DESCRIPTION

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

EPIDEMIOLOGY

• Two age distribution peaks: neonatal, pubertal
• Neonatal gynecomastia occurs in 60–90% of all newborns.
• Pubertal gynecomastia in males has its peak incidence at 13 to 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). Reported percentages in studies vary greatly, perhaps due to different examination techniques.

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 geriatric 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 carcinoma, ectopic tumors that produce human chorionic gonadotropin
  • Chronic disease: renal failure, liver cirrhosis, malnutrition with refeeding, HIV infection, hyperthyroidism
  • Congenital disorders causing gonadal hypofunction, androgen receptor issues, or increased aromatization: Klinefelter syndrome, vanishing testes syndrome, androgen resistance syndromes, ovotesticular difference 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

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 sensitivity of breast tissue to estrogen action
• Exposure to exogenous estrogen or estrogen-like compounds in commercial products
• 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 due to tumors or hyperthyroidism.
• Elevated leptin concentrations: 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: increased peripheral androgen aromatization