RU486-treated rats show endocrine and morphological responses to therapies analogous to responses of women with polycystic ovary syndrome treated with similar therapies.
Administration of 4 mg of the antiprogestagen RU486 to 4-day-cyclic rats over 8 consecutive days starting on the day of estrus (Day 1) induced and anovulatory cystic ovarian condition with endocrine and morphological features similar to those exhibited in polycystic ovarian disease (PCO). To determine whether the RU486-treated rat responds in an analogous fashion to therapies similar to those that have been used to treat human PCO, RU486-treated rats were injection on Days 5 and 7 with 1) 1 mg of an LHRH antagonist (LHRHa), 2) 5 IU of human FSH (hFSH), 3) 2 mg of the antiandrogen flutamide (FLU), 4) 1 mg of the antiestrogen tamoxifen (TMX), or 5) 1 mg of the dopamine agonist bromocriptine (BRC). Controls were intact cyclic rats decapitated on estrus and rats injected with RU486 and the corresponding vehicles (saline or 70% ethanol) used with LHRHa, hFSH, FLU, TMX, and BRC injections. RU486-treated rats were decapitated on Day 9, and the serum concentrations of LH, FSH, prolactin (PRL), testosterone (T), and estradiol-17 beta (E2) were determined. Pituitary and ovary weight, number of follicular cysts, size of the corpora lutea, and rates of follicular growth and atresia were also noted. Finally, the ovulatory response to ovine LH (oLH) in rats treated with RU486 and injected with various doses of hFSH (5, 10, or 20 IU) was evaluated. While administration of LHRHa and of TMX decreased the serum concentrations of LH, T and E2 and the LH/FSH and T/E2, ratios, and injections of BRC and of FLU increased the serum concentration of LH and T, the administration of hFSH (10 IU) to RU486-treated rats increased only the serum levels of E2. All treatments decreased, though in different degrees, both the number of cysts and the rate of follicular atresia, and stimulated follicular growth. The positive effects on follicular growth and atresia were significantly higher in those rats injected with hFSH. Moreover, RU486-treated rats injected with different doses of hFSH ovulated in a dose-dependent manner in response to oLH. Rates deprived of the actions of progesterone through the administration of the antiprogestagen RU486 had 1) endocrine and morphologic alterations comparable to those observed in women with PCO, 2) analogous responses to therapies similar to those that have been used to treat human PCO, and 3) an ovulatory response to combined treatment with FSH and LH. These results establish the fundamental adequacy of using the RU486-treated rat as a PCO model.
Ruiz
A
A
Department of Physiology, Faculty of Medicine, University of Córdoba, Spain.
Aguilar
R
R
Tébar
A M
AM
Gaytán
F
F
Sánchez-Criado
J E
JE
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D010053:Ovary / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology*; D010060:Ovulation / Q000187:drug effects; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced*; D011374:Progesterone / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000494:pharmacology
D000726:Androgen Antagonists; D018491:Dopamine Agonists; D004965:Estrogen Antagonists; D006727:Hormone Antagonists; D013629:Tamoxifen; D015735:Mifepristone; D007987:Gonadotropin-Releasing Hormone; D001971:Bromocriptine; D011374:Progesterone; D005485:Flutamide; D005640:Follicle Stimulating Hormone