Studies of the nature of 17-hydroxyprogesterone hyperresonsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism.
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)
Rosenfield
R L
RL
Department of Pediatrics, University of Chicago, Pritzker School of Medicine, Illinois 60637.
Barnes
R B
RB
Ehrmann
D A
DA
D006907:17-alpha-Hydroxypregnenolone / Q000097:blood; D019326:17-alpha-Hydroxyprogesterone; D000293:Adolescent; D000328:Adult; D000735:Androstenedione / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D006908:Hydroxyprogesterones / Q000097:blood*; D017588:Hyperandrogenism / Q000097:blood*; D007986:Luteinizing Hormone / Q000097:blood; D017274:Nafarelin; D010049:Ovarian Diseases / Q000097:blood*; D013739:Testosterone / Q000097:blood
D006908:Hydroxyprogesterones; D017274:Nafarelin; D006907:17-alpha-Hydroxypregnenolone; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D019326:17-alpha-Hydroxyprogesterone; D003907:Dexamethasone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone