Cyproteroneacetate and ACTH adrenal function.

Cyproteroneacetate, an antiandrogenic and gonadotropin-inhibiting steroid, has a marked ACTH suppressive effect. In rats, adrenal atrophy and severe impairment of ACTH and corticosterone responses to stress are induced by a 10-day treatment with 3-0.75 mg/100 g BW cyproteroneacetate/day. Two weeks after cessation of treatment, the ACTH adrenal system has not yet recovered. The ACTH suppression is evident 6 h after a single dose. In 25 human volunteers, a single dose of 200 mg cyproteroneacetate impaired their ACTH and 11-deoxycorticosteroid response to 1 g metyrapone. A similar impairment was seen in 12 women on sequential treatment with cyproteroneacetate and ethinyl estradiol. In 4 out of 11 children treated for precocious puberty, random plasma ACTH and cortisol measurements, cortisol responses to ACTH, and ACTH and cortisol responses to insulin-induced hypoglycemia revealed severely impaired ACTH adrenal function. Questionable impairment was found in 2 out of 11 and normal function in 5 out of 11 children. In 10 patients with endogenous elevated plasma ACTH, 10 days of treatment with cyproteroneacetate, in addition to the steroid substitution, diminished the morning plasma ACTH levels. It is concluded that cyproteroneactate has a pronounced ACTH-suppressive effect. The individual susceptibility of treated patients varies and the effect is dose dependent. A cortisol-like effect must be assumed, because cyproteroneacetate-treated animals and patients under therapy can withstand stress situations without signs of adrenal insufficiency. ACTH adrenal function must, however, be closely watched in treated patients and steroid cover must be considered in conditions of stress. Great care has to be taken when the drug, with its own "stress-protective" effect, is withdrawn. The recovery of ACTH adrenal function may take several months.

Dose-response study with a new LH-RH analogue, D-Ser (TBU)6 LH-RH 1-9 (EA)10 during the follicular phase of the menstrual cycle.

D-Ser (TBU)6 LH-RH 1-9 (EA)10 (HOE 766) a highly active LH-RH analogue, was studied with regard to its effects on the release of follicle stimulating hormone (FSH), luteinizing hormone (LH) and oestradiol-17beta (Oe2) during the follicular phase of the menstrual cycle. Forty-two regularly menstruating women were allowed to five different treatment groups with different doses (1.25 microgram; 2.5 microgram; 5.0 microgram; 10.0 microgram; 20.0 microgram) of HOE 766 given as intravenous bolus injections and the plasma concentrations of FSH, LH and Oe2 were measured up to 24 h after injection using specific radioimmunoassays. In the majority of cases, peak values of both FSH and LH occurred 4 h after injection being significantly different from pre-injection levels (P less than 0.02 in the 1.25 microgram treatment group, P less than 0.005 for the other treatment groups). Statistical analysis of maximum values as well as the absolute and relative increase in the different treatment groups revealed a dose-dependent effect of HOE 766. Maximum values of Oe2 occurred 8 h after injection and were found to be significantly different from pre-injection levels (P less than 0.005). However, no dose dependent effect was observed. It was concluded that HOE 766 is a potent and long-acting stimulator of FSH, LH and OE2 release in women. The effect of HOE 766 is dose dependent for FSH and LH but not for Oe2.

Human pituitary gonadotrophin index. II LHRH test and clomiphene response before and after LHRH stimulation.

To monitor the effect of LHRH treatment on hypothalamo-pituitary-gonadal function, women with functional amenorrhoea were investigated by standardized LHRH and repeated clomiphene tests before and after LHRH therapy. The actual pituitary gonadotrophin reserve was defined by a Human Pituitary Gonadotrophin Index (HPGI). Clomiphene response served as hypothalamic function test, plasma oestradiol and progesterone concentrations were measured for assessment of the gonadal function. LHRH treatment as performed in this study did not change basal gonadotrophin levels or the pituitary responsiveness in our standardized LHRH test. Plasma oestradiol concentrations remained unaltered at the lower limit of the early follicular phase values of a normal menstrual cycle. The inability to respond to clomiphene was changed to clomiphene responsiveness during therapy in eighteen out of twenty-nine women with anovulation. The majority of the responders had HPG-Indices of R2. Patients with hyperprolactinaemic anovulation did not convert. The possibility of an ultrashort feedback action of LHRH on its own production in the human is discussed.

Human pituitary gonadotropin index. I. Standardized LRH test criteria for evaluation of functional amenorrhea.

LRH test were carried out by giving 339 amenorrheic women and 74 normally menstruating volunteers an intravenous injection of 25 mug LRH (Hoe 471). Plasma LH and FSH were measured by RIA in two laboratories (Tuebingen and Ulm) using two standard reference preparations: LER 907 and 2nd IRP-HMG. The average conversion factors between the two standard preparations were calculated at 5.0 for LH and 25.0 for FSH. Furthermore, the estradiol-17beta levels were measured in 139 out of the 339 patients immediately before and 60 minutes after LRH injection. Taking the episodic and cyclic plasma gonadotropin fluctuations into consideration a shorthand system classifying the gonadotropin baseline (BI-BIV) and LH responses to 25 mug LRH (R0-R2) has been established and is referred to as Human Pituitary Gonadotropin Index (HPGI). It is possible to achieve reproducible gonadotropin results in two different laboratories using two different standard reference preparations. Two separate, randomly selected groups of amenorrheic women were found to have the same percent distribution of the HPGI. A correlation coefficient of r equal 0.67 between basal and LRH stimulated plasma LH levels does not sufficiently characterize the individual LH response behavior. A significant increase of plasma LH and FSH within the test period (60') reveals that the iv administration of 25 mug LRH represents an adequate dose for the LRH test in women. The HPGI which characterizes the functional state of gonadostat, may become a useful diagnostic index for evaluating women with anovulatory disease before, during, and after therapy.