Which medication is most likely to cause gynecomastia as a side effect?

Gynecomastia as a Medication Side Effect

Ketoconazole is the medication most strongly associated with gynecomastia among the options provided. 1, 2

Mechanism of Ketoconazole-Induced Gynecomastia

Ketoconazole causes gynecomastia through multiple mechanisms:

1. Altered hormone ratios: Ketoconazole selectively depresses serum testosterone concentrations more than estradiol levels, resulting in an elevated estradiol-testosterone ratio 1

2. Adrenal steroid synthesis inhibition: Ketoconazole blocks adrenal steroid synthesis, including androgens, which can disrupt the normal hormonal balance 3

3. Testicular steroid synthesis inhibition: Ketoconazole inhibits basal and gonadotropin-stimulated testosterone production in Leydig cells 4

Evidence for Ketoconazole and Gynecomastia

Ketoconazole is definitively associated with gynecomastia based on multiple studies:

• Research has demonstrated that ketoconazole administration at 600mg doses markedly depresses serum testosterone while having less effect on estradiol, creating the hormonal imbalance that leads to gynecomastia 1

• Expert reviews have classified ketoconazole among medications "definitely associated with the onset of gynecomastia" 2

• The CDC, NIH, and IDSA guidelines specifically mention gynecomastia as an endocrinologic abnormality related to ketoconazole's effects on steroid metabolism 5

Comparison with Other Antifungal Agents

Among the options listed in the question:

• Ketoconazole: Definitely associated with gynecomastia due to its effects on steroid synthesis 5, 1, 2

• Amphotericin B: Not commonly associated with gynecomastia; its side effects typically include infusion-related reactions, nephrotoxicity, and electrolyte abnormalities 5

• Fluconazole: While it's an azole antifungal like ketoconazole, it has been associated with alopecia rather than gynecomastia 5

• Miconazole: Not typically associated with gynecomastia in clinical guidelines or research

Clinical Implications

When prescribing ketoconazole, clinicians should:

• Monitor patients for early signs of gynecomastia
• Consider the risk-benefit ratio, especially for long-term or high-dose therapy
• Be aware that gynecomastia may persist as long as the estradiol-testosterone ratio remains elevated 1
• Recognize that ketoconazole's effects on steroid synthesis are dose-dependent and can occur at therapeutic doses 3, 4

Other Medications Associated with Gynecomastia

While not included in the question options, other medications strongly associated with gynecomastia include:

• Spironolactone (highest risk, approximately 10% of male patients) 6
• Hormone therapies (estrogens, hCG)
• Anti-androgens and 5-α reductase inhibitors
• Cimetidine
• Diethylstilbestrol (DES) 5