Can phenytoin (an antiepileptic medication) cause gynecomastia?

Phenytoin and Gynecomastia

Phenytoin can cause gynecomastia, though it is a relatively uncommon adverse effect that occurs through its effects on hormone metabolism and binding proteins. 1, 2

Mechanism of Action

Phenytoin can contribute to gynecomastia development through several mechanisms:

1. Hormone metabolism alterations: Phenytoin induces hepatic cytochrome P450 enzymes, which increases the breakdown of steroid hormones and production of sex hormone binding globulins (SHBG) 3

2. Reduced biologically active sex hormones: The increased SHBG production leads to reduced biologically active sex hormone serum concentrations 3

3. Altered estrogen-androgen ratio: These changes can potentially disrupt the estrogen-to-testosterone ratio, which is a key factor in gynecomastia development 2

Clinical Presentation

When phenytoin causes gynecomastia, it typically presents as:

• Breast tissue enlargement (true glandular proliferation)
• Possible breast tenderness or pain (mastodynia)
• May be unilateral or bilateral
• May resolve spontaneously over time, even with continued medication use 4

Risk Factors

Factors that may increase the risk of phenytoin-induced gynecomastia:

• Long-term phenytoin therapy
• Combination therapy with other medications that affect hormone metabolism
• Pre-existing hormonal imbalances
• Concomitant use of fluoresone (significantly increases risk) 2

Management Options

For patients experiencing phenytoin-induced gynecomastia:

1. Medication adjustment:

   • Consider alternative antiepileptic medications if seizure control allows
   • Newer antiepileptic drugs may have lower risk of endocrine side effects

2. Observation:

   • Mild cases may resolve spontaneously without intervention
   • Regular monitoring for progression or resolution

3. Specialist referral:

   • Endocrinology consultation for persistent or severe cases
   • Evaluation of hormone levels may be warranted

4. Surgical intervention:

   • Consider only for long-standing gynecomastia (>12-24 months)
   • Options include liposuction, direct excision, or combined approaches 1

Clinical Considerations

• Gynecomastia is relatively common in men, especially with increasing age, making causality assessment challenging 4
• Drugs account for approximately 20% of gynecomastia cases in men 5
• While phenytoin has been documented to cause gynecomastia, it is not among the most common drug causes (unlike antiandrogens, protease inhibitors, spironolactone, or cimetidine) 5
• Case reports have documented gynecomastia in epileptic patients taking phenytoin, particularly when combined with phenobarbital and fluoresone 2

Monitoring Recommendations

For patients on phenytoin therapy:

• Regular physical examination to detect early breast tissue changes
• Consider baseline hormone levels in high-risk patients
• Educate patients about potential side effects and when to report symptoms
• Monitor for other endocrine-related side effects that may accompany gynecomastia

Differential Diagnosis

When evaluating gynecomastia in a patient taking phenytoin, consider other potential causes:

• Other medications in the patient's regimen
• Underlying endocrine disorders
• Liver disease
• Malignancy (rare but important to exclude)
• Physiologic gynecomastia (especially in adolescents or older men)

Phenytoin-induced gynecomastia represents one of many potential medication-related causes of this condition, and careful evaluation is needed to establish causality and determine appropriate management.