BALTIMORE – Cyclical natural progesterone appears to reduce the frequency of catamenial seizures in some women, a placebo-controlled study has found.

Women with a large number of perimenstrually exacerbated seizures who used progesterone experienced a significant decrease in their number of catamenial seizures. The higher the seizure count, the stronger the association became, Dr. Andrew G. Herzog reported during the annual meeting of the American Epilepsy Society.

"As the level of perimenstrual seizure exacerbation increased, the responder rate for progesterone also increased, from 21% at the lowest number of seizures to 57% ... at the highest number," said Dr. Herzog, a neurologist at Beth Israel Deaconess Medical Center, Boston. "This was significant compared to a rate of 10% to 20% for those on placebo."

Studies suggest that about 40% of women with epilepsy experience this hormonally-mediated form. There are three types of catamenial seizure patterns. Women with type 1 experience a seizure exacerbation in the perimenstrual phase. Women with type 2 have an exacerbation around the time of ovulation, and those with type 3 can experience increased seizure frequency throughout the second half of the menstrual cycle.

The seizures are thought to be related to the rapid changes of estrogen and progesterone during the menstrual cycle. Both hormones act on the neurotransmitter gamma-aminobutyric acid (GABA). Estrogen, an excitatory hormone, seems to increase its release, while progesterone suppresses it. Progesterone may also interfere with the activity of benzodiazepine anticonvulsants, Dr. Herzog said.

The phase III study comprised 294 women with partial-onset epilepsy and intractable seizures. The investigators grouped them by catamenial (130) or noncatamenial (164) epilepsy.

Each group was then randomly assigned to placebo or to therapy with placebo or cyclical natural progesterone extracted from the soy plant. This was given in 200-mg lozenge form, with a dosage of one lozenge three times daily on cycle days 14-25, one-half of a lozenge three times daily from days 26-27, a quarter of a lozenge three times on day 28, and placebo treatment from day 29 through day 13 of the next cycle.

Overall, there was no significant difference between placebo and progesterone in the primary outcome of at least a 50% decrease in seizure count in patients with or without catamenial epilepsy, either by all seizure types or the most severe types of seizures. A 50% decrease in seizure count was considered a clinically meaningful difference.

But the results were much different in a prespecified secondary analysis that examined response according to the type of catamenial seizure pattern.

Among those with type 1 catamenial epilepsy, the responder rate was significantly greater in those taking progesterone. "As the level of perimenstrual seizure frequency increased compared to the mid-follicular and luteal seizure frequencies, the responder rate for those on progesterone went from 21% to 57%, while the placebo responder rates stayed between 10% and 20%," Dr. Herzog said.

In another multivariate analysis that controlled for demographics, type of epilepsy, use of antiepileptic drugs, and catamenial seizure pattern, progesterone decreased perimenstrual seizures by 25% to 71%. This improvement in response rate again varied by seizure frequency in the perimenstrual period, compared with frequency at other times in the menstrual cycle.