Catemenial epilepsy in ancient times was attributed to the moon, giving rise to the word, "lunatic. Epileptic seizures increase in frequency during menstruation and decrease during the luteal phase. Exacerbation of seizure activity with menses occurs in 50% of epileptic women. In addition, seizure frequency increases at the time of the midcycle peak in estrogen and during anovulatory cycles. In animal experiments, estrogen increases seizure activity and progesterone is antiepileptic. These observations suggest an antiepileptic effect of progesterone.
Progestational hormones are known to have a sedative effect on the central nervous system. This pharmacologic effect combined with the observations indicating increased seizure activity at times when circulating levels of progesterone are little indicated that treatment with a progestin would have a beneficial impact on seizures.

The administration of oral medroxyprogesterone acetate has little impact, but intramuscular injections of depot-medroxyprogesterone acetate can improve seizure control. Depot-medroxyprogesterone acetate, 150 mg im every 1-2 months, can decrease seizure frequency by approximately 50%. In a case report of an 8 year old girl, 150 mg administered every 2 weeks abolished seizure activity. Intravenous progesterone (producing luteal phase levels) can produce a significant decrease in spike frequency.
Antiepileptic drugs enhance hepatic metabolic activity, and therefore doses must be relatively high. Oral medroxyprogesterone acetate is relatively ineffectual, probably because it is difficult to achieve high blood levels.