Effect of androgen excess on inappropriate gonadotropin secretion as found in the polycystic ovary syndrome.

Hirsute and oligomenorrheic women with steroid biosynthetic enzymatic deficiencies (ED) such as 21-hydroxylase (21-HD) deficiency and 3 β -hydroxysteroid dehydrogenase-isomerase deficiency (3 β -olD) often exhibit inappropriate gonadotropin secretion (IGS) and clinically resemble women with the polycystic ovary syndrome (PCO). Furthermore, the manifestation of androgen excess in ED women varies with the extent as well as the type of enzymatic defect. This study was carried out in order to investigate the causes for the variability in the clinical signs of adrenal androgen excess in ED women and to explain the potential role of adrenal-derived androgens in the development of IGS. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E 2 ), testosterone (T), androstenediol (A 2 ), dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP), sex hormone–binding globulin binding capacity (SHBG-BC), and unbound T, A 2 , and E 2 were measured in five women with 21-HD, three women with 3 β -olD, 22 women with well-documented PCO, and 13 control subjects. In vitro incubation studies were also carried out by adding either T or A 2 to sera from four normal women with lowered SHBG-SC in order to study the effect of increasing androgen concentrations on the displacement of T, A 2 , and E 2 from SHBG. Unbound serum E 2 , A 2 , and T were elevated in all eight ED women whose SHBG-BCs were lower than those of control subjects (p 2 of PCO and ED women showed a positive correlation with LH levels and the LH:FSH ratios (p 2 which results in part from a lowered SHBG-BC may be responsible for the observed IGS. Four women with 21-HD treated for 1 month with 0.5 mg of dexamethasone nightly had a significant decrease in the percentage of unbound E 2 (p 2 explain the variable manifestation of androgen excess in ED women. The increased total A 2 as well as elevated unbound A2 and T explains the androgen excess of 3 β -olD women who have high levels of weak androgens (RHEA, DHEA-S) and normal total T. In vitro incubation studies indicated that two women with 21-HD had endogenous levels of serum T which could inhibit the binding of A 2 and E 2 , independent of SHBG, resulting in increased unbound fractions of A 2 and E 2 . Similarly five of the eight ED women had endogenous levels of serum A 2 which could inhibit steroid binding to SHBG and thereby result in increased fractions of unbound T, A 2 , and E 2 . Thus, primarily adrenal-derived androgens, in the case of ED subjects, and increases in the unbound fractions of T, A 2 , and E 2 explain both their androgen excess and in part their IGS. The unbound fractions of T, A 2 , and E 2 are increased because of lowered SHBG-BC, and when T and A 2 are sufficiently elevated, because of the inhibition of binding, independent of SHBG levels. It is suggested that this study of women with primarily adrenal androgen excess allows us to speculate on the possible role of the adrenal gland in the androgen excess and IGS of PCO women, many of whom are known to have elevated adrenal androgens. This is discussed and a diagrammatic scheme of our concept of the interrelationship of androgen excess, IGS, and PCO is presented.