Basics
Description
Visible or palpable proliferation of unilateral or bilateral breast glandular tissue in a male
Epidemiology
- 2 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: 10-16 years). Onset usually at 5-10-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 technique.
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 levels 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 high likelihood of spontaneous regression.
- Involutional: Breast enlargement occurs in elderly men.
- Physiologic gynecomastia usually 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
- 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, true hermaphroditism, excessive peripheral tissue aromatase
- Acquired testicular failure (viral, torsion, other)
- 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
- Miscellaneous masses: dermoid cyst
Diagnosis
Alert
- Do not mistake pseudogynecomastia (i.e., fatty enlargement of the breasts) for true gynecomastia.
- Do not overlook drug-related causes. Drug-related gynecomastia is usually reversible if diagnosed during year of onset.
History
- Family history: 1/2 of adolescents with gynecomastia have positive family history.
- Time of onset relative to puberty: Onset usually at testicular size 5-10 mL and Tanner stage III or IV pubic hair.
- Prepubertal more concerning than pubertal.
- Unilateral more concerning than bilateral.
- Rate of progression
- Rapidly enlarging, painful gynecomastia with acute onset is of more concern than long-standing enlargement.
- Drug exposures, including alcohol, marijuana, and heroin, along with exposure to exogenous estrogen and commercial products containing estrogens, lavender, tea tree oil, phthalates, ginseng, and others
- Symptoms suggestive of hyperthyroidism
- Symptoms suggestive of liver disease, such as cirrhosis
- Symptoms suggestive of renal failure
- Symptoms suggestive of neoplastic disease
- Symptoms suggestive of hypogonadism, such as decreased libido, erectile dysfunction, or infertility, may indicate an abnormal estrogen-to-androgen ratio.
Physical Exam
- Assess for malnourishment: may result in hepatic dysfunction causing higher estrogen-to-androgen ratio
- Perform a complete breast exam:
- With patient supine, grasp breast between thumb and forefinger and move digits toward the nipple: Look for a firm, rubbery, mobile, discoid mound of glandular tissue arising concentrically below the nipple and areola. Measure diameter of the disc. Asymmetry and tenderness are common.
- Check for galactorrhea, which is a sign of drug ingestion or hyperprolactinemia.
- Masses not concentric around the areola, that are hard, firm, fixed, that are unilateral, or have any skin dimpling, nipple retraction, nipple bleeding, or discharge, are concerning for carcinoma. This is very rare in male adolescents.
- Check for pseudogynecomastia: (fatty enlargement): If present, no glandular disc will be palpable under areola.
- If disc diameter is >5 cm, regression is very unlikely.
- Thyroid exam: Goiter may indicate hypothyroidism.
- Testicular exam: Consider testicular tumors with masses or significant asymmetry of testes. Consider gonadal failure for small, firm testes. Gynecomastia more likely to be pathologic if testes <5 mL (in this case, not defined as pubertal gynecomastia).
Diagnostic Tests & Interpretation
Lab
- Benign presentations do not need extensive workup. Neonatal gynecomastia can be monitored without workup for regression by 1 year of age. Bilateral pubertal gynecomastia arising after pubertal onset, <5 cm in diameter can be monitored as well for further growth.
- In other cases, direct workup to suspected causes based on history and exam:
- LH for pituitary function
- FSH to rule out testicular failure
- Prolactin for hyperprolactinemia
- TSH for hyperthyroidism
- Testosterone for gonadal function
- Estrogen for aromatization excess, estrogen excess, or estrogen-secreting tumors (Although in some cases, local aromatase activity can cause gynecomastia without high circulating estrogen.)
- DHEA-S for adrenal tumors
- hCG for germ cell tumors (Note that this specific lab is to be ordered, not a qualitative pregnancy test.)
- Karyotype to rule out Klinefelter syndrome (only indicated in suspicious cases via history or exam, or those with proven testicular failure via high FSH)
- Most of these labs are best done in the morning if possible.
Imaging
- None indicated for benign presentations.
- Testicular ultrasound in cases with concerns of testicular tumor via asymmetric exam, elevated estradiol or hCG, or pubertal level testosterone with suppressed LH
- Abdominal/adrenal CT or MRI
- To rule out adrenal neoplasm, if estradiol elevated, DHEA-S elevated, or in cases concerning for testicular tumor that turn out to have negative testicular ultrasound
- Consider chest CT in such cases as well.
- Brain MRI or CT, with and without contrast: if pituitary tumor is suspected
- Bone age can be an adjunct evaluation in cases with concerns for estrogen excess; estrogen results in bone age advance.
Differential Diagnosis
See "Etiology."
Treatment
Medication
- Generally, drug therapy should proceed under the guidance of an endocrinologist.
- Tamoxifen and aromatase inhibitors in off-label use have shown some benefit in benign pubertal gynecomastia if started within 1 year of onset.
- If hypogonadal, replace testosterone.
- If gynecomastia has been present for >1 year, pharmacologic therapy is of little benefit because of an increase in fibrosis.
Additional Treatment
Additional Therapies
- Reassurance for patients with pubertal gynecomastia measuring <5 cm
- Discontinue drugs or commercial products known or suspected to induce gynecomastia, and follow up in 1-2 months.
- Reexamine at 3-6-month intervals for size change.
- For gynecomastia >5 cm, consider surgical consultation once history, exam, and lab evaluation for pathology (along with imaging in indicated cases) have been conducted.
Issues for Referral
Consider surgical consultation in patients with >5-cm diameter glandular tissue near the end of puberty. Surgery prior to completion of puberty may increase risk of recurrence.
Surgery/Other Procedures
- Surgery is therapy of choice for macrogynecomastia or persistent gynecomastia refractory to medical therapy, although obtaining insurance coverage may be difficult.
- Obesity should not preclude surgical intervention.
- Surgical options include periareolar incision with adjunctive liposuction or glandular tissue removal through 2 incisions in the anterior axillary regions.
- Ultrasound-assisted liposuction has emerged as a new alternative surgical option.
Ongoing Care
Follow-up Recommendations
- Reexamine every 3-6 months for size and characteristics.
- Watch for signs of psychological stress.
- Significant issue in some male adolescents and should not be dismissed
- Reassure that eventually, they shall be referred for treatment.
- In those with significant psychological stress, referral before completion of puberty may result in repeat surgery later, but this can be considered after discussion with patient and family.
Prognosis
- In benign cases, prognosis is good.
- Neonatal gynecomastia usually resolves within the 1st year of life.
- Pubertal gynecomastia <5 cm: 50-75% disappear spontaneously within 2 years, 90% within 3 years. If size >5 cm, regression unlikely
- Medical therapy effective only if treatment initiated within a year of onset.
Complications
- In benign cases
- Pain (may interfere with sports)
- Psychological stress
- Embarrassment
- Skin erosion of the nipple owing to rubbing against clothing
Additional Reading
- Braunstein GD. Clinical practice. Gynecomastia. N Eng J Med. 2007;357(12):1229-1237. [View Abstract]
- Goldman RD. Drug-induced gynecomastia in children and adolescents. Can Fam Physician. 2010;56(4):344-345. [View Abstract]
- Ma NS, Geffner ME. Gynecomastia in prepubertal and pubertal men. Curr Opin Pediatr. 2008;20(4):465-470. [View Abstract]
- Mauras N, Bishop K, Merinbaum D, et al. Pharmacokinetics and pharmacodynamics of anastrazole in pubertal boys with recent onset gynecomastia. J Clin Endocrinol Metab. 2009;94(8):2975-2978. [View Abstract]
- Nordt CA, DiVasta AD. Gynecomastia in adolescents. Curr Opin Pediatr. 2008;20(4):375-382. [View Abstract]
- Rosen H, Webb ML, DiVasta AD, et al. Adolescent gynecomastia: not only an obesity issue. Ann Plast Surg. 2010;64(5):688-690. [View Abstract]
Codes
ICD09
- 611.1 Hypertrophy of breast
- 778.7 Breast engorgement in newborn
ICD10
- N62 Hypertrophy of breast
- P83.4 Breast engorgement of newborn
SNOMED
- 4754008 Gynecomastia (disorder)
- 34831003 Breast engorgement in newborn (disorder)
- 237451004 Pubertal gynecomastia
- 237449003 Drug-induced gynecomastia
FAQ
- Q: When should a neonate with gynecomastia be referred to a specialist?
- A: For male neonates, if galactorrhea persists at 3 months of age, or the gynecomastia not resolved by 1 year of age.
- Q: When should a nonneonatal, but prepubertal, male with gynecomastia be referred to a specialist?
- A: Gynecomastia in a prepubertal boy is rare and concerning. Urgent referral should be made to a pediatric endocrinologist.
- Q: When should a pubertal adolescent with gynecomastia be referred to a specialist?
- A: If gynecomastia is unilateral; if size is >5 cm; if size is <5 cm but with visible enlargement ongoing within 1 year of onset of problem; if started before onset of puberty; if nipple bleeding, discharge or retraction. Also, if testes are <5 mL or testicular mass present; if abnormal hormonal workup or imaging study.
- Q: How can gynecomastia be distinguished from breast cancer?
- A: Breast cancer usually presents as a unilateral, eccentric hard or firm mass fixed to underlying tissues. Location usually outside the nipple-areolar complex. Associated findings can include dimpling of the skin, retraction of the nipple, nipple discharge, and/or axillary lymphadenopathy. Breast cancer in the pediatric population is extremely rare: <0.1% of all breast cancers occur in patients <20 years of age. Benign tumors, such as fibroadenomas, much more common than malignant tumors. If differentiation between gynecomastia and breast carcinoma cannot be made by physical exam alone, patient should undergo diagnostic mammography.
- Q: Has the incidence of gynecomastia increased?
- A: As the prevalence of childhood and adolescent obesity has increased, the presence of pseudo gynecomastia has also increased. Pseudogynecomastia is best treated with diet and exercise.