Studies of the relation of plasma androgen levels to androgen action in women

Abstract

Testosterone-estradiol-binding-globulin (TEBG) is a major determinant of androgen disposition and action. TEBG levels, but not free testosterone levels, correlate with the metabolic clearance rate (MCR) of testosterone in normal women. This suggests that the testosterone MCR reflects androgen removal by the liver, an organ which removes a large fraction of steroid on a single passage, rather than the concentration of unbound androgen. Consequently, testosterone production seems more closely related to androgen catabolism than to androgen action. In support of this concept, we have studied a hirsute woman in whom testosterone clearance and production were elevated in the presence of a normal free testosterone level; her hirsutism seems related to androgens other than testosterone. Although testosterone is of major importance, androgen action seems to result from the net effect of several free plasma 17β-hydroxysteroids, including particularly androstenediol and dihydrotestosterone. About 25% of women with moderate male-pattern hirsutism have normal total and free plasma testosterone levels. In most such cases total 17β-hydroxysteroids are also normal. However, an abnormally low fraction of all these 17β-hydroxysteroids is bound to TEBG. As a result, an increase in the plasma “total androgenicity index” is present in this group of patients. Such women do not necessarily evidence increased testosterone production. Obesity appears to be another important determinant of androgen disposition and action. The testosterone MCR correlates well with adiposity independently of the TEBG levels in normal women. In addition, hyperandrogenism is frequently present with minimal or no hirsutism in obese women. This finding suggests that obesity increases the apparent “threshold” at which hirsutism appears in response to androgen or that obesity is a result of slight hyperandrogenism.