What is the cause of Polycystic Ovary Syndrome (PCOS) in women?

Etiology of Polycystic Ovary Syndrome (PCOS)

PCOS is a multifactorial disorder arising from complex interactions between genetic predisposition, intrauterine hormonal programming, and environmental triggers—particularly weight gain and lifestyle factors—that converge to produce the characteristic hormonal cascade of accelerated GnRH pulsatility, excessive LH secretion, hyperinsulinemia, and resultant hyperandrogenism. 1, 2, 3

Genetic and Familial Basis

• PCOS demonstrates clear familial inheritance patterns, with first-degree relatives of affected women showing significantly higher risk of developing the syndrome, suggesting autosomal dominant inheritance with multigene origins 4, 5

• Twin studies support a genetic etiology, though specific candidate genes remain unverified despite genome-wide association studies (GWAS) identifying multiple genetic loci 4, 5

• Genes affecting insulin resistance pathways, steroid hormone production, and inflammatory cytokine responses have all been implicated in disease susceptibility 4, 5

Intrauterine Programming Hypothesis

• Environmental factors during fetal development appear to predispose female fetuses to PCOS, with animal studies demonstrating clear correlation between hyperexposure to androgens in utero and subsequent development of PCOS symptoms in adult life 4

• The proposed mechanism involves high maternal anti-Müllerian hormone (AMH) levels blocking placental aromatase activity, allowing maternal testosterone to cross the placenta and "program" fetal ovaries to recruit excessive preantral follicles 4

• This intrauterine programming establishes the foundation for elevated AMH production when ovaries become functional around 36 weeks gestation, perpetuating the hyperandrogenic cycle into adulthood 4

The Central Hormonal Cascade

• Accelerated GnRH pulsatility initiates the pathogenic hormonal cascade, driving disordered gonadotropin secretion with LH/FSH ratios typically exceeding 2:1 2

• Elevated LH directly stimulates ovarian theca stromal cells to massively overproduce androgens, particularly testosterone, while FSH levels remain relatively low or normal, preventing proper follicular maturation 2

• This creates the characteristic hyperandrogenic state present in 75% of PCOS cases, serving as both a diagnostic criterion and central pathogenic driver 2

The Metabolic Amplification Loop

• Insulin resistance and compensatory hyperinsulinemia are present in the majority of PCOS patients independent of obesity status, representing a distinct and defining characteristic of the syndrome 1, 6

• Hyperinsulinemia directly amplifies androgen production through two mechanisms: (1) directly stimulating ovarian theca cells to produce more androgens independent of LH stimulation, and (2) suppressing hepatic production of sex hormone-binding globulin (SHBG), thereby increasing circulating free testosterone levels 1, 2

• This metabolic-reproductive feedback loop perpetuates both the hormonal and metabolic disturbances characteristic of PCOS 6

Environmental and Lifestyle Triggers

• Abdominal obesity and weight gain represent major triggers for PCOS development and symptom worsening in genetically susceptible women, with obesity prevalence in PCOS increasing from 51% in the 1990s to 74% in recent decades 1, 7

• Central obesity exacerbates metabolic, reproductive, and psychological features of PCOS, with weight gain escalating from adolescence and requiring early vigilance 7

• PCOS is increasingly recognized as a polygenic, polyfactorial, systemic inflammatory disorder manifesting largely due to lifestyle errors, including exposure to inflammatory agents and aberrant immune activation 8

Systemic Inflammatory Component

• PCOS represents an inflammatory, systemic endocrinopathy with dysregulated steroid metabolism and autoimmune features 8

• Chronic inflammation contributes to both the metabolic complications (insulin resistance, dyslipidemia) and reproductive dysfunction (anovulation, hyperandrogenism) 8

Critical Clinical Caveats

• Certain medications, particularly valproate, can exacerbate PCOS or trigger PCOS-like symptoms, including worsening hirsutism, representing an iatrogenic environmental factor 1, 2

• Ethnic variation exists in PCOS presentation, with East Asian women showing highest metabolic syndrome prevalence despite lower BMI and less pronounced hyperandrogenic features 1

• The heterogeneity of PCOS symptoms and characteristics reflects its multifactorial etiology, with different genetic, hormonal, and environmental factors predominating in individual patients 3, 5