Iatrogenic Causes of Gynecomastia
The most common iatrogenic causes of gynecomastia include medications that block androgen action, increase estrogen levels, or cause hormonal imbalances, with spironolactone, ketoconazole, cimetidine, estrogens, and androgen deprivation therapies having the strongest evidence for causing this condition. 1
Medication-Induced Gynecomastia
Medications with Strong Evidence
- Spironolactone causes dose-dependent gynecomastia, with approximately 9% of male heart failure patients developing this side effect at a mean dose of 26 mg daily 2
- Cimetidine has been reported to cause gynecomastia in approximately 4% of patients treated for pathological hypersecretory states and 0.3-1% in other conditions when used for one month or longer 3
- Ketoconazole can cause hypogonadism and gynecomastia in men, which may limit prolonged treatment 4
- Estrogens and medications with estrogenic activity directly stimulate breast tissue growth 4, 1
- Androgen deprivation therapies used in prostate cancer treatment, with incidence as high as 80% in those on estrogen therapy 5, 6
- Testosterone or androgenic anabolic steroids can cause gynecomastia through conversion to estrogens 4, 1
Medications with Moderate Evidence
- Progestogens, including cyproterone acetate 4
- 5-alpha reductase inhibitors (finasteride, dutasteride) 4, 1
- Gonadotropin-releasing hormone (GnRH) agonists or antagonists 4, 1
- Hyperprolactinemia-inducing drugs 4
- Glucocorticoids 4
Medications with Some Evidence
- Calcium channel blockers (verapamil, nifedipine) 1
- Proton pump inhibitors (omeprazole) 1
- HIV medications (efavirenz) 1
- Alkylating agents used in chemotherapy 1
- Risperidone and other antipsychotics 1
Hormonal Therapies and Treatments
- Exogenous estrogens used for various conditions can directly stimulate breast tissue growth 4, 1
- Androgen receptor blockers (steroidal antiandrogens, cyproterone acetate, spironolactone) 4, 5
- Non-steroidal antiandrogens (flutamide, bicalutamide, nilutamide) commonly used in prostate cancer treatment 4, 6
- Human chorionic gonadotropin (hCG) therapy 1
- Human growth hormone (hGH) administration 1
Iatrogenic Procedures and Interventions
- Surgical hypophysectomy can lead to hormonal imbalances resulting in gynecomastia 4
- Pituitary or cranial irradiation may affect hormone production 4
- Orchidectomy or testicular damage from procedures or treatments 6
Management Considerations
- For patients requiring mineralocorticoid receptor antagonists who develop gynecomastia on spironolactone, switching to eplerenone is recommended as it has a significantly lower risk of this side effect 5
- To prevent painful gynecomastia in patients starting antiandrogen therapy, breast irradiation (8-15 Gy in 1-3 fractions) should be given 1-2 weeks before initiation 7
- Gynecomastia from spironolactone is usually reversible upon discontinuation 2
- Early identification of medication-induced gynecomastia is important as fibrotic changes after 12 months make the condition less responsive to medical therapy 8
Clinical Pearls and Pitfalls
- Always differentiate true gynecomastia (glandular tissue proliferation) from pseudogynecomastia (fatty tissue deposition), especially in patients with elevated BMI 7, 8
- The risk of gynecomastia with spironolactone increases in a dose-dependent manner with onset varying from 1-2 months to over a year 2
- When evaluating gynecomastia, consider both the medication and any underlying conditions that might contribute to hormonal imbalance 8
- Unnecessary imaging in clear cases of medication-induced gynecomastia can lead to additional unnecessary benign biopsies 7
- Men with gynecomastia who are interested in fertility should have a reproductive health evaluation performed prior to treatment 7
By identifying and addressing iatrogenic causes of gynecomastia promptly, clinicians can help prevent progression to fibrotic changes and minimize physical and psychological distress for patients.