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The behaviour of 5 alpha-reduced metabolites of testosterone, dihydrotestosterone1, 3 alpha-androstanediol and 3 beta-androstanediol, was studied in 36 hirsute women: Group I: 24 patients with high plasma levels of testosterone, androstenedione and/or dehydroepiandrosterone sulphate and Group II: 12 patients with normal plasma concentrations of these steroids. Testosterone and its 5 alpha-reduced metabolites were determined by radioimmunoassay after chromatographic separation on celite 535 microcolumns. Plasma 3 alpha-androstanediol was found to be elevated both in Group I (26.9 +/- 10.8 SD ng/100 ml) and in Group II patients (23.2 +/- 10.5 SD ng/100 ml). 3 beta-Androstanediol and dihydrotestosterone, on the contrary, were elevated in only a few cases: in 6 cases in Group I and in 2 and in 1 case, respectively, in Group II. The finding of high plasma 3 alpha-androstanediol levels in hirsute women, with normal values of the other androgens, may be an index of hirsutism of peripheral origin, since this steroid is produced almost exclusively in the extraglandular compartment.

The possibility that hirsutism is an evolving syndrome rather than a static condition involving only one gland has been considered. To assess this proposal 60 untreated hirsute patients aged 12-32 years were divided into five groups according to the duration of the hirsutism (less than 1, 1-2, 2-3, 3-5 and greater than 5 years). Peripheral plasma concentrations of LH and FSH, androstenedione, dehydroepiandrosterone sulphate, testosterone, 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, cortisol, oestradiol-17 beta and oestrone were determined by radioimmunoassay. When the values obtained were compared with those from normal menstruating women, the results showed that in group I there was a significant increase only in the mean plasma 5 alpha-androstane-3 alpha, 17 beta-diol concentration. The mean concentration of this steroid was also raised in all other groups. In groups II and III mean basal levels of plasma dehydroepiandrosterone sulphate were also significantly increased and showed a marked increase after ACTH stimulation (1 mg tetracosactide acetate, i.m.) as did the concentrations of androstenedione and 17 alpha-hydroxyprogesterone. Finally, in groups IV and V, a significant increase in mean plasma concentrations of LH, androstenedione, oestrone and testosterone was found in the basal condition. The clinical picture also became gradually more severe from group I to group V. These data suggest that hirsutism could be an evolving syndrome progressively involving peripheral androgen metabolism, the adrenal gland and finally the ovary possibly through alterations of hypothalamic-pituitary function.

Plasma 3 alpha-androstanediol levels are increased in a high percentage of hirsute women, including those with normal plasma levels of its precursors, repeatedly evaluated during the menstrual cycle. To better ascertain the origin of this form of hirsutism, so called "idiopathic", 17 hirsute women (aged 19.5 +/- 4.8 SD yr), with normal bw, showing an isolated increase in plasma 3 alpha-androstanediol (0.65 +/- 0.18 SD nmol/l) were studied in basal conditions (on day 6, 7, 17, 18 of the menstrual cycle). A hirsute female (aged 14 yr) with congenital adrenal hyperplasia due to 21-hydroxylase deficiency was also included in the protocol. Sex hormone binding globulin was evaluated using a saturation method (dihydrotestosterone- 3H 0.5-25 nM) with and without 200x cold dihydrotestosterone. Maximum number of binding sites and Ka were calculated in all cases with Scatchard analysis. Free testosterone was evaluated by the equilibrium dialysis technique. The results obtained showed a significant increase in Ka values in 10 out of the 17 cases; low plasma levels of sex hormone binding globulin in 13 cases and normal levels in 4 cases; high levels of free testosterone fraction in 5 cases and in the upper limits of the normal range or normal in the remaining 12. These findings demonstrate that some cases of "idiopathic" hirsutism may present an alteration in the binding affinity of the sex hormone binding globulin which may be genetically transmitted, being found to be increased in two sisters and in their brother.