What is the pathophysiological basis for gynecomastia?

Pathophysiological Basis of Gynecomastia

Gynecomastia results from an imbalance between estrogen and androgen action at the breast tissue level, specifically an increased estrogen-to-androgen ratio that stimulates glandular proliferation beneath the nipple. 1, 2, 3

Core Hormonal Mechanism

The fundamental pathophysiology involves either:

• Increased estrogen production – through enhanced peripheral aromatization of androgens to estrogens, direct estrogen secretion from tumors, or exogenous estrogen exposure 4, 5
• Decreased androgen production – from testicular dysfunction, hypothalamic-pituitary suppression, or androgen-blocking medications 3, 6
• Combined mechanisms – simultaneous elevation of estrogen and reduction of testosterone, creating a marked shift in the hormonal ratio 2, 7

Specific Pathophysiological Pathways

Enhanced Aromatization

• Obesity increases peripheral aromatase activity in adipose tissue, converting androgens to estrogens and creating pseudogynecomastia with superimposed true glandular enlargement 4, 5
• Aging naturally increases aromatase activity while testicular testosterone production declines, explaining the high prevalence in older men 4, 3
• Liver disease impairs hepatic clearance of steroid precursors, allowing excessive peripheral conversion to estrogenic compounds 8, 4
• Thyrotoxicosis enhances aromatase activity and increases sex hormone-binding globulin (SHBG), reducing free testosterone while total estrogen remains elevated 4

Direct Estrogen Excess

• Adrenal tumors and adrenocortical carcinomas secrete estrogen directly into the circulation, bypassing normal regulatory mechanisms 5
• Testicular tumors (particularly Leydig cell and Sertoli cell tumors) produce estrogen autonomously 5, 4
• Exogenous estrogens (diethylstilbestrol, digoxin, phytoestrogens) directly activate breast tissue estrogen receptors 1

Androgen Deficiency States

• Klinefelter syndrome (47,XXY karyotype) causes primary testicular failure with markedly elevated LH and FSH, minimal testosterone production, and relative estrogen dominance (relative risk of gynecomastia: 24.7) 5, 4
• GnRH agonists (leuprolide, goserelin) suppress testicular testosterone production, creating an estrogen-dominant milieu in men treated for prostate cancer 1
• Alcohol suppresses testicular steroidogenesis both directly (inhibiting testosterone synthesis) and indirectly (through hypothalamic-pituitary dysfunction and liver-mediated impaired steroid clearance) 8

Medication-Induced Mechanisms

• Anti-androgens block androgen receptors at the breast tissue level, allowing unopposed estrogen action even when absolute estrogen levels are normal 1
• Chemotherapeutic agents damage testicular Leydig cells, reducing testosterone production while aromatase activity continues 5
• Cannabis may disrupt hypothalamic-pituitary-gonadal axis function, particularly when initiated during adolescence, though the mechanism remains less well-characterized than alcohol 8

Tissue-Level Changes

• Estrogen stimulates ductal proliferation, stromal edema, and periductal fibrosis in male breast tissue, creating the palpable subareolar mass characteristic of gynecomastia 2, 6
• Early gynecomastia (< 6 months) is predominantly proliferative and edematous, explaining why it is often painful and potentially reversible with medical therapy 1, 6
• Long-standing gynecomastia (> 12 months) becomes fibrotic and hyalinized, rendering it unresponsive to hormonal manipulation and requiring surgical correction 1, 2

Physiological vs. Pathological Gynecomastia

• Neonatal gynecomastia results from transplacental transfer of maternal estrogens, which stimulates breast tissue before being metabolized in the first weeks of life 6
• Pubertal gynecomastia reflects transient estrogen excess during the hormonal surges of adolescence, when estrogen production temporarily outpaces testosterone production before adult ratios are established 3, 6
• Senescent gynecomastia combines age-related testicular decline with increased aromatase activity and often coexisting obesity, creating a multifactorial estrogen-to-androgen imbalance 4, 3

Important Clinical Distinction

• True gynecomastia involves glandular tissue proliferation (palpable as a firm, rubbery, mobile subareolar mass), whereas pseudogynecomastia represents only fat deposition without glandular enlargement 1, 5
• Transgender women receiving feminizing hormone therapy develop histologically normal female breast tissue (ducts, lobules, acini) that should not be termed gynecomastia, as it represents intended therapeutic mammary development 9