Gynecomastia

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Gynecomastia is the proliferation of mammary gland tissue in male individuals, including those with Klinefelter syndrome; neonatal gynecomastia manifests in both male and female infants. Gynecomastia is caused by an increased estrogen/testosterone ratio that can be physiological (typically in neonates, during puberty, or in older adults), pathological (e.g., due to medications, liver cirrhosis, chronic kidney disease, estrogen-secreting tumors), or idiopathic. Gynecomastia is a clinical diagnosis confirmed by identifying palpable glandular tissue on physical examination. A medication review should be performed in all patients; drug-induced gynecomastia accounts for 25% of cases. Diagnostics are not routinely recommended for individuals with physiological gynecomastia. Breast imaging may be considered to rule out differential diagnoses or if physical examination findings are inconclusive. Diagnostic workup for pathological gynecomastia should be guided by clinical evaluation and includes laboratory studies to evaluate for chronic diseases (e.g., liver chemistries, renal function tests, thyroid function tests), hypogonadism (e.g., sex hormone profile), or malignancy (e.g., tumor markers, imaging, biopsy). Pathological gynecomastia can usually be managed by treating the underlying cause. Physiological gynecomastia usually regresses spontaneously. Surgery (e.g., nipple-sparing mastectomy) may be considered for pathological gynecomastia unresponsive to treatment of the underlying cause, longstanding gynecomastia, or cosmesis.

Gynecomastia is caused by an increased estrogen/testosterone ratio (e.g., elevated estrogen levels, decreased testosterone levels, or both) but can be idiopathic in upto 25% of patients. It is the most common abnormality of the male breast. ^[2][3][4]

Physiological gynecomastia ^[2]

• Neonatal gynecomastia ^[5]
  • Occurs in ∼ 90% of neonates due to placental transfer of maternal estrogens
  • Gynecomastia is bilateral, sex independent, and spontaneously resolves within a few weeks or months.
• Pubertal gynecomastia ^[6]
  • Occurs in ∼ 50% of adolescent boys (typically occurs in patients aged 10–14 years)
  • Caused by pubertal estrogen/androgen imbalance
  • Clinical features
    • Small, mobile, firm plaques of breast tissue in the subareolar region that develop during puberty
    • Can be tender, unilateral/bilateral, and associated with fatty development around the nipple
    • Spontaneously resolves (usually by 17 years of age)
  • Pharmacotherapy or surgery can be considered for persistent pubertal gynecomastia or if symptoms cause significant distress.
• Senile gynecomastia: occurs in ∼ 50% of men > 50 years

Pathological gynecomastia ^[2]

Due to estrogen excess

• Malignancies
  • Leydig cell tumor
  • Sertoli cell tumor
  • Ectopic hCG-producing tumors (e.g., lung cancer, hepatocellular carcinoma)
  • Adrenocortical tumors
• Liver cirrhosis: due to increased conversion of adrenal androgen precursors to estrogen
• Hyperthyroidism: due to
  • ↑ peripheral conversion of androgens to estrogens
  • ↑ hepatic production of sex hormone binding globulin (SHBG), which has a higher affinity for testosterone → ↓ free testosterone and a relative increase in estrogen ^[7]
• Refeeding (after prolonged starvation) ^[2]

Due to decreased testosterone

• Klinefelter syndrome
• Chronic kidney disease ^[8]
• Testicular disorders (e.g., mumps orchitis, castration, trauma to both testes)
• Hypogonadism
• Hyperprolactinemia ^[9]
• Starvation

Drug-induced ^[10][11]

Drug-induced gynecomastia accounts for up to 25% of cases. ^[9][10]

• Inhibitors of testosterone receptors
  • Antiandrogens; (e.g., finasteride, bicalutamide, cyproterone acetate, flutamide)
  • High-dose cimetidine (H₂ receptor blocker)
  • Spironolactone
• Inhibitors of testosterone synthesis
  • Ketoconazole
  • Spironolactone
  • Chemotherapy drugs (e.g., cyclophosphamide, methotrexate, bleomycin, cisplatin, vincristine)
• Exogenous androgens and androgenic steroids ; ^[12]
  • Exogenous testosterone
  • Androgen precursors (e.g., DHEA, androstenedione)
  • Androgenic steroids
• Estrogen receptor stimulators
  • Estrogens
  • Digitalis compounds
• Marijuana
• Opioids
• cART drugs

Some Hormones Cause Fulminant Kleavage: Spironolactone, Hormones, Cimetidine, Finasteride, Ketoconazole cause gynecomastia.

• Firm, concentric, typically mobile mass in the subareolar region
• May be tender
• Typically bilateral
• In pathological gynecomastia: possible features of undervirilization, hyperthyroidism, liver/kidney disease, etc.

General principles ^[2][9][13]

• Obtain a detailed medical history (including a medication review; see drug-induced gynecomastia).
• Perform a thorough physical examination.
• Confirm gynecomastia (i.e., palpable glandular breast tissue) on physical examination.
• Distinguish between physiological and pathological gynecomastia based on clinical evaluation.
  • Physiological gynecomastia likely: Diagnostic workup is not routinely recommended.
  • Suspected pathological gynecomastia or symptom onset in adulthood: Evaluate for an underlying etiology; consider specialist (e.g., endocrinology) referral.

Examine the breasts and testes in all patients with gynecomastia. Expedite further diagnostics (e.g., imaging, biopsies) if malignancy is suspected (e.g., features of breast cancer; testicular mass on palpation or imaging). ^[9]

Assess all patients with symptom onset in adulthood for pathological gynecomastia, even when an apparent cause has been identified. ^[13]

Laboratory studies

Routine studies ^[2]

• Liver chemistries
• Urea and creatinine
• Thyroid function tests

Suspected hypogonadism

• Sex hormone profile ^[13]
  • ↑ LH (with ↓ or normal testosterone): primary hypogonadism ^[2][9][13]
  • ↓ LH and ↑ estradiol: testicular tumor, stress, or exogenous estrogen ^[2][9]
  • ↓ LH and ↓ testosterone: secondary hypogonadism or prolactinoma
• Serum prolactin levels: Elevated levels are suggestive of prolactinoma. ^[2][9][14]

Suspected estrogen-secreting tumors

• Tumor markers
  • Elevated hCG or alpha-fetoprotein: suggestive of testicular germ cell tumors ^[2][13]
  • Elevated dehydroepiandrosterone: suggestive of adrenal tumors ^[2]

Elevated hCG, alpha-fetoprotein, and/or dehydroepiandrosterone is suggestive of malignancy. ^[2][13]

If all laboratory tests are normal, including the hormone profile, gynecomastia is likely idiopathic. ^[2]

Imaging

Breast imaging ^[15]

Breast imaging is not routinely recommended in patients with clinical features consistent with gynecomastia or pseudogynecomastia. ^[9][15]

• Indications and preferred first-line modalities
  • Indeterminate breast mass on physical examination
    • Age < 25 years: ultrasound breast
    • Age ≥ 25 years: mammography or digital breast tomosynthesis
  • Examination findings concerning for breast cancer: mammography, digital breast tomosynthesis, or ultrasound breast
• Supportive findings of gynecomastia ^[15][16]
  • On ultrasound: subareolar hypoechoic mass
  • On mammography: normal breast tissue

Consider routinely screening for breast cancer in all patients with Klinefelter syndrome who present with gynecomastia; these individuals have a significantly higher risk (16–30 times) of breast cancer than those with XY chromosomes. ^[2]

Breast lesions concerning for malignancy on imaging or physical examination should be urgently biopsied (e.g., core needle biopsy). ^[9]

Testicular ultrasound

Some guidelines recommend testicular ultrasound for all individuals with gynecomastia; others recommend imaging only in the following cases: ^[2][9][13]

• Suspected testicular tumor ^[9][14]
• Suspected hypogonadism ^[14]
• Gynecomastia > 5 cm ^[2]
• Pathological gynecomastia of unknown etiology ^[2]

Neuroimaging ^[2]

• To evaluate for pituitary adenoma (e.g., in patients with elevated serum prolactin levels)
• See “Diagnostics of pituitary adenoma” for details.

• Pseudogynecomastia ^[2][13][14]
  • Subareolar fatty tissue without evidence of a discrete subareolar mass on palpation
  • Most commonly seen in obese individuals
  • Clinical diagnosis; if imaging is performed, no evidence of breast tissue ^[15]
  • Often resolves spontaneously with weight loss
• Male breast cancer: examination findings may include hard immobile mass, skin changes, axillary lymphadenopathy, and nipple retraction or discharge ^[2][13]
• Lipoma: well-defined mobile typically unilateral mass; not necessarily subareolar in location ^[2]
• Mastitis: signs of local (e.g., erythema, edema, tenderness) and systemic (e.g., fever, leukocytosis) infection

The differential diagnoses listed here are not exhaustive.

Pathological gynecomastia ^[2]

Treat the underlying cause and monitor for regression. Examples include:

• Drug-induced gynecomastia: If feasible, discontinue the causative agent.
• Hyperthyroidism: See “Treatment of hyperthyroidism.”
• Testicular tumor: See “Management of testicular cancer.”
• Confirmed hypogonadism: testosterone replacement ^[9][13]

Most patients with gynecomastia experience spontaneous regression or respond well to management of the underlying condition. ^[13]

After discontinuing medications or treating the underlying cause, an observation period is recommended to monitor for regression. Surgery can be considered for patients with persistent gynecomastia. ^[13]

Physiological and idiopathic gynecomastia ^[2][9][13]

Watchful waiting can be considered if no pathological cause is suspected and the patient is not disturbed by their symptoms.

• Reassurance and follow up every 6 months. ^[2][13]
• Provide adequate analgesia.
• Persistent gynecomastia
  • Consider pharmacotherapy for persistent pubertal gynecomastia of recent onset.
  • Consider surgery for long-standing gynecomastia and cosmesis.

Pharmacotherapy ^[9][13]

• Agents: (off-label): selective estrogen receptor modulators (tamoxifen, raloxifene)
• Indications (limited evidence of benefit)
  • Painful or persistent pubertal gynecomastia (duration < 2 years) ^[13]
  • Treatment or prevention of gynecomastia secondary to androgen ablation therapy for prostate cancer (tamoxifen in particular)

Surgery ^[9][13]

• Indications (not routinely required ;)
  • Gynecomastia unresponsive to medical therapy or treatment of the underlying cause
  • Long-standing symptomatic gynecomastia
  • Cosmesis
• Examples
  • Nipple-sparing subcutaneous mastectomy ,
  • Suction lipectomy