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

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.

The role of macrophages phenotypes in the activation of resolution pathways within human granulosa cells

“…4 d). This result contrasts with the one published by Liao et al [ 34 ], in which the authors demonstrated that 15-LOX expression was up-regulated in GCs isolated from women with PCOS. In regard to COV434 cells, a significant increase in 15-LOX expression is observed when these cells are also exposed to CMs of M1 and M2 macrophages (Fig.…”

Comparison of pregnancy outcomes of letrozole-induced frozen-thawed embryo transfer cycles in PCOS women with two different abnormal ovulation patterns: A retrospective cohort study

“…[30] Additionally, androgen exposure significantly affects the metabolic state of GCs in PCOS women, and impairs follicular growth and oocyte maturation, while the potential molecular mechanism remains to be explored in the future. [31] Moreover, the endocrine and ovulatory disturbances observed in PCOS exist on a continuum, with a milder phenotype of elevated androgen and follicles evident in eumenorrheic women with oligo-ovulation, which is indicative of factors that exist along a continuum of testosterone levels, including those without clinical hyperandrogenism (HA). [32] In parallel, a proof-of-concept study proposes that menstrual shedding may improve endometrial progesterone sensitivity, general endometrial function, and, possibly, pregnancy outcomes, in women with PCOS.…”

Bioengineered 3D Ovarian Models as Paramount Technology for Female Health Management and Reproduction

“…For this, alginate-encapsulated mouse secondary follicles were treated with 10 µM dehydroepiandrosterone (DHEA) to simulate the hyperandrogenic environment characteristic of PCOS. Their findings revealed that excessive androgen concentrations blocked follicular growth, cumulus expansion and ovulation in vitro [79]. These effects were associated with impaired steroidogenesis and reduced lipid metabolism in granulosa cells.…”

“…Traditionally, animal models, such as dihydrotestosterone (DHT)-induced PCOS mice, or 2D culture of granulosa cells isolated from PCOS patients have been used to study the effects of elevated androgen levels on the ovary and specifically on the granulosa cells [77,78]. Recently, Liao and colleagues used ovarian organoids to investigate the metabolic effects of androgen on granulosa cells during follicular growth [79]. For this, alginate-encapsulated mouse secondary follicles were treated with 10 µM dehydroepiandrosterone (DHEA) to simulate the hyperandrogenic environment characteristic of PCOS.…”