A Systematic Review of Randomized Controlled Trials Investigating the Efficacy and Safety of Testosterone Therapy for Female Sexual Dysfunction in Postmenopausal Women

Channa N. Jayasena; Fatima M. Alkaabi; Curtis S. Liebers; Thomas Handley; Stephen Franks; Waljit S. Dhillo


Clin Endocrinol. 2019;90(3):391-414. 

In This Article

Androgens and Their Role in Sexual Function

Oestrogens are the dominant sex hormones required for female reproductive maturation and activity. However, androgens also play a biological role in women. Further, in premenopausal women, circulating T and E2 have similar picomolar concentrations. The major androgens in the serum of normal cycling women are dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, testosterone and dihydrotestosterone (DHT). Though abundant in the circulation, DHEAS, DHEA and androstenedione may be considered pro-hormones, requiring conversion to testosterone or DHT to express their androgenic effects.[12] As testosterone requires conversion to E2 or DHT to express its biological effects, it too can be considered a pro-hormone in males and females.

The ovaries and the adrenal glands are the major sources of androgen synthesis in women. Testosterone is the major ovarian androgen, and dehydroepiandrosterone (DHEA) is the major adrenal androgen.[13] Androgen hormones circulate in the blood stream bound to carrier proteins such as sex hormone binding globulin (SHBG) and albumin and corticosteroid binding globulin. Circulating testosterone is highly bound to plasma proteins, with about 66% bound to SHBG and 33% to albumin. SHBG weakly binds DHEA but not DHEAS.[14,15,16] Androgens exert biological effects by activating androgen receptors (AR), and indirectly by conversion to oestrogen via aromatization. Androgen receptors are located in several organs of the body, including breast, brain, ovaries, bone, muscle, fat, liver and skin.[17] Moreover, testosterone is known to have multiple anabolic effects on muscles, body fat and bone mineral content in women.[18] Androgens are likely to influence behaviour through organizational or activational effects on the brain, which may be either directly, or indirectly mediated through aromatization to oestrogen.[19] It is also important to recognize that effects of sex hormones on sexual function, sexual thoughts and behaviour may be (at least partially) mediated indirectly through improved vaginal lubrication.[20] Of relevance in men, penile injury following intercourse reduces libido, and circumcision to prevent future penile injury is associated with recovery of libido.[21]

A cross-sectional study of 1423 women between the ages of 18 and 75 suggested total testosterone measured via radioimmunoassay, calculated free testosterone, dehydroepiandrosterone sulphate and androstenedione declined steeply in the early reproductive years and do not vary as a consequence of natural menopause, and the postmenopausal ovary seems to be an ongoing site of testosterone production.[22,23] It is however important to highlight that there are many limitations using immunoassays to measure testosterone in women; this is due to limited accuracy and sensitivity at low concentrations of total testosterone when compared with mass spectrometry.[24]

Some studies measuring serum androgen levels in premenopausal and menopausal women (whether natural or surgically induced) have failed to demonstrate any consistent relationship between low androgen concentrations and low sexual function. However, other studies have shown associations between androgens and sexual function in women. Davis SR et al reported the results of a community-based study of 1021 randomly recruited healthy women observed a direct association between an endogenous level of DHEAS below the tenth percentile and low sexual responsiveness in women aged 45 years or older. In women aged 18-44 years, concentrations of DHEAS below the tenth percentile were directly associated with low libido, arousal and responsiveness. No associations with androstenedione or total and free testosterone were seen. Wahlin-Jacobsen et al reported that the serum level of free testosterone and androstenedione was statistically significantly correlated with libido in the total cohort of women including 560 healthy women aged 19-65 years. Moreover, a prospective longitudinal study of 3266 women aged 42-52 years reported by Randolph JF et al demonstrated that endogenous testosterone was associated with masturbation frequency, libido and arousal, and DHEAS was positively associated with masturbation frequency and desire.[22,25,26,27] Data correlating androgen levels with specific signs or symptoms are unavailable. Consequently, the American Endocrine Society[28] recommends against making the diagnosis of androgen deficiency in women. In summary, it is accepted that androgens may influence sexual behaviour, but it is unclear whether a reduction in endogenous androgen production contributes to sexual dysfunction during the postmenopause.

The 11-ketotestosterone (11 KT) and 11-ketodihydrotestosterone (11KDHT) are androgen derivatives of the adrenal steroid precursor, 11β-hydroxyandrostenedione (11OHA4). Both 11 KT and 11KDHT are potent agonists of the human androgen receptor (AR). Studies are required to investigate whether levels of 11 KT and 11KDHT are significantly related to sexual function in women during menopause transition.[29]