Causes and Risk Factors of PCOS

Introduction

Despite its status as the most common endocrine disorder in reproductive-age women, the precise causes of PCOS remain incompletely understood. What is clear is that PCOS is not caused by a single gene or a simple hormonal imbalance. Rather, it emerges from the interaction of genetic susceptibility, developmental programming, metabolic dysfunction, and environmental exposures. This article examines the current evidence on each contributing factor.

Genetic Factors

PCOS is strongly familial. First-degree female relatives of women with PCOS have a 20–40% risk of having the condition themselves — far higher than the general population prevalence. Male relatives often have elevated androgen levels and metabolic features (insulin resistance, male-pattern baldness).

Genome-wide association studies (GWAS) have identified dozens of genetic loci associated with PCOS. Key susceptibility genes include:

• LHCGR (LH/hCG receptor gene): Variants affect LH receptor sensitivity — relevant given that elevated LH drive is central to PCOS pathophysiology.
• FSHR (FSH receptor gene): Affects follicle sensitivity to FSH.
• INSR (insulin receptor gene): Variants in the insulin receptor affect insulin signalling — relevant to insulin resistance in PCOS.
• RAB5B/HMGA2: Implicated in cell signalling and adipose biology.
• YAP1 and THADA: Genes involved in gonadotropin signalling and thyroid function.

However, no single "PCOS gene" has been identified that is necessary or sufficient to cause the condition. PCOS is polygenic, and gene-environment interactions are critical.

Intrauterine and Developmental Programming

Emerging research suggests that PCOS may partly be "programmed" before birth. Animal models (sheep and rodents) demonstrate that exposing female fetuses to excess androgens in utero produces PCOS-like features in adulthood. Daughters of women with PCOS have elevated AMH levels and more irregular cycles, suggesting in utero hormonal exposure plays a role. Maternal obesity and gestational diabetes (both associated with elevated androgens and insulin) may create an intrauterine hormonal environment that predisposes female fetuses to PCOS.

Neuroendocrine Dysregulation

A key feature of PCOS is abnormal GnRH pulsatility from the hypothalamus. GnRH pulses occur more rapidly in PCOS than in normal cycles, leading to a chronically elevated LH:FSH ratio. Elevated LH over-stimulates ovarian theca cells to produce androgens, while the relatively low FSH is insufficient to fully mature follicles for ovulation.

This GnRH dysregulation involves KNDy neurons (kisspeptin/neurokinin B/dynorphin) in the hypothalamus. In normal cycles, progesterone exerts negative feedback on these neurons to slow GnRH pulsatility after ovulation. In PCOS — because ovulation rarely occurs and progesterone is chronically low — this negative feedback is absent, maintaining rapid GnRH pulses and the elevated LH:FSH ratio.

Insulin Resistance as a Driver

Insulin resistance is the most important metabolic contributor to PCOS. It is present in approximately 50–80% of PCOS women, including lean women. The key mechanism:

This explains why treatments that reduce insulin resistance — lifestyle change (diet and exercise

Adipose Dysfunction and Inflammation

Adipose tissue in PCOS patients is metabolically abnormal — adipocytes are larger, more insulin resistant, and secrete pro-inflammatory adipokines (leptin, resistin, TNFα, IL-6) in excess. Even lean women with PCOS have subtle adipocyte dysfunction. This low-grade inflammation further impairs insulin signalling and may worsen ovarian androgen production.

Environmental Factors

References: Teede H et al., Nat Rev Endocrinol 2023; Franks S et al. Clin Endocrinol 2018; McAllister JM et al. — Insulin signalling in PCOS, Semin Reprod Med 2014; 2023 International PCOS Guideline.