madman
Super Moderator
Summary
Background
The benefits and risks of testosterone treatment for women with diminished sexual wellbeing remain controversial. We did a systematic review and meta-analysis to assess potential benefits and risks of testosterone for women.
Methods
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for blinded, randomised controlled trials of testosterone treatment of at least 12 weeks’ duration completed between Jan 1, 1990, and Dec 10, 2018. We also searched drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data. Primary outcomes were the effects of testosterone on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42018104073.
Findings
Our search strategy retrieved 46 reports of 36 randomised controlled trials comprising 8480 participants. Our meta-analysis showed that, compared with placebo or a comparator (eg, oestrogen, with or without progestogen), testosterone significantly increased sexual function, including satisfactory sexual event frequency (mean difference 0·85, 95% CI 0·52 to 1·18), sexual desire (standardised mean difference 0·36, 95% CI 0·22 to 0·50), pleasure (mean difference 6·86, 95% CI 5·19 to 8·52), arousal (standardised mean difference 0·28, 95% CI 0·21 to 0·35), orgasm (standardised mean difference 0·25, 95% CI 0·18 to 0·32), responsiveness (standardised mean difference 0·28, 95% CI 0·21 to 0·35), and self-image (mean difference 5·64, 95% CI 4·03 to 7·26), and reduced sexual concerns (mean difference 8·99, 95% CI 6·90 to 11·08) and distress (standardised mean difference –0·27, 95% CI –0·36 to –0·17) in postmenopausal women. A significant rise in the amount of LDL-cholesterol, and reductions in the amounts of total cholesterol, HDL-cholesterol, and triglycerides, were seen with testosterone administered orally, but not when administered non-orally (eg, by transdermal patch or cream). An overall increase in weight was recorded with testosterone treatment. No effects of testosterone were reported for body composition, musculoskeletal variables, or cognitive measures, although the number of women who contributed data for these outcomes was small. Testosterone was associated with a significantly greater likelihood of reporting acne and hair growth, but no serious adverse events were recorded.
Interpretation
Testosterone is effective for postmenopausal women with low sexual desire causing distress, with administration via non-oral routes (eg, transdermal application) preferred because of a neutral lipid profile. The effects of testosterone on individual wellbeing and musculoskeletal and cognitive health, as well as long-term safety, warrant further investigation.
Our study has several strengths. First, we included data not only from studies identified by a comprehensive search of the published literature but also from completed but unpublished randomised controlled trials from the clinical development programme of the transdermal testosterone patch, identified from EMA and FDA submissions. Second, after contacting corresponding authors and accessing source data, we included several published studies previously excluded from reviews because of insufficient outcome data.These strengths make our study the most comprehensive systematic review and meta-analysis of testosterone treatment for women yet undertaken.
Our analysis has several limitations. First, a limitation of the included studies was attrition bias. In several studies, withdrawal and lost to follow-up was enhanced in women randomly allocated placebo compared with those assigned the active treatment. This bias is an issue for studies of several months’ duration in which the main outcome is self-reported and the active treatment is effective. In the largest of the included studies,8 women randomly allocated placebo were more likely to discontinue because of a lack of benefit, resulting in participants who persisted possibly being more likely to be placebo responders. A second limitation was that not all studies that reported sexual function outcomes recruited women with sexual dysfunction, and among those that had sexual dysfunction as an inclusion criterion, the definition of sexual dysfunction was not consistent. Third, we were unable to include the outcomes of two large double-blind randomised controlled trials of a transdermal testosterone gel, in which a therapeutic effect of testosterone on satisfying sexual events was not detected, because the findings have only been reported in abstract form, with insufficient numerical and methodological data to enable inclusion.Not only were the overall increases in satisfying sexual events per month in these two studies greater than seen across the transdermal testosterone patch studies, but the placebo groups in these two trials had increases in satisfying sexual events three fold to fourfold greater than seen with placebo in other testosterone patch studies.This finding suggests there could have been some fundamental differences in either the study populations or the conduct of these studies, compared with other published studies. Finally, the reporting of outcomes for premenopausal women was limited by the paucity of studies. Similarly, findings for several of our a priori outcomes—notably, effects on musculoskeletal health, cognitive performance, mood and wellbeing, breast cancer risk, and cardiovascular disease— are inconclusive. This drawback is attributable to scant published data (these being mostly secondary outcomes for which data were available and analyses underpowered) and use of different outcome measures.
Our comprehensive systematic review provides robust support for a trial of testosterone treatment, using a dose appropriate for women, when clinically indicated in postmenopausal women. The absence of any approved testosterone formulations for women in any country, however, is a major treatment barrier. This shortfall urgently needs to be addressed to eradicate the widespread practice of women being treated with male formulations and compounded products, resulting in testosterone concentrations several fold greater than appropriate for women. Further research is needed to clarify the effects of testosterone treatment in premenopausal women and the effects on musculoskeletal and cognitive health and longterm safety.
Background
The benefits and risks of testosterone treatment for women with diminished sexual wellbeing remain controversial. We did a systematic review and meta-analysis to assess potential benefits and risks of testosterone for women.
Methods
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for blinded, randomised controlled trials of testosterone treatment of at least 12 weeks’ duration completed between Jan 1, 1990, and Dec 10, 2018. We also searched drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data. Primary outcomes were the effects of testosterone on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42018104073.
Findings
Our search strategy retrieved 46 reports of 36 randomised controlled trials comprising 8480 participants. Our meta-analysis showed that, compared with placebo or a comparator (eg, oestrogen, with or without progestogen), testosterone significantly increased sexual function, including satisfactory sexual event frequency (mean difference 0·85, 95% CI 0·52 to 1·18), sexual desire (standardised mean difference 0·36, 95% CI 0·22 to 0·50), pleasure (mean difference 6·86, 95% CI 5·19 to 8·52), arousal (standardised mean difference 0·28, 95% CI 0·21 to 0·35), orgasm (standardised mean difference 0·25, 95% CI 0·18 to 0·32), responsiveness (standardised mean difference 0·28, 95% CI 0·21 to 0·35), and self-image (mean difference 5·64, 95% CI 4·03 to 7·26), and reduced sexual concerns (mean difference 8·99, 95% CI 6·90 to 11·08) and distress (standardised mean difference –0·27, 95% CI –0·36 to –0·17) in postmenopausal women. A significant rise in the amount of LDL-cholesterol, and reductions in the amounts of total cholesterol, HDL-cholesterol, and triglycerides, were seen with testosterone administered orally, but not when administered non-orally (eg, by transdermal patch or cream). An overall increase in weight was recorded with testosterone treatment. No effects of testosterone were reported for body composition, musculoskeletal variables, or cognitive measures, although the number of women who contributed data for these outcomes was small. Testosterone was associated with a significantly greater likelihood of reporting acne and hair growth, but no serious adverse events were recorded.
Interpretation
Testosterone is effective for postmenopausal women with low sexual desire causing distress, with administration via non-oral routes (eg, transdermal application) preferred because of a neutral lipid profile. The effects of testosterone on individual wellbeing and musculoskeletal and cognitive health, as well as long-term safety, warrant further investigation.
Our study has several strengths. First, we included data not only from studies identified by a comprehensive search of the published literature but also from completed but unpublished randomised controlled trials from the clinical development programme of the transdermal testosterone patch, identified from EMA and FDA submissions. Second, after contacting corresponding authors and accessing source data, we included several published studies previously excluded from reviews because of insufficient outcome data.These strengths make our study the most comprehensive systematic review and meta-analysis of testosterone treatment for women yet undertaken.
Our analysis has several limitations. First, a limitation of the included studies was attrition bias. In several studies, withdrawal and lost to follow-up was enhanced in women randomly allocated placebo compared with those assigned the active treatment. This bias is an issue for studies of several months’ duration in which the main outcome is self-reported and the active treatment is effective. In the largest of the included studies,8 women randomly allocated placebo were more likely to discontinue because of a lack of benefit, resulting in participants who persisted possibly being more likely to be placebo responders. A second limitation was that not all studies that reported sexual function outcomes recruited women with sexual dysfunction, and among those that had sexual dysfunction as an inclusion criterion, the definition of sexual dysfunction was not consistent. Third, we were unable to include the outcomes of two large double-blind randomised controlled trials of a transdermal testosterone gel, in which a therapeutic effect of testosterone on satisfying sexual events was not detected, because the findings have only been reported in abstract form, with insufficient numerical and methodological data to enable inclusion.Not only were the overall increases in satisfying sexual events per month in these two studies greater than seen across the transdermal testosterone patch studies, but the placebo groups in these two trials had increases in satisfying sexual events three fold to fourfold greater than seen with placebo in other testosterone patch studies.This finding suggests there could have been some fundamental differences in either the study populations or the conduct of these studies, compared with other published studies. Finally, the reporting of outcomes for premenopausal women was limited by the paucity of studies. Similarly, findings for several of our a priori outcomes—notably, effects on musculoskeletal health, cognitive performance, mood and wellbeing, breast cancer risk, and cardiovascular disease— are inconclusive. This drawback is attributable to scant published data (these being mostly secondary outcomes for which data were available and analyses underpowered) and use of different outcome measures.
Our comprehensive systematic review provides robust support for a trial of testosterone treatment, using a dose appropriate for women, when clinically indicated in postmenopausal women. The absence of any approved testosterone formulations for women in any country, however, is a major treatment barrier. This shortfall urgently needs to be addressed to eradicate the widespread practice of women being treated with male formulations and compounded products, resulting in testosterone concentrations several fold greater than appropriate for women. Further research is needed to clarify the effects of testosterone treatment in premenopausal women and the effects on musculoskeletal and cognitive health and longterm safety.
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