ay-25-205 and Body-Weight

Long-term treatment with gonadoliberin analogs is used to block the hypothalamic-pituitary-gonadal axis. The use of these agents is generally considered to be safe; however, some observations suggest the possibility of adverse effects.. We investigated whether a 3-months administration of a low dose (6 µg/kg b.w.) of dalarelin - a new agonist, and cetrorelix - a known antagonist of GnRH to female rats causes morphological changes in pituitary gland, ovaries, uterus and liver (HE and VG staining); effects on pituitary, hepatic and blood enzyme activities (histochemical and kinetic methods, respectively), and on the blood lipid profile (colorimetric methods); and to what extent these changes are reversible.. Applying analogs effectively inhibited ovulation, affected the uterine endometrium and changed histological appearance of the liver (e.g., steatosis). They altered activities of marker enzymes of cellular respiration, gluconeogenesis and intracellular digestion in the liver and, partially in the pituitary gland, caused undesirable changes in the activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase, and a concentration of cholesterol HDL fraction and triglycerides in the blood. Both morphological and enzymatic effects were more evident after antagonist administration; changes in the blood lipid profile were more evident after agonist administration. In both analogs histological and enzymatic changes persisted a relatively long time after the discontinuation of the treatment.. The low dose of dalarelin and cetrorelix is sufficient to cause limited damage of hepatic cells and may modify the function of pituitary, ovaries, uterus and liver as well as other organs, even after discontinuation of the treatment.

Topics: Animals; Body Weight; Densitometry; Dose-Response Relationship, Drug; Enzymes; Female; Gonadotropin-Releasing Hormone; Immunohistochemistry; Liver; Organ Size; Organ Specificity; Ovary; Pituitary Gland; Rats; Rats, Sprague-Dawley; Time Factors; Uterus

Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.

Topics: Adult; Body Weight; Female; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Hematopoietic Stem Cells; Hormones; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Monocytes; Polycystic Ovary Syndrome; Receptor, Insulin

The inhibitory effect of treatment with a potent LHRH agonist on testicular gonadotropin-receptor levels was compared in intact and diabetic rats. Basal and LHRH-induced pituitary gonadotropin secretion as well as the testicular steroidogenic response to oLH were assessed. A single injection of alloxan (65 mg/kg) led, after 6 weeks, to a 40% decrease of testicular LH- and prolactin-receptor levels. Treatment for 2 weeks with [D-Ala6,des-Gly-NH 1/2 0] LHRH ethylamide (100 ng every second day) led to a 70% reduction of LH-receptor levels accompanied by decreased testicular weight, a similar inhibition being found in intact and diabetic animals. Seminal vesicle and ventral prostate weight were markedly reduced in diabetic animals, a further decrease being obtained after treatment with the LHRH agonist. The loss of accessory sex-organ weight in alloxan-diabetic rats was accompanied by a reduction in the basal testicular content of pregnenolone, progesterone, 17-OH-progesterone, androstenedione, testosterone and dihydrotestosterone whereas the steroid response to oLH was within normal limits. We next examined the possible changes of LH and FSH secretion which could be responsible for the reduced testicular function in diabetic animals. Basal plasma-LH levels were 30% reduced in rats 6 weeks after treatment with alloxan while basal plasma-FSH levels remained unchanged. When the pituitary gonadotropin response to LHRH was measured in chronically cannulated freely-moving intact and diabetic rats, an approx. 50% inhibition of the LH and FSH responses to LHRH was observed in diabetic animals.

Topics: Alloxan; Animals; Body Weight; Diabetes Mellitus, Experimental; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Luteinizing Hormone; Male; Pituitary Gland; Rats; Receptors, Cell Surface; Testis