What causes Polycystic Ovary Syndrome (PCOS)?

Causes of Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS) is a highly heritable, complex endocrine disorder caused by a combination of genetic predisposition, hormonal imbalances, and environmental factors that lead to accelerated pulsatile gonadotropin-releasing hormone (GnRH) secretion, insulin resistance, and downstream metabolic dysregulation. 1

Pathophysiological Mechanisms

Hormonal Dysfunction

• Hypothalamic-Pituitary-Ovarian Axis Abnormalities:

  • Accelerated GnRH pulse secretion leads to increased luteinizing hormone (LH) production 1
  • Elevated LH/FSH ratio (>2) is characteristic of PCOS 2
  • Hypersecretion of LH causes ovarian theca stromal cell hyperactivity 1
  • Hypofunction of the FSH-granulosa cell axis results in follicular arrest 1

• Hyperandrogenism:

  • Increased androgen production from ovarian theca cells
  • Elevated testosterone levels (>2.5 nmol/l) 2
  • Elevated androstenedione levels (>10.0 nmol/l) 2
  • Clinical manifestations include hirsutism, acne, and male-pattern hair loss

Metabolic Dysfunction

• Insulin Resistance and Hyperinsulinemia:

  • Present in up to 70% of women with PCOS, even in those with normal weight
  • Contributes to hyperandrogenism by stimulating ovarian androgen production
  • Decreases sex hormone-binding globulin (SHBG) production, increasing free testosterone
  • Glucose/insulin ratio <4 indicates insulin resistance 2

• Obesity and Adipose Tissue Dysfunction:

  • Weight gain can trigger the development of PCOS in genetically predisposed individuals 1
  • Abdominal adiposity is common in PCOS and worsens metabolic and reproductive features 1
  • Adipose tissue dysfunction contributes to chronic low-grade inflammation

Genetic and Environmental Factors

Genetic Components

• PCOS is highly heritable with a complex multigenic pattern 3
• Multiple genes related to androgen synthesis, insulin action, and inflammation are implicated
• Family history is a significant risk factor - first-degree relatives have increased risk

Environmental Influences

• Lifestyle Factors:

  • Diet quality is often poorer in women with PCOS 1
  • Higher cholesterol intake (MD: 12.78 mg/day) 1
  • Lower magnesium and zinc intake 1
  • Lower total physical activity levels 1
  • These factors may exacerbate underlying genetic predisposition

• Fetal Programming:

  • Exposure to excess androgens in utero may predispose to PCOS development 4
  • Maternal PCOS, obesity, or gestational diabetes may increase risk in offspring

Comorbid Conditions and Their Relationship to PCOS

• Epilepsy Connection:

  • Higher prevalence of PCOS (10-25%) in women with temporal lobe epilepsy, even without antiepileptic drugs 1
  • Some antiepileptic drugs may affect sex hormone levels and trigger PCOS development

• Cardiovascular and Metabolic Risk:

  • PCOS increases risk for metabolic syndrome, type 2 diabetes, and cardiovascular disease 1
  • Annual screening for these conditions is recommended 2

Diagnostic Considerations

• Rotterdam Criteria typically used for diagnosis, requiring two of three:

  1. Oligo/anovulation
  2. Clinical or biochemical hyperandrogenism
  3. Polycystic ovaries on ultrasound (≥20 follicles per ovary and/or ovarian volume ≥10ml) 2

• Laboratory Testing:

  • LH/FSH ratio >2 suggests PCOS 2
  • Elevated testosterone, androstenedione, and DHEAS levels 2
  • Fasting glucose/insulin ratio to assess insulin resistance 2

Clinical Implications

• PCOS affects 5-18% of reproductive-aged women globally 1, 3
• Presents with reproductive (irregular menses, infertility), metabolic (insulin resistance), and dermatological (hirsutism, acne) manifestations
• Requires lifelong management as complications evolve from reproductive issues in younger years to metabolic complications later in life 4

Management Considerations

• Lifestyle Modifications:

  • First-line approach, especially with excess body weight 2
  • Improving diet quality and increasing physical activity can improve symptoms

• Pharmacological Approaches:

  • Hormonal therapy to regulate menstrual cycles and reduce androgen levels 2
  • Metformin for insulin resistance (starting at 500mg daily, increasing to 1500-2000mg) 2

Understanding the complex, multifactorial etiology of PCOS is essential for appropriate diagnosis and management of this common endocrine disorder that affects women throughout their lifespan.