STUDIES OF THE NATURE OF 17-HYDROXYPROGESTERONE HYPERRESPONSIVENESS TO GONADOTROPIN-RELEASING-HORMONE AGONIST CHALLENGE IN FUNCTIONAL OVARIAN HYPERANDROGENISM

Plasma 17-hydroxyprogesterone (17PROG) hyperresponsiveness to GnRH ago nist (nafarelin) testing is typical of polycystic ovary syndrome and o ther functional ovarian hyperandrogenism (FOH) that does not meet cust omary criteria for the diagnosis of polycystic ovary syndrome. We have postulated that this results from abnormal regulation of androgen sec retion. Whether this dysregulation is the result of a normal physiolog ical response to ovarian hyperstimulation or escape from down-regulati on of steroidogenesis is unknown. To distinguish between these possibi lities, we have analyzed the ovarian steroid responses to nafarelin fo r the apparent efficiency of the steroidogenic steps and the apparent dose-response relationships between blood LH and steroid levels. We co mpared normal women (n = 18) with three groups of hyperandrogenic wome n (n = 15-19/group): patients with 17PROG hyperresponsiveness with or without elevated LH levels (type 1 and type 2 FOH, respectively) and p atients with normal 17PROG responses to nafarelin (nafarelin negative) . Subjects were pretreated with dexamethasone to suppress coincidental adrenal contributions to plasma steroid-levels. The pattern of steroi d secretion was similarly abnormal in both types of FOH, with the high LH group having generally more severe abnormalities in the levels of steroid intermediates. Baseline 17PROG and 17-hydroxypregnenolone and the ratio of 17PROG to androstenedione (AD) were increased (P < 0.05). In addition, the apparent slope of the 17PROG response to LH was sign ificantly increased. Baseline levels of both AD and dehydroepiandroste rone and the AD response to nafarelin were increased, yet the ratio of peak minus baseline (Delta) AD/Delta 17PROG (another index of 17,20-l yase activity) was subnormal in FOH. The apparent slope of the testost erone (T) response to LH was significantly increased, and indexes of a romatase activity [estradiol (E(2))/T and Delta estradiol/Delta T] wer e significantly decreased. Nafarelin stimulated plasma E(2) in all gro ups to rise along an apparently similar LH-E(2) dose-response slope. W e interpret these results as indicating that FOH patients have general ized overactivity of thecal steroidogenesis, but nevertheless compensa te so as to maintain a normal dose-response relationship between blood levels of LH and E(2). FOH patients, whether they have LH excess or n ot, seem to form excessive 17PROG and incompletely dampen (down-regula te) thecal cell 17PROG, AD, and T secretion in response to LH stimulat ion. 17PROG hyperresponsiveness to nafarelin seems to be prominent bot h because it is formed in excess and because 17,20-lyase efficiency is rate limiting. The T elevation seems to arise mainly from overactive steroidogenesis, but also partly from an additional functional decreas e in aromatase efficiency, which is secondary to negative feedback by the substrate-driven tendency toward estrogen excess. The apparently a bnormal dose-response relationship between LH and 17PROG suggests that factors other than LH excess may contribute to this dysregulation of steroidogenesis in FOH.