Sex differences in the epilepsies and associated comorbidities: implications for use and development of pharmacotherapies
Open accessAbstract
The epilepsies are common neurologic disorders characterized by spontaneous recurrent seizures. Boys, girls, men, and women of all ages are affected by epilepsy and, in many cases, by associated comorbidities as well. The primary courses of treatment are pharmacological, dietary, and/or surgical, depending on several factors, including the areas of the brain affected and the severity of the epilepsy. There is a growing appreciation that sex differences in underlying brain function and in the neurobiology of epilepsy are important factors that should be accounted for in the design and development of new therapies. In this review, we discuss the current knowledge on sex differences in epilepsy and associated comorbidities, with emphasis on those aspects most informative for the development of new pharmacotherapies. Particular focus is placed on sex differences in the prevalence and presentation of various focal and generalized epilepsies; psychiatric, cognitive, and physiologic comorbidities; catamenial epilepsy in women; sex differences in brain development; the neural actions of sex and stress hormones and their metabolites; and cellular mechanisms, including brain-derived neurotrophic factor signaling and neuronal-glial interactions. Further attention placed on potential sex differences in epilepsies, comorbidities, and drug effects will enhance therapeutic options and efficacy for all patients with epilepsy. SIGNIFICANCE STATEMENT: Epilepsy is a common neurological disorder that often presents together with various comorbidities. The features of epilepsy and seizure activity as well as comorbid afflictions can vary between men and women. In this review, we discuss sex differences in types of epilepsies, associated comorbidities, pathophysiological mechanisms, and antiepileptic drug efficacy in both clinical patient populations and preclinical animal models.
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Estrogen is synthesized in the hippocampus and increases intrinsic neuronal excitability and long-term potentiation in the hippocampus while decreasing inhibitory transmission.
“Synthesized in the hippocampus, estrogen is shown to increase intrinsic neuronal excitability and long-term potentiation in the hippocampus (Christian et al., 2020) while decreasing inhibitory transmission (Rudick and Woolley, 2001).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Christian et al., 2020
The hormonal-mechanisms section (page unavailable) says estradiol increases neuronal excitability and reports greater hippocampal excitability at estrous-cycle stages associated with higher estradiol. It also describes conversion of testosterone to estradiol in the brain, but does not establish synthesis specifically in the hippocampus or increased hippocampal long-term potentiation. The decrease in inhibitory transmission is attributed to a different citation in the citing sentence and is not judged here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe ovarian-derived hormone estrogen exacerbates seizures in women with epilepsy and rodent KA acute seizure models.
“Furthermore, the ovarian-derived hormone such as estrogen exacerbates seizures in women with epilepsy and rodent KA acute seizure models (Christian et al., 2020).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Christian et al., 2020
Cerebral glucose hypometabolism occurs in both the early stage of AD and epilepsy.
“Importantly, cerebral glucose hypometabolism occurs in both the early stage of AD (Christian et al., 2020; Yamazaki et al., 2019) and epilepsy (McDonald et al., 2018; Patel, 2018).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Christian et al., 2020
Christian et al. is cited for the early-stage Alzheimer disease (AD) portion of the sentence, not the epilepsy portion. The paper’s Cognitive and Learning Deficits section discusses AD risk, and its Focal Seizures discussion mentions hypometabolism in temporal lobe epilepsy, but neither passage addresses cerebral glucose hypometabolism in early-stage AD (searched: Alzheimer disease, glucose metabolism, hypometabolism). (LLM, conf=0.76)
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- Authors
- Christian, C. A., Reddy, D. S., Maguire, J., & Forcelli, P. A.
- Affiliations
- Tufts University (US)
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 72
- Issue
- 4
- Pages
- 767-800
- ISSN
- 0031-6997 (ISSN-L)
- PMC
- PMC7495340
- OpenAlex
- W3074825168
- Cited by
- 105
- References
- 17
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 21 · 2023: 18 · 2022: 18 · 2021: 13 · 2020: 2
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Epilepsy Society
- Epilepsy Society
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS105628, R01NS051398, R01NS105825, U01NS083460, R21NS052158, R03NS103029, R01NS097762, R01NS102937)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD091994)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Keywords
- sex differences, epilepsy, comorbidities, antiepileptic drugs, catamenial epilepsy, sex hormones, stress hormones, brain-derived neurotrophic factor, neuron-glia interactions, sex differences in brain development, psychiatric comorbidity, cognitive comorbidities, focal epilepsy, generalized epilepsy, drug development
- MeSH terms
- Animals, Anticonvulsants, Disease Models, Animal, Epilepsy, Female, Humans, Male, Sex Factors, Comorbidity, Randomized Controlled Trials as Topic
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