Invited papers: androgens – too much or too little?

In women, androgens are essential for the development of reproductive function and the growth and maintenance of secondary sexual characteristics. The most significant biologically active circulating androgen, influencing many tissues and organs critically involved in the sexual response, is testosterone (T), which is tightly bound to sex hormone binding globulin and loosely to albumin. Other androgens in women include dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA) and androstenedione (A), which are considered to be proandrogens because they have to be converted to T to express their effects. At the central nervous system level, T directly, through aromatization to estradiol (E2) and non-genomic action by its metabolites, contributes to initiation of and receptivity to sexual behaviour. At the genital level, androgens directly modulate vaginal and clitoral physiology by influencing the muscular tone of erectile tissue and of the vaginal walls. Androgens facilitate vaginal smooth muscle relaxation, especially in the proximal vagina, producing distinct physiological responses in comparison with those produced by E2. In addition, T may enhance lubrication being converted to E2. While estrogens decrease sharply at menopause, plasma T levels fall slowly with age in the years preceding menopause. Levels do not vary significantly as a consequence of natural menopause, but are reduced by 50% following bilateral oophorectomy, giving origin to the so-called ‘androgen insufficiency syndrome’, an increasingly accepted clinical entity comprising specific symptoms such as low libido, persistent and inexplicable fatigue, blunted motivation and a general reduced sense of well-being. Indeed, no cut-off level for a normal range of T has been agreed on and data correlating poor libido at menopause and low plasma androgen levels are not definitive. Randomized controlled trials have shown that various combinations of systemically exogenous estrogens and androgens, even administered genitally, promote a significant improvement in mood, libido, enjoyment, ability to reach orgasm and initiation of in surgically estrogenized menopausal women, while less information is available in naturally menopausal women and premenopausal women.