Causes and Consequences of Polycystic Ovary Syndrome: Insights From Mendelian Randomization

Abstract

Context: Although polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age, risk factors that may cause the syndrome are poorly understood. Based on epidemiologic studies, PCOS is thought to cause several adverse outcomes such as cardiovascular disease; however, the common presence of comorbidities such as obesity may be responsible for such associations, rather than PCOS in and of itself. To overcome the limitations of observational studies, investigators have employed Mendelian randomization (MR), which uses genetic variants to interrogate causality between exposures and outcomes.

Evidence acquisition: To clarify causes and consequences of PCOS, this review will describe MR studies involving PCOS, both as an exposure and as an outcome. The literature was searched using the terms "Mendelian randomization," "polycystic ovary syndrome," "polycystic ovarian syndrome," and "PCOS" (to May 2021).

Evidence synthesis: MR studies have suggested that obesity, testosterone levels, fasting insulin, serum sex hormone-binding globulin concentrations, menopause timing, male-pattern balding, and depression may play a causal role in PCOS. In turn, PCOS may increase the risk of estrogen receptor-positive breast cancer, decrease the risk of endometrioid ovarian cancer, and have no direct causal effect on type 2 diabetes, coronary heart disease, or stroke.

Conclusions: The accumulation of genome-wide association studies in PCOS has enabled multiple MR analyses identifying factors that may cause PCOS or be caused by PCOS. This knowledge will be critical to future development of measures to prevent PCOS in girls at risk as well as prevent complications in those who have PCOS.

Keywords: Mendelian randomization; genome-wide association study; polycystic ovary syndrome.

Figure 1.

Advantage of Mendelian randomization over observational studies. (A) Observational studies can demonstrate association between a risk factor and a possible outcome but provide limited information on causation because the relationship may be mediated by confounding variables or reverse causation. (B) In Mendelian randomization, the risk factor is replaced by a genetic instrument variable that strongly represents the risk factor, avoiding the effect of confounding variables or reverse causation. This allows a more robust analysis of possible causation.

Figure 2.

Overview of Mendelian randomization studies involving polycystic ovary syndrome. Mendelian randomization studies of polycystic ovary syndrome as the outcome or as the exposure are summarized, with significant results at the top of the figure. Results of borderline significance are denoted with a question mark. Abbreviations: AMH, anti-Mullerian hormone; BMI, body mass index; CHD, coronary heart disease; DHEAS, dehydroepiandrosterone sulfate; ER, estrogen receptor; FEV₁, forced expiratory volume in 1 second; FVC forced vital capacity; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SHBG, sex hormone-binding globulin; T2D, type 2 diabetes.