Treatment of Women With Epilepsy

Alison M. Pack, MD, Martha J. Morrell, MD

Disclosures

Semin Neurol. 2002;22(3) 

In This Article

Antiepileptic Drug Effects on Reproductive Hormones and Health

Fertility

Women with epilepsy are less likely to have children. Birth rates of women with epilepsy are reduced by one third to two thirds compared with those of women without epilepsy.[46,47,48,49,50] Social disability may contribute to lower birth rates; women with epilepsy are less likely to marry and may choose not to have children. Perhaps more significant than social factors is disruption of reproductive physiology caused by seizures and AEDs.[51]

Hypothalamic and Pituitary Abnormalities

The hypothalamic-pituitary axis supports the female reproductive cycle, and disruption of this axis is associated with anovulatory cycles in women with epilepsy. Seizures alter hypothalamic hormone release, disrupting gonadotropin hormone and pituitary hormone release.[52] In humans, high-frequency epileptic discharges in the hippocampus are associated with a surge in pituitary prolactin.[53,54] In addition, ictal elevations in LH and interictal elevations or reductions in LH are observed. Pulsatile LH release is increased in women with generalized epilepsy[55] and reduced in women with temporal lobe epilepsy.[56] Disturbances in LH release in either direction are associated with anovulatory cycles.[57]

AED Effects on Sex Steroid Hormones

AEDs that alter the hepatic cytochrome P450 enzyme system change the concentration of sex steroid hormones. Inducers of the hepatic cytochrome P450 enzyme system cause a decrease in the concentration of estradiol and adrenal and gonadal androgens and increase sex hormone-binding globulin (SHBG), which binds steroid hormones.[58,59] Increased protein binding decreases the free, biologically active fraction of hormone. VPA, an inhibitor of the cytochrome P450 enzyme system, increases gonadal and adrenal androgens. Gabapentin and lamotrigine are AEDs that have no effect on the cytochrome P450 enzyme system. Women receiving these AEDs show no difference in gonadal steroids when compared with nonepileptic controls.[59]

Menstrual Cycle Disturbances

The menstrual cycle is a well-regulated cycle that can be susceptible to a number of stressors such as physical or emotional stress. A normal cycle length is between 23 and 35 days, and cycle-to-cycle variability should not exceed 5 days. One third of women with epilepsy have abnormal cycle lengths, compared with 8% of controls.[60] Women with epilepsy also have more frequent midcycle bleeding and metrorrhagia (irregular intervals and excessive flow and duration). In addition, anovulatory cycles have been described in more than 30% of women with epilepsy.[57] The clinical manifestations of anovulation include amenorrhea, irregular menses, and hirsutism. Serious consequences of chronic anovulation are infertility and a greater risk for developing carcinoma of the endometrium and perhaps the breast.

Polycystic Ovaries

Polycystic ovary syndrome (PCOS) is a gynecologic condition affecting 7-10% of women of reproductive age.[61] Obesity, acne and hirsutism, elevated androgens, elevated LH/FSH ratio, abnormal lipid profile, chronic anovulation, and polycystic ovaries characterize PCOS. Not all of these features need be present. The required features are hyperandrogenism and frequent anovulatory cycles. An abnormality in the insulin receptor causing insulin resistance is the basis for PCOS.[62] Long-term consequences of PCOS include infertility, dyslipidemia, glucose intolerance and diabetes, and endometrial cancer.[63]

Approximately 30% of women with epilepsy have polycystic-appearing ovaries[64] compared with 15% of reproductive-aged women. Studies suggest that VPA is particularly associated with polycystic ovaries, hyperandrogenism, hyperinsulinemia, and obesity.[65,66] Up to 60% of women with epilepsy receiving VPA have polycystic-appearing ovaries, compared with 25-30% of women with epilepsy receiving other AEDs.[57,65] In one study, the prevalence was highest in women receiving VPA prior to age 20.[65]

The signs and symptoms associated with VPA use appear to be reversible. In one study, 16 women taking VPA with polycystic-appearing ovaries, hyperandrogenism, and hyperinsulinemia were changed to lamotrigine.[58] Polycystic-appearing ovaries resolved within 1 year in most. Testosterone and insulin became normal within several months. Another study[57] also found an association between current or recent use of VPA for epilepsy and anovulatory cycles and polycystic ovaries. Therefore, the reproductive and metabolic effects of VPA appear to be reversible for women with epilepsy.

Sexual Dysfunction

Sexual dysfunction affects 30 to 40% of persons with epilepsy. In women this may be manifested as diminished sexual interest and desire[60,66] and a disorder of sexual arousal including dyspareunia, vaginismus, and lack of vaginal lubrication.[67] AEDs may contribute to sexual dysfunction by direct cortical effects or secondarily through alterations in the hormone effects on sexual behavior.[68,69,70,71,72]

Reproductive Evaluation in the Woman with Epilepsy

Clinicians must be alert to signs of reproductive dysfunction in women with epilepsy receiving AEDs ( Table 3 ). Keeping a diary with length of the menstrual cycle and timing and duration of menstrual flow is the most sensitive indicator for anovulatory cycles. Intermittent checking of ovulation with over-the-counter ovulation kits done over a consecutive 3-month period can be used to determine whether or not ovulation is occurring. Women with menstrual dysfunction should be referred for gynecological evaluation and care.

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