- Benign glandular proliferation of male breast tissue
- Increase in estrogen activity relative to androgen 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)
- 60–90% of infants and 50–60% of pubertal males have transient gynecomastia.
- Up to 70% of men between 50 and 69 years of age report gynecomastia.
A study out of Bulgaria in 2007 put the incidence of pubertal gynecomastia at 3.9% in Caucasian boys ages 10 to 19 years.
Prevalence in adolescents varies from 22% to 69% and in adult males ranges from 36% to 57% (1).
Etiology and Pathophysiology
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: persistent or adult-onset gynecomastia. 25% of cases are idiopathic, most secondary to age-associated decline in free testosterone and adipose tissue–mediated aromatase activity.
- Illicit drugs: marijuana, heroin, methadone, alcohol, amphetamines, and over-the-counter bodybuilding 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, ACE inhibitors, amiodarone, methyldopa, reserpine, minoxidil, and recently statins can be added to this list.
- 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
Medications and age-associated decline in testosterone production and increase in SHBG production leads to low free testosterone levels. The increased ratio of fat mass to lean mass leads to adipose tissue–mediated peripheral conversion of androgens to estrogen.
Commonly Associated Conditions
- Prostate carcinoma—treatment estrogen and antiandrogen leads to gynecomastia in 50–75% of patients.
- Primary hypogonadism; especially Klinefelter syndrome—primary hypogonadism; at risk for breast cancer
- Testicular tumors; Leydig or Sertoli cell tumors especially when associated with Peutz-Jeghers syndrome or Carney complex
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