By Robert W. Rebar, MD
Founding Chair Emeritus and Professor, Department of Obstetrics and Gynecology, Western Michigan Homer Stryker M.D. School of Medicine, Kalamazoo, MI
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: Exogenous testosterone is currently indicated only for women with documented hypoactive sexual desire disorder/dysfunction.
SOURCE: Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. J Clin Endocrinol Metab 2019;104:4660-4666.
Although there are no definitive indications for the use of testosterone in women and there are no FDA-approved products containing testosterone for women, clinicians have used several different preparations of testosterone to alleviate a variety of symptoms despite uncertain benefits and risks. The need for clarity in the management of women asking or using exogenous testosterone led to the establishment of a task force of representatives from several leading international societies. The purpose of this task force was to make recommendations based on a systematic review and meta-analysis based only on findings from blinded placebo/comparator randomized controlled trials of at least 12 weeks’ duration. The international panel produced several recommendations:
- The only evidence-based indication for testosterone therapy for women is for the treatment of hypoactive sexual desire disorder (HSDD), with available evidence suggesting a moderate therapeutic effect.
- The diagnosis of HSDD involves complete clinical assessment and does not involve the measurement of serum testosterone concentrations. Diagnosis should be guided by available diagnostic criteria such as the International Society for the Study of Women’s Sexual Health1,2 or the International Classification of Diseases, 11th edition.
- Doses that approximate physiological testosterone concentrations in premenopausal women should be used.
- Testosterone therapy exerts a beneficial effect on sexual function, including an increase of an average of one satisfying sexual event per month, as well as increases in sexual desire, arousal, orgasmic function, pleasure, and sexual responsiveness, together with a reduction in sexual concerns, including sexual distress.
- Meta-analyses of short-term data do not document severe adverse events with physiological testosterone administration, but the long-term safety of testosterone therapy has not been established.
- Systemic testosterone therapy for postmenopausal women in doses that approximate levels in premenopausal women is associated with mild increases in acne and body and facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change; no such changes occur in premenopausal women.
- Non-oral testosterone therapies (percutaneous and injectable) may be preferred because there are no statistically significantly adverse effects on lipid profiles.
- Because randomized controlled trials of testosterone therapies have excluded women at high cardiometabolic disease risk, recommendations regarding the effect of physiologic doses on cardiovascular health are not generalizable to more at-risk individuals or to long-term therapy.
- Because women with a prior diagnosis of breast cancer were excluded from the randomized trials for HSDD, caution is recommended for testosterone use in women with hormone-sensitive breast cancer.
- In the absence of any approved female product, formulations for males can be used at female doses with careful monitoring of serum testosterone concentrations.
- The use of compounded testosterone preparations is not recommended.
- Systemic dehydroepiandrosterone is not associated with significant improvement in libido or sexual function in postmenopausal women with normal adrenal function and cannot be recommended for women with HSDD.
- The panel cited the pressing need for additional research into the use of testosterone in women and highlighted the need for development and licensing of products indicated specifically for women.
COMMENTARY
Whether these recommendations will be observed remains to be determined. They were formulated by a distinguished panel and endorsed by several international societies. Still, I say this because clinicians have administered androgens to women for many reasons for decades; yet the analysis of the available data does not justify widespread use at this time. Perhaps the last recommendation of the panel is the most important: Additional research is badly needed to determine if there are other uses for physiologic doses of testosterone in women. If so, then the appropriate products need to be developed, tested, and approved for use.
Several years ago, one commercial FDA-approved product combined esterified estrogens (0.625 or 1.25 mg) with methyltestosterone (1.25 or 2.5 mg) (Estratest). It also was marketed in a form containing only esterified estrogens (Estratab). These products were approved because their effects were broadly equivalent to products containing conjugated estrogens. They are no longer produced, and it is unlikely that the same products containing methyltestosterone would be approved today without additional studies.
Randomized studies with the estrogen-only and the combined estrogen-methyltestosterone preparation indicated that those containing androgen produced nonsignificantly greater improvements in well-being and sexual interest.3 Somatic symptom relief in the low-dose preparation containing methyltestosterone was the same as with those containing the higher dose of esterified estrogens.4
It is possible that the effects of the methyltestosterone added to the esterified estrogens may be due, at least in part, to higher doses of circulating estrogens. This is true because methyltestosterone is efficiently aromatized to estrogens. In fact, in a study supported by the manufacturer but never published because of the untimely death of the first author, the study showed that more than 90% of the effect of esterified estrogens plus methyltestosterone was due to the estrogen alone, making it possible that the entire effect on well-being and sexual satisfaction was merely due to estrogen.5
Women with primary ovarian insufficiency (POI) are documented to have lower levels of circulating androgens than do age-matched controls. Yet in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy in 128 women with POI, the addition of physiologic amounts of testosterone failed to have any significant effects on quality of life, self-esteem, and mood.6
The conclusion from studies published to date can be summarized succinctly: Until we have additional data, the long-term administration of testosterone in women should be discouraged except in the treatment of women with documented HSDD.
REFERENCES
- Parish SJ, Meston CM, Althof SE, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions-part III. J Sex Med 2019;16:452-462.
- Parish SJ, Goldstein AT, Goldstein SW, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions-part II. J Sex Med 2016;13:1888-1906.
- Barrett-Connor E, Young R, Notelovitz M, 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;44:1012-1020.
- Simon J, Klaiber E, Wiita B, et al. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6:138-146.
- Mortola JF, Rebar RW, Bachmann GA, Wiita B. Combined androgen-estrogen provides better symptom relief than estrogen alone in surgically menopausal women. Society for Gynecologic Investigation Abstracts, 45th Annual Meeting, March 11-14, 1998.
- Guerrieri GM, Martinez PE, Klug SP, et al. Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency. Menopause 2014;21:952-961.
Exogenous testosterone is currently indicated only for women with documented hypoactive sexual desire disorder/dysfunction.
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