Genetic overlap between polycystic ovary syndrome and bipolar disorder: The endophenotype hypothesis

Summary

Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible genomic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and menstrual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Valproate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be the result of common genetic markers. This paper postulates that shared clinical endophenotypes between PCOS and BD indicate common pathophysiological platforms and will review these for the potential of genetic overlap between the two disorders.

Introduction

Polycystic Ovary Syndrome (PCOS) is a serious endocrine disorder and a leading cause of female infertility. PCOS affects approximately 4–11% of reproductive-aged women and is associated with ovulatory and menstrual abnormalities, hyperandrogenism, and insulin resistance [1]. Several authors have suggested that PCOS is caused by a combination of genetic, neuroendocrine, and metabolic factors.

A connection between PCOS and Bipolar Disorder (BD) was suggested by Matsunaga and Sarai and further clarified by one of us (Rasgon) [2], [3]. In these studies, the authors suggested that a relationship might exist between abnormal menstrual cycles and bipolar symptoms, resulting in a higher prevalence of PCOS in women with bipolar disorder. Theories have been formulated to explain the high prevalence of PCOS in these populations, which include the effects of anti-bipolar agents, such as valproic acid, a commonly prescribed mood stabilizer. This connection was first presented in a paper by Isojarvi et al. [4], which found ultrasound evidence of polycystic ovaries in 43% of epileptic outpatients taking Valproate [4]. Along with a later publication by Isojarvi et al. in 1998, the conclusion was that PCOS may be positively associated with Valproate use [5]. Similarly, a study by O’Donovan et al. [6] found that 47% of female bipolar patients taking Valproate had menstrual abnormalities compared with 13% of female bipolar patients not taking Valproate [6].

Similar metabolic disorders are associated with both PCOS and BD, such as insulin resistance, obesity, hyperleptinemia, and hyper-activation of the Hypothalamus–Pituitary–Adrenal (HPA) axis. These common morbidities may represent an indirect link between PCOS and bipolar disorder. For instance, a paper by Lewy et al. supports the hypothesis that PCOS is stimulated by decreased peripheral insulin sensitivity and hyperinsulinemia while a review by Rossum et al. suggests that glucocorticoid resistance results in impaired negative feedback mechanisms, HPA hyperactivity, and overproduction of mineralcorticoids and androgens in PCOS patients [7], [8]. Likewise, insulin resistance, disturbances in HPA, and hypersecretion of cortisol have been documented in both depressive and manic phases of BD [9], [10]. The commonalities between the diseases and the predisposition for common symptoms suggest possible pathophysiological overlap. Moreover, since both disorders are genetic in origin, the endophenotype similarities seem to suggest molecular overlap on the genetic level. This paper proposes that genetic vulnerabilities common to overlapping endophenotypes of both PCOS and BD may account for the link between the two disorders and reviews the evidence herein.