Perspectives in Polycystic Ovary Syndrome: From Hair to Eternity

Abstract

Context: Polycystic ovary syndrome (PCOS) is a common complex genetic disease. It is characterized by hyperandrogenism, gonadotropin secretory changes, polycystic ovarian morphology, and insulin resistance. The etiology of PCOS remains unknown, but modern genetic approaches, such as genome-wide association studies (GWAS), Mendelian randomization, and next-generation sequencing, promise to identify the pathways that are primarily disrupted.

Evidence acquisition: The literature on PCOS, including the author's research, is discussed.

Evidence synthesis: Recent genetic analyses are reviewed.

Conclusions: Considerable progress has been made mapping PCOS susceptibility genes. GWAS have implicated gonadotropin secretion and action as important primary defects in disease pathogenesis in European and Han Chinese PCOS cohorts, respectively. European women with the National Institutes of Health and Rotterdam phenotypes as well as those with self-reported PCOS have some gene regions in common, such as chromosome 11p14.1 region containing the FSH B polypeptide (FSHB) gene, suggesting shared genetic susceptibility. Several chromosomal signals are significant in both Han Chinese and European PCOS cohorts, suggesting that the susceptibility genes in these regions are evolutionarily conserved. In addition, GWAS have suggested that DENND1A, epidermal growth factor signaling, and DNA repair pathways play a role in PCOS pathogenesis. Only a small amount of the heritability of PCOS is accounted for by the common susceptibility variants mapped so far. Future studies should clarify the contribution of rare genetic variants and epigenetic factors to the PCOS phenotype. Furthermore, Mendelian randomization can be used to clarify causal relationships, and phenome-wide association studies can provide insight into health risks associated with PCOS susceptibility variants.

Figure 1.

Number of annual citations 1960–2015 in Web of Science to original research articles on Stein-Leventhal syndrome or PCOS (including name variants polycystic ovary/ovarian syndrome/disease or multicystic ovaries). There were very few citations before 1960, despite the fact that the disorder was first reported by Stein and Leventhal in 1935 (121). The number of citations was relatively stable at approximately 100 annually until 1980 when it began to in increase steadily.

Figure 2.

The pathophysiology of PCOS and replicated genetic loci. PCOS is characterized by increased pulsatile GnRH release that selectively increases LH secretion while relatively suppressing FSH secretion. LH stimulates ovarian theca cell T production. T is not completely aromatized to estradiol (E2) because of insufficient FSH-stimulated granulosa cell aromatase activity. PCOS theca cells produce increased androgens basally as well as in response to LH. Circulating T produces masculinizing symptoms of PCOS. In addition, T feeds back on the hypothalamic-pituitary axis to decrease sensitivity to effects of E2 and progesterone (not noted in figure) to slow the GnRH pulse generator. These abnormalities are self-perpetuating, the so-called vicious cycle of PCOS. Insulin resistance is commonly associated with PCOS, and insulin amplifies the reproductive abnormalities. Seventeen genetic loci have been reproducibly mapped for PCOS, one by family-based association testing, fibrillin-3 (FBN3), and 16 by GWAS. LHCGR and FSHR modulate gonadotropin action, and FSHB modulates FSH secretion. FBN3 and DENND1A may regulate ovarian steroidogenesis. RAD50 may be involved in ovarian aging. THADA and INSR are T2D susceptibility genes. The function of the remaining genes in the pathogenesis of PCOS remains unknown. Used with permission of Andrea Dunaif.