Follicular atresia and infertility in rats treated with a gonadotropin-releasing hormone antagonist.
Adverse effects of the GnRH antagonist Antide on folliculogenesis and fertility were noted when we were evaluating the therapeutic value of Antide on endometriosis in a rat model. Cyclic rats with (n = 56) and without (n = 18) surgically induced endometriosis received Antide (2 mg/kg) or vehicle at noon on days 0 (proestrus), 3, 6, and 9. Rats were killed at noon on days 0, 6, 12, 18, 24, 30, 42, and 165. The number of antral follicles and the number of atretic antral follicles evaluated did not differ (P greater than 0.05) between endometriosis and control rats. Antide-treated rats had more (P less than 0.05 ) atretic antral follicles (64.7%) than vehicle-treated rats (15.3%). Antide-treated rat ovaries contained fewer corpora lutea than those of vehicle-treated rats on days 6, 12, and 18. No corpora lutea were found in Antide-treated rat ovaries after day 18. The abnormal ovarian morphology of the Antide-treated rats persisted for the duration of the project (165 days). Fertility (rats without endometriosis) was assessed by mating vehicle-and Antide-treated rats at spontaneous proestrus (n = 8) for eight posttreatment cycles as well as after follicular stimulation (n = 2). All vehicle-treated and no Antide-treated rats became pregnant. No oocytes were found in the oviducts of Antide-treated rats after eight cycles, indicating that ovulation had not occurred. The serum FSH and estradiol concentrations in the rats treated with Antide were lower (P less than 0.05) on days 6, 12, and 18, but rose to values equal to (days 24 and 30) or greater than (day 42) those in vehicle-treated rats. Serum progesterone levels in rats treated with Antide were lower (P less than 0.05) than those in vehicle-treated rats on all days tested. In conclusion, at a dosage sufficient to suppress reproductive cyclicity (and elicit the regression of endometriosis), Antide also caused long term follicular atresia and infertility.
Sharpe
K L
KL
Department of Obstetrics and Gynecology, University of Kentucky, Lexington 40536.
Bertero
M C
MC
Lyon
B P
BP
Muse
K N
KN
Vernon
M W
MW
D000818:Animals; D004715:Endometriosis / Q000188:drug therapy; D004958:Estradiol / Q000097:blood; D004971:Estrus / Q000187:drug effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005496:Follicular Atresia / Q000187:drug effects*; D005498:Follicular Phase / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D007247:Infertility, Female / Q000139:chemically induced* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains
D009842:Oligopeptides; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D005640:Follicle Stimulating Hormone; C057022:iturelix