ABSTRACT
In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS.
Subject(s)
Leuprolide/pharmacology , Polycystic Ovary Syndrome/drug therapy , Reproduction/drug effects , Animals , Anovulation/drug therapy , Anovulation/metabolism , Estrous Cycle/drug effects , Female , Gonadotropin-Releasing Hormone/metabolism , Male , Ovarian Follicle/metabolism , Polycystic Ovary Syndrome/metabolism , Rats , Rats, Wistar , Testosterone/metabolism , Virilism/drug therapy , Virilism/metabolismABSTRACT
Metformin improved the glucose rate and the homeostasis model assessment-insulin resistance (HOMA-IR) index and caused partial reversion of ovaries and uterine morphology in female rats androgenized with testosterone.
Subject(s)
Metformin/therapeutic use , Reproduction/drug effects , Reproduction/physiology , Virilism/drug therapy , Animals , Female , Insulin Resistance/physiology , Male , Metformin/pharmacology , Rats , Rats, Wistar , Virilism/chemically induced , Virilism/metabolismABSTRACT
Abnormal exposure to steroid hormones within a critical developmental period elicits permanent alterations in female reproductive physiology in rodents, but the impact on the female GH axis and the underlying sexual differences in hepatic enzymes have not been described in detail. We have investigated the effect of neonatal androgenization of female mice (achieved by s.c. injection of 100 µg testosterone propionate (TP) on the day of birth: TP females) on the GHRH-somatostatin-GH axis and downstream GH targets, which included female and male predominant liver enzymes and secreted proteins. At 4 months of age, an organizational effect of neonatal testosterone was evidenced on hypothalamic Ghrh mRNA level but not on somatostatin (stt) mRNA level. Ghrh mRNA levels were higher in males than in females, but not in TP females. Increased expression in TP females correlated with increased pituitary GH content and somatotrope population, increased serum and liver IGF-I concentration, and ultimately higher body weight. Murine urinary proteins (MUPs) that were excreted at higher levels in male urine, and whose expression requires pulsatile occupancy of liver GH receptors, were not modified in TP females and neither was liver Mup 1/2/6/8 mRNA expression. Furthermore, a male predominant liver gene (Cyp2d9) was not masculinized in TP females either, whereas two female predominant genes (Cyp2b9 and Cyp2a4) were defeminized. These data support the hypothesis that neonatal steroid exposure contributes to the remodeling of the GH axis and defeminization of hepatic steroid-metabolizing enzymes, which may compromise liver physiology.