Prenatal androgen exposure affects ovarian lipid metabolism and steroid biosynthesis in rats

Abstract

Prenatal androgen exposure affects reproductive functions and has been proposed as an underlying cause of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal androgen exposure on ovarian lipid metabolism and to deepen our understanding of steroidogenesis regulation during adulthood. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. This treatment leads to two different phenotypes: irregular ovulatory and anovulatory animals. Our results showed that prenatally hyperandrogenized (PH) animals displayed altered lipid and hormonal profile together with alterations in steroidogenesis and ovarian lipid metabolism. Moreover, PH animals showed alterations in the PPARg system, impaired mRNA levels of cholesterol receptors (Ldl-r and Srb-1) and decreased expression of the rate-limiting enzyme of de novo cholesterol production (Hmgcr). Anovulatory PH animals presented an increase of ovarian cholesteryl esters levels and lipid peroxidation index. Together with alterations in cholesterol metabolism, we found an impairment of the steroidogenic pathway in PH animals in a phenotype-specific manner. Regarding fatty acid metabolism, our results showed, in PH animals, an altered expression of Srebp1 and Atgl, which are involved in fatty acid metabolism and triglycerides hydrolysis, respectively. In conclusion, fatty acid and cholesterol metabolism, which are key players in steroidogenesis acting as a source of energy and substrate for steroid production, were affected in animals exposed to androgens during gestation. These results suggest that prenatal androgen exposure leads to long-term effects that affect ovary lipid metabolism and ovarian steroid formation from the very first steps.

Effects of Androgen Excess-Related Metabolic Disturbances on Granulosa Cell Function and Follicular Development

“…In terms of the effect of androgen on lipid metabolism, Abruzzese et al established a prenatally hyperandrogenized rat model and clarified the effect of prenatal androgen exposure on ovarian lipid metabolism (34). Sun et al compared the steroid and metabolic parameters between women with PCOS and healthy women and found the significantly increased serum androgen levels and upregulated lipid profiles in women with PCOS, which is consistent with previous studies; besides, the cholesterol level was also upregulated in PCOS offspring, indicating that lipid disorders, just like hyperandrogenism and insulin resistance, is a heritable clinical manifestation which may participated in the pathophysiology of PCOS from fetal stage (40).…”

“…More specific roles that androgen-induced metabolic disorders played in granulosa cells dysfunction were further demonstrated in the PPI network. Among the 10 hub genes we identified through Cytoscape, the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme catalyzing cholesterol production, was decreased in human PCOS granulosa cells and prenatally hyperandrogenized animals ( 34 ), which may be caused by the feedback inhibition of elevated androgen levels in PCOS ( 35 ). Besides, the decline of fatty acid desaturase genes 2 ( FADS2 ) expression was also found in women with PCOS, which was correlated with altered androgen levels and dyslipidemia ( 36 ).…”

The Effects of Statins on Hyperandrogenism In Women With Polycystic Ovary Syndrome: A Systematic Review And Meta-analysis of Randomized Controlled Trials

“…Cholesterol is a key substrate for the production of androgens, inhibition of the biosynthesis of cholesterol will lead to a decrease of androgens [39][40][41] . In this way, a competitive inhibition of statin to HMG-CoA reductase, a key enzyme of cholesterol biosynthesis, possibly lead to a decrease of androgens [42,43] .…”

ANGPTL4 expression in ovarian granulosa cells is associated with polycystic ovary syndrome

“…As we all know, Polycystic ovary syndrome (PCOS) is a highly heterogeneous endocrine disorder characterized by hyperandrogen, rare ovulation and polycystic ovary, and its pathogenesis is debated [14][15][16] .Previous studies have demonstrated that the core etiology and primary endocrine characteristics of PCOS are insulin resistance (IR) and hyperandrogenemia (HA), and they can interplay each other leading to metabolic syndrome, especially dyslipidemia [17][18][19][20][21] . AMH are often used as clinical observation indicators reflecting the ovarian reserve 22,23 , and the LH/FSH and T levels were significantly higher in PCOS patients compared with control patients 24,25 .Compared with those characteristics related to PCOS, the expression level of ANGPTL4 in ovarian GCs might be a independent factor which affected incidence of PCOS and could serve as a new predictor for PCOS according to results of ROC cure and binary logistic regression analysis.…”