What drugs can cause gynecomastia?

Medications That Cause Gynecomastia

Spironolactone is the medication most strongly associated with gynecomastia, with approximately 9% of male patients developing this side effect when used for heart failure treatment. 1

Medications with Strong Evidence for Causing Gynecomastia

• Hormonal agents:

  • Estrogens and estrogen-containing medications 2
  • Anti-androgens (used in prostate cancer treatment) 2
  • GnRH analogs 2
  • Human chorionic gonadotropin (hCG) 2
  • Human growth hormone (hGH) 2
  • 5-α reductase inhibitors (finasteride, dutasteride) 2
  • Anabolic steroids 2

• Non-hormonal medications:

  • Spironolactone - causes dose-dependent gynecomastia with onset varying from 1-2 months to over a year 1
  • Cimetidine (H2 blocker) 2
  • Ketoconazole (antifungal) 2

Medications with Moderate Evidence for Causing Gynecomastia

• Cardiovascular medications:

  • Calcium channel blockers - particularly verapamil and nifedipine 2, 3
  • ACE inhibitors - some evidence suggests association 4
  • Digoxin - evidence is contradictory regarding sex-specific adverse effects 5

• Psychiatric medications:

  • Risperidone (antipsychotic) 2
  • Tricyclic antidepressants 4
  • SSRI antidepressants - sertraline has been implicated 6
  • SNRI antidepressants - venlafaxine and duloxetine have case reports 6, 7
  • Diazepam and other benzodiazepines 4

• Gastrointestinal medications:

  • Proton pump inhibitors - particularly omeprazole 2, 3

• Other medications:

  • HIV medications - particularly efavirenz 2
  • Alkylating agents (chemotherapy) 2, 4
  • Opioids 2
  • Alcohol (chronic use) 2

Clinical Considerations

Mechanism of Gynecomastia

• Medications typically cause gynecomastia through one of three mechanisms:
  • Creating an imbalance in the estrogen/androgen ratio 3
  • Increasing prolactin levels 3, 7
  • Direct effects on breast tissue 2

Management Considerations

• For patients requiring mineralocorticoid receptor antagonists (MRAs) who develop gynecomastia on spironolactone, switching to eplerenone is recommended as it has a significantly lower risk of this side effect 5, 8
• Gynecomastia from spironolactone is usually reversible upon discontinuation 1
• The risk of gynecomastia with spironolactone increases in a dose-dependent manner 1
• When evaluating male patients with breast enlargement, consider both true gynecomastia (glandular tissue proliferation) and pseudogynecomastia (fatty tissue deposition), especially in patients with elevated BMI 5

Monitoring

• For medications with high risk of gynecomastia (particularly spironolactone), monitor patients regularly during the first year of treatment 1
• When gynecomastia occurs, consider medication review and possible alternatives before invasive diagnostic procedures 2, 3
• Drug-induced gynecomastia is estimated to account for 10-25% of all gynecomastia cases 2

Special Considerations

• In heart failure patients, the absolute difference in gynecomastia rates between MRA users and placebo is relatively small (approximately 0.9%), but this is primarily attributed to spironolactone rather than eplerenone 5
• Male patients receiving androgen deprivation therapy (ADT) for prostate cancer commonly experience gynecomastia, with incidence as high as 80% in those on estrogen therapy 5
• The quality of evidence for many drug-gynecomastia associations is limited, with strongest evidence for hormonal agents and spironolactone 2, 3