Predictors of ovulatory failure in women with epilepsy

Abstract

Women with epilepsy (WWE) are at increased risk for reproductive disorders. This study was designed to evaluate whether WWE are more likely to have anovulatory cycles and to assess the relative association of the epilepsy syndrome category and antiepileptic drugs (AEDs) to ovulatory dysfunction. Subjects included women aged 18 to 40 years not receiving hormones. Women without epilepsy (23 controls) and women with localization-related epilepsy (LRE, n = 59) or idiopathic (primary) generalized epilepsy (IGE, n = 35) receiving either a cytochrome P450 enzyme (cP450) inducing AED (carbamazepine, phenytoin, and phenobarbital), a cP450 inhibiting AED (valproate), or an AED that does not alter cP450 enzymes (lamotrigine and gabapentin) in monotherapy for 6 months or more were followed for three menstrual cycles. A transvaginal ovarian ultrasound was obtained. Endocrine and metabolic variables were measured and luteinizing hormone sampled over 8 hours on days 2 to 5 of one cycle. Anovulatory cycles occurred in 10.9% of cycles in controls, 14.3% of cycles with LRE, and 27.1% of cycles with IGE. Of women using valproate currently or within the preceding 3 years, 38.1% had at least one anovulatory cycle in contrast with 10.7% of women not using valproate within the preceding 3 years. Predictors of ovulatory failure included IGE syndrome, use of valproate currently or within 3 years, high free testosterone, and fewer numbers of luteinizing hormone pulses, but not polycystic-appearing ovaries. WWE are more likely to experience anovulatory menstrual cycles and the effects of epilepsy syndrome, and AED therapy may be additive. Women with IGE receiving valproate were at highest risk for anovulatory cycles, polycystic-appearing ovaries, elevated body mass index, and hyperandrogynism. WWE with anovulatory cycles may have no other signs of reproductive dysfunction. Therefore, clinicians must be alert to this potential complication of epilepsy.

Estradiol Induces Diurnal Shifts in GABA Transmission to Gonadotropin-Releasing Hormone Neurons to Provide a Neural Signal for Ovulation

“…Lower GABA levels may be required to diminish inhibition on upstream excitatory inputs to GnRH neurons, and thereby induce increases in GnRH neuron firing activity characteristic of the surge. Although speculative, an imbalance of hypothalamic GABA levels and disruption of estradiol-induced shifts in GABA transmission may account for the clinical finding of increased incidence of anovulatory cycles in women with epilepsy, and further impairment of ovulation with antiepileptic treatments such as valproate (Morrell et al, 2002). …”

Hormon- und Sexualstörungen bei Epilepsie

“…Mehr als ein Drittel der Zyklen bei Frauen mit einer fokalen Epilepsie sind anovulatorisch, bei Kontrollen sind diese nur bei 8-10 % [11][12][13]. Es gibt widersprüchli-che Beweise, dass anovulatorische Zyklen häufiger bei fokalen als bei generalisierten Epilepsien sind [12,13].…”

Safety and Tolerability of Antiepileptic Drugs at Women With Epilepsy (Data of Svt. Luka’s Institute of Child Neurology and Epilepsy)

“…Необходимо учиты-вать, что нейроэндокринные нарушения у женщин могут быть следствием как самого заболевания -эпи-лепсии (в этом случае нарушения зависят от возраста дебюта, формы эпилепсии, локализации очага, дли-тельности заболевания и других факторов, связанных с заболеванием), так и проводимой терапии [2]. При проведении антиэпилептической терапии у жен-щин необходимо учитывать возможные побочные эф-фекты АЭП, значительно снижающие качество жизни.…”