What causes gynaecomastia?

Causes of Gynecomastia

Gynecomastia is primarily caused by an imbalance between estrogen and androgen action at the breast tissue level, resulting in proliferation of glandular breast tissue in males. 1, 2

Physiological Causes

• Newborn period: Due to maternal estrogens
• Puberty: Hormonal fluctuations during adolescent development
• Aging: Age-related reduction in testicular function 3

Pathological Causes

Medications

1. Hormonal agents:

   • 5-α reductase inhibitors (finasteride, dutasteride) 1
   • Anabolic steroids 4, 5
   • Estrogens and human chorionic gonadotropin (hCG) 5
   • GnRH analogs and anti-androgens 5

2. Cardiovascular medications:

   • Spironolactone: Well-documented cause with dose-dependent risk (9% in heart failure patients at mean dose of 26mg daily) 1, 6, 5
   • Calcium channel blockers (verapamil, nifedipine) 5

3. Gastrointestinal medications:

   • Cimetidine: Causes gynecomastia in 0.3-4% of patients depending on treatment duration 7, 5
   • Proton pump inhibitors (omeprazole) 5

4. Antipsychotics:

   • Cause hyperprolactinemia by blocking dopamine D2 receptors in the tuberoinfundibular pathway 1
   • Risperidone has stronger association than others 5

5. Other medications:

   • Anticonvulsants (phenytoin) 1
   • Ketoconazole 5
   • HIV medications (efavirenz) 5
   • Alkylating agents 5

Medical Conditions

• Liver disease: Cirrhosis 8
• Kidney disease: Renal insufficiency 8
• Endocrine disorders:
  • Hypogonadism 8
  • Hyperprolactinemia 1
• Tumors (rare):
  • Testicular tumors
  • Adrenal tumors
  • Pituitary tumors 8

Substance Use

• Alcohol 5
• Opioids 5
• Anabolic steroids (52% prevalence in users) 4, 5

Pathophysiological Mechanisms

Gynecomastia develops through three primary mechanisms:

1. Increased estrogen production
2. Decreased testosterone production
3. Altered estrogen-to-androgen ratio at tissue level 2, 3

Key Mechanism Examples:

• Spironolactone: Blocks androgen receptors and inhibits testosterone synthesis 1, 6
• Cimetidine: Blocks androgen receptors 7, 5
• Phenytoin: Induces hepatic cytochrome P450 enzymes, increasing steroid hormone breakdown and sex hormone binding globulin production 1
• Antipsychotics: Elevate prolactin by blocking dopamine, leading to breast tissue growth 1

Clinical Pearls and Pitfalls

• Important distinction: True gynecomastia (glandular tissue enlargement) vs. pseudogynecomastia (fatty tissue deposition) 1, 3
• Timing matters: Painful gynecomastia of recent onset (<12 months) may respond better to medical therapy than long-standing cases 3
• Medication review: Always conduct a thorough medication review in patients presenting with gynecomastia, as drugs account for 10-25% of cases 5
• Cancer risk: While rare, male breast cancer should be considered in older men (median age 63), as it represents <1% of all breast cancers 1
• Untreated hyperprolactinemia: Can lead to bone mineral density loss in both men and women 1

In patients with sportive habits who develop gynecomastia, anabolic steroid use should be suspected early, as discontinuation plus medical therapy can achieve high remission rates 4.