By Jeffrey T. Jensen, MD, MPH

Abstract

Clinicians lack clearly established guidance and indications for testosterone therapy for women, which has led to considerable variation in practice patterns. The absence of clear indications and approved products for women has resulted in the use of compounded therapies or off-label prescription of testosterone formulations approved for men. To address concerns regarding current prescribing practice, representatives from the International Menopause Society, the European Menopause and Andropause Society, the International Society for Sexual Medicine, and the Endocrine Society established a task force to conduct a systematic review and meta-analysis of the risks and benefits of testosterone therapy in women. The task force met in Berlin in May 2019 and drafted a consensus position paper that was published simultaneously in the journals ClimactericMaturitasJournal of Sexual Health, and Journal of Clinical Endocrinology and Metabolism.

The task force developed this consensus position statement to inform healthcare professionals of the known benefits and potential risks of testosterone therapy with the aim of providing clear guidance for treatment, considering benefit and risk. They also addressed conditions for which evidence does not support prescribing testosterone. Wherever possible, the task force based recommendations on findings from blinded placebo/comparator randomized controlled trials (RCTs) of at least 12 weeks’ duration. They reported findings with Levels of Evidence (e.g., Level I, experimental studies [RCTs]; Level II, quasi-experimental studies [prospective studies]; Level III, non-experimental studies [case-control]; Level IV, opinion of respected authorities [clinical practice guidelines, consensus panels]; Level V, experiential and non-research [literature reviews, case reports]) and Grades of Recommendations (A = high quality [Level I] to recommend; B = good quality [Level II]; C = weak evidence).

Here are the highlights of the recommendations:

• Measurement of testosterone, female sexual dysfunction, and endogenous androgen levels. The task force noted that testosterone concentrations decline during the reproductive years, but are maintained during menopause (Level IIB). They found direct assays highly unreliable (Level A) for diagnosis within the normal female range of values, but useful to exclude high baseline concentrations in the setting of suspected pathology or to rule out supra-physiologic doses during treatment (expert opinion). The task force recommended the use of high accuracy liquid/gas chromatography and tandem mass spectrometry (LC/GC-MS/MS) assays for total testosterone.

• Recommendations for the terminology for female sexual dysfunction (FSD). Grade B evidence supports the categorization of hypoactive sexual desire disorder/dysfunction (HSDD) and female sexual arousal disorder (FSAD) as distinct conditions. They have different etiologies, risk factors, clinical features, and responses to psychological and biological interventions, including androgen therapy. The task force recommended basing the diagnosis of HSDD in clinical practice on a thorough clinical assessment1 guided by diagnostic criteria, such as those proposed by the International Society for the Study of Women’s Sexual Health (expert opinion).2-4

• Recommendations pertaining to the associations between endogenous androgen concentrations and female sexual function. The task force categorized the evidence for using androgen concentrations as a diagnostic test for sexual function as “insufficient,” and found no cut-off blood level for any measured circulating androgen to differentiate women with and without sexual dysfunction (Grade C).

• Recommendations regarding systemic testosterone therapy. The task force found insufficient evidence to make any recommendations regarding the use of testosterone in premenopausal women for treatment of sexual function or any other outcome. In contrast, high-quality (Level I, Grade A) evidence supports the beneficial effect of testosterone replacement at physiologic levels on sexual function in naturally or surgically postmenopausal women with HSDD. The benefit over placebo includes an average of one satisfying sexual event per month, and increases in the subdomains of sexual desire, arousal, orgasmic function, pleasure, and sexual responsiveness, along with a reduction in sexual concerns including sexual distress. The group of experts found insufficient evidence to support the use of testosterone to enhance cognitive performance or delay cognitive decline in postmenopausal women. They found high-quality evidence that testosterone does not improve bone density or increase lean body mass (Level I, Grade A). They also found systemic testosterone therapy in postmenopausal women at physiologic levels associated with mild side effects in some women (acne, increased body/facial hair) but not with alopecia, clitoromegaly, or voice change (Level I, Grade A).

With respect to cardiovascular health, oral testosterone therapy results in adverse changes in lipid profiles, but these effects are not seen with transdermal therapy (Level I, Grade A). Short-term transdermal testosterone therapy does not increase mammographic breast density or affect breast cancer risk (Level I, Grade A), but insufficient data exist to assess long-term breast cancer risk or to support safety in women with hormone-sensitive breast cancer (expert opinion). The experts found high-quality evidence supporting an absence of serious adverse events associated with physiologic testosterone replacement in postmenopausal women, but noted that safety data do not exist beyond 24 months of treatment.

• Considerations for clinical care of postmenopausal women with FSD. The task force noted that clinicians should consider the multiple biopsychosocial etiologies (neuroendocrine imbalance, health status, interpersonal difficulties, psychological distress, and sexually repressive cultural or religious values) that contribute to FSD (Grade C). They offer treatments that follow this biopsychosocial model, including pharmacologic options (hormone therapies and other pharmacologic agents), psychotherapy, or multimodal treatments that combine both (Grade B). The only evidence-based female indication for the use of testosterone is HSDD in postmenopausal women (Level I, Grade A). Use of supra-physiologic doses of testosterone is not recommended (expert opinion). To keep levels in the physiologic range, the task force recommended measurement of a baseline total testosterone prior to initiation of treatment, and a repeat level three to six weeks later (Level II, Grade C). They further recommended monitoring patients for signs of androgen excess, monitoring testosterone levels every six months to screen for overuse (expert opinion), and discontinuing treatment at six months in the absence of benefit. The group found high-quality evidence to recommend against the use of systemic DHEA for the treatment of HSDD (Level I, Grade A).

Commentary

This statement by an international panel of experts provides useful guidance to clinicians considering the use of androgen therapy to treat FSD. The task force reviewed the available literature to determine the quality of evidence both for and against the use of testosterone. For many recommendations, little data exist, and for this reason, many recommendations are conservative and based on expert opinion only.

The take-home recommendation is that postmenopausal women with a diagnosis of HSDD benefit from testosterone (T) replacement in the physiologic range of normal premenopausal women. This recommendation is based on a meta-analysis of seven RCTs by Achilli and colleagues.5 The testosterone-treated women reported significantly more satisfying sexual episodes, sexual activity, orgasms, and desire; a decrease in Personal Distress Scale score; and minor androgenic adverse events compared with the placebo group. Most of the studies used transdermal doses of T at 150-300 mcg per day.

As only postmenopausal women meeting the criteria of HSDD have been shown to benefit from T therapy, the task force cautioned clinicians not to generalize the findings to other groups. Another caveat is that more is not better, and, in fact, more T may be worse from the perspective of side effects. Measure T levels and keep these in the normal range of premenopausal women for your reference lab. Use a lab that measures T with state-of-the-art LC/GC-MS/MS methods if possible.

Another consideration is that RCTs of T therapy have excluded women at high risk for cardiovascular disease, and that most studies have included women taking concurrent estrogen therapy. Furthermore, all studies have been of relatively short duration. Therefore, we have much less information regarding risks and benefits of T therapy than we do with estrogen only or combined estrogen/progestogen treatment. Keeping up to date on this evolving literature remains important.

SOURCE

• Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. Climacteric 2019; Sep. 2. doi: 10.1080/13697137.2019.1637079. [Epub ahead of print].

REFERENCES

  1. Simon JA, Davis SR, Althof SE, et al. Sexual well-being after menopause: An International Menopause Society white paper. Climacteric 2018;21:415-427.
  2. Derogatis LR, Sand M, Balon R, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions-part I. J Sex Med 2016;13:1881-1887.
  3. 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.
  4. 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.
  5. Achilli C, Pundir J, Ramanathan P, 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;107:475-482.e15.