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Gynecomastia
Christine C. Zacharia, MD
Geetha Gopalakrishnan, MD
image BASICS
DESCRIPTION
  • Benign glandular proliferation of male breast tissue
  • Increase in estrogens relative to androgens leads to the development of gynecomastia.
  • Gynecomastia can be transient and represent the normal physiologic changes that occur in utero or in adolescence. However, gynecomastia presenting or persisting in adulthood is typically pathologic in nature.
EPIDEMIOLOGY
  • 60-90% of infants have transient gynecomastia (1).
  • 48-64% of pubertal males have mild transient gynecomastia (onset at 10 to 12 years of age and resolution by age 18 years in most individuals) (1).
  • 24-65% of men between 50 and 80 years of age report gynecomastia (2).
ETIOLOGY AND PATHOPHYSIOLOGY
Increase in estrogen activity relative to androgen activity leads to the development of gynecomastia (3). 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
RISK FACTORS
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 leads to gynecomastia.
  • Pathologic gynecomastia refers to persistent or adult-onset gynecomastia. Multiple medications and medical conditions can alter the estrogen to androgen ratio and precipitate gynecomastia. However, 25% of cases are idiopathic in nature.
    • Medications: spironolactone, calcium channel blockers, proton pump inhibitors, cimetidine, efavirenz, ketoconazole, phenytoin, cytotoxic drugs, antidepressants, antiandrogen, estrogen, gonadotropin-releasing hormone (GnRH) agonists, 5-alpha reductase inhibitors, growth hormone (4,5)
  • Primary or secondary hypogonadism
  • Testicular tumor: germ cell (secrete human chorionic gonadotropin or hCG), Leydig cell (secrete estrogen), Sertoli cell (excessive aromatization to estrogens)
  • Adrenal tumors (secrete DHEA-S and estrogens)
  • Ectopic hCG tumors (hepatoblastoma, gastric tumors, renal cell carcinomas)
  • Prolactinemia: leads to secondary hypogonadism and gynecomastia. Prolactin can stimulate milk production in breast tissue.
  • Hyperthyroidism
  • Cirrhosis
  • Renal disease or dialysis
  • Malnutrition/starvation
  • Androgen insensitivity syndromes (defect in the androgen receptor)
  • True hermaphroditism (both testicular and ovarian tissue present)
  • Aromatase excess syndrome (increased peripheral conversion of androgens to estrogen)
  • Idiopathic: most likely secondary to age-associated decline in free testosterone and adipose tissue-mediated aromatase activity
Pediatric Considerations
Transient gynecomastia is seen in neonates or pubertal boys. Typically resolves within 6 to 24 months.
Geriatric Considerations
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. Both factors contribute to the development of idiopathic gynecomastia in the elderly. Medications also play a significant role in the development of gynecomastia in this population.
COMMONLY ASSOCIATED CONDITIONS
  • Peutz-Jeghers syndrome—autosomal dominant disorder associated with Sertoli cell tumors, benign hamartomatous polyps, and mucocutaneous hyperpigmentation
  • Carney complex—autosomal dominant disorder associated with Sertoli cell tumors, myxoma, hyperpigmentation of the skin (lentiginosis), and endocrine disorders like Cushing syndrome
  • Prostate carcinoma—treatment with estrogen and antiandrogen leads to gynecomastia in 50% of patients
  • Klinefelter syndrome—congenital abnormality leads to primary hypogonadism and gynecomastia. These patients are at risk for breast cancer and need regular breast exams.
image DIAGNOSIS
PHYSICAL EXAM
  • Careful breast exam to evaluate characteristics:
    • Firm, concentric glandular tissue beneath the nipple and areola palpable by pinching the thumb and forefinger together from either side of the breast toward the nipple
    • May involve one or both breasts
    • Usually asymptomatic but may be painful or tender if it is of recent onset
    • Off center, hard, fixed mass is concerning for malignancy while palpation of subareolar fat is more consistent with pseudogynecomastia.
    • Breast discharge should raise concern for malignancy or prolactinemia. In the latter, the discharge is typically clear or milky.
  • Thyroid exam (evaluate for diffuse enlargement and palpable nodules and check extremities for tremor and brisk reflexes)
  • Abdominal exam (evaluate for masses and liver size)
  • Genitourinary exam (evaluate for testicular size, hair pattern, and presence of ovary or uterus)
  • Visual field exam (evaluate for peripheral field defect)
DIFFERENTIAL DIAGNOSIS
  • Pseudogynecomastia—fat deposition without glandular proliferation often seen in obesity
  • Breast cancer—on exam the lesion is typically unilateral, firm, eccentric to the nipple, and associated with skin dimpling, nipple retraction/discharge, and lymphadenopathy
  • Lipomas
  • Sebaceous cyst
  • Dermoid cyst
  • Mastitis
  • Hematoma
  • Hamartoma
DIAGNOSTIC TESTS & INTERPRETATION
  • Laboratory and radiologic investigations should be tailored to fit history and physical exam findings.
  • Idiopathic gynecomastia is a diagnosis of exclusion and therefore, laboratory tests to rule out medical conditions associated with gynecomastia is recommended.
Initial Tests (lab, imaging)
  • Luteinizing hormone (LH)—elevated in primary hypogonadism and decreased in secondary hypogonadism (6)[C]
  • Morning total and free testosterone—decreased testosterone level in hypogonadism (6)[C]
  • Human chorionic gonadotropin (hCG)—elevated in germ cell tumors and ectopic hCG tumors (6)[C]
  • Estradiol—elevated in Leydig cell tumors, Sertoli cell tumors, adrenal tumors, and with increased aromatase activity (6)[C]
  • Urine for drugs of abuse (UDA)
  • Other tests to consider include creatinine, liver function test, thyroid function tests, and prolactin.
Follow-Up Tests & Special Considerations
Consider imaging studies based on laboratory findings.
  • Testicular ultrasound (testicular tumor)
  • Chest x-ray (CXR) and abdominal CT/MRI (extragonadal germ cell tumor, ectopic hCG tumor, and adrenal tumor)
  • MRI of pituitary (pituitary tumor)
Diagnostic Procedures/Other
Based on physical exam findings, consider biopsy of breast mass to rule out malignancy (i.e., off center, hard, fixed, discharge).
P.433

Test Interpretation
  • Elevated hCG: Check testicular ultrasound. If positive for a mass, likely a testicular germ cell tumor. If the ultrasound is negative, consider extragonadal germ cell tumor or hCG-secreting neoplasm and order a CXR and CT abdomen (6)[C].
  • Elevated LH: if in relation to low testosterone, likely primary hypogonadism. If elevated in relation to high testosterone, check thyroid-stimulating hormone (TSH) and free thyroxine (FT4). If FT4 elevated and TSH is suppressed, likely hyperthyroidism; if TSH and FT4 are normal, likely androgen resistance (6)[C]
  • Normal or decreased LH in relation to low testosterone: Check prolactin level. If prolactin is elevated, likely due to a prolactin-secreting pituitary tumor; if normal, likely due to secondary hypogonadism (6)[C]
  • Normal or decreased LH in relation to increased estradiol: Check testicular ultrasound. If positive for a mass, likely Leydig or Sertoli cell tumor. If negative for mass, check CT abdomen to evaluate the adrenals. If mass is present, possible adrenal neoplasm versus adenoma; if no mass is detected, then likely due to increased aromatase activity in extraglandular tissue (6)[C]
  • hCG, LH, testosterone, and estradiol are normal: likely idiopathic or medication/drug-induced gynecomastia (6)[C]
image TREATMENT
GENERAL MEASURES
  • Gynecomastia usually regresses spontaneously within 6 months of onset. This is true even for adult males. Therefore, patients can be monitored for the first 6 months and treatment considered if gynecomastia persists.
  • The histologic changes early in the disease process can be reversed with medical therapy. However, with the development of fibrotic tissue, surgery is typically required. Typically, 1 to 2 years after the onset of gynecomastia, fibrotic changes can be seen and medical intervention is less effective (7)[C].
  • Neonatal and pubertal gynecomastia spontaneously resolves within 6 to 24 months. Persistent pubertal gynecomastia (>24 months) occurs in 8% of pubertal boys. In adult males, 75% of gynecomastia is secondary to persistent pubertal gynecomastia, medications, and idiopathic conditions. Only 25% is related to an underlying medical condition.
  • All illicit drug use and offending medications should be stopped if appropriate, and patients monitored for clinical improvement.
  • Underlying medical conditions need to be treated (i.e., testosterone replacement for hypogonadal men, dopamine agonist for prolactinoma, appropriate treatment for thyrotoxicosis, and tumor resection).
  • Medical and surgical therapy to reduce gynecomastia should be considered in patients with significant physical or psychological discomfort.
MEDICATION
  • There are no FDA-approved medications for the treatment of gynecomastia but clinical trials involving selective estrogen receptor modulators and aromatase inhibitors demonstrate partial regression and symptom relief (i.e., breast tenderness).
    • Selective estrogen receptor modulators (SERMs): Clinical trials of both tamoxifen (10 to 20 mg/day) and raloxifene (60 mg/day) showed partial reduction in pubertal gynecomastia in 90% of study participants after 3 to 9 months but 40% of patients in both treatment groups were not satisfied with the final results and underwent surgical removal (7)[B]. Tamoxifen has also been shown to reduce breast tenderness and prevent the development of gynecomastia in prostate cancer patients on androgen deprivation therapy. Therefore, SERMs (particularly tamoxifen) can be considered in men with 6 to 12 months of severe, painful gynecomastia symptoms.
    • Aromatase inhibitors block peripheral conversion of androgens to estrogens. In clinical trials, anastrozole (1 mg daily) has shown mixed results with one study reporting reduced breast volume in pubertal males and others not reporting a benefit. In prostate cancer patients, anastrozole prevented the development of gynecomastia in patients undergoing androgen deprivation therapy (8,9)[B].
ISSUES FOR REFERRAL
  • Refer patients to an endocrinologist if abnormally elevated hormone levels are confirmed.
  • If patients have refractory gynecomastia despite medical therapy and have prolonged gynecomastia characterized by the late fibrotic stage or symptoms concerning for breast cancer, referral to a surgeon would be appropriate.
ADDITIONAL THERAPIES
In clinical trials, prophylactic radiotherapy (10 to 15 Gy in one fraction over 3 days) prevented the development of gynecomastia in prostate cancer patients on androgen deprivation therapy. Higher doses (20 Gy in five fractions) improved pain symptoms in the same population. More studies are needed to evaluate the use of radiation therapy in other populations.
SURGERY/OTHER PROCEDURES
Surgery to remove breast tissue is recommended if:
  • Gynecomastia does not regress within 12 months either spontaneously or after medical therapy
  • Significant discomfort (i.e., pain, tenderness)
  • Causes embarrassment or anxiety
  • Biopsy suspicious for malignancy
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Every 3 to 6 months for 24 months; consider medical therapy (i.e., tamoxifen) if severe, painful symptoms persist after 6 to 12 months and surgery after 12 to 24 months. In individuals with asymptomatic or mild disease, routine yearly breast and physical exam is recommended.
  • Patients with Klinefelter syndrome are at increased risk of breast cancer and should have routine breast exams done.
PATIENT EDUCATION
Patients should be encouraged to do periodic breast examination and to alert their clinical provider if a nodule is palpated in the breast or axilla, skin discoloration occurs, or nipple discharge develops.
PROGNOSIS
  • Good in physiologic cases, as they often regress spontaneously within 3 to 6 months (6)
  • Majority of patients experience regression once underlying disorder is treated or offending agents are eliminated (6).
  • In patients who undergo surgery, majority are satisfied with the postop cosmetic appearance (10).
REFERENCES
1. Bembo SA, Carlson HE. Gynecomastia: its features, and when and how to treat it. Cleve Clin J Med. 2004;71(6):511-517.
2. Cuhaci N, Polat SB, Evranos B, et al. Gynecomastia: clinical evaluation and management. Indian J Endocrinol Metab. 2014;18(2):150-158.
3. Boccardo F, Rubagotti A, Battaglia M, et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol. 2005;23(4):808-815.
4. Bowman JD, Kim H, Bustamante JJ. Drug-induced gynecomastia. Pharmacotherapy. 2012;32(12):1123-1140.
5. Jover F, Cuadrado JM, Roig P, et al. Efavirenz-associated gynecomastia: report of five cases and review of the literature. Breast J. 2004;10(3): 244-246.
6. Braunstein GD. Clinical practice. Gynecomastia. N Eng J Med. 2007;357(12):1229-1237.
7. Lawrence SE, Faught KA, Vethamuthu J, et al. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr. 2004;145(1):71-76.
8. Mauras N, Bishop K, Merinbaum D, et al. Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia. J Clin Endocrinol Metab. 2009;94(8):2975-2978.
9. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2004;89(9):4428-4433.
10. Gioffrè Florio MA, Alfio AR, Famà F, et al. Evaluation of complications and long-term results after surgery for gynaecomastia [in Italian]. Chir Ital. 2004;56(1):113-116.
Additional Reading
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Eckman A, Dobs A. Drug-induced gynecomastia. Expert Opin Drug Saf. 2008;7(6):691-702.
See Also
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Algorithm: Gynecomastia
Codes
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ICD10
N62 Hypertrophy of breast
Clinical Pearls
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  • Gynecomastia can be transient and represents the normal physiologic changes in neonates or adolescents. However, gynecomastia presenting or persisting in adulthood is typically pathologic in nature.
  • Thorough history and physical exam should be performed on all patients and offending medications eliminated.
  • Lab and radiologic studies should be conducted to rule out medical conditions associated with gynecomastia including thyrotoxicosis, prolactinemia, hypogonadism, testicular tumors, adrenal tumors, and ectopic hCG tumors. Treatment should be tailored to exam findings.
  • ˜25% of gynecomastia is idiopathic in nature and treatment should focus on symptom control.
  • Clinical trials of SERMs, aromatase inhibitors, and radiation therapy seem promising. Surgery is the treatment of choice for refractory gynecomastia.