Plasma
17-hydroxyprogesterone (17PROG) hyperresponsiveness to
GnRH agonist (
nafarelin) testing is typical of
polycystic ovary syndrome and other functional ovarian
hyperandrogenism (FOH) that does not meet customary criteria for the diagnosis of
polycystic ovary syndrome. We have postulated that this results from abnormal regulation of
androgen secretion. Whether this dysregulation is the result of a normal physiological response to ovarian hyperstimulation or escape from down-regulation of steroidogenesis is unknown. To distinguish between these possibilities, we have analyzed the ovarian
steroid responses to
nafarelin for the apparent efficiency of the steroidogenic steps and the apparent dose-response relationships between blood LH and
steroid levels. We compared normal women (n = 18) with three groups of hyperandrogenic women (n = 15-19/group): patients with 17PROG hyperresponsiveness with or without elevated LH levels (type 1 and type 2 FOH, respectively) and patients 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
steroid 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 significantly increased. Baseline levels of both AD and
dehydroepiandrosterone and the AD response to
nafarelin were increased, yet the ratio of peak minus baseline (delta) AD/delta 17PROG (another index of
17,20-lyase activity) was subnormal in FOH. The apparent slope of the
testosterone (T) response to LH was significantly increased, and indexes of
aromatase activity [
estradiol (E2)/T and delta
estradiol/delta T] were significantly decreased.
Nafarelin stimulated plasma E2 in all groups to rise along an apparently similar LH-E2 dose-response slope. We interpret these results as indicating that FOH patients have generalized overactivity of thecal steroidogenesis, but nevertheless compensate so as to maintain a normal dose-response relationship between blood levels of LH and E2. FOH patients, whether they have LH excess or not, seen to form excessive 17PROG and incompletely dampen (down-regulate) thecal cell 17PROG, AD, and T secretion in response to LH stimulation. 17PROG hyperresponsiveness to
nafarelin seems to be prominent both 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 decrease in
aromatase efficiency, which is secondary to negative feedback by the substrate-driven tendency toward
estrogen excess.(ABSTRACT TRUNCATED AT 400 WORDS)