Polycystic Ovary Syndrome: An Overview of a Complex, Heterogenous Genetic Condition

Abstract

Polycystic Ovary Syndrome (PCOS) is a heterogenous, complex, genetic trait of unclear etiology, comprising of ovarian hyperandrogenism and hyperinsulinemia. It is the most common endocrine abnormality in women of reproductive age and the most common cause of anovulatory infertility. PCOS has been shown to be associated with certain autoimmune diseases like Autoimmune Thyroid Disease (AITD) and Systemic Lupus Erythematosus (SLE). Furthermore, over a hundred candidate genes have been linked to PCOS and Genome Wide Association Studies on these are ongoing. Two among these, are the most promising chromosome 9p33.3 DENND1A (DENN/MADD domain-containing protein 1A) and 2–21 THADA (Thyroid adenoma-associated) susceptibility loci. In the majority of PCOS patients, the fundamental defect is intrinsic androgenic dysfunction termed Primary Ovarian Hyperandrogenism. Primary Ovarian Hyperandrogenism is believed to be due to the rapid, high-amplitude pulsation of Gonadotropin-Releasing Hormone (GnRH) from the hypothalamus, which causes preferential release of Luteinizing Hormone (LH) over Follicle Stimulating Hormone (FSH) from the anterior pituitary gland. Hyperandrogenemia may present as hirsutism, acne or alopecia. The pathophysiology of PCOS is multifactorial but is related to insulin resistance in many cases. Hyperinsulinemia may manifest as obesity, difficulty losing weight, prediabetes or Diabetes Mellitus Type II. Many PCOS women also have irregular and anovulatory cycles, and some have polycystic ovaries on transvaginal ultrasound. Overall, PCOS encompasses a wide range of metabolic and reproductive disorders ranging from prediabetes, to infertility, endometrial hyperplasia and endometrial cancer. Treatment of PCOS is multifaceted and aims at targeting the underlying hyperinsulinemia, hyperandrogenemia and menstrual irregularity. Biguanides (i.e., Metformin) and Glucagon-like peptide 1 (GLP-1) receptor agonists are insulin sensitizers that have been studied in the treatment of PCOS.