Induced Pluripotent Stem Cells as a Possible Approach for Exploring the Pathophysiology of Polycystic Ovary Syndrome (PCOS)

Abstract

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine condition among women with pleiotropic sequelae possessing reproductive, metabolic, and psychological characteristics. Although the exact origin of PCOS is elusive, it is known to be a complex multigenic disorder with a genetic, epigenetic, and environmental background. However, the pathogenesis of PCOS, and the role of genetic variants in increasing the risk of the condition, are still unknown due to the lack of an appropriate study model. Since the debut of induced pluripotent stem cell (iPSC) technology, the ability of reprogrammed somatic cells to self-renew and their potential for multidirectional differentiation have made them excellent tools to study different disease mechanisms. Recently, researchers have succeeded in establishing human in vitro PCOS disease models utilizing iPSC lines from heterogeneous PCOS patient groups (iPSC_PCOS). The current review sets out to summarize, for the first time, our current knowledge of the implications and challenges of iPSC technology in comprehending PCOS pathogenesis and tissue-specific disease mechanisms. Additionally, we suggest that the analysis of polygenic risk prediction based on genome-wide association studies (GWAS) could, theoretically, be utilized when creating iPSC lines as an additional research tool to identify women who are genetically susceptible to PCOS. Taken together, iPSC_PCOS may provide a new paradigm for the exploration of PCOS tissue-specific disease mechanisms.

Keywords: Embryonic stem cell; Genome wide association study; Induced pluripotent stem cell; Polycystic ovary syndrome; Polygenic risk score.

Fig. 1

(a) Pathophysiology of polycystic ovarian syndrome (PCOS). Women with PCOS have impaired neuronal circuits in the brain, resulting in increased GnRH pulsatility, which in turn causes the hypersecretion of LH and subsequent HA from the ovarian theca cells. Follicular maturation is inhibited by excessive AMH secretion, which downregulates FSH action. This results in follicular arrest, polycystic ovarian morphology, and ovulatory dysfunction. The high AMH concentration also stimulates GnRH neuron activity and directly drives the GnRH-dependent production of LH, which may further promote ovarian HA. Predisposition to excessive ovarian androgen production is the primary defect in PCOS. Additionally, IR leads to hyperinsulinemia, which elevates GnRH release and increases androgen production in ovarian theca cells while suppressing SHBG production, causing HA; (b) Rotterdam criteria diagnostic consensus 2004. Includes at least two of three features: phenotype A (polycystic ovaries + ovulatory dysfunction + excessive androgen/HA), phenotype B (ovulatory dysfunction + HA), phenotype C (polycystic ovaries + HA), and phenotype D (polycystic ovaries + ovulatory dysfunction); (c) Possible etiological factors in PCOS pathogenesis. GnRH, gonadotrophin-releasing hormone, LH, luteinizing hormone, HA, hyperandrogenism, AMH, anti-Müllerian hormone, FSH, follicle-stimulating hormone, IR, insulin resistance, SHBG, sex hormone-binding globulin. Solid line arrows are used to indicate increase or decrease. Dashed line arrows are used to indicate influence. Created with BioRender.com