Hormone Replacement Therapy in Women with Epilepsy: A Randomized, Double‐Blind, Placebo‐Controlled Study

Department of Epidemiology, Columbia University, New York, New York, United States
Epilepsia (Impact Factor: 4.57). 10/2006; 47(9):1447-51. DOI: 10.1111/j.1528-1167.2006.00507.x
Source: PubMed


Previous reports have suggested that hormone replacement therapy (HRT) could increase seizure activity in women with epilepsy. We sought to determine whether adding HRT to the medication regimen of postmenopausal women with epilepsy was associated with an increase in seizure frequency.
This was a randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy, taking stable doses of antiepileptic drugs (AEDs), and within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period.
Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years; SD, +/-5), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25-30% while taking CEE/MPA.
CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.

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Available from: Cynthia L Harden
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    • "This may occur because of changes in estrogenic modulation of synaptic regulation. Peri-menopausal hormone replacement therapy (HRT) has been associated with modulatory effects in these other neurologic [27] and inflammatory diseases [26]. To our knowledge there are no clinical data specifically assessing an association between menopause and disease trajectory in multiple sclerosis, and prior patient reports have been variable, with a subset of women reporting worsening of symptoms with menopause [28-30]. "
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    • "Provera (medroxyprogesterone acetate) was reported as a 3α-hydroxysteroidoxidoreductase inhibitor which implies that this agent might enhance synthesis of inhibitory neurosteroids in the brain (Belelli and Herd, 2003). However, there are many factors to consider in the choice of AED therapy and hormonal contraception since some AEDs can reduce the efficacy of OCs due to pharmacokinetic interactions (Crawford, 2005; Harden and Leppik, 2006). The enzyme-inducing AEDs cause enhanced metabolism of either or both the estrogenic or progestogenic component of OCs, thereby reducing their efficacy in preventing pregnancy. "
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    ABSTRACT: Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Generally, a twofold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy. Based on this criteria, recent clinical studies indicate that catamenial epilepsy affects 31-60% of the women with epilepsy. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. However, there is no specific drug available today for catamenial epilepsy, which has not been successfully treated with conventional antiepileptic drugs. Elucidation of the pathophysiology of catamenial epilepsy is a prerequisite to develop specific targeted approaches for treatment or prevention of the disorder. Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy. There is emerging evidence that endogenous neurosteroids with anticonvulsant or proconvulsant effects could play a critical role in catamenial epilepsy. It is thought that perimenstrual catamenial epilepsy is associated with the withdrawal of anticonvulsant neurosteroids. Progesterone and other hormonal agents have been shown in limited trials to be moderately effective in catamenial epilepsy, but may cause endocrine side effects. Synthetic neurosteroids, which enhance the tonic GABA-A receptor function, might provide an effective approach for the catamenial epilepsy therapy without producing hormonal side effects.
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    • "Although this trial was terminated prematurely, resulting in greatly reduced statistical power, the results provide evidence that intake of estrogen/medroxyprogesterone acetate HRT in postmenopausal women with epilepsy is associated with some worsening in seizure control. A more recent study by Harden and colleagues (Harden et al., 2006) confirms the results of their previous survey (Harden et al., 1999), and raises a number of interesting points for discussion: • Although HRT was widely used at the time the trial was initiated, intriguing ethical issues exist in conducting a placebo-controlled study to test the hypothesis that active treatment could cause seizure aggravation . One may argue, however, that based on evidence available at the time, HRT might have been a safe option in the enrolled population. "

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