What seizure medicines, such as (antiepileptic drugs), can cause gynecomastia?

Antiepileptic Drugs That Can Cause Gynecomastia

Valproate is the antiepileptic drug most strongly associated with hormonal disturbances that can lead to gynecomastia through mechanisms involving hyperandrogenism, hyperinsulinemia, and altered steroidogenesis. 1 Other antiepileptic drugs that may contribute to gynecomastia include carbamazepine, gabapentin, and vigabatrin, primarily through weight gain mechanisms and hormonal alterations.

Mechanisms of Antiepileptic Drug-Induced Gynecomastia

Antiepileptic drugs can cause gynecomastia through several pathways:

1. Direct hormonal effects:

   • Valproate alters steroidogenesis and increases testosterone-to-estradiol ratios in animal models 1
   • Enzyme-inducing antiepileptics (carbamazepine, phenobarbital, phenytoin) affect sex hormone metabolism by:
     • Inducing hepatic cytochrome P450 enzymes
     • Increasing sex hormone binding globulin (SHBG) production
     • Reducing biologically active sex hormone concentrations 1

2. Weight gain mechanisms:

   • Several antiepileptic drugs cause weight gain, including:
     • Valproate
     • Carbamazepine
     • Vigabatrin
     • Gabapentin 1
   • Weight gain reduces insulin sensitivity and can trigger hormonal imbalances 1

3. Hypothalamic-pituitary effects:

   • Antiepileptic drugs may directly influence endocrine control centers in the brain 1
   • Seizures themselves can cause acute changes in prolactin and gonadotropin levels 1

Specific Antiepileptic Drugs Associated with Gynecomastia

Valproate

• Strongest evidence for causing hormonal disturbances that can lead to gynecomastia
• Mechanisms include:
  • Altered steroidogenesis with increased testosterone-to-estradiol ratios 1
  • Weight gain leading to hyperinsulinemia and hormonal imbalances 1
  • Direct effects on peripheral endocrine glands 1
• Clinical evidence shows:
  • 45% of women on valproate monotherapy developed menstrual irregularities
  • 30% had raised testosterone levels 1
  • Discontinuation led to reversal of hyperinsulinemia and hyperandrogenism 1

Carbamazepine

• Associated with weight gain that can contribute to hormonal imbalances 1
• Induces hepatic enzymes that alter sex hormone metabolism 1
• 25% of women on carbamazepine showed menstrual disturbances with low estradiol and estradiol/SHBG ratios 1

Gabapentin and Vigabatrin

• Both associated with weight gain that can contribute to hormonal disturbances 1
• Less direct evidence for gynecomastia compared to valproate

Clinical Monitoring and Management

When prescribing antiepileptic drugs with potential for gynecomastia:

1. Monitor for early signs:

   • Breast tenderness
   • Breast enlargement
   • Weight changes

2. Consider hormonal evaluation if gynecomastia develops:

   • Testosterone levels
   • Estradiol levels
   • Prolactin levels
   • Luteinizing hormone/follicle-stimulating hormone ratio 2

3. Management options:

   • Consider medication switch if clinically appropriate
   • Note that discontinuation of valproate has shown reversal of hormonal abnormalities 1
   • Be aware that switching medications carries risk of seizure relapse 1

Important Caveats

• Individual susceptibility varies significantly
• The risk-benefit ratio must always favor seizure control as the primary outcome
• Gynecomastia may be multifactorial, with medications being one of several contributing factors 3, 4
• Many reports of drug-induced gynecomastia are based on case reports rather than high-quality studies 3, 5

While various antiepileptic drugs can potentially cause gynecomastia, valproate has the strongest evidence for hormonal effects that could lead to this condition, followed by carbamazepine, gabapentin, and vigabatrin primarily through weight gain mechanisms.