This randomized, placebo-controlled, double-blind, multicenter clinical trial will assess the efficacy of adjunctive cyclic progesterone therapy in lessening the frequency of intractable seizures in women with localization-related epilepsy. There is considerable scientific evidence to suggest that estrogen generally increases while progesterone decreases neuronal excitability and seizures. Preliminary open trials suggest that the cyclic administration of adjunctive natural progesterone supplement may lessen seizure frequency by over 50% in the majority of women with catamenially exacerbated intractable seizures. Oral synthetic progestins, in contrast, have not shown significant efficacy. Progesterone is not widely prescribed because its benefits have yet to be conclusively demonstrated. We have shown the feasibility and safety of a progesterone trial, using 150 subjects in the initial phase of this investigation. We now propose proceding with the completion of this definitive investigation of 640 subjects. During the baseline phase, seizure and menstrual charts document baseline seizure frequency and determine if seizure occurrence shows a catamenial pattern of exacerbation. The subjects are then divided into catamenial and non-catamenial strata. Each stratum is randomized in a 2:1 ratio into progesterone and placebo treatment groups. Seizure frequency during 3 months of treatment is compared to baseline, while monitoring antiepileptic drug and hormone levels. This clinical trial has considerable potential significance for women with epilepsy. Approximately 30% have persistent seizures despite antiepileptic drug use. It is estimated that 35% of these women have catamenial seizure exacerbation. If this group responds favorably to hormonal therapy, one would expect that progesterone may benefit approximately (1,000,000 x .30 x .35) 100,000 women with catamenial epilepsy and perhaps many more women with no a priori demonstrated hormonal sensitivity to seizure occurrence.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Herzog, Andrew G (2015) Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial. Seizure 28:18-25
Herzog, Andrew G; Fowler, Kristen M; Sperling, Michael R et al. (2015) Distribution of seizures across the menstrual cycle in women with epilepsy. Epilepsia 56:e58-62
Herzog, Andrew G; Frye, Cheryl A; Progesterone Trial Study Group (2014) Allopregnanolone levels and seizure frequency in progesterone-treated women with epilepsy. Neurology 83:345-8
Herzog, A G; Fowler, K M; Smithson, S D et al. (2012) Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology 78:1959-66
Herzog, Andrew G; Fowler, Kristen M; Sperling, Michael R et al. (2011) Variation of seizure frequency with ovulatory status of menstrual cycles. Epilepsia 52:1843-8
Quigg, M; Smithson, S D; Fowler, K M et al. (2009) Laterality and location influence catamenial seizure expression in women with partial epilepsy. Neurology 73:223-7
Meador, Kimford J (2009) The essential neurologic examination: what should medical students be taught? Neurology 73:2133-4; author reply 2134
Quigg, Mark; Fowler, Kristen M; Herzog, Andrew G et al. (2008) Circalunar and ultralunar periodicities in women with partial seizures. Epilepsia 49:1081-5
Herzog, Andrew G; Fowler, Kristen M; NIH Progesterone Trial Study Group (2008) Sensitivity and specificity of the association between catamenial seizure patterns and ovulation. Neurology 70:486-7
Harden, Cynthia L; Maroof, David Aaron; Nikolov, Blagovest et al. (2007) The effect of seizure severity on quality of life in epilepsy. Epilepsy Behav 11:208-11

Showing the most recent 10 out of 13 publications