Pathological Causes of Gynecomastia
Gynecomastia is primarily caused by an imbalance between estrogen and androgen action at the breast tissue level, resulting from various pathological conditions that alter this hormonal balance. 1, 2
Hormonal Disorders
- Hypogonadism - decreased testosterone production leads to relative estrogen excess 3
- Hyperprolactinemia - can disrupt normal testosterone production 3
- Hyperthyroidism - increases peripheral conversion of androgens to estrogens 1
- Adrenal tumors - can secrete estrogen directly, causing gynecomastia 4
- Testicular tumors - Leydig cell tumors may produce estrogen or disrupt normal testosterone production 1
- Klinefelter syndrome - significantly increases gynecomastia risk (relative risk of 24.7) due to primary testicular failure 3
Systemic Diseases
- Liver cirrhosis - impairs hormone metabolism and increases peripheral aromatization of androgens to estrogens 3
- Renal insufficiency/failure - disrupts hormone clearance and metabolism 5
- Malnutrition followed by refeeding - causes hormonal fluctuations that can trigger gynecomastia 2
Neoplastic Causes
- Adrenocortical carcinomas - may secrete estrogen directly 4
- Testicular tumors - can produce estrogen or disrupt normal testosterone production 1
- Human chorionic gonadotropin (hCG)-secreting tumors - stimulate testicular production of estrogen 5
- BRCA2 mutation carriers - have significantly higher risk of male breast disorders including gynecomastia 3
Medication-Induced Gynecomastia
- Spironolactone - dose-dependent risk with onset varying from 1-2 months to over a year 6
- Cimetidine - reported in approximately 4% of patients with pathological hypersecretory states and 0.3-1% in other patients 7
- Antiandrogens - used in prostate cancer treatment can cause painful gynecomastia 8
- Other medications known to cause gynecomastia include:
- Antipsychotics
- Certain antibiotics
- Chemotherapeutic agents
- Anti-ulcer medications
- Calcium channel blockers 9
Other Pathological Causes
- Obesity - increases peripheral conversion of androgens to estrogens in adipose tissue 3
- Primary hypogonadism - decreased testosterone production leads to relative estrogen excess 5
- Secondary hypogonadism - pituitary or hypothalamic dysfunction affecting gonadotropin release 5
- Androgen insensitivity syndromes - reduced androgen effect at tissue level 2
Diagnostic Considerations
- Differentiate true gynecomastia (glandular tissue enlargement) from pseudogynecomastia (fatty tissue deposition) 8
- Unilateral or asymmetric breast enlargement requires careful evaluation to rule out male breast cancer, especially in older men 8
- Endocrine evaluation should include measurement of:
- Serum testosterone levels
- Serum estradiol levels
- Luteinizing hormone (LH) levels
- Prolactin levels 8
Common Pitfalls in Evaluation
- Failing to distinguish between true gynecomastia and pseudogynecomastia, especially in obese patients 3
- Missing underlying serious pathology by assuming gynecomastia is physiologic without proper evaluation 5
- Overlooking medication history and temporal relationship between medication initiation and onset of gynecomastia 3
- Unnecessary imaging in clear cases of gynecomastia can lead to additional unnecessary benign biopsies 3
Remember that while many cases of gynecomastia are benign and self-limiting, persistent or rapidly developing gynecomastia warrants thorough evaluation to identify potentially serious underlying pathological causes.