Hormone Replacement Therapy in Women with Epilepsy

Abstract

To the Editors: Changes in reproductive hormone levels may influence seizure activity (Scharfman and MacLusky, 2006). A previous survey suggested that hormone replacement therapy (HRT) may adversely affect seizure control in women with epilepsy (Harden et al., 1999). 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. Because an adverse influence on seizure control was confirmed, the question arises, what HRT component was responsible for the effect? The bulk of the evidence points to estrogens, which can have a facilitating effect on seizure activity (Logothetis et al., 1959; Logothetis and Harner, 1960; Hom and Buterbaugh, 1986; McEwen, 2002), although evidence on this is not univocal (Scharfman and MacLusky, 2006). Whether medroxyprogesterone acetate contributed to seizure deterioration is unknown. The authors elected to test the HRT preparation most widely prescribed in the United States. However, it might have been preferable in this population to combine estrogens with natural progesterone. Natural progesterone is converted to neuroactive metabolites, such as allopregnanolone, which have anticonvulsant activity in animal models by acting as positive allosteric modulators at the GABAA receptor (Kokate et al., 1994; Herzog, 1995; Reddy, 2001; Lonsdale and Burnham, 2003; Scharfman and MacLusky, 2006). Preliminary evidence suggests a positive effect of progesterone in catamenial epilepsy (Herzog, 1995, 1999). Whether use of natural progesterone instead of MPA would be a safer option for HRT is unknown. From a practical point of view, the relevance of this study has been reduced by the drastic decline in the use of HRT in postmenopausal women, after publication of the WHI results (Rossouw et al., 2002). Today, HRT is no longer recommended as preventive treatment in asymptomatic women, because the increased risks of breast cancer, coronary heart disease, stroke, and pulmonary embolism clearly outweigh any benefits. The authors are correct in pointing out that their results should not be interpreted as contraindicating the use of HRT for short-term control of postmenopausal symptoms in women with epilepsy. Their results do suggest, however, that the HRT regimen tested may not be the optimal one to use in these women. An interesting ancillary observation was that serum lamotrigine (LTG) levels decreased after initiation of HRT in both women who were treated with this drug. Although exclusion of these women from the analysis did not alter the results, these findings confirm previous reports that serum LTG levels can be reduced to a clinically significant extent by estrogen-containing preparations, including oral contraceptives (Sabers, 2003; Reimers et al., 2005; Sidhu et al., 2006). Careful clinical observation and, if possible, monitoring of serum LTG levels are recommended whenever estrogen-containing preparations are started or discontinued in women taking LTG.