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- Benign glandular proliferation of male breast tissue
- Increase in estrogens relative to androgens leads to the development of gynecomastia.
- Gynecomastia can be transient and may represent the normal physiologic changes that occur in utero or in adolescence. However, gynecomastia presenting or persisting in adulthood is typically pathologic in nature.
- Pseudogynecomastia which is lipomastia (subareolar fat)
Etiology and Pathophysiology
Increase in estrogen activity relative to androgen activity leads to the development of gynecomastia (2). Estrogen stimulates ductal cell hyperplasia, facilitates ductal branching and lengthening, increases vascularity, and results in the proliferation of periductal fibroblasts. These changes occur within 12 months and are followed by fibrosis in the later stages of gynecomastia. Multiple factors can alter the estrogen to androgen ratio and precipitate gynecomastia:
- Decrease in androgen production
- Increase in estrogen production
- Increase in peripheral conversion to estrogen
- Inhibition of the androgen receptor
- Increase in the level of sex hormone–binding globulin (SHBG) or the affinity of androgens to SHBG (decreases free or bioavailable testosterone)
- Displacement of estrogen relative to testosterone from SHBG due to medications
Gynecomastia can be physiologic or pathologic in nature.
- Physiologic gynecomastia presents in infants and adolescent boys and resolves spontaneously.
- Neonatal gynecomastia: The placenta converts dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) to estrone and estradiol resulting in transient gynecomastia.
- Adolescent gynecomastia: Transient increases in estradiol levels at the onset of puberty lead to gynecomastia.
- Pathologic gynecomastia refers to persistent or adult-onset gynecomastia. 25% of cases are idiopathic in nature most likely secondary to age-associated decline in free testosterone and adipose tissue–mediated aromatase activity.
- Multiple medications have been implicated (1).
- Illicit drugs: marijuana, heroin, methadone, alcohol, amphetamines, and over-the-counter body building supplements
- Hormones: androgens, anabolic steroids, estrogens, estrogen agonist, and human chorionic gonadotropin (hCG)
- Antiandrogens or inhibitors of androgen synthesis: bicalutamide, flutamide, nilutamide, cyproterone, and GnRH agonists (leuprolide and goserelin)
- Anti-infectives: metronidazole, ketoconazole, minocycline, isoniazid
- Antiulcer medications: cimetidine, ranitidine, metoclopramide, and proton pump inhibitors
- Cytotoxic agents: methotrexate, alkylating agents, and vinca alkaloids
- Cardiovascular drugs: Digoxin, spironolactone, calcium channel blockers, ACEIs, amiodarone, methyldopa, reserpine, minoxidil, and recently statins can be added to this list (3).
- Psychoactive drugs: antidepressants, benzodiazepines, phenothiazines, antipsychotics (typical and atypical) (i.e., haloperidol and risperidone)
- Medications: HIV medications like efavirenz, phenytoin, penicillamine, sulindac, or theophylline
- Causes to rule out:
- Primary hypogonadism: androgen insensitivity syndromes (defect in the androgen receptor), Klinefelter syndrome
- Testicular tumor: germ cell (secretes hCG), Leydig cell (secretes estrogen), Sertoli cell (excessive aromatization to estrogens)
- Adrenal tumors (secrete DHEA-S and estrogens)
- Ectopic hCG tumors (hepatoblastoma, gastric tumors, renal cell carcinomas)
- Secondary hypogonadism: Kallmann syndrome or prolactinemia, which can also stimulate milk production in breast tissue
- Renal disease or dialysis
- Rare (true hermaphroditism [both testicular and ovarian tissue present])
Transient gynecomastia is seen in neonates or pubertal boys; typically resolves within 6 to 24 months
Age-associated decline in testosterone production and increase in SHBG production leads to low free testosterone levels in the elderly population. Furthermore, the increased ratio of fat mass to lean mass noted with aging leads to adipose tissue–mediated peripheral conversion of androgens to estrogen. Medications also play a significant role in the development of gynecomastia in this population.
Commonly Associated Conditions
- Prostate carcinoma—treatment with estrogen and antiandrogen leads to gynecomastia in 50–75% of patients.
- Primary hypogonadism; especially Klinefelter syndrome—congenital abnormality leads to primary hypogonadism and gynecomastia. These patients are at risk for breast cancer and need regular breast exams.
- Testicular tumors; Leydig or Sertoli cell tumors especially when associated with Peutz-Jeghers syndrome or Carney complex