Which of the following medications, Ketoconazole (antifungal), Amphotericin B (antifungal), Fluconazole (antifungal), or Miconazole (antifungal), is most likely to cause gynaecomastia (enlargement of breast tissue in males) as a side effect?

Ketoconazole Causes Gynecomastia Among Antifungal Medications

Among the given choices (Ketoconazole, Amphotericin B, Fluconazole, and Miconazole), Ketoconazole is the antifungal medication that causes gynecomastia as a side effect.

Mechanism of Gynecomastia with Ketoconazole

Ketoconazole causes gynecomastia through its effects on steroid hormone synthesis:

1. Inhibition of testosterone synthesis: Ketoconazole blocks multiple adrenal enzymes involved in steroid biosynthesis, particularly affecting testosterone production 1.

2. Altered estradiol-testosterone ratio: Ketoconazole selectively decreases testosterone more than estradiol, resulting in an elevated estradiol-testosterone ratio that promotes breast tissue development in males 2.

3. Endocrinologic effects: Even at conventional doses, ketoconazole can transiently block testosterone synthesis, with higher doses (800-1200 mg/day) causing more prolonged blockade 3.

Evidence from Clinical Guidelines

The 2021 consensus guidelines on Cushing's disease management specifically identify gynecomastia as an adverse effect of ketoconazole treatment 1. The guidelines state:

• "Ketoconazole blocks multiple adrenal enzymes, including those involved early in the steroid biosynthetic pathway... it may also decrease gonadal steroid synthesis; men may experience hypogonadism and gynecomastia, which can limit prolonged treatment."

• In the summary table of medical therapies, gynecomastia is explicitly listed as an adverse effect for ketoconazole but not for other antifungal medications 1.

Comparison with Other Antifungal Agents

None of the other antifungal medications in the question (Amphotericin B, Fluconazole, or Miconazole) are specifically associated with gynecomastia in the provided evidence:

• Amphotericin B: The CDC guidelines mention gastrointestinal disturbances as side effects but do not list gynecomastia 1.

• Fluconazole: Associated with gastrointestinal effects, skin rash, and rarely alopecia, but not gynecomastia 1.

• Miconazole: No mention of gynecomastia as a side effect in any of the provided evidence.

Clinical Significance

Gynecomastia with ketoconazole:

• Appears in approximately 7.5% of male patients (3 of 40 men in one study) 4
• Can occur even with short-term therapy
• May resolve spontaneously despite continued therapy in some cases 4
• Is more common with higher doses (800-1200 mg/day) 3
• Results from the direct hormonal effects rather than from other mechanisms

Practical Implications

When prescribing ketoconazole:

• Male patients should be informed about the possibility of gynecomastia
• Consider monitoring testosterone levels in men on long-term therapy
• Be aware that the risk increases with higher doses and longer treatment duration
• Consider alternative antifungal agents if gynecomastia would be particularly problematic for the patient

In conclusion, among the four antifungal medications listed, only ketoconazole has been clearly documented to cause gynecomastia as a side effect due to its interference with steroid hormone synthesis.