Should gynecomastia in a male be investigated to determine the underlying cause?

Should Gynecomastia in Males Be Investigated?

Yes, gynecomastia in adult males (≥18 years) should be investigated because an underlying, often treatable, cause can be identified in 43% of cases, whereas investigation is less critical in adolescent-onset gynecomastia where only 7.7% have an identifiable pathologic cause. 1

Investigation Algorithm by Age and Presentation

Adult-Onset Gynecomastia (≥18 years)

Full hormonal and clinical workup is mandatory because nearly half of adult cases have an identifiable and potentially serious underlying cause 1:

Step 1: Clinical Assessment

• Calculate BMI or measure waist circumference to differentiate true gynecomastia from pseudogynecomastia (fatty tissue deposition) 2
• Palpate for a soft, rubbery, or firm mobile mass directly under the nipple to confirm true glandular enlargement 2
• Perform complete testicular examination assessing size, consistency, masses, and varicocele presence 2
• Examine body hair patterns in androgen-dependent areas to evaluate virilization status 2
• Check for visual field defects (bitemporal hemianopsia) suggesting pituitary pathology 2
• Review medication history with temporal correlation to gynecomastia onset 3
• Assess for alcohol and cannabis use, as both can cause gynecomastia through hormonal disruption 4

Step 2: Laboratory Investigation

Measure morning total testosterone as the primary baseline test 2:

• If borderline, calculate free testosterone using total testosterone, SHBG, and albumin 2
• Measure serum estradiol in all patients before any hormonal therapy 2, 4
• Obtain LH and FSH to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 2
• If testosterone is low with low/normal LH, add prolactin to exclude hyperprolactinemia 2, 4
• Consider thyroid function tests, as thyrotoxicosis can cause gynecomastia 5, 6

Mandatory endocrinology referral for all patients with elevated baseline estradiol 2, 4

Step 3: Imaging (Only When Clinically Indicated)

Most men do not require imaging if clinical findings are consistent with benign gynecomastia 2:

• No routine imaging for clear bilateral gynecomastia to avoid unnecessary biopsies 2
• Imaging is indicated if differentiation from breast cancer cannot be made clinically or if presentation is suspicious (unilateral, hard, fixed, eccentric mass) 2
• Immediate imaging required for bloody nipple discharge or retracted skin/nipple 2

For men ≥25 years requiring imaging: Mammography or digital breast tomosynthesis first (sensitivity 92-100%, specificity 90-96%) 2

For men <25 years requiring imaging: Ultrasound first, followed by mammography if suspicious features found 2

Adolescent/Pubertal Gynecomastia (<18 years)

Investigation is generally not warranted unless specific red flags are present 1:

• Only 7.7% of adolescent-onset cases have an identifiable underlying cause 1
• No routine imaging for clinical findings consistent with physiologic pubertal gynecomastia 2
• Spontaneous resolution occurs in up to 50% of cases with non-cyclical breast symptoms 2, 4
• Ultrasound only if clinical examination is indeterminate or suspicious in boys <25 years 2

High-Priority Underlying Causes to Rule Out

Neoplastic Causes (Must Not Miss)

• Testicular tumors (Leydig cell tumors producing estrogen) 5, 7
• Adrenal tumors or adrenocortical carcinomas secreting estrogen 3
• Male breast cancer (rare, <1% of all breast cancers, median age 63 years) 2
• hCG-secreting tumors 5, 6

Endocrine Disorders

• Klinefelter syndrome (relative risk 24.7 for gynecomastia) 3
• Primary or secondary hypogonadism 2, 5
• Hyperprolactinemia 2, 3
• Hyperthyroidism 5, 8, 6

Systemic Diseases

• Liver cirrhosis (impairs hepatic clearance of steroid precursors) 4, 3, 5
• Chronic renal failure 5, 6
• Diabetes (associated with lower testosterone levels) 2

Medication-Induced

• Anti-androgens (GnRH agonists, spironolactone) 2, 3
• Exogenous estrogens (DES, digoxin, phytoestrogens) 2
• Chemotherapeutic agents 3
• Cardiac and antihypertensive medications 8

Common Pitfalls to Avoid

• Failing to distinguish true gynecomastia from pseudogynecomastia, especially in obese patients, leads to inappropriate workup 2, 3
• Ordering unnecessary imaging in clear benign cases increases false-positive biopsies without improving outcomes 2, 3
• Missing medication review as iatrogenic causes are extremely common and reversible 3, 8
• Delaying investigation beyond 12 months when gynecomastia becomes fibrotic and less responsive to medical therapy 3, 8
• Not measuring estradiol before testosterone therapy in hypogonadal men, which can worsen gynecomastia 2

Special Populations Requiring Enhanced Surveillance

• BRCA2 mutation carriers have significantly higher risk of male breast cancer and gynecomastia 3
• Men with diabetes should have morning testosterone measured, as diabetes lowers testosterone levels and worsens gynecomastia 2
• Men interested in fertility require reproductive health evaluation (testicular exam, FSH) before treatment 2
• Patients starting anti-androgen therapy should receive prophylactic breast irradiation (8-15 Gy in 1-3 fractions, 1-2 weeks before initiation) to prevent painful gynecomastia 2