What causes Polycystic Ovary Syndrome (PCOS)?

Causes of Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS) is caused by a complex interaction of genetic predisposition and environmental factors that lead to insulin resistance, hormonal dysregulation, and metabolic abnormalities. 1

Primary Pathophysiological Mechanisms

Genetic Factors

• PCOS has a strong hereditary component with polygenic inheritance patterns 2, 3
• Family clustering is evident with increased prevalence among first-degree relatives
• No single gene has been identified; instead, multiple gene polymorphisms contribute to the syndrome
• Genetic alterations affecting:
  • Initial steps of ovarian steroidogenesis (leading to hyperandrogenism)
  • Insulin signaling pathways (IRS-1, IRS-2, calpain-10, PPARγ) 2

Hormonal Dysregulation

• Acceleration of pulsatile gonadotropin-releasing hormone (GnRH) secretion 1
• Hypersecretion of luteinising hormone (LH) 1
• Ovarian theca stromal cell hyperactivity producing excess androgens 1
• Hypofunction of follicle-stimulating hormone (FSH)-granulosa cell axis 1
• Resulting in:
  • Hyperandrogenism
  • Follicular arrest
  • Ovarian acyclicity

Insulin Resistance and Hyperinsulinemia

• Present in 50-70% of women with PCOS, independent of obesity
• Leads to:
  • Increased ovarian androgen production
  • Decreased sex hormone binding globulin (SHBG) synthesis
  • Higher levels of free, biologically active androgens 1
  • Downstream metabolic dysregulation 1

Environmental Contributors

Lifestyle Factors

• Diet high in processed carbohydrates and saturated fats
• Sedentary behavior
• Obesity (especially abdominal adiposity) exacerbates insulin resistance 2
• Weight gain can trigger PCOS development in genetically susceptible individuals 1

Medication Effects

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

Associated Conditions and Complications

Metabolic Abnormalities

• Dyslipidemia (elevated LDL, triglycerides; decreased HDL) 1
• Glucose intolerance and increased risk of type 2 diabetes 1
• Metabolic syndrome features (abdominal obesity, hypertension) 1

Reproductive Consequences

• Chronic anovulation leading to oligomenorrhea or amenorrhea 1
• Infertility due to ovulatory dysfunction 4
• Increased risk of endometrial cancer (at least twofold) 4

Diagnostic Considerations

PCOS is diagnosed when at least two of the three Rotterdam criteria are present:

1. Oligo-anovulation or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries on ultrasonography 4

Common Pitfalls in Understanding PCOS Causes

• Misidentification: PCOS should not be confused with isolated polycystic ovaries, which occur in 17-22% of women without the syndrome 1
• Overlooking other causes: Other conditions causing androgen excess must be excluded, including:
  • Cushing's syndrome
  • Androgen-secreting tumors
  • Congenital adrenal hyperplasia
  • Thyroid disorders
  • Hyperprolactinemia 1
• Focusing only on ovarian appearance: The name "polycystic ovary syndrome" is somewhat misleading as the condition is primarily a metabolic and endocrine disorder

PCOS represents a heterogeneous condition with multiple phenotypes, reflecting the varying combinations of genetic susceptibility and environmental triggers that lead to its development. Understanding these complex interactions is essential for proper diagnosis and management of affected women.