What causes Polycystic Ovary Syndrome (PCOS)?

Causes of Polycystic Ovary Syndrome (PCOS)

PCOS is caused by a complex interaction of genetic predisposition, hormonal dysregulation, insulin resistance, and environmental factors that lead to accelerated pulsatile gonadotropin-releasing hormone (GnRH) secretion, hyperinsulinemia, and downstream metabolic dysregulation. 1, 2

Pathophysiological Mechanisms

Hormonal Dysregulation

• Hypothalamic-Pituitary-Ovarian Axis Abnormalities:
  • Hypersecretion of luteinizing hormone (LH)
  • Elevated LH/FSH ratio (>2) 1
  • Hypofunction of follicle-stimulating hormone (FSH)–granulosa cell axis
  • Ovarian theca stromal cell hyperactivity 1

Insulin Resistance and Hyperinsulinemia

• Present in both obese and non-obese women with PCOS
• Characterized by:
  • Reduced glucose/insulin ratio (<4) 1
  • Impaired metabolic insulin signaling but intact mitogenic and steroidogenic activity 1
  • Promotes ovarian androgen production 1

Hyperandrogenism

• Results from:
  • Insulin-stimulated androgen production in the ovaries
  • Decreased sex hormone binding globulin (SHBG) production
  • Increased free testosterone levels (>2.5 nmol/L) 1
  • Hirsutism, acne, and androgenic alopecia are clinical manifestations 2

Genetic and Epigenetic Factors

• Strong genetic component with familial clustering
• Multiple genes involved in steroid hormone metabolism and insulin signaling
• Obesity genes are noted in genetic studies of PCOS 1

Chronic Inflammation

• Mediates long-term cardiometabolic complications
• Present in both lean and obese PCOS patients 2

Triggering Factors

Weight Gain and Obesity

• Significant trigger for PCOS development 1
• Bidirectional relationship:
  • Obesity can cause and exacerbate PCOS features
  • PCOS can promote weight gain through metabolic disturbances 1

Environmental and Lifestyle Factors

• Diet high in processed foods and refined carbohydrates
• Sedentary lifestyle
• Exposure to endocrine-disrupting chemicals 2

Medications

• Some antiepileptic drugs (particularly valproate) can trigger or worsen PCOS 1
• Other medications affecting hormone metabolism may contribute

Clinical Manifestations Resulting from These Causes

Reproductive Manifestations

• Chronic anovulation leading to:
  • Oligomenorrhea or amenorrhea
  • Infertility
  • Polycystic ovarian morphology (≥20 follicles per ovary measuring 2-9mm and/or ovarian volume ≥10ml) 2

Metabolic Manifestations

• Insulin resistance
• Impaired glucose tolerance
• Type 2 diabetes risk
• Dyslipidemia
• Cardiovascular disease risk 2

Dermatological Manifestations

• Hirsutism
• Acne
• Androgenic alopecia
• Acanthosis nigricans (sign of insulin resistance) 2

Diagnostic Considerations

• PCOS diagnosis requires ruling out other conditions that can mimic its presentation:

  • Thyroid disorders
  • Hyperprolactinemia
  • Non-classic congenital adrenal hyperplasia
  • Cushing's syndrome
  • Androgen-secreting tumors 2

• Laboratory findings often show:

  • Elevated total and free testosterone
  • Increased LH/FSH ratio
  • Decreased SHBG
  • Insulin resistance markers 1, 2

Clinical Implications

Understanding the multifactorial causes of PCOS is crucial for effective management, which should target:

1. Insulin resistance through lifestyle modifications and insulin-sensitizing agents
2. Hyperandrogenism through anti-androgen therapies or combined hormonal contraceptives
3. Metabolic complications through regular screening and early intervention
4. Psychological support for associated mental health conditions 2

The complex pathophysiology explains why PCOS presents with different phenotypes and requires individualized management approaches based on the predominant underlying mechanisms and clinical presentation.