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Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data

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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drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data.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.

Funding

Australian National Health and Medical Research Council.

Introduction

No international consensus exists to guide use of testosterone in women. Nonetheless, clinicians have treated women with various forms of testosterone for decades, primarily for diminished sexual wellbeing.1 Previous systematic reviews of testosterone treatment for women have indicated favourable effects on sexual function,2, 3 but these analyses have included scant data for safety or adverse effects. We did a systematic review and meta-analysis of randomised controlled trials that reported the effects of systemic testosterone treatment compared with placebo or a comparator (eg, oestrogen, with or without progestogen) on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health, including previous unpublished data.

Section snippets

Search strategy and selection criteria

This systematic review and meta-analysis was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.4 We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science using Ovid software. The full search strategy and keywords used have been published elsewhere.5 We also searched drug registration applications to the European Medicine Agency (EMA) and the US Food and Drug Administration (FDA).

Research

Results

A PRISMA flowchart of study selection is presented in figure 1. The overall search resulted in 6491 citations. 2651 duplicate studies were excluded; a further 3769 studies were excluded on review of title and abstract, and 25 reports did not meet inclusion criteria. Thus, 46 publications from 36 randomised controlled trials were included in the meta-analysis. 44 reports8, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,

Discussion

The findings of our systematic review and meta-analysis show beneficial treatment effects of testosterone for postmenopausal women on a comprehensive array of sexual function domains, the frequency of satisfying sexual events, and sexually associated personal distress. For premenopausal women, the only observed benefit was a reduction in sexually associated personal distress in one small study. Although testosterone treatment was associated with an increase in acne and hair growth, these

References (69)

  • NB Watts et al.

    Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause

    Obstet Gynecol

    (1995)
  • J Richters et al.

    Sex in Australia: sexual and emotional satisfaction in regular relationships and preferred frequency of sex among a representative sample of adults

    Aust NZ J Public Health

    (2003)
  • K Witting et al.

    Couples' sexual dysfunctions: female sexual dysfunction, sexual distress, and compatibility with partner

    J Sex Med

    (2008)
  • JA Simon et al.

    Sexual well-being after menopause: an International Menopause Society White Paper

    Climacteric

    (2018)
  • R Gera et al.

    Does transdermal testosterone increase the risk of developing breast cancer? A systematic review

    Anticancer Res

    (2018)
  • RB Greenblatt et al.

    Hormone therapy for sexual dysfunction: the only “true aphrodisiac”

    Postgrad Med

    (1983)
  • W Somboonporn et al.

    Testosterone for peri- and postmenopausal women

    Cochrane Database Syst Rev

    (2005)
  • C Achilli et al.

    Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis

    Fertil Steril

    (2017)
  • D Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann Intern Med

    (2009)
  • RM Islam et al.

    Effects of testosterone therapy for women: a systematic review and meta-analysis protocol

    Syst Rev

    (2019)
  • Scientific discussion: INTRINSA testosterone transdermal patch

  • Procter & Gamble Pharmaceuticals. Advisory committee briefing document: Intrinsa (testosterone transdermal system) NDA...
  • SR Davis et al.

    Testosterone for low libido in postmenopausal women not taking estrogen

    N Engl J Med

    (2008)
  • JP Higgins et al.

    The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

    BMJ

    (2011)
  • RD Riley et al.

    Interpretation of random effects meta-analyses

    BMJ

    (2011)
  • JA Sterne et al.

    Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials

    BMJ

    (2011)
  • JPT Higgins et al.

    Cochrane handbook for systematic reviews of interventions, version 5.1.0

  • E Barrett-Connor et al.

    A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women: effects on bone mineral density, symptoms and lipid profiles

    J Reprod Med

    (1999)
  • S Basaria et al.

    Effect of methyl testosterone administration on plasma viscosity in postmenopausal women

    Clin Endocrinol

    (2002)
  • GD Braunstein et al.

    Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial

    Arch Intern Med

    (2005)
  • JE Buster et al.

    Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial

    Obstet Gynecol

    (2005)
  • S Davis et al.

    Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial

    Ann Intern Med

    (2008)
  • SR Davis et al.

    The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy

    J Clin Endocrinol Metab

    (2009)
  • SR Davis et al.

    Transdermal testosterone improves verbal learning and memory in postmenopausal women not on oestrogen therapy

    Clin Endocrinol

    (2014)
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