tamoxifen" or "tibolone" or Title CONTAINS "SERM"or"selective oestrogen receptor modulator"or "*Clomiphene"or"raloxifene"or "toremifen"or"toremifene"or "bazedoxifene acetate"or "Evista"or"tamoxifen" or"Hormone Replacement Therapy" or "*Hormone Substitution" or "hormone therapy" or "hormone therapy oestrogen" or "tibolone

AND

Keywords CONTAINS "sex drive"or"sexual"or "*Sexuality"or "dyspareunia"or "hypoactive sexual desire"or"hypoactive sexual desire disorder"or "orgasm"or"vaginal acidification"or"vaginal atrophy"or "vaginal dryness"or"vaginal lubrication"or "vaginal matuation "or "vaginal symptoms"or"*Vaginitis"or "vaginosis"or"libido"

MDSG (Dec-12-2012) = 319 records

Appendix 6. MEDLINE search strategy

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Search Strategy (Feb-10-2012):
--------------------------------------------------------------------------------
1 exp climacteric/ or exp menopause/ or exp menopause, premature/ or exp perimenopause/ or exp postmenopause/ (44136)
2 climacter$.tw. (3701)
3 menopaus$.tw. (31119)
4 perimenopaus$.tw. (2770)
5 post?menopaus$.tw. (35844)
6 or/1-5 (73512)
7 exp hormone replacement therapy/ or exp oestrogen replacement therapy/ (18958)
8 HRT.tw. (7112)
9 exp oestrogens/ or exp epimestrol/ or exp estradiol/ or exp oestrogenic steroids, alkylated/ or exp "oestrogens, conjugated (usp)"/ or exp "oestrogens, esterified (usp)"/ or exp estrone/ or exp ethinyl estradiol/ or exp mestranol/ or exp quinestrol/ (134303)
10 (oestrogen$ or oestrogen$).tw. (113373)
11 estradiol$.tw. (60864)
12 oestradiol$.tw. (11652)
13 CEE.tw. (806)
14 (estrone$ or estriol$).tw. (9606)
15 exp Dienestrol/ (102)
16 Dienestrol$.tw. (166)
17 exp estriol/ or exp estetrol/ or exp ethinyl estradiol-norgestrel combination/ (5988)
18 (estriol or estetrol).tw. (3579)
19 premarin.tw. (476)
20 prempro.tw. (25)
21 exp selective oestrogen receptor modulators/ or exp clomiphene/ or exp raloxifene/ or exp tamoxifen/ or exp toremifene/ (21731)
22 SERMS.tw. (928)
23 selective oestrogen receptor modulator$.tw. (1834)
24 (clomiphene or clomid).tw. (4195)
25 (clomifene or clomifert).tw. (97)
26 serophene.tw. (3)
27 raloxifene.tw. (2304)
28 keoxifene.tw. (48)
29 ly?139481.tw. (8)
30 ly?156758.tw. (32)
31 evista.tw. (57)
32 tamoxifen.tw. (15775)
33 dimethylamine$.tw. (1071)
34 novaldex.tw. (1)
35 tomaxithen.tw. (0)
36 soltamox.tw. (0)
37 zitazonium.tw. (6)
38 menerba.tw. (0)
39 MF?101.tw. (8)
40 femarelle.tw. (10)
41 DT56a.tw. (12)
42 LY?117018.tw. (81)
43 toremifene.tw. (545)
44 serm.tw. (779)
45 bazedoxifene.tw. (104)
46 or/7-45 (229169)
47 6 and 46 (34784)
48 exp sexual dysfunction, physiological/ or exp dyspareunia/ (21135)
49 exp Sexual Dysfunctions, Psychological/ (24741)
50 sex$.tw. (414972)
51 dyspareunia.tw. (2057)
52 (vagina$ adj2 atroph$).tw. (308)
53 (vagina$ adj2 dry$).tw. (578)
54 orgasm.tw. (1767)
55 libido.tw. (2907)
56 orgasmic.tw. (656)
57 frigid$.tw. (555)
58 arousal.tw. (16362)
59 HSDD.tw. (128)
60 (hypoactive adj2 desire).tw. (291)
61 exp Libido/ (3788)
62 psychosexual$.tw. (1365)
63 or/48-62 (448656)
64 randomized controlled trial.pt. (319060)
65 controlled clinical trial.pt. (83446)
66 randomized.ab. (234849)
67 placebo.tw. (136377)
68 clinical trials as topic.sh. (157497)
69 randomly.ab. (172796)
70 trial.ti. (100523)
71 (crossover or cross-over or cross over).tw. (52167)
72 or/64-71 (781696)
73 exp animals/ not humans.sh. (3649774)
74 72 not 73 (721570)
75 47 and 63 and 74 (862)

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Search Strategy (Dec-12-2012):
--------------------------------------------------------------------------------
1 exp climacteric/ or exp menopause/ or exp menopause, premature/ or exp perimenopause/ or exp postmenopause/ (46777)
2 climacter$.tw. (3917)
3 menopaus$.tw. (33201)
4 perimenopaus$.tw. (2967)
5 post?menopaus$.tw. (38423)
6 or/1-5 (78280)
7 exp hormone replacement therapy/ or exp oestrogen replacement therapy/ (19904)
8 HRT.tw. (7512)
9 exp oestrogens/ or exp epimestrol/ or exp estradiol/ or exp oestrogenic steroids, alkylated/ or exp "oestrogens, conjugated (usp)"/ or exp "oestrogens, esterified (usp)"/ or exp estrone/ or exp ethinyl estradiol/ or exp mestranol/ or exp quinestrol/ (140214)
10 (oestrogen$ or oestrogen$).tw. (120909)
11 estradiol$.tw. (64020)
12 oestradiol$.tw. (11920)
13 CEE.tw. (845)
14 (estrone$ or estriol$).tw. (9986)
15 exp Dienestrol/ (103)
16 Dienestrol$.tw. (169)
17 exp estriol/ or exp estetrol/ or exp ethinyl estradiol-norgestrel combination/ (6099)
18 (estriol or estetrol).tw. (3700)
19 premarin.tw. (485)
20 prempro.tw. (25)
21 exp selective oestrogen receptor modulators/ or exp clomiphene/ or exp raloxifene/ or exp tamoxifen/ or exp toremifene/ (22819)
22 SERMS.tw. (1007)
23 selective oestrogen receptor modulator$.tw. (2005)
24 (clomiphene or clomid).tw. (4319)
25 (clomifene or clomifert).tw. (108)
26 serophene.tw. (3)
27 raloxifene.tw. (2489)
28 keoxifene.tw. (48)
29 ly?139481.tw. (8)
30 ly?156758.tw. (32)
31 evista.tw. (59)
32 tamoxifen.tw. (16790)
33 dimethylamine$.tw. (1150)
34 novaldex.tw. (1)
35 tomaxithen.tw. (0)
36 soltamox.tw. (0)
37 zitazonium.tw. (6)
38 menerba.tw. (0)
39 MF?101.tw. (10)
40 femarelle.tw. (10)
41 DT56a.tw. (12)
42 LY?117018.tw. (82)
43 toremifene.tw. (560)
44 serm.tw. (852)
45 bazedoxifene.tw. (137)
46 tibolone.tw. (850)
47 or/7-46 (242112)
48 6 and 47 (36682)
49 exp sexual dysfunction, physiological/ or exp dyspareunia/ (22169)
50 exp Sexual Dysfunctions, Psychological/ (25876)
51 sex$.tw. (447873)
52 dyspareunia.tw. (2223)
53 (vagina$ adj2 atroph$).tw. (334)
54 (vagina$ adj2 dry$).tw. (625)
55 orgasm.tw. (1877)
56 libido.tw. (3040)
57 orgasmic.tw. (690)
58 frigid$.tw. (587)
59 arousal.tw. (17583)
60 HSDD.tw. (153)
61 (hypoactive adj2 desire).tw. (329)
62 exp Libido/ (3914)
63 psychosexual$.tw. (1410)
64 or/49-63 (483405)
65 randomized controlled trial.pt. (343011)
66 controlled clinical trial.pt. (85733)
67 randomized.ab. (259790)
68 placebo.tw. (146292)
69 clinical trials as topic.sh. (163875)
70 randomly.ab. (189320)
71 trial.ti. (111769)
72 (crossover or cross-over or cross over).tw. (55756)
73 or/65-72 (843064)
74 exp animals/ not humans.sh. (3813901)
75 73 not 74 (777893)
76 48 and 64 and 75 (925)
77 2012$.ed. (998359)
78 76 and 77 (51)

MEDLINE (Dec-12-2012): Total combining the searches and excluding duplicates = 467 records

Appendix 7. PsycINFO search strategy

Database: PsycINFO <1806 to January Week 5 2012>
Search Strategy (Feb-10-2012):
--------------------------------------------------------------------------------
1 exp menopause/ (2575)
2 climacter$.tw. (416)
3 menopaus$.tw. (3221)
4 perimenopaus$.tw. (424)
5 post?menopaus$.tw. (1675)
6 or/1-5 (4574)
7 exp Hormone Therapy/ or exp oestrogens/ (5583)
8 HRT.tw. (448)
9 exp Estradiol/ (2168)
10 (oestrogen$ or oestrogen$).tw. (5755)
11 (estradiol$ or oestradiol$).tw. (4355)
12 CEE.tw. (94)
13 (estrone$ or estriol$).tw. (166)
14 Dienestrol.tw. (0)
15 exp Estradiol/ (2168)
16 (estriol or estetrol).tw. (33)
17 premarin.tw. (32)
18 prempro.tw. (10)
19 selective oestrogen receptor modulator$.tw. (80)
20 (clomiphene or clomid).tw. (35)
21 (clomifene or clomifert).tw. (0)
22 raloxifene.tw. (77)
23 tamoxifen.tw. (286)
24 toremifene.tw. (3)
25 (SERMS or SERM).tw. (55)
26 serophene.tw. (0)
27 bazedoxifene.tw. (3)
28 menerba.tw. (0)
29 MF?101.tw. (0)
30 or/7-29 (9457)
31 exp sexual satisfaction/ or exp sexuality/ (9955)
32 sexual$.tw. (114735)
33 dyspareunia.tw. (381)
34 (vagina$ adj2 atroph$).tw. (21)
35 (vagina$ adj2 dry$).tw. (88)
36 orgasm$.tw. (2218)
37 libido.tw. (2308)
38 orgasmic.tw. (643)
39 frigid$.tw. (408)
40 arousal.tw. (20766)
41 HSDD.tw. (107)
42 (hypoactive adj2 desire).tw. (289)
43 exp Libido/ (525)
44 psychosexual$.tw. (2953)
45 or/31-44 (135878)
46 6 and 30 and 45 (233)
47 random.tw. (34389)
48 control.tw. (268123)
49 double-blind.tw. (15580)
50 clinical trials/ (5750)
51 placebo/ (3108)
52 exp Treatment/ (506819)
53 or/47-52 (766677)
54 46 and 53 (169)

Database: PsycINFO <1806 to December Week 1 2012>
Search Strategy (Dec-12-2012):
--------------------------------------------------------------------------------
1 exp menopause/ (2724)
2 climacter$.tw. (426)
3 menopaus$.tw. (3437)
4 perimenopaus$.tw. (449)
5 post?menopaus$.tw. (1796)
6 or/1-5 (4862)
7 exp Hormone Therapy/ or exp oestrogens/ (5878)
8 HRT.tw. (466)
9 exp Estradiol/ (2267)
10 (oestrogen$ or oestrogen$).tw. (6083)
11 (estradiol$ or oestradiol$).tw. (4598)
12 CEE.tw. (104)
13 (estrone$ or estriol$).tw. (180)
14 Dienestrol.tw. (0)
15 exp Estradiol/ (2267)
16 (estriol or estetrol).tw. (35)
17 premarin.tw. (34)
18 prempro.tw. (10)
19 selective oestrogen receptor modulator$.tw. (86)
20 (clomiphene or clomid).tw. (36)
21 (clomifene or clomifert).tw. (0)
22 raloxifene.tw. (84)
23 tamoxifen.tw. (317)
24 toremifene.tw. (3)
25 (SERMS or SERM).tw. (63)
26 serophene.tw. (0)
27 bazedoxifene.tw. (5)
28 menerba.tw. (0)
29 MF?101.tw. (0)
30 tibolone.tw. (31)
31 or/7-30 (10002)
32 exp sexual satisfaction/ or exp sexuality/ (10706)
33 sexual$.tw. (120764)
34 dyspareunia.tw. (410)
35 (vagina$ adj2 atroph$).tw. (26)
36 (vagina$ adj2 dry$).tw. (98)
37 orgasm$.tw. (2319)
38 libido.tw. (2355)
39 orgasmic.tw. (667)
40 frigid$.tw. (416)
41 arousal.tw. (21687)
42 HSDD.tw. (130)
43 (hypoactive adj2 desire).tw. (318)
44 exp Libido/ (533)
45 psychosexual$.tw. (3021)
46 or/32-45 (142767)
47 6 and 31 and 46 (254)
48 random.tw. (36640)
49 control.tw. (284926)
50 double-blind.tw. (16487)
51 clinical trials/ (6446)
52 placebo/ (3345)
53 exp Treatment/ (532822)
54 or/48-53 (809167)
55 47 and 54 (185)
56 limit 55 to yr="2012 -Current" (10)

PSYCInfo (Dec-12-2012): Total combining the searches and excluding duplicates = 180 records

Appendix 8. ClinicalTrials.gov search strategy

Search strategy (Dec-12-2012)

(menopause) AND (sexual)

ClinicalTrials.gov (Dec-12-2012) = 121 records

Appendix 9. Controlled-Trials search strategy

Search strategy (Dec-12-2012)

(menopaus*) AND (sexual)

Controlled-Trials (Dec-12-2012) = 8 records

Appendix 10. WHO International Clinical Trials Registry Platform search strategy

Search strategy (Dec-12-2012)

(menopause) AND (sexual)

WHO International Trials Registry Platform (Dec-12-2012) = 44 records

Appendix 11. ISI Web of Knowledge search strategy

Search strategy (Dec-12-2012)

(menopaus$) AND (sexual) AND ((trial) OR (random$))

ISI Web of Knowledge (Dec-12-2012) = 256 records

Appendix 12. OpenGrey search strategy

Search strategy (Dec-12-2012)

(menopause) AND (sexual)

OpenGrey (Dec-12-2012) = 0 records

Appendix 13. DARE search strategy

Search strategy (Dec-12-2012)

(menopaus$) AND (sexual)

DARE (Dec-12-2012) = 63 records

Contributions of authors

Drafting the protocol: Carolina O Nastri, Lucia AS Lara, and Wellington P Martins. Ana Carolina JS Rosa e Silva, Jaqueline BP Figueiredo, and Rui A Ferriani helped

Development of search strategy: Lucia AS Lara, and Wellington P Martins

Search for trials: Carolina O Nastri, and Wellington P Martins

Obtaining copies of trials: Jaqueline BP Figueiredo, Lucia AS Lara, and Wellington P Martins

Contact authors from trials: Carolina O Nastri, and Lucia AS Lara

Selection of which trials to include: Carolina O Nastri, Jaqueline BP Figueiredo, Lucia AS Lara, and Wellington P Martins

Extraction of data from trials: Carolina O Nastri, Lucia AS Lara, and Wellington P Martins

Assessment of risk of bias in included studies: Carolina O Nastri, and Wellington P Martins

Entry of data into RevMan: Carolina O Nastri, and Wellington P Martins

Drafting the review: Carolina O Nastri, and Wellington P Martins. Ana Carolina JS Rosa e Silva, Jaqueline BP Figueiredo, Lucia AS Lara, Rui A Ferriani helped

Declarations of interest

All authors declare no relationships or activities that could appear to have influenced the submitted work.

Sources of support

Internal sources

  • Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Brazil.

    Authors' salary

External sources

  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.

    Scholarship

  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.

    Scholarship

  • Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA), Brazil.

    Funded the purchase of articles

Differences between protocol and review

The present review includes several changes from the planned protocol.

  • Primary outcome: we expanded the evaluation of sexual function by also assessing its domains. We kept the composite score as the primary outcome to assess the global effect on sexual function. As secondary outcomes we evaluated the individual domains of sexual function.

  • Secondary outcomes: we previously planned to evaluate the genitourinary system, quality of life, depression, and body mass index. However, evidence for the planned secondary outcomes would just be a subset of the overall body of evidence because the present review only includes the studies reporting sexual function. In this way we performed only the evaluation of sexual function.

  • Structure of data synthesis: we did not plan stratification of data, however the results were confusing and we therefore stratified by participant characteristics.

  • We performed sensitivity analysis only by excluding studies with high risk of bias. We were not able to perform sensitivity analysis using alternative imputation strategies and the random-effects model, as initially planned.

  • We added two summary of findings tables as they are important tools for presentation of results.

  • There were not enough studies to perform the planned subgroup analyses by the type of menopause and sexual symptom status at baseline.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Czarnecka 2000

MethodsRCT, Single-centre, Poland
Participants

Inclusion: postmenopausal women (amenorrhoea >6 months and estradiol  < 50 pg/ml +  FSH 21U/L with mild and moderate essential hypertension

Exclusion criteria are unclear

Interventions

Intervention: 17-β-estradiol and norethisterone acetate (Estracomb Tts, Norvatis).

Control: no treatment

Outcomes

Subjective Symptoms Assessment Profile (SSA-P)

Final scores

Notes

Age: intervention (49.4±5.8 years), control (52.0±6.4 years)

BMI: intervention (27.4±4.7kg/m²), control (25.0±3.6kg/m²)

Follow up: 12 weeks

Do not report conflict of interest

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described in detail
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described in details
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up
Selective reporting (reporting bias)Low riskNot suspected
Other biasHigh riskThe groups differed in baseline characteristics. We observed relevant differences in the baseline sexual function (74.8±24.7 versus 66.0±22.4, treatment and control respectively), quality of life (12.6±2.3 vs. 11.4±2.5), and hot flashes (74.8±24.7 versus 66.0±22.4) scores. Authors did not present the results as change from baseline.

Dayal 2005

MethodsRCT, Single-centre, USA
Participants

Inclusion:menopausal women, aged 44–70 years, with a history of no menstrual cycle for at least 1 year or at least 6 months of amenorrhoea with a documented FSH level>40 mIU/ml. These subjects had no exposure to hormone therapy (specifically estrogen therapy (ET) or DHEA supplementation) for at least 60 days prior to enrolment, had a normal Pap smear and mammogram within the last year, and had normal liver transaminase levels, renal function, total cholesterol, and triglyceride (TG) levels.

Exclusion: any contraindication to ET (known or suspected cancer of the breast, endometrial hyperplasia/carcinoma, undiagnosed vaginal bleeding, active thromboembolic disorders, or history of cerebrovascular disease, coronary artery disease [CAD], or myocardial infarction (MI)), a current diagnosis of diabetes mellitus, uncontrolled hypertension, abnormal liver or renal function, major psychiatric disorder (major depression, bipolar disorder, psychotic disorder, drug addiction), or any contraindication to the use of MRI (pacemaker, magnetic aneurysm clip, severe claustrophobia).

Interventions

Intervention: conjugated equine estrogen (CEE) 0.625 mg daily

Control: placebo

(Only the arms without DHEA were included in this review)

OutcomesWomen’s Health Questionnaire - WHQ (bigger values to correspond to better conditions)
Notes

Two arms with use of DHEA were excluded from analysis

Follow up: 3 months

Mean age = 56.6; ranging from 44 and 77

Corresponding author did not respond our contact via email

Article presents the differences from baseline (in %) without SD or P values

For sexual function, depression, and quality of life, we determined the final value based in the (%) difference and considered the final SD to be equal to the baseline SD

This study was supported by an unrestricted grant from the Berlex Foundation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised program generating random numbers
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss after allocation
Selective reporting (reporting bias)Low riskNot suspected
Other biasHigh riskThere was a relevant difference in baseline values between intervention and control groups for sexual function (4.33±1.53 vs. 5.00±2.12, intervention and control respectively), and quality of life (15.25±3.40 vs. 13.00±4.90). Although authors provided relative change from baseline (in %) we could not use these data because we were not able to properly estimate SDs.

Estonian blind trial

Methods

RCT, Parallel-group, 3 clinical centres in Estonia

777 were randomised

Between January 1999 and December 2001

Participants

Inclusion: aged 50–64 years, postmenopausal

Exclusion: none

Interventions

Intervention: CEE 0.625 mg/day + MPA 5.0 mg/day

Control: matching placebo

Outcomes

WHQ

Percentage of women satisfied and that lost interest in sex

Notes

Follow-up: 1 year for the included evaluation (3.6 years total)

Trial register: ISRCTN35338757

Potentially eligible women were randomised into four trial groups resulting in two substudies

1) blind hormone therapy group versus blind placebo group (Estonian blind trial)

2) non-blind hormone therapy group versus non-treatment group (Estonian non-blind trial).

1001 women were recruited into the non-blind subtrial and 777 in the blind subtrial.

The Estonian Postmenopausal Hormone Therapy trial was originally planned to be a part of the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM)

The study was financially supported by grants from the Academy of Finland (grants 69838, 201490, 115088), STAKES (National Research and Development Centre for Welfare and Health), Finland, and the Estonian Ministry of Education and Research
Drugs were donated by Wyeth Ayerst Company via the Women's International Study of Long Duration Oestrogen After Menopause (WISDOM) in the United Kingdom

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation in permuted blocks, each of a size 16 and each block of the three clinics separately, at the National Research and Development Centre for Welfare and Health in Finland
Allocation concealment (selection bias)Low riskThe treatment allocation was enclosed in a non-transparent sealed envelope and sent to trial clinics
Blinding of participants and personnel (performance bias)
All outcomes
Low riskUse of matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Balanced dropouts

Blind trial - intervention 98/404; control 101/372

Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Estonian non-blind trial

Methods

RCT, Parallel-group, 3 clinical centres in Estonia

1001 were randomised

Between January 1999 and December 2001

Participants

Inclusion: aged 50–64 years, postmenopausal

Exclusion: none

Potentially eligible women were randomised into four trial groups: 1) blind hormone therapy group, 2) blind placebo group, 3) non-blind hormone therapy group, 4) non-treatment group

Interventions

Intervention: EC 0.625 mg + MPA 5.0 mg daily (2 groups: open and blind)

Control: matching placebo in the blind arm and no intervention in the open arm

Outcomes

WHQ

Percentage of women satisfied and that lost interest in sex

Notes

Follow-up: 1 year for the included evaluation (3.6 years total)

Trial register: ISRCTN35338757

Potentially eligible women were randomised into four trial groups resulting in two substudies

1) blind hormone therapy group vs. blind placebo group (Estonian blind trial)

2) non-blind hormone therapy group vs. non-treatment group (Estonian non-blind trial).

1001 women were recruited into the non-blind sub-trial and 777 in the blind subtrial.

The Estonian Postmenopausal Hormone Therapy trial was originally planned to be a part of the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM)

The study was financially supported by grants from the Academy of Finland (grants 69838, 201490, 115088), STAKES (National Research and Development Centre for Welfare and Health), Finland, and the Estonian Ministry of Education and Research
Drugs were donated by Wyeth Ayerst Company via the Women's International Study of Long Duration Oestrogen After Menopause (WISDOM) in the United Kingdom

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation in permuted blocks, each of a size 16 and each block of the three clinics separately, at the National Research and Development Centre for Welfare and Health in Finland
Allocation concealment (selection bias)Low riskThe treatment allocation was enclosed in a non-transparent sealed envelope and sent to trial clinics
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study compared with no treatment
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Balanced dropouts

Blind trial - intervention 98/404; control 101/372

Open trial - intervention 130/494; control 125/507

Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Fonseca 2007

Methods

Crossover, single-centre, Brazil

March 2001 to February 2003

Participants

Inclusion: postmenopausal women between 42–61 years; with uterus and no contraindications to HT

Exclusion: systemic, psychiatric or endocrine disease; smoking >10 cigarettes/day; use of any medication that could interfere with climacteric symptoms or with their sexuality

Interventions

Intervention: 17β-estradiol 2mg with norethisterone acetate 1mg (Cliane, Schering)

Control: matching placebo

Outcomes

Golombok-Rust Inventory of Sexual Satisfaction (GRISS)

Data not suitable for meta-analysis

Notes

Follow-up: 6 months each part of the crossover trial

No available data to report

Financial support for this study from Schering do Brasil Quimica e Farmaceutica Ltda

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, do not report details
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up
Selective reporting (reporting bias)High riskThe authors do not report the results obtained, only in which domains they found statistically significant differences
Other biasLow riskNot suspected

Gambacciani 2011

MethodsRCT, parallel-group, single-centre, Italy
Participants

Inclusion: amenorrhoea for at least 12 months before treatment, plasma gonadotropin and estradiol levels in the postmenopausal range, office blood pressures in the normal range. Vasomotor symptoms.

Exclusion: age > 60 years; previous intolerance to HRT;absence of vasomotor symptoms; history of hypertension and/or treatment with antihypertensive drugs within the last 3 months; diabetes or any other metabolic disorder including dyslipidaemia, history of CVD, venous thromboembolic disease or haemostatic disorder predisposing to thromboembolic complications; abnormal uterine bleeding; any unstable medical condition; or history of alcoholism, drug abuse, psychosis, or other emotional or intellectual problems likely to invalidate informed consent or to limit compliance with protocol requirements.

Interventions

Intervention: Estradiol 1 mg + drosperinone 2 mg (Angeliq, Bayer Schering Pharma AG, Berlin, Germany)

Control: calcium (1g/day)

Outcomes

Women’s Health Questionnaire (WHQ)

Data not suitable for meta-analysis

Notes

Follow-up: 3 months

70 women evaluated; 35 allocated

Data from WHQ is not given in numbers. It is just presented as a graphic

No third-party sources provided financial support for the study

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSeventy consecutive eligible women were randomised to treatment using a randomisation list (yes – no)
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts: 3/23 in the control group; 0/32 in the intervention group
Selective reporting (reporting bias)High riskAlthough sexual function was measured by a questionnaire, the numeric results are not given. The authors just state that the scores have improved
Other biasLow riskNot suspected

Gast 2009

Methods

RCT, double-blind, placebo-controlled, multi-centre (25 sites), Brazil and USA

From May 2001 to April 2004

Participants

Inclusion: Women were aged 45 to 65 years at enrolment, had a sexual partner or partners, and had an intact uterus. Women must have completed their last natural menstrual cycle at least 12 months before screening (or 6m and high FSH). Maximum of 10% superficial cells on the Vaginal Maturation Index.Endometrial double-wall thickness was not to exceed 5 mm by transvaginal ultrasound of the uterus.

Exclusion:history or presence of neoplasia or endometrial hyperplasia. Women were not included if they had a history of thrombophlebitis, thrombosis, or thromboembolic disorders related to oestrogen use; cerebrovascular accident, stroke, or transient ischemic attack; neuro-ocular disorders; myocardial infarction or ischemic heart disease; chronic renal or hepatic disease; or a known hypersensitivity to estrogens, progestins, or other ingredients of the hormonal preparations used in the study. Women who had used any oral or vaginal estrogen-, progestin-, or androgen-containing medications within 8 weeks of screening or any transdermal hormone therapy within 4 weeks before screening were excluded, as were those with sexual dysfunctions other than dyspareunia (eg, prior diagnosis of primary anorgasmia or sexual arousal dysfunction).

Interventions

Intervention: conjugated estrogen 0.45 mg + 1.5 mg MPA for six 28-day cycles along with initial vaginal priming with 1 g CE (PREMARIN) cream (0.625 mg CE/g) intravaginally for the first 6 weeks.

Control: matching placebo

Outcomes

McCoy Female Sexuality Questionnaire (MFSQ)

Brief Index of Sexual Functioning-Women (BISF-W)

Data not suitable for meta-analysis.

Notes

Report the results of the questionnaire in figures, no numeric data presented

This study was funded by Wyeth, Collegeville, PA. PREMARIN and PREMARIN Vaginal Cream are manufactured and marketed by Wyeth. Alberta Vieweg and Michael Gast are current or former employees of Wyeth

Follow-up: 3 months

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod not reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskClaim to be double-blind, no details described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts: 41/144 in the intervention group; 29/112 in the control group
Selective reporting (reporting bias)High riskAlthough sexual function is evaluated with a validated questionnaire the scores are not reported, the results are given in graphics
Other biasLow riskNone

Haines 2009

MethodsRCT, Multi-centre: Thailand, the Philippines, Singapore, Hong Kong
and Malaysia
Participants

Inclusion: aged between 40 and 65 years, had undergone natural menopause (12 months’ amenorrhea or 6 months’ amenorrhea with FSH > 40 mIU/ml) or bilateral oophorectomy (6 weeks postsurgery) and had at least 24 hot flashes (of any severity) within a 7- day screening period.

Exclusion: recently used oestrogen-containing products, an abnormal cervical smear test, endometrial thickness of 5.0 mm, any condition that could interfere with study medication or interpretation of results, concomitant use of inducers or inhibitors of CYP3A4 or drugs effective in treating hot flashes, received anticoagulant treatment for the past 6 months, or known severe dyslipoproteinemia.

Interventions

Intervention: transdermal patch delivering micro-dose E2 (0.014 mg/day)

Control: placebo

Outcomes

Menopause Quality of Life (MENQoL) questionnaire

Change from baseline scores

Notes

Follow-up: 12 weeks

Age: intervention (52.6±3.99 years); control (52.2±4.73 years)

The following outcomes could not be pooled because of lack of details:

BMI: intervention (24.0±3.69 kg/m²); control (24.0±3.70kg/m²).

Hot flashes: reduction in mean weekly number of hot flashes - data not described in details, could not be pooled

Involuntary urination: intervention (28.6%); control (18.7%)

Urge-incontinence: intervention (10.4%); control (6.7%)

Vaginal dryness: intervention (37.7%); control (46.7%)

This study was supported financially by Bayer Schering Pharma AG. Editorial support was provided by Parexel MMS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization was by a centrally provided computer-generated list.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
High riskAlthough it is not clear how many women were assessed for sexual function; we assumed it was only those how completed the study. Those participants had > 75% overall study drug compliance; thus not respecting the ITT principle.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasLow riskNot suspected.

Huang 2008

MethodsRCT, Multi-centre, 9 clinical centres in USA - ULTRA trial
Participants

Inclusion: aged 60 to 80 years, with an intact uterus but who had not had a menstrual period in at least 5 years, normal bone mineral density for age (z-score 2.0 or greater at the lumbar spine) and could not have used oestrogen or progestin in the 3 previous months.

Exclusion: unexplained uterine bleeding, endometrial hyperplasia, abnormal mammogram suggestive of breast cancer, cardiovascular disease, venous thromboembolism, uncontrolled
hypertension, uncontrolled thyroid disease, liver disease, fasting triglyceride level higher than 300 mg/dL, or fasting glucose level higher than 180 mg/dL.

Interventions

Intervention: 3.25 cm² patch releasing 0.014 mg of estradiol per day

Control: matching placebo

Outcomes

Medical Outcomes Study (MOS) Sexual Problems Index

Final scores, data sent by the authors

Notes

Follow up: 24 months

Age: intervention = 66.8 (±5.1); control = 66.7 (±4.8) years

This research was supported in part by a grant from Berlex Laboratories Inc and manufacturer of the estradiol patch used; and by Grant KLZRR024130 from the National Center for Research Resource, a component of the NIH

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomly permuted blocks of size 4
Allocation concealment (selection bias)Low riskParticipants, investigators and outcome assessors were blinded to treatment assignment
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants, investigators and outcome assessors were blinded to treatment assignment, and no unblinding occurred during the trial
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskParticipants, investigators and outcome assessors were blinded to treatment assignment, and no unblinding occurred during the trial
Incomplete outcome data (attrition bias)
All outcomes
High riskSexual function evaluated only in women who were sexually active during in the previous 4 weeks: sexual function was evaluated on 186/208 participants in the intervention group, and on 180/209 in the control group
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Hudita 2003

MethodsRCT, parallel-group, single-centre, Romania
Participants

Inclusion: healthywomen aged between 40
and 65 years, non-obese,postmenopausal women, with an intact uterus

Exclusion: (1) previous deep thrombophlebitis or cerebral apoplexia; (2) mammary or gynaecological neoplasia; (3) uncontrolled diabetes; (4) abnormal mammography; (5) abnormal values of C-reactive and S-coagulative protein; (6) endometrial thickness > 4 mm or an abnormal Papanicolaou smear; (7) abnormal bleeding of undetermined origin; (8) history of hepatic or renal diseases; (9) use of estrogenic, progestinic or androgenic drugs in the 8 weeks preceding enrolment into the study; (10) use of IUD in the preceding 3 months; (11) use of medications known to affect vasomotor system in the 2 weeks prior to enrolment; (12) known hypersensitivity to study drugs; (13) glucose intolerance (blood glucose > 125 mg/dl), hypercholesterolaemia (total cholesterol > 300 mg/dl) or hypertriglyceridaemia (triglycerides > 300 mg/dl), hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 90 mm Hg).

Interventions

Intervention 1: tibolone 1.25 mg

Interventions 2: tibolone 2.5 mg

Control > matching placebo

Outcomes

McCoy sex scale questionnaire

Data not suitable for meta-analysis

Notes

Follow-up: 24 weeks

Tibolone 1.25 and 2.50 mg tablets were supplied by Libbs as LIBIAM

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described in detail
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskUsing of matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk42/162 women dropout after inclusion, groups not described
Selective reporting (reporting bias)High riskAlthough the authors applied a validated tool to asses sexual function, they do not report the scores. It is only reported the proportion of women with acceptable quality of sexual life
Other biasLow riskNot reported

Laan 2001

MethodsCrossover trial, single-centre, the Netherlands
Participants

Inclusion: postmenopausal women with intact uteri and ovaries, aged < 65 years with a body mass index of 18–29 kg/m², last menstrual period ≥ 12 months prior to the study.

Exclusion: women using medication known to influence sexual desire and/or response or who had used hormone replacement therapy in the 3 months prior to enrolment.

Interventions

Intervention: Tibolone 2.5mg/day for 3 months

Control: Placebo

Outcomes

Greene Climacteric Scale

Change from baseline scores of the first phase of the cross-over; provided by the author

Notes

Only the results concerning to the first phase (before crossover) were included: these data were obtained by correspondence with the authors.

This work was supported by NV Organon

Follow-up: 3 months

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
High riskData was available from only 37 women (17 in the intervention group and 20 in the control group): 44 women were randomly allocated
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

LIBERATE

Methods

RCT, Multi-centre, 245 sites from 31 countries. Sexual function was examined only in women from 8 countries (Austria, Belgium, Germany, Spain, France, United Kingdom, Italy, The Netherlands)

From June 2002 to July 2007

ParticipantsInclusion: women with climacteric symptoms were eligible if they had been surgically treated within the previous five years for histologically confirmed breast cancer. Participants had to be postmenopausal and <75 years.
Exclusion: non-hysterectomised women with endometrial abnormalities.
Interventions

Intervention: tibolone 2.5 mg daily, orally
Control: matching placebo

About 75% of participants in both groups were using either tamoxifen, aromatase inhibitor, or GnRH analogues

Outcomes

Women s Health Questionnaire (WHQ).

Change from baseline scores.
WHQ 'sexual' and 'depression': the smaller the values the better condition.

Notes

Follow up: 26 weeks
Mean age: 52.7 (±7.3) years
For sexual function and vasomotor domain/hot flashes, SD was calculated from P values

Depression could not be included because p values was lacking

Vaginal dryness could not be included because only stratified data was reported (no difference observed on any strata)

Funding: Schering-Plough (formerly NV Organon, Oss, Netherlands). The sponsor conducted the trial and collected the data. An Advisory Board had overall scientific responsibility for trial design and protocol, and advised the sponsor as to the conduct of the trial. The corresponding author had full access to all data relevant for the article publication and all authors were involved in its submission.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentralised interactive voice response system, stratified by centre, with a block size of four
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants, investigators, sponsor personnel, and outcome assessors were blinded to treatment assignment
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded
Incomplete outcome data (attrition bias)
All outcomes
High riskSexual function was evaluated in only 438/1575 women in the treatment group, and on 445/1558 in the placebo group
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Maki 2007

MethodsRCT, Multi-centre, 19 medical centres, USA
Participants

Inclusion: healthy postmenopausal women with intact uteri and whose last natural menstrual cycle had been completed ≥12 and ≤36 months prior to screening. Participants were also enrolled if their last natural menstrual cycle occurred ≥6 but ≤12 months before screening, provided their serum FSH > the lower limit of normal for postmenopausal women at the local laboratory. Participants spoke English as their primary language and were required to demonstrate verbal knowledge with a total score 10 on the Primary Mental Abilities Vocabulary Test. Women were required to have reported at least one cognitive complaint on the Self-Reported Cognitive Function Questionnaire, a brief subjective survey of memory and concentration, and to be free of neurologic, systemic, or psychiatric disease that would influence cognition.

Exclusion: known or suspected oestrogen-dependent neoplasia, endometrial hyperplasia, thrombophlebitis, thrombosis, thromboembolic disorders, myocardial infarction, ischemic heart disease, cerebrovascular accident, stroke, TIA, or hypersensitivity to estrogens or progestins were not included in the study. Other exclusion criteria included recent (≤8 weeks prior to screening) use of estrogen or progestin, excessive smoking (≥0.5 pack of cigarettes/day), a history of alcohol abuse (based on a Michigan Alcohol Screening Test score of ≥5), evidence of cognitive impairment on the Mini-Mental State Examination (total score <24), or use of any medication that might influence CNS function.

Interventions

Wash out: 8 weeks

Intervention: conjugated equine estrogen 0.625mg + medroxyprogesterone acetate 2.5 mg daily

Control: matching placebo

Outcomes

Greene Climacteric Scale

Change from baseline

Notes

Standard deviation calculated from the P values of the differences between the groups

MFSQ–level of interest in sex was considered as sexual function

Mean age: intervention (51.9±3.6 years); control (52.4±3.3 years)

Weight: intervention (70±16.1 kg); control (67.8±16.4 kg)

Follow up: 4 months

This study was funded by Wyeth, Collegeville, PA. Prempro is manufactured and marketed by Wyeth. Dr. Maki has received grants (in excess of $10,000) and honoraria from Wyeth. Dr. Yaffe has received grants (in excess of $10,000) and honoraria from Wyeth. Dr. Gast, A.J. Vieweg, and S.W. Burriss are current or former employees of Wyeth. Dr. Gast has ownership interest in the company. Dr. Yaffe received compensation through the University of California for her role as a consultant throughout the trial.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPermuted block design
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts: intervention (11), control (11)
Selective reporting (reporting bias)High riskAlthough in the methods section the authors state that sexual function had been assessed with the Greene Climateric Scale, the Utian Quality of life outcomes, and MFSQ; only sexual function results from MFSQ were reported. Partial reports - only a total score and some domains (not sexual function) - of the first two scales were reported.
Other biasUnclear riskStatistical analyses were performed by Wyeth Research, whose conflict of interest was stated in the article

Mameri Filho 2005

MethodsRCT, Single-Centre, Brazil
ParticipantsThe diagnosis of menopause was based on clinical data, ie, amenorrhoea for at least 12 months confirmed by elevated gonadotropin, follicle stimulating hormone (FSH above 40 mIU / mL). Included were patients with vasomotor symptoms or moderate or marked Kupperman index greater than 39 points, with complaints of sexual dysfunction. But women with absolute contraindication to hormone replacement, body mass index (BMI) greater than 30 (obese) or Ferriman, Gallwey and Lorenzo greater than eight (hirsute) were excluded. In addition, patients who were not on hormone therapy prior and did not use herbal or diet high in soy-based foods (use prior six months) were selected for this study.
Interventions

Control = placebo

Intervention 1 = conjugated equine estrogens (CEE) (0.625 mg per day)

Arm not included: CEE (0.625 mg per day) associated with methyltestosterone (2.5 mg per day)

Outcomes

Women Health Questionnaire (WHQ): composite scores

Modified Sexuality Questionnaire (Mc Coy): sexual domains

Final scores

Notes

The group using intervention 2 was not included in this review

Autors provided baseline and final values for WHQ without SD. We estimate the SD from P value

The article does not report any conflict of interest disclosure

The drugs were donated by the university hospital

Follow-up: 3 months

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer based
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskUse of placebo matching pills
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Modugno 2003

Methods

RCT, Multi-centre, USA and Canada

This trial is a subset of older postmenopausal women participating in the Multiple Outcomes of Raloxifene Evaluation study, a multicenter, randomised, double-blind, placebo-controlled trial. However, only English-speaking participants at select study sites in the United States and Canada were administered the sexual function questionnaire (n = 1218).

ParticipantsInclusion: women aged 31–80 years, postmenopausal for at least 2 years, meet the World Health Organization criteria for having osteoporosis, English as a native language, completing the sexual function questionnaire at both the baseline and the 36-month follow-up visits
Interventions

Intervention 1: raloxifene 60 mg/d

Intervention 2: raloxifene 120 mg/d

Control: matching placebo

Outcomes

McCoy’s Sex Scale Questionnaire

Percentage of women that improved scores

Notes

Follow-up: 36 months

This work was supported by Eli Lilly and Company, maker of raloxifene. The company provided salary support to SE and research support to JAC, who is also a member of the speaker’s bureau of Eli Lilly and Company

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskBlock randomisation by clinical site
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
High risk7705 women were randomised in 25 countries, data of women from only 2 countries were included in this analysis (1218). Women with unsatisfactory questionnaire answers were excluded from analysis (275)
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Morais-Socorro 2012

MethodsRCT, Single-centre, Brazil
Participants

Inclusion: age between 40 and 55 years; menstrual irregularity during the previous 6 months but fewer than 12 months of amenorrhoea; the presence of a uterus without anomalies in an initial vaginal ultrasonography evaluation and an endometrial thickness measurement ≤ 10 mm; plasma FSH level ≥ 30 mUI/ml; total cholesterol < 250 mg/dl; triglycerides ≤ 200 mg/dl; glycaemia ≤ 100 mg/dl; a Blatt-Kupperman Menopausal Index score ≥ 14; mammography with BI-RADS = 1 or 2.

Exclusion criteria: current smoker; use of any hormonal, psychotropic or other medications that could interfere with the lipidglycaemic profile within 90 days of trial; history of clinical hepatic or kidney disease or diabetes mellitus; cerebrovascular, thyroid, cardiovascular or thromboembolic disorders; any neoplastic disease; hypertensive disorder (systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 105 mmHg); body mass index (BMI) > 30 kg/m²; and mammography with BI-RADS = 3 or 4.

Interventions

Intervention: Tibolone 2.5mg/day (ReduClim®, Farmoquímica, Brazil)

Control: Placebo (identical capsules containing lactose)

Outcomes

Greene Climacteric Scale

Final scores

Notes

Age: intervention (48.0±3.6 years), control (49.0±3.6 years)

BMI: intervention (26.2±0.6kg/m²), control (26.0±0.6kg/m²)

Follow up: 12 weeks

Lost of follow-up: 3/30 in the intervention group; 5/35 in the control group

ReduClin® 2.5 mg was donated by the laboratory Farmoquímica, Brazil

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskUse of placebo matching pills
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskBalanced dropouts (3/30 in the intervention group; 5/35 in the control group)
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Nathorst-Böös 1993

MethodsRCT, Parallel-group, 15 centres in Sweden
Participants

Inclusion: Postmenopausal women between 45 and 65 years of age requiring hormonal replacement therapy (HRT) for climacteric symptoms

Exclusion: malignant tumors, surgical menopause, cardiovascular or respiratory diseases, diabetes, psychiatric illness, endometriosis or vaginal
bleeding

Interventions

Intervention: estradiol therapy (Estraderm 50 mcg/24h)

Control: matching placebo

Outcomes

McCoy's Sex Scale Questionnaire

WHQ

Change form baseline scores

Notes

Follow-up: 12 weeks

No conflict of interests disclosure

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described in detail
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts: 3/242; groups not specified
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Nielsen 2006

MethodsRCT, Multi-centre, 2 centres, Denmark
Participants

Inclusion: 40–65 years of age at baseline,were randomised if they were less than 5 years past menopause at study entry. Menopause was defined as amenorrhoea > 12 months or > 6 months and a concomitant serum level of estradiol <0.16 nmol/l and a FSH>42 IU/l. All women who had undergone hysterectomy had menopause confirmed by measurement of serum estradiol and FSH at least 2 months before study entry. Women who had undergone surgical menopause (bilateral ovariectomy) could be included, provided the operation was performed at least 6 weeks before study entry. Women who previously had received estrogen replacement therapy, had to go through a 6-month wash-out period before randomisation. To be in good general health with no clinical or laboratory evidence of systemic disease or conditions with known influence on bone metabolism.Women had to be osteopenic (BMD T score <−1) and not to complain of severe climacteric symptoms.

Exclusions: subjects with nasal disease incompatible with nasal therapy such as frequent epistaxis, chronic rhinitis or sinusitis, severe allergic rhinitis, or frequent nasal treatment; subjects with contraindications for the use of HRT.

Interventions

Wash out: 6 months

Intervention: intranasal sprays estrogen (Aerodiol, France) 150mcg/day (N=114) or 300mcg/day . Women with an intact uterus also received 200 mg of micronized progestogen (Effik, Spain), combined with the nasal spray for the last 14 days of each 28-day cycle

Control: matching placebo (N=118)

Outcomes

Women’s Health Questionnaire (WHQ)

Change from baseline scores

Notes

Age: mean 53 years

BMI: mean 25.2 kg/m²

6.3% of subjects did not have uterus and therefore used only estrogen

Follow up: 2 years

The article does not report any conflict of interest disclosure

Included women up to five years of amenorrhoea

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was performed due to the order of inclusion. Thus, the first patient received the lowest numbered therapeutic unit in the block of units supplied to the centre concerned
Allocation concealment (selection bias)Low riskThe treatment allocation lists were drawn up and encoded by Servier Laboratoires
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
High riskOnly 268 women from the 335 allocated completed the evaluation questionnaires
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Osmanagaoglu 2006

MethodsRCT, Single-centre, Turkey
Participants

Inclusion: postmenopausal women (amenorrhoea> 1 year, confirmed by FSH ≥30 IU/l), had not undergone any gynaecological operation, and no absolute contraindication for HT.

Exclusion: aged >60 years, smokers, with diabetes, cancer, liver, renal or hematological, disease or other medical disorders or with a, history of sexual pain disorders or disharmony with their husbands.

Interventions

Intervention 1: tibolone 2.5 mg (Livial, Organon)

Intervention 2: estradiol valerate 2 mg + dienogest 2 mg (Climodien, Schering)

Control: no intervention

Outcomes

Rosen’s female sexual function index (FSFI)

Final scores.

Notes

Age: intervention 1 (50±1.87 years); intervention 2 (50±2.20years);control (51+1.94 years)

BMI: intervention 1 (26±0.84Kg/m²); intervention (25±0.97kg/m²); control (25±0.97kg/m²)

Follow up: 6 months

Report no conflict of interest and no external funding

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described in details
Allocation concealment (selection bias)Unclear riskNot described in details
Blinding of participants and personnel (performance bias)
All outcomes
High riskAlthough the authors claim to be single-blind, the studies limitations make it an open-label design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskFew and balanced dropouts
Selective reporting (reporting bias)Low riskNot suspected
Other biasHigh riskThe groups differed in baseline characteristics. The baseline sexual function score in tibolone (13.23±6.63) group was higher than in control group (12.60±3.58) and results were presented only as final score (not change from baseline)

Simon 2007

MethodsRCT, Multi-centre: 28 sites in USA and Canada
Participants

Inclusion: healthy women aged 18 years or older who had undergone natural (amenorrhoea for 12 months or more) or surgical menopause (bilateral oophorectomy with or without hysterectomy 6 months or more before screening), who had serum E2 less than 20 pg/mL, FSH > 40 mUImL, and BMI of 18 to 35 kg/m2.

Exclusion: history of oestrogen-dependent neoplasia; endometrial hyperplasia; active hepatic, gallbladder, renal, or endocrine disease other than controlled thyroid abnormalities; or if they were receiving concomitant medications that could potentially interfere with hot flush frequency, severity, or their assessment.

Interventions

Interventions 1: estradiol gel 0.87 g/d

Intervention 2: estradiol gel 1.7 g/d

Intervention 3: estradiol gel 2.6 g/d. This regiment was discontinued from further enrolment in the middle of the study because FDA advised so, in light of WHI results

Control: placebo

Outcomes

Utian Quality of Life

Change from baseline scores

Notes

Follow up: 12 weeks

Age: interventions 1 (54.4±6.3 years); intervention 2 (53.9±6.2 years); intervention 3 (55.3±8.5 years); control group (54.4±5.8 years); range = 28 to 74.

BMI: interventions 1 (26.4±4.0 kg/m²); intervention 2 (26.2±3.8 kg/m²); intervention 3 (26.6±3.6 kg/m²); control (25.8±3.8kg/m²)

As intervention 3 was was considered unsafe in the middle of the study, and is not used in clinical practice, we did not included this group in the analysis.

For sexual function only data of intervention 2 (1.7g/d) could be retrieved, data from intervention 1 (0.87 g/d) was omitted in the report.

For vaginal maturation and pain outcomes, data from groups 1 and 2 were combined.

This study was supported by a grant From BioSante Pharmaceuticals, Inc. (Lincolnshire, IL). Drs Bouchard, Simon, Waldbaum, and Utian have participated in clinical research as principal investigators for estradiol gel supported by BioSante Pharmaceuticals. They received payment under a research contract for the conduct of the study. Dr Simon was a consultant on this research and was paid by BioSante Pharmaceuticals. Ms Zborowski and Dr Snabes are paid independent consultants for BioSante Pharmaceuticals. Writing support was paid for by BioSante Pharmaceuticals.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation list
Allocation concealment (selection bias)Unclear riskStudy co-ordinators assigned treatment numbers to participants entering the 12-week double-blind treatment period
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants, investigators, and outcome assessors were blinded to treatment assignment, and no unblinding occurred during the trial
Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants, investigators, and outcome assessors were blinded to treatment assignment, and no unblinding occurred during the trial
Incomplete outcome data (attrition bias)
All outcomes
High riskThe assessment of sexual function is only reported for the higher doses - 1.7 g/d and 2.6g/d. The intervention group of 2.6g/d has discontinued from further enrolment in the middle of the study because of safety issues. The results for sexual function for the lower dose group 'E2 gel 0.87 g/day' is omitted.
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

SMART-3

MethodsRCT, Multi-centre, 66 sites in USA
Participants

Inclusion: healthy women with an intact uterus, aged 40 to 65 years, BMI ≤ 34.0 kg/m2, postmenopausal - defined as ≥ 12 months of spontaneous amenorrhoea or ≥ 6 months of spontaneous amenorrhoea with FSH > 40 mIU/mL. At screening, all women had to have a vaginal cytological smear showing 5% or less superficial cells and vaginal pH > 5 and had to identify on the symptom questionnaire at least one moderate to severe vulvar/vaginal symptom that was most bothersome to them - either vaginal dryness, irritation/itching, or pain with intercourse.

Exclusion: history of or clinically active medical disease such as endometrial hyperplasia; known or suspected ostrogen dependent neoplasia; undiagnosed vaginal bleeding; chronic renal or hepatic disease; thrombophlebitis, thrombosis, or thromboembolic disorders; cerebrovascular accident; neuro-ocular disorders; myocardial infarction or Ischaemic heart disease; gallbladder disease; malignancy or treatment for malignancy within the previous 5 years (with the exception of carcinoma of the skin); or history of breast cancer, melanoma, or any gynecologic cancer at any time. In addition, women with a screening TV US that could not measure endometrial thickness or indicating double-walled endometrial thickness > 4 mm, focal endometrial abnormality (other than fluid), complex ovarian cyst of any diameter, or simple ovarian cyst larger than 20 mm were excluded. Women who were hypersensitive to oestrogens, had an active endocrine disease, had a known alcohol or drug abuse, were heavy smokers (>15 cigarettes/d), had unresolved or abnormal cervical cytologic smear reports, had unresolved findings suspicious for malignancy on breast examination, and had uncontrolled hypertension were also excluded. All women should have had a normal endometrial biopsy at baseline.

Interventions

Wash out: 8 weeks

Intervention 1: bazedoxifene 20 mg + conjugated estrogens 0.45 mg daily

Intervention 2: bazedoxifene 20 mg + conjugated estrogens 0.625 mg

Intervention 3: bazedoxifene 20 mg

Control: placebo

Outcomes

Arizona Sexual Experiences (ASEX) scale: domains

Menopause-specific Quality of Life (MENQOL): composite

Final scores

Notes

Follow-up: 12 weeks

Mean age in each group: 56.4 (±4.7); 56.3 (±4.4); 56.4 (±4.5); 56.1 (±4.2)

BMI: Intervention 1 (25.4±3.8); 2 (25.2±3.8); 3 (25.3±3.9); and placebo (25.7±4.1)

Intervention groups 1 and 2 were merged for analysis

Wyeth Research, Collegeville, PA, sponsored the study and supported the medical writing assistance of Kathleen Ohleth PhD, and Chastity Bradley PhD.

G Bachmann has served as a Research Consultant-PI for Wyeth, Bayer, GlaxoSmithKline, Duramed, Novartis, Pfizer, Boehringer-Ingelheim, Johnson & Johnson, Roche, Boston Scientific, Novo Nordisk, Procter & Gamble, Merck, Xanodyne, Hormos, and Femme Pharma. J Bobula and S Mirkin are current employees of Wyeth. Dr Risa Kagan received research grants from Proctor & Gamble, Lilly, Boehringer Ingelheim, Depomed, and Wyeth. Dr Kagan is a consultant for Proctor & Gamble, Lilly, Medtronic, and Wyeth and is a speaker for GlaxoSmithKline, Roche, Novogyne, Novartis, and Lilly. Dr Williams received research grants from Wyeth, Xanodyne, and Organon and is also a speaker for Wyeth. Drs Mirkin and Pickar and Kaijie Pan are full-time employees of Wyeth Research, Collegeville, PA.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation / enrolment system generated by Wyeth Research
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded, matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIt is not clear how many women in fact answered the final questionnaires, and if the women who withdrew from treatment had the final evaluation
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Speroff 2003

MethodsRCT, Multi-centre, 35 sites in USA
Participants

Inclusion: postmenopausal woman, with or without a uterus, with at least seven moderate to severe hot flashes per day or an average of at least 56 moderate to severe vasomotor symptoms per week for the 2 weeks before randomisation. In addition, a woman with a uterus was required to have had amenorrhoea > 12 months before randomisation; if amenorrhoea <12 months and>6 months, she was also required to have a FSH>40 IU and an E2<20 pg/mL. A woman was also eligible if she had had a hysterectomy and bilateral oophorectomy performed more than 6 weeks before randomisation. Finally, a woman who had had a hysterectomy without bilateral oophorectomy was eligible if she had FSH>40IU and an E2<20pg/mL.

Exclusion: past or current thromboembolic disorder, or cerebrovascular accident; endometriosis; allergy or intolerance to previous ERT or HRT, including disabling breakthrough bleeding; past or current oestrogen-dependent neoplasia; abnormal uninvestigated vaginal bleeding within 6 months of randomisation; and known or suspected pregnancy. Previous treatment with any of the following was also reason for exclusion: estrogen, progestogen, androgen, or systemic corticosteroids by the oral route within 8 weeks of screening, by transdermal or buccal delivery within 4 weeks of screening, or by injection within 6 months of screening; hormone pellets or implants inserted within the previous 5 years or an implant removed within the past 3 months; unopposed ERT for 6 months or more in women with an intact uterus; or selective estrogen receptor modulators within 8 weeks of screening.

Interventions

Intervention: vaginal ring (Femring, United Kingdom) delivering estradiol 50mcg/day (N=113) or 100mcg/day (N=112). The ring contains E2 acetate in a reservoir system within the ring polymer, which is released steadily over 3 months

Control: matching placebo (N=108)

Outcomes

Greene Climacteric Scale

Change from baseline scores

Notes

Follow up: 13 weeks

Mean age: 51.7 (±7.2) years

BMI = 28 kg/m²

Standard deviation calculated from P values of the 'changes from baseline' values between the groups.

There were no differences on 'vaginal dryness' and 'urinary leakage' between groups, but there were not sufficient detail to pool data.

Not enough data to pool the outcome 'vaginal maturation', the authors claim it was significantly improved with the treatment.

This study was supported by Warner Chilcott, a division of Galen Holdings PLC, which has developed this product. Research support was provided for costs of the study. Authors have received speaking and consulting honoraria from the company. Dr Speroff owns stock in the company.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated schedule
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskFew and balanced dropouts
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

Strickler 2000

MethodsRCT, Multi-centre (USA), 32 sites
Participants

Inclusion: 47 to 60 years, 2 to 8 years after final menstrual period, serum E2<73 pmol/L (< 20 pg/mL), and lumbar spine bone mineral density between 2 and 2.5 SD the mean peak lumbar spine bone mineral density of premenopausal women.

Exclusion: intolerable menopausal symptoms requiring therapy; uterine bleeding of unknown cause; BMI <18 kg/m2 or >31 kg/m2, history of deep venous thromboembolic disease; use of corticosteroids, oestrogen, or progestin within 6 months before beginning the study; and chronic illness.

Interventions

Wash out: 6 months

Intervention 1: conjugated equine estrogens 0.625 mg/day

Intervention 2: raloxifene 60mg/day (N=97) or 150mg/day (N=100)

Control: placebo

Outcomes

Women’s Health Questionnaire

Change from baseline scores

Notes

Age: 54.7±3.6 years

BMI: intervention groups = (25.9±3.3kg/m2), (25.5±3.5kg/m2), (25.4±3.4kg/m2); control group = (25.5±3.5kg/m2)

Follow-up: 12 months

Standard deviation calculated from P values

Sponsored study: the research was supported by Eli Lilly and Company, maker of raloxifene. Doctors Shen, Wong, and Silfen are employees of and hold stock in Eli Lilly and Company. Doctors Strickler, Stovall, and Merritt have received honoraria for their services to Eli Lilly and Company.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were assigned randomly in blocks of four to one of four therapy groups
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Double-blind, placebo was similar to the drug

 

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat approach on data from women who had at least one follow-up visit after randomisation. Missing values were replaced with values from a previous post-randomization visit (last observation carried forward)
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNot suspected

WHI

MethodsRCT, Multi-centre (40 clinical centres), USA
Participants

Inclusion criteria: women aged 50 to 79 years with either an intact uterus or with hysterectomy more than 3 months earlier (with or without oophorectomy), and were likely to reside in the area for 3 years.

Exclusion criteria: medical condition predicted survival of less than 3 years or if there were diagnoses of previous breast cancer or melanoma, other cancer within the past 10 years (except non melanoma skin cancer), low hematocrit or platelet counts, or any condition that would interfere with acceptable adherence and retention (e.g., alcoholism or dementia). Failing the 4-weeks  compliance schedule of placebo pill taking.

Potential participants who were using postmenopausal hormones at the initial screening visit were required to undergo a 3-month “washout” period before enrolment. Women who reported moderate or severe menopausal symptoms during the washout period were discouraged from participating in the study but were not excluded.

Interventions

Intervention 1: conjugated equine estrogen 0.625 mg, (Premarin; Wyeth, St Davids, Pa) orally, daily

Intervention 2: conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg (Prempro, Wyeth)

Control: matching placebo pills

Outcomes

Modified Mini-Mental State Examination (QOL): sexual satisfaction (range from 1/worst to 4/best)

Change from baseline scores

Notes

Part of WHI study; included data from 1-year follow-up period

Intervention: 5310 women allocated

Control: 5429 women allocated

Funding: The WHI is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services, National Institutes of Health (NIH), Bethesda, MD, USA. Drs Shumaker and LaCroix report having served as paid consultants to Pfizer. Dr Shumaker reports having served as a paid lecturer for Wyeth–Ayerst and Pfizer. Drs Hays, Brunner, and Shumaker report having received grant support from Wyeth–Ayerst. Dr Shumaker reports having received grant support from Pfizer. Dr Brzyski reports having received grant support from Berlex.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised permuted block algorithm, stratified by clinical centre site and age group
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. All study medication bottles had a unique bottle number and bar code to allow for blinded dispensing
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
High riskAbout half of the allocated participants was evaluated for sexual function
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Wiklund 1993

MethodsRCT, Multi-centre, 15 sites, Sweden
Participants

Inclusion: postmenopausal women between 45 and 65 years old requiring hormone replacement therapy for climacteric symptoms, amenorrhoea > 6 months, no hormone replacement therapy within the last 6 months.

Exclusion: surgically induced menopause, previous or current estrogen-dependent tumours, other current malignant or life-threatening disease, severe metabolic, endocrine, or gastrointestinal disease, concomitant heart disease, insulin-treated diabetes, uncontrolled hypertension, endometriosis, undiagnosed vaginal bleeding, active skin disease, and unstable medical conditions such as rheumatoid arthritis or chronic obstructive lung disease. Women with psychiatric disorders and/or those receiving continuous tranquillizer or antidepressant therapy.

Interventions

Wash out: 6 months

Intervention: transdermal estradiol therapy, 50mcg/24 hours, changed twice a week

Control: matching placebo

Outcomes

Simplified McCoy Sex Scale ('sexual problems' was included as 'dyspareunia', because it refers to the question 'do you currently experience any pain during intercourse?')

Change from baseline

Notes

Follow up: 12 weeks

Mean age: intervention = 52.4 (±4.3) years; control = 52.9 (±4.0) years

Do not report conflict of interest

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed in details
Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts: intervention (5), control (10)
Selective reporting (reporting bias)Low riskNot suspected
Other biasUnclear riskThe article does not report any conflict of interest disclosure

WISDOM

MethodsRCT, Multi-centre (499 general practices): UK, Australia, New Zealand (WISDOM trial)
Participants

Inclusion: Postmenopausal women aged 50 to 69 years at randomisation were eligible for the trial. Postmenopausal was defined as no menstrual period in the last twelve months or having had a hysterectomy. Women who had started taking HRT before their menstrual periods had stopped were considered eligible when they had been taking HRT for 12 months.

Exclusion:

- For the placebo controlled components: oral or transdermal HRT use in the last six months, ever use of HRT implant in women with a uterus, HRT implant inserted in last eight months in women with a hysterectomy

 - History of endometriosis (hysterectomised or non-hysterectomised woman) or endometrial hyperplasia in a woman with a uterus

 History of invasive breast cancer, lobular carcinoma in-situ (LCIS), ductal carcinoma in-situ (DCIS), Paget's disease of the nipple or atypical hyperplasia of the breast

 - Known BRCA1 or BRCA2 mutation carrier

 - History of melanoma

 - Invasive cancer at any other site apart from basal and squamous cell skin cancer within the last 10 years

 - History of meningioma

 - Myocardial infarction, cerebrovascular accident, sub-arachnoid haemorrhage or transient Ischaemic attack within the last six months

 - History of currently active liver disease or chronic liver disease but excluding Hepatitis A unless currently active

 - Evidence of severe current renal impairment

 - History of gall bladder disease in a woman who had not had a cholecystectomy or of gallstones following a cholecystectomy

 - History of deep vein thrombosis, pulmonary embolism or retinal vein occlusion

 - Positive thrombophilia screen (Factor V Leiden or prothrombin mutations, Protein C, Protein S or anti-thrombin III deficiencies, APC resistance, dysfibrinogenaemia or antiphospholipid antibodies)

 - Otosclerosis

 - Porphyria

 - History of hepatitis B, hepatitis C or HIV (not an exclusion in New Zealand)

 - Currently pregnant

 - Currently taking or has taken contraceptive drugs in the last 12 months

 - Current triglyceride level (fasting) > 5.5 mmol/l

 - Active participant in any other intervention trial likely to affect trial outcomes

 - Taking tamoxifen, toremifene, raloxifene or any other selective oestrogen receptor modulator (SERM)

 - Other conditions/circumstances where the general practitioner judged that it would not be possible to obtain fully informed consent and/or successfully complete trial procedures

Interventions

Intervention: oral conjugated equine oestrogen 0.625 mg daily, plus oral medroxyprogesterone acetate 2.5/5.0 mg daily (Prempro, Wyeth Ayerst, USA)

Control: matching placebo

Outcomes

Women’s health questionnaire

Final scores

Notes

Follow up: 1 year

Mean age at randomisation: 63.8 years

Drugs were donated by Wyeth Ayerst Company

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-based, stratified block randomisation program
Allocation concealment (selection bias)Low riskRandomised centrally and appropriate medication dispatched to the practice
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo-one involved with assessment of outcomes was aware of treatment assignment
Incomplete outcome data (attrition bias)
All outcomes
High riskSexual function was evaluated in only 588/1043 participants in the intervention group and in only 569/1087 participants in the control group
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Yang 2004

MethodsRCT, Single-centre, Taiwan
Participants

Inclusion: postmenopausal women with intact uterus and natural menopause of at least 6 months’ duration, FSH>18 mIU/L, and estradiol level<30 pg/mL.

Exclusion: history of liver disease, breast cancer, endometrial cancer, thrombophlebitis, thromboembolic disorders related to oestrogen use, myocardial infarction or ischemic heart disease, chronic renal disease, cerebrovascular accident, uncontrolled hypertension, diabetes or metabolic bone disease, or had received any hormone treatment within one year previous, chronic use of steroids, fluoride, Vitamin D, rifampin, barbiturates, sulfonamide, and herbal medications, or the use of oestrogen and progestins other than the study medications.

Interventions

Intervention: conjugated estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg orally daily for 5.5 months

Control: matching placebo

Outcomes

Greene Climacteric Scale

Change from baseline

Notes

Follow-up: 6 months

Age: intervention (53.2±3.1 years); control (53.3±3.4 years)

Weight: intervention (56.0±8.3 kg); control (55.7±6.6 kg)

Do not report conflict of interest

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported in detail
Allocation concealment (selection bias)Unclear riskNot reported in detail
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskHigh rates, but balanced, dropouts: intervention (6/33); control (8/33)
Selective reporting (reporting bias)Low riskNot suspected
Other biasUnclear risk

We observe relevant difference between intervention and control groups at baseline (0.6±0.8 vs. 1.0±0.9, intervention vs. control respectively). However, data could be analysed as change from baseline.

There is no conflict of interest disclosure.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Adler 2005Not randomised
Almeida 2006Did not evaluate sexual function
Archer 2012Did not evaluate sexual function
Argyroudis 1997Not randomised
Bachmann 2008Did not evaluate sexual function
Bachmann 2009Did not evaluate sexual function
Bachmann 2010bDid not evaluate sexual function
Bachmann 2011Did not evaluate sexual function
Barnabei 2002Did not evaluate sexual function
Binder 2001Did not evaluate sexual function
Blumel 2008Addition of testosterone to estrogen/progesterone in the study group
Bruno 2012Pseudo-randomised
Cano 2012Did not evaluate sexual function
Cardozo 2001Did not evaluate sexual function
Casper 1999Did not evaluate sexual function
Castelo-Branco 2000Pseudo-randomised
Cayan 2008Pseudo-randomised
Concepcion 2011Did not evaluate sexual function
Dennerstein 1980Did not evaluate sexual function
Dessole 2004Did not evaluate sexual function
Diem 2006Did not evaluate sexual function
Ditkoff 1991Did not evaluate sexual function
Duka 2000Did not evaluate sexual function
Eftekhar 2009Not randomised, compares before and after treatment
Eriksen 1992Did not evaluate sexual function
Eriksen 1999Did not evaluate sexual function
Freedman 2009Did not evaluate sexual function
Galhardo 2006Did not evaluate sexual function by a validated questionnaire
Gonenne 2006Did not evaluate sexual function
Gorenstein 2011Did not evaluate sexual function
Griesser 2012Did not evaluate sexual function
Guan 2010Did not evaluate sexual function
Hachul 2008Did not evaluate sexual function
Hedrick 2009Did not evaluate sexual function
Hendrix 2005Did not evaluate sexual function
Hodis 2001Did not evaluate sexual function
Hofling 2005Did not evaluate sexual function
Jensen 1983Did not evaluate sexual function
Kenny 2005Did not evaluate sexual function
Kessel 2003No group without hormone therapy
Kimura 1995Not randomised
Kocoska-Maras 2011Did not evaluate sexual function
Kornafel 1992Did not evaluate sexual function
Kumru 2008Did not evaluate sexual function
Lin 2011Did not evaluate sexual function
Lindsay 2002Did not evaluate sexual function
Liu 2012Did not evaluate sexual function
Lobo 2009No group without hormone therapy
MacDonald 1994Did not evaluate sexual function
Marsden 2000Did not evaluate sexual function
Marx 2004Did not evaluate sexual function
Mizunuma 2011Did not evaluate sexual function
Naessen 2001Did not evaluate sexual function
Nevinny-Stickel 1983Did not evaluate sexual function by a validated questionnaire
Notelovitz 2000Did not evaluate sexual function
Obel 1993Did not evaluate sexual function
Palacios 1995Control group used a different intervention, did not use a validated questionnaire
Palacios 2005Did not evaluate sexual function
Poetry 2011Did not evaluate sexual function
Polo-Kantola 1998Did not evaluate sexual function
Prestwood 2003Did not evaluate sexual function
Rebar 2000A questionnaire that includes assessment of sexual function is applied; however, the authors do not report the results for the sexual domains
Reindollar 2002Did not evaluate sexual function
Ribom 2011Did not evaluate sexual function
Rigano 2001Did not evaluate sexual function by a validated questionnaire
Saletu 2002Did not evaluate sexual function
Samaras 1999Did not evaluate sexual function by a validated questionnaire
Shah 2006Did not evaluate sexual function
Sherman 2003Did not evaluate sexual function
Shulman 2002Did not evaluate sexual function
Simon 1999Did not evaluate sexual function
Simon 2008aDid not evaluate sexual function
Simon 2008bDid not evaluate sexual function
Simon 2012Did not evaluate sexual function
Simunic 2003Did not evaluate sexual function
Sorensen 2001Did not evaluate sexual function
Speroff 2006Did not evaluate sexual function
Stening 2011Did not evaluate sexual function
Stevenson 2010Did not evaluate sexual function
Swanson 2006Did not evaluate sexual function
Tinelli 2002Did not evaluate sexual function by a validated questionnaire
Tuomikoski 2010Did not evaluate sexual function
Usall 2011Did not evaluate sexual function
Utian 2001Did not evaluate sexual function
Utian 2004Did not evaluate sexual function
Vardy 2003Did not evaluate sexual function
Veldhuis 2011aDid not evaluate sexual function
Veldhuis 2011bDid not evaluate sexual function
Vestergaard 2003Did not evaluate sexual function
Voipio 2002Did not evaluate sexual function
Wolff 1982Did not evaluate sexual function
Woo 2003Did not evaluate sexual function
Zervoudis 2009Did not evaluate sexual function
Zhou 2011Did not evaluate sexual function
Zullo 2005Did not evaluate sexual function

Characteristics of studies awaiting assessment [ordered by study ID]

Ceausu 2011

MethodsRCT
Participants

Eligibility criteria: healthy, postmenopausal women, aged 40-65 years with an intact uterus, hormonal levels of FSH>30 mIU/ml and of 17 beta-estriol below 50pg/m and body mass index<30 kg/m².

Exclusion criteria: hypersensitivity to the active principle and/or other ingredients, previous deep thrombophlebitis or cerebral apoplexy, mammary or gynecological neoplasia, uncontrolled diabetes mellitus, abnormal mammography, abnormal values of C and S proteins, endometrial thickness >4mm or abnormal PAP smear, abnormal bleeding of undetermined origin, history of hepatic or renal diseases, use of estrogenic, progesteronic or androgenic drugs in the 8 weeks before enrolling.

Interventions

Intervention groups: tibolone 2.5mg/day; or tibolone 1.25mg/day

Control group: placebo

OutcomesHot flashes, sweating episodes, vaginal dryness, vaginal bleeding pattern, endometrial thickness, McCoy sexual rating scale
NotesConference abstract. Authors did not reply our e-mails

Russu 2011

MethodsProspective study
ParticipantsPostmenopausal women
Interventions

Intervention groups: promestriene or estriol

Control group: placebo

OutcomesQuality of life questionnaire
NotesConference abstract. Authors did not reply our e-mails

Silverman 2012

MethodsRCT
ParticipantsPostmenopausal women with osteoporosis
Interventions

Intervention groups: bazedoxifene 20 mg/day; bazedoxifene 40 mg/day; raloxifene 60 mg/day

Control group: placebo

OutcomesNew vertebral fractures; non-vertebral fractures, changes in bone mineral density; and changes in bone turnover markers
NotesConference abstract. Authors did not reply our e-mails

SMART-5

MethodsRCT
ParticipantsPostmenopausal women with an intact uterus
Interventions

Intervention groups: bazedoxifene 20 mg/day + conjugated estrogens 0.45mg/day; bazedoxifene 20 mg/day + conjugated estrogens 0.625 mg/day; bazedoxifene 20 mg/day; conjugated estrogens 0.45 mg/day + medroxyprogesterone acetate 1.5 mg

Control group: placebo

OutcomesMenopause-Specific Quality of Life questionnaire; sleep adequacy, sleep disturbance, sleep quantity, somnolence, snoring, shortness of breath or headache, and time to fall asleep; overall sleep problems; endometrial biopsy; breast density; breast tenderness; and uterine bleeding
NotesConference abstracts. Authors did not reply our e-mails

Ancillary