nafarelin and Hyperandrogenism

A controlled clinical study was designed to investigate the value of human chorionic gonadotrophin (HCG) challenge as a test for functional ovarian hyperandrogenism. Dexamethasone administration was followed by 5000 IU HCG and blood samples for steroid hormone assay were obtained 0, 8, 16, and 24 h thereafter. Study subjects were normal women (n = 13); women with functional ovarian hyperandrogenism, defined by androgen excess, amenorrhoea and an increased 17-hydroxyprogesterone response to nafarelin (n = 6); and normal men (n = 4). The responses of 17-hydroxyprogesterone, androstenedione and testosterone to HCG in women with functional ovarian hyperandrogenism were significantly greater than in normal women. However, the 17-hydroxyprogesterone response to HCG in functional ovarian hyperandrogenism was significantly lower after HCG than after nafarelin. The oestradiol response was also significantly lower after HCG than nafarelin, although oestradiol concentration more than doubled in normal women as well as in women with functional ovarian hyperandrogenism. The responses to HCG confirm that functional ovarian hyperandrogenism abnormalities are luteinizing hormone (LH)-dependent. Therefore, the 17-hydroxyprogesterone response to HCG could represent a useful test for the diagnosis of ovarian hyperandrogenism. The lower 17-hydroxyprogesterone response to HCG than to nafarelin in functional ovarian hyperandrogenism suggests that a follicle-stimulating hormone (FSH)-responsive factor modulates thecal 17-hydroxyprogesterone secretion. The oestradiol response to HCG is consistent with HCG directly stimulating the oestradiol secretion by thecal cells.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Androstenedione; Chorionic Gonadotropin; Female; Hormones; Humans; Hyperandrogenism; Kinetics; Male; Nafarelin; Pilot Projects; Testosterone

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.

Topics: Adolescent; Adrenal Gland Diseases; Adrenal Gland Neoplasms; Adult; Child; Dexamethasone; Female; Humans; Hydrolases; Hyperandrogenism; Luteinizing Hormone; Nafarelin; Neurosecretory Systems; Ovarian Diseases; Sex Characteristics; Testosterone; Virilism

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 t

Topics: 17-alpha-Hydroxypregnenolone; 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Androstenedione; Dexamethasone; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hydroxyprogesterones; Hyperandrogenism; Luteinizing Hormone; Nafarelin; Ovarian Diseases; Testosterone

Topics: Adolescent; Adult; Age Determination by Skeleton; Case-Control Studies; Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hyperandrogenism; Hypogonadism; Injections, Subcutaneous; Luteinizing Hormone; Nafarelin; Puberty, Precocious; Testosterone