What are the causes and treatment options for gynecomastia in men?

Gynecomastia in Men: Causes and Treatment

Definition and Clinical Presentation

Gynecomastia is benign enlargement of male breast glandular tissue caused by an imbalance in the estrogen-to-androgen ratio, presenting as a soft, rubbery, or firm mobile mass directly under the nipple that is often painful, especially when present for less than 6 months. 1

• Affects at least 30% of males during their lifetime, with prevalence of asymptomatic gynecomastia up to 65% 2, 3
• Bilateral in approximately 50% of patients 1
• Must be differentiated from pseudogynecomastia (fatty tissue deposition rather than glandular enlargement), especially in patients with elevated BMI 1

Major Causes

Physiologic Causes

• Pubertal gynecomastia: Common during three life phases—neonatal period, puberty, and senescence 4
• Age-related: Median age for male breast cancer is 63 years, but benign gynecomastia occurs across all ages 1

Hormonal Disorders

• Hyperprolactinemia 5
• Hypogonadism (primary or secondary gonadal failure) 2
• Hyperthyroidism 2
• Androgen resistance syndromes 2

Systemic Diseases

• Liver cirrhosis 5
• Chronic liver disease 2
• Renal dysfunction 5

Genetic Conditions

• Klinefelter syndrome: Significantly increases risk with relative risk of 24.7 5
• BRCA2 mutation carriers have significantly higher risk 5

Medication-Induced Gynecomastia

Common culprit medications include:

• Spironolactone: For patients developing gynecomastia on spironolactone, switch to eplerenone which has significantly lower risk 6
• Antiandrogens: Bicalutamide, flutamide, nilutamide, cyproterone acetate 6
• 5-alpha reductase inhibitors: Finasteride, dutasteride 6
• GnRH agonists or antagonists 6
• Ketoconazole 6
• Digoxin (contradictory evidence) 6
• Glucocorticoids 6
• Chemotherapeutic agents 5

Hormonal therapies:

• Testosterone or anabolic steroids (through conversion to estrogens) 6
• Estrogens and medications with estrogenic activity 6
• Androgen deprivation therapy for prostate cancer (incidence up to 80% with estrogen therapy) 6

Other Causes

• Chronic cannabis use, especially when started at young age 6
• Adrenal tumors or adrenocortical carcinomas secreting estrogen 5
• Obesity (increases peripheral conversion of androgens to estrogens) 5

Diagnostic Evaluation Algorithm

Step 1: Clinical Assessment

Physical examination should include:

• Body habitus and BMI calculation or waist circumference measurement 1
• Virilization status by examining body hair patterns in androgen-dependent areas 1
• Complete testicular examination for size, consistency, masses, and varicocele 1
• Prostate size and morphology assessment 1
• Visual field examination for bitemporal hemianopsia suggesting pituitary disorders 1
• Differentiation between true gynecomastia (glandular tissue) and pseudogynecomastia (fatty tissue) 1

Step 2: Laboratory Testing

For patients with elevated baseline estradiol, refer to endocrinologist who will order: 1

• Serum testosterone levels
• Serum estradiol levels
• Luteinizing hormone (LH) levels
• Prolactin levels (if testosterone is low with low/normal LH)

Measure serum estradiol in testosterone-deficient patients who present with breast symptoms prior to starting testosterone therapy. 1

Step 3: Imaging Decision

Most men with breast symptoms can be diagnosed based on clinical findings without imaging. 1

Imaging is indicated only if:

• Differentiation between benign disease and breast cancer cannot be made clinically 1
• Presentation is suspicious (unilateral mass, hard, fixed, or eccentric) 1
• Bloody nipple discharge present 1
• Retracted skin or nipple present 1

Imaging modality selection:

• Men younger than 25 years: Ultrasound is initial study 1
• Men 25 years and older: Mammography or digital breast tomosynthesis (sensitivity 92-100%, specificity 90-96%, negative predictive value 99-100%) 1

Step 4: Biopsy (If Needed)

Core needle biopsy is superior to fine-needle aspiration in sensitivity, specificity, and histological grading. 1

Guidance method:

• Ultrasound-guided for lesions visible on ultrasound (preferred for patient comfort, real-time visualization, no radiation) 1
• Stereotactic-guided for lesions only visible on mammography 1
• DBT-guided for lesions only visible on DBT 1

Post-biopsy marker clip should be placed to confirm tissue sampling and aid correlation. 1

Treatment Algorithm

Step 1: Address Underlying Causes

Medication review:

• Discontinue causative medications when possible (e.g., switch spironolactone to eplerenone) 6
• Evaluate temporal relationship between medication initiation and gynecomastia onset 5

Treat underlying conditions:

• Hyperthyroidism 2
• Benign Leydig cell tumors of testis 7
• Hypogonadism with androgen administration 7

Step 2: Observation for Physiologic Gynecomastia

Pubertal gynecomastia resolves spontaneously in majority of adolescents; reassurance and observation is best approach. 4

• Noncyclical breast pain tends to be of shorter duration, with spontaneous resolution in up to 50% of patients 1
• Men with testosterone deficiency who develop gynecomastia on testosterone treatment should undergo monitoring as symptoms sometimes abate 1

Important note: Anastrozole is NOT effective for pubertal gynecomastia—a randomized controlled trial showed no statistically significant difference versus placebo in reduction of gynecomastia 8

Step 3: Medical Therapy for Persistent, Painful Gynecomastia

Medical therapy should be considered only in early-stage gynecomastia (less than 12 months duration), as gynecomastia persisting beyond 12 months becomes fibrotic and less responsive. 5, 2

Options include:

• Tamoxifen: May be considered at early stage with 30% response rate 2, 9
• Estrogen receptor modulators: For testosterone-deficient patients with low or low/normal LH 1
• Antiestrogen therapy: For men with endogenous overproduction of estrogens 7

Medical therapy should not be considered in chronic established cases. 9

Step 4: Surgical Treatment

For chronic, bothersome gynecomastia persisting over 12 months, surgical excision is the treatment of choice. 2, 4

Surgical options depend on grade:

• Simple liposuction for predominant fatty component 9
• Direct excision when glandular tissue is predominant 9

Special Considerations

Prophylactic breast irradiation:

• To prevent painful gynecomastia in patients starting antiandrogen therapy, give breast irradiation (8-15 Gy in 1-3 fractions) 1-2 weeks before initiation 1

Fertility concerns:

• Men with gynecomastia interested in fertility should have reproductive health evaluation performed prior to treatment 1

Critical Pitfalls to Avoid

• Unnecessary imaging in clear cases leads to additional unnecessary benign biopsies 1, 5
• Failing to distinguish true gynecomastia from pseudogynecomastia, especially in obese patients 5
• Attempting medical therapy for chronic gynecomastia (>12 months) when fibrosis has already occurred 5
• Not measuring estradiol before starting testosterone therapy in patients with breast symptoms 1
• Using anastrozole for pubertal gynecomastia—it is ineffective 8