What are the causes, diagnosis, and treatment options for gynecomastia in males with a history of liver or kidney disease, hypogonadism, or those taking medications like spironolactone (aldosterone antagonist), cimetidine (histamine H2-receptor antagonist), or anabolic steroids?

Gynecomastia: Causes, Diagnosis, and Treatment in High-Risk Populations

Causes of Gynecomastia

Gynecomastia results from an imbalance between estrogen and androgen action in breast tissue, with medications accounting for 10-25% of all cases. 1, 2

Medication-Induced Gynecomastia (Definite Associations)

Spironolactone causes gynecomastia in approximately 9% of male patients at a mean dose of 26 mg daily, with risk increasing in a dose-dependent manner and onset varying from 1-2 months to over a year. 3 The condition is usually reversible upon discontinuation. 3, 4

• For patients requiring mineralocorticoid receptor antagonists who develop gynecomastia on spironolactone, switch to eplerenone as it has significantly lower risk of this side effect. 5, 4
• Cimetidine (H2-receptor antagonist) has definite association with gynecomastia. 2
• Ketoconazole causes hypogonadism and gynecomastia in men, which may limit prolonged treatment. 5, 2

Hormonal Medications

• Anabolic steroids cause gynecomastia through peripheral conversion to estrogens, with prevalence as high as 52% in high-consumption users. 5, 6, 2
• Testosterone or androgenic anabolic steroids paradoxically cause gynecomastia via aromatization to estrogen. 5
• 5-alpha reductase inhibitors (finasteride, dutasteride) may cause gynecomastia. 5, 2
• GnRH agonists/antagonists can lead to gynecomastia. 5, 2
• Anti-androgens (flutamide, bicalutamide, nilutamide) commonly cause gynecomastia, with incidence as high as 80% in prostate cancer patients on estrogen therapy. 5

Disease-Related Causes

In patients with liver disease, gynecomastia occurs due to impaired metabolism of endogenous hormones and increased peripheral conversion of androgens to estrogens. 7, 8

• Painful gynecomastia can be caused or exacerbated by spironolactone in cirrhotic patients receiving diuretic therapy for ascites. 7
• Kidney disease increases risk through impaired hormone clearance and altered drug metabolism. 8
• Hypogonadism causes gynecomastia through deficient androgen action; boys with prolactinomas may present with gynecomastia as a result of hypogonadism. 7, 1

Other Medications with Probable Association

• Risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), alcohol, and opioids. 2
• Digoxin has contradictory evidence regarding gynecomastia. 5
• Glucocorticoids may contribute to gynecomastia. 5

Diagnostic Approach

When evaluating male patients with breast enlargement, differentiate true gynecomastia (glandular tissue proliferation) from pseudogynecomastia (fatty tissue deposition), especially in patients with elevated BMI. 5

Essential History Elements

• Obtain detailed medication history including all prescription drugs, over-the-counter medications, herbal supplements, and anabolic steroids. 7, 8, 9
• Document temporal relationship between medication initiation and gynecomastia onset. 8, 4
• Assess for symptoms of hypogonadism: delayed/arrested puberty, erectile dysfunction, decreased libido, fatigue. 7
• Screen for liver disease symptoms: jaundice, ascites, spider angiomata, palmar erythema. 7
• Evaluate for kidney disease: edema, oliguria, uremic symptoms. 8

Physical Examination Specifics

• Palpate for firm, rubbery, subareolar glandular tissue (true gynecomastia) versus soft adipose tissue (pseudogynecomastia). 5, 9
• Assess for unilateral versus bilateral presentation (spironolactone can cause unilateral gynecomastia). 4
• Examine for signs of hypogonadism: small testes, decreased body hair, eunuchoid proportions. 7
• Look for stigmata of chronic liver disease: jaundice, ascites, spider angiomata, hepatomegaly. 7

Laboratory Evaluation

In men with symptomatic hypogonadism, measure morning total testosterone using an accurate assay; if levels are near the lower limit, determine free testosterone via equilibrium dialysis or calculation using total testosterone, SHBG, and albumin. 7

• Measure serum prolactin in patients with delayed puberty, galactorrhea, visual field loss, growth/pubertal arrest, or menstrual disturbance. 7
• For patients with liver disease, use FIB-4 index (age, ALT, AST, platelets) to screen for clinically significant liver fibrosis. 7
• Monitor serum electrolytes, particularly potassium in patients on spironolactone. 3
• Consider serum estradiol, LH, FSH, hCG, and thyroid function tests. 1, 9

Imaging

• Ultrasound or mammography to differentiate gynecomastia from breast cancer when clinically indicated. 5, 9
• MRI of pituitary if prolactin elevated to evaluate for prolactinoma. 7

Treatment Approach

Medication Management

The first-line intervention for drug-induced gynecomastia is discontinuation of the causative agent, with spontaneous resolution often occurring within months. 8, 1

• For spironolactone-induced gynecomastia: switch to eplerenone or reduce dose; gynecomastia is usually reversible. 5, 3, 4
• For anabolic steroid-induced gynecomastia: discontinue steroids immediately; consider tamoxifen for persistent cases with high remission rates. 6
• Avoid potassium supplementation, potassium-containing salt substitutes, and drugs that increase potassium when using spironolactone. 3

Disease-Specific Treatment

For hypogonadism-related gynecomastia, testosterone replacement may be beneficial in men with symptomatic hypogonadism, improving sexual function, well-being, muscle mass, and bone density. 7, 1

• Monitor cardiovascular risk in older men receiving testosterone replacement. 7
• For prolactinoma-related hypogonadism: treat underlying prolactinoma with dopamine agonists. 7
• In cirrhotic patients requiring diuretics: use lowest effective spironolactone dose or switch to eplerenone if gynecomastia develops. 7

Medical Therapy for Persistent Gynecomastia

• Antiestrogen therapy (tamoxifen, raloxifene) may be effective in men with endogenous estrogen overproduction. 1, 6
• Consider medical therapy before surgical intervention. 1, 9

Surgical Management

Surgery to remove enlarged breast tissue is indicated when gynecomastia does not resolve spontaneously or with medical therapy, causing significant psychosocial distress or pain. 1, 9

Critical Monitoring Parameters

Monitor serum potassium within 1 week of spironolactone initiation or titration and regularly thereafter; more frequent monitoring is needed with concomitant drugs causing hyperkalemia or in patients with impaired renal function. 3

• Monitor volume status and renal function periodically in patients on diuretics. 3
• Monitor serum electrolytes, uric acid, and blood glucose periodically in patients on spironolactone. 3
• Educate patients about gynecomastia risk before prescribing spironolactone. 4

Common Pitfalls

• Failing to recognize unilateral gynecomastia as potentially drug-induced; clinicians should consider spironolactone even with unilateral presentation. 4
• Overlooking herbal supplements and anabolic steroids in medication history. 8, 6
• Not screening for underlying liver or kidney disease in at-risk populations. 7, 8
• Continuing spironolactone unnecessarily when eplerenone is a viable alternative. 5, 4