Emerging Role of Testosterone in Menopause

‘…the only well-documented benefit has been an improvement in sexual function with various regimens of testosterone use.’

Testosterone therapy is being increasingly used in the management of postmenopausal women and has now been approved for the treatment of surgically postmenopausal women in European countries. However, neither the US FDA nor my own country, Thailand, have approved the administration of testosterone for any indication for women.

The derivation of the word testosterone is from the stems of testicle and sterol and the suffix of ketone [1]. Testosterone was originally used for the treatment of males with low or no natural endogenous testosterone production, so-called male hypogonadism. It was not until 1950 that the importance of testosterone on female sexuality was first mentioned [2–4], but since then research into this aspect has progressed significantly.

Many studies have been conducted to establish the symptoms or syndrome caused by low levels of endogenous testosterone. However, the results remain inconclusive. This may be attributable to the complexity of the proposed symptoms of female androgen insufficiency. Nonetheless, the term ‘female androgen insufficiency’ is derived from the effects of pharmacological androgen-replacement regimens [5].

Despite an uncertain association between low testosterone levels and a female androgen insufficiency syndrome, several clinical trials have been conducted and have shown some benefits of adding exogenous testosterone to traditional hormone therapy in postmenopausal women. The proposed benefits of the addition of exogenous testosterone to hormone therapy are the improvements in wellbeing, sexual function, unexplained fatigue, bone health, body composition and cognition. Among these, the only well-documented benefit has been an improvement in sexual function with various regimens of testosterone use. The supporting evidence is level 1 [6]. All randomized, controlled studies that have used validated questionnaires for monitoring sexual function [7], and our own Cochrane review [8], indicate the benefits of adding testosterone to hormone therapy on sexual function in every questionnaire domain, including libido, fantasy, amount of sexual activity and number of orgasms. In general, parenteral administration of physiological doses of testosterone seems to have few androgenic adverse effects in the short term, such as hirsutism and acne [9–12].

In light of findings that other estrogen–progestin therapies increase the risk of breast cancer, long-term safety of testosterone therapy remains a concern [13]. So far, the evidence on these long-term effects of testosterone is from surrogate outcomes. For the lipid profile, the addition of oral methyltestosterone or testosterone undecanoate to hormone therapy is associated with a decrease in the high-density lipoprotein cholesterol level as well as an increase in the low-density lipoprotein cholesterol [7]. The testosterone patch studies consistently demonstrated no significant changes in blood lipids [9–12, 14].

The assessment of the effects of adding testosterone into hormone therapy on the incidence of breast cancer from epidemiological studies is inconclusive because of significant methodological limitations [15–18]. Evidence from preclinical studies is very encouraging. In experimental studies, testosterone action is antiproliferative and proapoptotic, and mediated via the androgen receptor, despite the potential for testosterone to be aromatized to estrogen [19]. Animal studies suggest that testosterone may serve as a natural, endogenous protector of the breast and limit mitogenic and cancer-promoting effects of estrogen on mammary epithelium [19]. These effects were recently reported in postmenopausal women. A randomized, double-blind, placebo-controlled study examined the effects of testosterone addition on breast cell proliferation and mammographic density during postmenopausal estrogen/progestogen therapy [20,21]. In the placebo group, a more than fivefold increase (p < 0.001) was observed in total breast cell proliferation from baseline (median: 1.1%) to 6 months (median: 6.2%). During testosterone addition, no significant increase was recorded (1.6 vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells [20]. In addition, mammographic breast density, both at baseline (r_s: −0.35; p < 0.01) and during treatment (r_s: −0.28; p < 0.01), showed a negative association with free testosterone levels [21]. These results in postmenopausal women were consistent with the data derived from experimental and animal studies and supported the concept that testosterone may serve as a natural, endogenous protector of the breast and limit the mitogenic and cancer-promoting effects of estrogen on mammary epithelium. The concept that testosterone combined with an estrogen/progestin regimen may prevent breast cancer is a challenging one.

While the use of testosterone in postmenopausal women is still off-label, hypoactive sexual desire disorder is common amongst postmenopausal women. The reported prevalence of hypoactive sexual desire disorder from the Women's International Study of Health and Sexuality ranged from 9% in naturally postmenopausal women to 26% in younger, surgically postmenopausal women [22]. In untreated cases, hypoactive sexual desire disorder was associated with emotional and psychological distress, as well as significantly lower sexual and partner satisfaction. When a clinician is facing a postmenopausal woman who has presented with hypoactive sexual desire disorder, decision making is highly critical. To date, evidence is strong to support the addition of exogenous testosterone to hormone therapy for improving sexual function. However, it is essential that potentially treated patients are informed that safety data is limited. Longitudinal postmarketing surveillance of the use of testosterone in European countries is likely to provide the main source of safety information to inform future clinical practice.

‘That testosterone combined with an estrogen/progestin regimen may prevent breast cancer is a challenging concept.’