Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study

Harden CL, Herzog AG, Nikolov BG, Koppel BS, Christos PJ, Fowler K, et al.; Epilepsia 2006; 47 (9); 1447-1451

Commented by Professor Emilio Perucca, 24 Nov 2006

Background

Changes in reproductive hormone levels may influence seizure activity (ref. 1). A previous survey suggested that hormone replacement therapy (HRT) may adversely affect seizure control in women with epilepsy (ref. 2).

Aim

To determine whether HRT increases seizure frequency in postmenopausal women with partial epilepsy.

Methods

the study used a randomized double-blind parallel-group design
after an 84-day prospective baseline, women were randomized to receive 84-day treatment with (i) placebo, or (ii) Prempro (0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate), as a single daily dose, or (iii) Prempro, as a double daily dose
treatments were added to pre-existing antiepileptic medication, with exit criteria in case of excessive seizure deterioration
the primary endpoint was an increase in seizure frequency vs baseline.

Results

the study was interrupted after 21 of the planned 120 patients were randomized, because publication of the Women Health Initiative (WHI) study altered the indications for HRT
an increase in any seizure type occurred in 1/6 women on placebo (17%), 4/8 women on single dose HRT (50%) and 5/7 women on double dose HRT (71%). The magnitude of increases in seizure frequency was mild in all groups
the association of increased seizure frequency with increasing HRT dose was significant for any seizure type, for complex partial seizures, and for most severe seizure type.

Professor Perucca's comments

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. This trial, which confirms the findings of a previous survey (ref. 2), raises a number of interesting points for discussion:

although HRT was widely used at the time the trial was initiated, there are intriguing ethical issues in conducting a placebo-controlled study to test the hypothesis that active treatment should 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
since an adverse influence on seizure control was confirmed, the question arises of 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 (ref. 4, ref. 5, ref. 6, ref. 7), although evidence on this is not univocal (ref. 1). Whether medroxyprogesterone acetate contributed to seizure deterioration is unknown
the authors elected to test the HRT preparation most widely prescribed in the U.S. 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 GABA-A receptor (ref. 1, ref. 8, ref. 9, ref. 10, ref. 11).
There is also preliminary evidence for a positive effect of progesterone in catamenial epilepsy (ref. 1, ref. 12, ref. 13). Whether use of natural progesterone instead of medroxyprogesterone acetate 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, following publication of the WHI results (ref. 3). 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 levels decreased following 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 lamotrigine levels can be reduced to a clinically significant extent by estrogen containing preparations, including oral contraceptives (ref. 14, ref. 15, ref. 16).

Careful clinical observation and, if possible, monitoring of serum lamotrigine levels are recommended whenever estrogen containing preparations are started or discontinued in women taking lamotrigine.

References

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