What medication is likely causing hirsutism and oligomenorrhea in a 34-year-old woman with epilepsy, taking phenytoin, amlodipine, and spironolactone, with a body mass index (BMI) of 35 kg/m2?

Phenytoin is Causing Hirsutism and Oligomenorrhea in This Patient

Phenytoin is the medication most likely aggravating this patient's hirsutism and oligomenorrhea through its effects on the endocrine system. 1

Mechanism of Phenytoin's Effects on Hormones

Phenytoin causes reproductive dysfunction in women with epilepsy through several mechanisms:

1. Hepatic enzyme induction: Phenytoin induces cytochrome P450 enzymes, which:

   • Increases steroid hormone breakdown
   • Increases production of sex hormone binding globulin (SHBG)
   • Reduces biologically active sex hormone concentrations 1

2. Endocrine disruption: Phenytoin can directly influence:

   • The hypothalamic-pituitary axis
   • Peripheral endocrine glands
   • Metabolism of hormones and binding proteins 1

Clinical Evidence Supporting Phenytoin as the Culprit

The patient's presentation strongly points to phenytoin as the causative agent:

• Timeline: The patient had regular menses until age 25, with irregular cycles developing afterward, suggesting an acquired condition
• Symptoms not improving with OCPs: Despite 7 months of combined oral contraceptive pills, her menstrual irregularity persists
• Physical findings: Excessive hair growth on face, areolas, and abdomen is consistent with hyperandrogenism

Ruling Out Other Medications

• Spironolactone: This medication actually treats hirsutism rather than causing it. It acts as an antiandrogen and is used therapeutically for hirsutism 2. It would be expected to improve, not worsen, the patient's symptoms.

• Amlodipine: This calcium channel blocker has no known effects on the reproductive endocrine system.

• Oral contraceptive pills: OCPs typically improve hirsutism and regulate menstrual cycles rather than worsen them 3.

Phenytoin's Known Side Effects

Phenytoin is well-documented to cause:

• Hirsutism
• Coarsening of facial features
• Menstrual irregularities 4

Long-term phenytoin therapy is associated with alterations in reproductive hormonal function through its enzyme-inducing properties 1.

Management Recommendations

1. Consult with neurology about switching to an alternative antiepileptic medication with fewer endocrine side effects

2. Consider alternative antiepileptic drugs:

   • Lamotrigine has fewer reproductive endocrine effects compared to enzyme-inducing antiepileptics 5
   • Levetiracetam or other newer antiepileptic drugs may be options

3. Continue spironolactone as it is actually therapeutic for hirsutism:

   • Spironolactone 100mg daily has shown significant improvement in hirsutism compared to placebo 2
   • It should help counteract the hirsutism caused by phenytoin

4. Consider increasing OCP duration or changing to a formulation with higher anti-androgenic activity

Pitfalls and Caveats

1. Don't mistake spironolactone as the cause: A common error is to assume spironolactone causes hirsutism when it actually treats it.

2. Don't overlook underlying PCOS: The patient's BMI of 35 kg/m² and irregular menses suggest possible polycystic ovary syndrome, which may be exacerbated by phenytoin.

3. Avoid abrupt discontinuation of phenytoin: This could precipitate seizures. Any medication changes should be done gradually under neurological supervision.

4. Monitor for drug interactions: When changing antiepileptic medications, be aware of potential interactions with other medications the patient is taking.

Phenytoin's effects on the endocrine system are well-documented, and in this case, it is the most likely culprit for the patient's hirsutism and menstrual irregularities, particularly given the timeline of symptom development and lack of response to OCPs.