Seizure Activity Linked to Ovulation Cycles

Pauline Anderson

July 21, 2011

July 21, 2011 — Secondary generalized tonic clonic seizures (GTCSs) occur with almost a 30% greater frequency during anovulatory than during ovulatory phases of menstrual cycles, and women with these seizures have significantly higher estrogen-to-progesterone ratios, lending more weight to the theory that female hormones play a role in seizure activity, according to new research.

The frequency of complex partial seizures (CPSs) and simple partial seizures (SPSs) did not differ according to ovulation status, the study shows.

About a third of menstrual cycles in women with epilepsy are anovulatory, which is 3 times greater than women in the general population. Having more such cycles may be linked to the tendency to have more generalized convulsive seizures.

The new results support earlier evidence that estradiol may promote seizures, whereas progesterone may inhibit them.

"The findings from this study suggest that the ratio of estrogen to progesterone may be an important factor," said lead study author Andrew G. Herzog, director, Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, Wellesley, Massachusetts. "This is something that one can alter by adding progesterone or lessening estrogen."

The question of whether female hormones play a role in epilepsy treatment will be answered, at least in part, at the next American Epilepsy Society (AES) meeting, where results of a randomized controlled trial of progesterone will be released, said Dr. Herzog.

The current study was published online June 14 in Epilepsia.

Own Controls

The study included 92 women with intractable focal onset seizures who were on stable antiepileptic drug (AED) regimens and who had both anovulatory and ovulatory cycles during the baseline phase of a double-blind, placebo-controlled, randomized investigation of a progesterone treatment (the study to be released at the upcoming AES meeting).

The women charted seizure occurrence, type of seizure, and date of onset of menstrual flow for 3 consecutive menstrual cycles. To determine the ovulatory status of cycles, researchers measured serum estradiol and progesterone levels from blood samples during the midluteal phase of each cycle. Progesterone levels of 5 ng/mL or higher indicated an ovulatory cycle.

Because the women had both anovulatory and ovulatory cycles, the design of the trial allowed each woman to act as her own control with regard to age, seizure types, duration of epilepsy, and AED regimen. Average daily seizure frequency was compared for the 92 women between the days of anovulatory and ovulatory cycles for all seizures combined and for each seizure type separately.

The study found that secondary GTCSs occurred in 29.3% of the 92 women, whereas CPSs occurred in 72.8% and SPSs in 33.7%. Seizure frequency was 29.5% greater for secondary GTCSs during anovulatory than during ovulatory cycles.

The proportional increases in anovulatory vs ovulatory secondary GTCS frequencies correlated with the proportional increases in midluteal estradiol-to-progesterone serum level ratios.

"If you don't ovulate, you don't make progesterone, hence the importance of estrogen-to-progesterone ratio," explained Dr. Herzog. "Estrogen tends to promote seizure occurrence and progesterone has a metabolite that has powerful antiseizure properties comparable to barbiturates and benzodiazepines."

Ovulation occurred with equal frequency among all women with seizures, but the estrogen-to-progesterone ratio was higher only in those with generalized convulsive seizures, said Dr. Herzog. It's possible that having generalized convulsive seizures disrupts the hypothalamic-pituitary-ovarian axis more than having less severe seizures like complex partial or simple partial, he said.

"Prolactin can go up after seizures, and it is much more likely to go up after a generalized convulsive seizure — and it goes up to higher levels after generalized convulsive seizure — than after partial seizures," he added. "So there is evidence to support this notion that generalized convulsive seizures impact the reproductive system more than partial seizures."

Seizures tend to increase perimenstrually, possibly related to the rapid premenstrual withdrawal of progesterone, and midcycle, perhaps in relation to the preovulatory estrogen surge, said the study authors. Seizures may also increase during the entire second half or luteal phase, during anovulatory cycles, perhaps in relation to lower progesterone levels relative to estrogen, or during some ovulatory cycles that have high estrogen-to-progesterone ratios.

About a third of women with epilepsy have seizures that show hormonal sensitivity, said Dr. Herzog.

The distribution of the different seizure types among the 92 study subjects was not significantly different than among the other 281 women with epilepsy who completed the baseline phase of the progesterone study.

Hormonal Influences

Asked to comment, Orrin Devinsky, MD, professor and director of the Comprehensive Epilepsy Center at New York University Langone Medical Center and School of Medicine, New York City, said the study provides additional data on the importance of hormonal influences on seizure susceptibility.

"Secondarily generalized tonic-clonic seizures are the most severe seizures affecting individuals with partial epilepsy and evidence suggests that these seizures increase the risk of sudden death in epilepsy," he wrote in an email to Medscape Medical News. "These findings suggest that preventing anovulatory cycles may reduce the frequency of tonic-clonic seizures."

Dr. Herzog reports having received research grants from the National Institutes of Health, GlaxoSmithKline, Astra/Zeneca, and the Epilepsy Foundation. For conflict of interest information for the other authors, see the original paper.

Epilepsia. Published online July 14, 2011.

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