A review of genetic polymorphisms in the receptors for gonadotropic and sex hormones in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome is a complex, heterogeneous disease that affects 5-10% of reproductive-aged women. It is characterized by clinical or biochemical hyperandrogenism, oligo-anovulation, and polycystic ovary morphology. Instigating endocrine findings include aberrantly rapid gonadotropin-releasing hormone pulsatile secretion, elevated luteinizing hormone, sub-optimal levels of follicle-stimulating hormone, and hyperandrogenism. Metabolic symptoms are also present including hyperinsulinemia, insulin resistance, and dyslipidemia. These endocrine and metabolic findings are also accompanied by ovarian dysfunction and improper folliculogenesis. Because aberrant functioning of the hypothalamic-pituitary-gonadal axis is central to the pathophysiology of polycystic ovary syndrome, it is beneficial to examine it for abnormalities. Polycystic ovary syndrome has been shown to have both genetic and environmental components. Its strong genetic component has been demonstrated in twin studies, family association studies, candidate gene studies, and genome-wide association studies. Previous genome-wide association studies have found many candidate genes including those for DENND1A (differentially expressed in normal and neoplastic cells domain containing 1A), THADA (thyroid adenoma-associated protein), FSHR (follicle-stimulating hormone receptor), and LHR (luteinizing hormone receptor). This, together with the central endocrine abnormalities, prompted this review on polymorphisms of receptors of the hypothalamic-pituitary-gonadal axis, including those for gonadotropin-releasing hormone, luteinzing hormone, follicle-stimulating hormone, estrogen, and progesterone, as well as anti-müllerian hormone. Studies on single-nucleotide polymorphisms of these receptors were found on PubMed, Web of Science, and Google Scholar and subsequently analyzed. Many different single-nucleotide polymorphisms were studied, but only a handful of them have been subjected to repeated studies. Only rs2293275 of the luteinizing hormone receptor and rs2349415 of the follicle-stimulating hormone receptor, both at 2p16.3, were found to have a possible role in the etiology of polycystic ovary syndrome, but all eight were found to have a possible phenotypic role: rs13405728, rs2293275, and rs4539842 of the luteinizing hormone receptor; rs6165, rs6166, rs2268361, and rs2349415 of the follicle-stimulating hormone receptor; and rs2002555 of the anti-müllerian hormone receptor. The limitations most affecting the results of these studies include small sample sizes, heterogeneous study populations, lack of generalizability due to ethnicity, and lack of control or adjustment for confounders. It is necessary to develop a standardized study protocol and separate polycystic ovary syndrome patients based on phenotype in order to obtain stronger results in the future.