Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis. Androgen excess alters liver lipid metabolism

Prenatal hyperandrogenism is able to induce polycystic ovary syndrome (PCOS) in rats. The aim of the present study was to establish if the levels of prenatal testosterone may determine the extent of metabolic and endocrine alterations during the adult life. Pregnant Sprague Dawley rats were prenatally injected with either 2 or 5 mg free testosterone (groups T2 and T5 respectively) from day 16 to day 19 day of gestation. Female offspring from T2 and T5 displayed different phenotype of PCOS during adult life. Offspring from T2 showed hyperandrogenism, ovarian cysts and ovulatory cycles whereas those from T5 displayed hyperandrogenism, ovarian cysts and anovulatory cycles. Both group showed increased circulating glucose levels after the intraperitoneal glucose tolerance test (IPGTT; an evaluation of insulin resistance). IPGTT was higher in T5 rats and directly correlated with body weight at prepubertal age. However, the decrease in the body weight at prepubertal age was compensated during adult life. Although both groups showed enhanced ovarian steroidogenesis, it appears that the molecular mechanisms involved were different. The higher dose of testosterone enhanced the expression of both the protein that regulates cholesterol availability (the steroidogenic acute regulatory protein (StAR)) and the protein expression of the transcriptional factor: peroxisome proliferator-activated receptor gamma (PPAR gamma). Prenatal hyperandrogenization induced an anti-oxidant response that prevented a possible pro-oxidant status. The higher dose of testosterone induced a pro-inflammatory state in ovarian tissue mediated by increased levels of prostaglandin E (PG) and the protein expression of cyclooxygenase 2 (COX2, the limiting enzyme of PGs synthesis). In summary, our data show that the levels of testosterone prenatally injected modulate the uterine environment and that this, in turn, would be responsible for the endocrine and metabolic abnormalities and the phenotype of PCOS during the adult life.

The objective of this work was to study the ovarian function when follicular development is induced during a hyperandrogenic condition. Female rats were injected with either equine chorionic gonadotropin (eCG group) to induce folliculogenesis or eCG together with DHEA to induce folliculogenesis in a hyperandrogenic condition (eCGCHA group). The control group was injected with vehicle. Ovarian mRNA levels of the peroxisome proliferator-activated receptor gamma (PPARg) co-activator PGC1a, the PPARg co-repressor NCoR, the main enzymes involved in the ovarian steroidogenesis (CYP17, 3b-hydroxysteroid dehydrogenase (3b-HSD), 17b-HSD, and CYP19A), and cyclooxygenase 2 (COX2) were evaluated only by real-time PCR. COX2 was evaluated by both real-time PCR and western blot. Serum steroid hormones and both the oxidative and inflammatory statuses were also quantified. We found that eCG-induced folliculogenesis induced increased mRNA levels of PGC1a and decreased those of NCoR when compared with controls. In addition, we found an increase in serum estradiol (E 2 ) levels and enhanced mRNA expression of CYP19A. A pro-inflammatory status and a pro-oxidant status were also established. When folliculogenesis was induced in a hyperandrogenic condition, the mRNA levels of the PPARg co-repressor NCoR remained higher than in controls and the pro-inflammatory and pro-oxidant statuses were enhanced. In addition, the enzymes involved in ovarian steroidogenesis were altered leading to the accumulation of testosterone and an unfavorable E 2 /testosterone ratio. These alterations led to abnormal follicular development.