Conference 2005 back to Programme ANDROGENS IN WOMEN: PHYSIOLOGY AND PATHOPHYSIOLOGY Traish, A.M., Guay, A., Munarriz,R. and I Goldstein Institute for Sexual Medicine, Boston Univ. School of Medicine, Boston, MA, USA Center for Sexual Function, Lahey Clinic, Peabody, MA, USA Objective: To review and discuss the physiology and pathophysiology of androgens in women's sexual function. Historical perspective: The action of androgens in women's sexual interest was first noted by Shorr (1938) as an incidental finding in studies on the effects of androgens on menopause. Shortly thereafter, Loeser (1940) reported that all women treated with testosterone experienced an enlargement of the clitoris and increased sexual drive, suggesting that androgens play an important role in enhancing libido in women. This observation was confirmed by several studies (Greenblatt & Wilcox, 1941; Greenblatt et al., 1942; Salmon, 1941; Salmon & Geist, 1943; Carter et al., 1947). Based on these observations, the effects of androgens on increasing libido in women were considered universal. The increased libido and sexual response was attributed, in part, to changes in the external genitalia (increased sensitivity to engorgement and hypertrophy of the clitoris and the vulva) and to increased sensation secondary to sexual stimulation. While stimulation of sex drive in women by estrogen alone is not commonly encountered in clinical experience (Dorfman & Shipley 1956), libido and sexual response were greater when testosterone was administered together with estrogen (Shorr, 1938). This combined estrogen-androgen treatment resulted in heightened sexual desire, easier attainment of orgasm and heightened satisfaction during intercourse. It was postulated that androgens not only act at the central nervous system but also at the peripheral genital level. Androgens were postulated to have a three-fold action in women: a) increase the susceptibility to psychosexual stimulation, b) increase the sensitivity of external genitalia, and c) increase the intensity of sexual gratification (Salmon & Geist, 1943). Endogenous androgens in the normal mature woman may act as physiological sensitizers of both the psychic and somatic components of the sexual mechanism (Salmon & Geist, 1943). Sexual dysfunction in women: An estimated 40% of women experience some form of sexual dysfunction, highlighting the need for research in this field in order to define the potential contribution of androgen deficiency. Further, the availability of products, such as dehydroepiandrosterone (DHEA) supplements and testosterone preparations in the forms of transdermal patches, gels, creams, or percutaneous implants necessitates better understanding of the role of androgens in women's health. Androgen treatment results in improvements in libido and sexual function, mood and well-being. Evidence points to other potential benefits of androgen treatment, including preservation of bone mass and potential beneficial effects on cognition. Adverse effects of androgen treatment in women are dose-dependent and include virilisation, mood disturbance and acne, requiring the need for close clinical and biochemical monitoring. Androgen insufficiency in women: The concept of androgen insufficiency syndrome in women (Bachman et al., 2002), although not altogether new (see above), remains controversial. However, this concept has gained substantially increased attention in recent years. The mere fact that in women androgens serve as precursors for the synthesis of estrogens and that serum androgen levels are expected to be greater than estrogens suggests that androgen insufficiency may exist in both premenopausal as well as postmenopausal women. However, this hypothesis remains to be confirmed. Androgen insufficiency in premenopausal and postmenopausal women may be considered a valid clinical concern, under specific conditions. Clinical symptoms of androgen insufficiency include diminished well-being, lethargy, tiredness, loss of sex drive and interest, fatigue and blunted motivation. Androgen insufficiency occurs in a number of circumstances, including hypopituitarism, premature ovarian failure, adrenal failure, exogenous corticosteroid use and oral estrogen therapy. Nevertheless, there is a great deal of skepticism regarding the therapeutic potential of androgens in treating women's sexual function disorders. Unfortunately, an accurate appraisal of the usefulness of the therapeutic value of androgens in the management of female sexual dysfunction remains elusive; in part due to the paucity of objective clinical criteria and in part due to the limited pre-clinical and clinical studies investigating the underlying pathophysiology. Despite such hurdles and limited controlled clinical studies, an increasing body of evidence is emerging, suggesting that women with signs and symptoms of androgen insufficiency respond well to androgen replacement without significant side-effects. Better understanding of the role of androgens in modulating female sexual function requires investigation of the biochemical, cellular and physiological mechanisms by which androgens modulate sexual function. Clinical and pre-clinical studies: To date, limited data are available on the serum androgen levels of healthy, pre- and postmenopausal women with and without complaints of sexual dysfunction. In preliminary clinical studies of healthy women between the ages of 20-49 without complaints of sexual dysfunction, we have observed that serum androgen levels exhibit a progressive stepwise decline (Guay et al., 2004 a,b). Comparing values obtained in women age 20-29 to those obtained in women 40-49, specific hormone decrements were DHEAS 195.6 µg/dL to 140.4 µg/dL, total serum testosterone 51.5 to 33.7 ng/dL, and free serum testosterone 1.5 to 1.0 pg/mL. SHBG did not change significantly in women in this age group. The Free Androgen Index (FAI) reflected the age-related decrease in female serum androgen levels. In women with and without complaints of sexual dysfunction, there were no differences in the basal ovarian or cortisol levels. After ACTH stimulation, both groups had increased cortisol as well as adrenal and ovarian androgens. However, women with complaints of sexual dysfunction had significantly lower adrenal androgens than those without sexual dysfunction. These observations point to the potential role of androgens in modulating sexual function in healthy pre-menopausal women. In pre-clinical studies, we have demonstrated that androgen administration into ovariectomized animals facilitates vaginal smooth muscle relaxation to electric field stimulation and VIP (Kim et al., 2004 a,b). Also, androgens increase vaginal blood flow and vaginal nerve network fibers (Traish et al., unpublished observations), suggesting that androgens play an important role in maintaining genital tissue structural and functional integrity. Summary: Considerable body of literature is accumulating regarding the therapeutic value of androgens in women with sexual dysfunction (Sherwin & Gelfand, 1987; Sherwin, 1991; Davis, 1998; Davis & Burger, 1998; Bachmann et al., 2002; Davison & Davis, 2003; Goldstat et al., 2003; Sarrel, 1987, 1998, 2000; Shifren et al., 2000; Shifren, 2004; Arlt et al., 1999, 2000; Hackbert & Heiman, 2002; Tuiten et al., 2002 a,b). 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