Abstract
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age. Ovarian dysfunction including abnormal steroid hormone synthesis and follicular arrest play a vital role in PCOS pathogenesis. Hyperandrogenemia is one of the important characteristics of PCOS. However, the mechanism of regulation and interaction between hyperandrogenism and ovulation abnormalities are not clear. To investigate androgen-related metabolic state in granulosa cells of PCOS patients, we identified the transcriptome characteristics of PCOS granulosa cells by RNA-seq. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs) revealed that genes enriched in lipid metabolism pathway, fatty acid biosynthetic process and ovarian steroidogenesis pathway were abnormally expressed in PCOS granulosa cells in comparison with that in control. There are close interactions among these three pathways as identified by analysis of the protein-protein interaction (PPI) network of DEGs. Furthermore, in vitro mouse follicle culture system was established to explore the effect of high androgen and its related metabolic dysfunction on follicular growth and ovulation. RT-qPCR results showed that follicles cultured with dehydroepiandrosterone (DHEA) exhibited decreased expression levels of cumulus expansion-related genes (Has2, Ptx3, Tnfaip6 and Adamts1) and oocyte maturation-related genes (Gdf9 and Bmp15), which may be caused by impaired steroid hormone synthesis and lipid metabolism, thus inhibited follicular development and ovulation. Furthermore, the inhibition effect of DHEA on follicle development and ovulation was ameliorated by flutamide, an androgen receptor (AR) antagonist, suggesting the involvement of AR signaling. In summary, our study offers new insights into understanding the role of androgen excess induced granulosa cell metabolic disorder in ovarian dysfunction of PCOS patients.
Highlights
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder in women of reproductive age
These results indicated that lipid metabolism disorders are important characteristics of granulosa cells in PCOS patients
The RT-qPCR result indicated the evident decreased expression of Lss, Insig1and Srebf1, which suggested the impairment of lipid metabolism in DHEA-treated follicles and further verified that androgen excess had metabolically harmful effect on granulosa cells (Figure 3E). These results suggested that DHEA treatment induced failure of ovarian steroidogenesis and lipid metabolism, which may subsequently contribute to the disruption of follicle development
Summary
PCOS is a common reproductive endocrine disorder in women of reproductive age. Characterized by menstrual disorder, hirsutism and acne induced by hyperandrogenism and polycystic ovarian morphology, PCOS affects 5–10% of women worldwide and is the primary cause of anovulatory infertility in women of reproductive age [1]. As an important cell type in follicular formation and ovulation, the function of granulosa cells is closely related to anovulation and metabolic disorder in PCOS [3–6]. Li et al revealed a positive correlation between serum testosterone levels and the expression of autophagy-related genes, suggesting that androgen excess contributed to the activation of autophagy and apoptosis in granulosa cells, which subsequently impairs ovarian function [9, 10]. Combined, these results suggested androgens promote apoptosis of granulosa cells in PCOS, while the specific role and mechanism of androgens in regulating follicular growth and ovulation remains unclear
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