Description

Visible or palpable proliferation of unilateral or bilateral breast glandular tissue in a male

Epidemiology

• Two age distribution peaks: neonatal, pubertal
• Neonatal gynecomastia occurs in 60–90% of all newborns.
• Peak incidence for pubertal gynecomastia in males is 14 years of age (range: 10 to 16 years). Onset usually at 5- to 10-mL testicular size and pubic hair Tanner III or IV.
• ~40% of pubertal boys develop transient gynecomastia (measuring ≥0.5 cm). This percentage varies greatly in studies, perhaps due to examination techniques.

Risk Factors

Any state that leads to an increase in the net effect of estrogen relative to androgens on breast glandular tissue, such as the following:

• Increased endogenous estrogen
• Increased exogenous estrogen or estrogen-like compounds in commercial products
• Increased sensitivity of breast tissue to estrogen action
• Decreased androgen concentrations
• Androgen receptor defects
• Pharmacologic or commercial product interference with androgen receptors
• Increased aromatase action. Aromatase converts androgens to estrogens. This can be intrinsic as in aromatase excess syndrome or as a result of tumors or hyperthyroidism.
• Elevated leptin concentrations, which may increase aromatase enzyme activity, stimulate growth of mammary cells or increase breast receptor sensitivity to estrogens.
• High serum gonadotropin concentrations altering sex steroid production ratios
• Increased sex hormone–binding globulin, which reduces free testosterone levels
• Hyperthyroidism, which increases aromatization of androgens to estrogens
• Hyperprolactinemia interfering with gonadotropin production, thus altering sex steroid production
• Obesity: may increase leptin concentrations and may increase aromatization. Obesity correlates with true gynecomastia in some studies only. Other studies find obesity correlates with pseudogynecomastia but not true ductal breast tissue development.

Etiology

• Physiologic
  • Neonatal: Transient palpable breast tissue develops in newborns, owing to elevated estrogen levels in the fetoplacental unit; resolves as estrogen levels decline
  • Pubertal: benign transient gynecomastia occurring in otherwise healthy males. In this setting, breast tissue measuring <5 cm in diameter has a high likelihood of spontaneous regression.
  • Involutional: Breast enlargement occurs in elderly men.
  • Physiologic gynecomastia usually is bilateral.
• Pathologic
  • Drug-induced
    • Hormones: estrogen, androgens, gonadotropins, growth hormone, antiandrogens, commercial products containing estrogenic or antiandrogenic compounds
    • Anti-infective agents: can cause gynecomastia through antiandrogenic properties; ethionamide, isoniazid, ketoconazole, metronidazole, antiretrovirals
    • Antiulcer drugs: usually cause gynecomastia through antiandrogenic properties; cimetidine, ranitidine, omeprazole
    • Chemotherapeutic agents: usually cause gynecomastia by causing hypogonadism; alkylating agents, methotrexate, vinca alkaloids
    • Cardiovascular agents: spironolactone—androgen receptor blocker; unknown mechanism of action: amiodarone, captopril, digitoxin, diltiazem, enalapril, methyldopa, nifedipine, reserpine, verapamil
    • Psychotropic agents: may act by increasing prolactin levels or decreasing androgen levels: diazepam, risperidone, haloperidol, phenothiazines, antidepressants
    • Drugs of abuse: alcohol, heroin, amphetamines, marijuana, methadone
    • Miscellaneous: metoclopramide, phenytoin, penicillamine, theophylline, gabapentin, clonidine, pregabalin
• Hypogonadism/acquired testicular failure
• Infectious: breast abscess
• Tumors: testicular (including Sertoli cell and germ cell), adrenal, ectopic tumors that produce human chorionic gonadotropin
• Chronic disease: renal failure, liver cirrhosis, malnutrition with refeeding, HIV infection
• Congenital disorders causing gonadal hypofunction, androgen receptor issues, or increased aromatization: Klinefelter syndrome, vanishing testes syndrome, androgen resistance syndromes, ovotesticular disorder of sex development
• Late-onset congenital adrenal hyperplasia—elevated androgens converted to estrogen
• Spinal cord injury leading to testicular failure over the long term
• Neoplasms: breast carcinoma, neurofibroma, lymphangioma, lipoma, neuroblastoma metastasis
• Trauma: hematoma
• Peutz-Jeghers syndrome: prepubertal gynecomastia
• Miscellaneous masses: dermoid cyst