Efeitos do uso do acetato de leuprolide nas caraterísticas reprodutivas de roedores submetidos ao tratamento com testosterona propionato pré e pós-natal

Abstract

Androgen excess induces in female rats reproductive and metabolic disturbances that are similar to polycystic ovary syndrome in women. In these animals, the degree of changes may vary according to the timeline intervention, suggesting that the hypothalamic and pituitary axis may present different actions at pituitary-hypothalamic level before and after birth. The present study employed an agonist GnRH, leuprolide acetate, administrated as a single dose upto 48h of life in Wistar rats under prenatal or postnatal androgenisation protocols, looking for its effects on reproductive endpoints. Prenatal androgenisation (PreN) consisted in the administration of testosterone propionate 2.5 mg s.c. to mothers at the days 16,17 and 18, while postnatal androgenisation (PostN) was performed through the injection of 1.25 mg s.c. to animals within 5 day of life. Between 90 - 100 days of life, these rats were evaluated to the present of estral cycles (defined by vaginal smears and the presence of corpus luteum (CL), steroid levels (serum testosterone and androstenedione measured by liquid chromatography (HLPC MS/MS), ovarian morphology (histology), and the expression of mRNA for hypothalamic Kiss1, Gnrhr, and Gnrh and ovarian genes (Cyp17a1, Cyp19a1, CYp11a1,and Gnrhr).We observed that in PostN group, characterized by anovulation and increased number of cysts/atretic follicles), a single injection of a leuprolide acetate depot (lasting 4 weeks) (PostN L)was able to increase ovulatory rates, as defined by vaginal smears. The treatment with this GnRH agonist in PostN L also reduced testosterone serum levels as well the number of cysts/atretic follicles in contrast with PostN group (p=0.04). Prenatally androgenized rats (PreN) exhibited significant abnormalities at hypothalamic genes, such as a reduction of Kiss1 and increased of Gnrh,in comparison with control and PostM groups. To the best of our knowledge, this is the first study to show that previous administration of a single dose of GnRH agonist (leuprolide acetate) could successfully preserve regular cycles, reduce androgen levels and the number of cysts/atretic follicles in rats submitted to androgen excess postnatally. Indeed, the results obtained with this model of PCOS suggest a clear participation of GnRH disruption to the progress to anovulation and cysts development.