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Review ArticleReview Article

Sex Differences in the Epilepsies and Associated Comorbidities: Implications for Use and Development of Pharmacotherapies

Catherine A. Christian, Doodipala Samba Reddy, Jamie Maguire and Patrick A. Forcelli
Lori L. Isom, ASSOCIATE EDITOR
Pharmacological Reviews October 2020, 72 (4) 767-800; DOI: https://doi.org/10.1124/pr.119.017392
Catherine A. Christian
Department of Molecular and Integrative Physiology, Neuroscience Program, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois (C.A.C.); Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas (D.S.R.); Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts (J.M.); and Departments of Pharmacology and Physiology and Neuroscience, Georgetown University, Washington, D.C. (P.A.F.)
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Doodipala Samba Reddy
Department of Molecular and Integrative Physiology, Neuroscience Program, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois (C.A.C.); Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas (D.S.R.); Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts (J.M.); and Departments of Pharmacology and Physiology and Neuroscience, Georgetown University, Washington, D.C. (P.A.F.)
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Jamie Maguire
Department of Molecular and Integrative Physiology, Neuroscience Program, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois (C.A.C.); Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas (D.S.R.); Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts (J.M.); and Departments of Pharmacology and Physiology and Neuroscience, Georgetown University, Washington, D.C. (P.A.F.)
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Patrick A. Forcelli
Department of Molecular and Integrative Physiology, Neuroscience Program, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois (C.A.C.); Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas (D.S.R.); Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts (J.M.); and Departments of Pharmacology and Physiology and Neuroscience, Georgetown University, Washington, D.C. (P.A.F.)
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Lori L. Isom
Roles: ASSOCIATE EDITOR
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    Fig. 1.

    Changes in seizure susceptibility associated with fluctuations in ratios of estradiol (E, pg/ml) and progesterone (P, ng/ml) levels in the human menstrual and rodent estrous cycles. (A) E:P (solid line) and P:E (dashed line) ratios in the human menstrual cycle and associated catamenial seizure clustering. Hormone data are adapted from Thorneycroft et al. (1971). See section III. Catamenial Epilepsy: Fluctuations in Seizure Occurrence across the Menstrual Cycle for discussion of catamenial seizure clustering. (B) E:P and P:E ratios in the rat estrous cycle. Hormone data are adapted from Smith et al. (1975). (C) E:P and P:E ratios in the mouse estrous cycle. Hormone data are adapted from Walmer et al. (1992). See section IV.B.1. Estrous Cycle–Associated Changes in Seizure Susceptibility for discussion of changes in seizure susceptibility associated with the estrous cycle in rats and mice.

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    Fig. 2.

    Sex differences in impacts of epilepsy on GnRH neuron firing activity. Mean ± S.E.M. for mean firing rate of GnRH neurons from saline-injected controls (white bars) and KA-injected female mice recorded on diestrus and on estrus (A) and male mice (B). KA-injected females are divided into KA-long (red bars) and KA-regular (blue bars) groups based on estrous cycle length (long = ≥7 days, regular = 4–6 days). Cells are classified based on anatomic location of somata in medial septum (MS), preoptic area (POA), and anterior hypothalamic area (AHA). Adapted from Li et al. (2018).

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    Fig. 3.

    Biosynthetic pathways of neurosteroid synthesis in the brain and nervous system. Enzymatic pathways for the production of three prototype neurosteroids allopregnanolone (now called brexanolone), allotetrahydrodeoxycorticosterone (THDOC), and androstanediol are illustrated from cholesterol and intermediate steroid precursors. Cholesterol is converted to pregnenolone by P450scc in the inner mitochondrial membrane. Pregnenolone is the precursor for progesterone and other neurosteroids. Progesterone, deoxycorticosterone, and testosterone undergo two sequential A-ring reduction steps catalyzed by 5α-reductase and 3α-HSOR to form the 5α, 3α-reduced neurosteroids. The conversion of progesterone, deoxycorticosterone, or testosterone into neurosteroids occurs in several regions within the brain. The 5α-reductase, 3α-HSOR, and other enzymes are present in the brain. 3β-HSD, 3β-hydroxysteroid dehydrogenase; 3α-HSOR, 3α-hydroxysteroid oxidoreductase; 17β-HSD, 17β-hydroxysteroid dehydrogenase; P450c21, cytochrome P450 21-hydroxylase; P450scc, cholesterol side-chain cleavage enzyme. Adapted from Reddy (2013).

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    Fig. 4.

    Sex differences in allopregnanolone potentiation of tonic GABAAR-mediated currents in hippocampal dentate gyrus granule cells (DGGCs) in wild-type (WT) and δ GABAAR subunit knockout mice (δKO). (A) Representative tonic current recordings from DGGCs in slices from WT male and female mice. Allopregnanolone (AP, 0.1–1.0 µM) was applied to the bath in addition to 1 μM GABA to measure allosteric enhancement of tonic current. (B) Summarized data of AP concentration response from male and female DGGCs in WT mice. (C) Representative tonic current recordings in the presence of AP or/and GABA from DGGCs in slices from δKO mice. (D) Summarized data of AP concentration response from male and female DGGCs in δKO mice. Tonic current was normalized to cell capacitance (pA/pF) as a measure of current density. The GABA-A receptor tonic current was expressed as the outward shift in holding current after the application of gabazine (50 mM). *P < 0.05 vs. males; #P < 0.05 vs. 1 µM GABA baseline current in the same sex (n = 6−8 cells per group). Adapted from Reddy et al. (2019).

Tables

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    TABLE 1

    Sex differences in models of epilepsy and seizure induction

    Sex Difference
    Generalized (Motor)
    PicrotoxinRats: ♀ > sensitivity
    Mouse: ♀ < sensitivity
    PentlyenetetrazoleRats: ♀ < sensitivity
    Mouse: ♀ > sensitivity
    BicucullineRats: ♀ < sensitivity
    ElectroshockRats, mouse: ♀ > sensitivity
    Generalized (Absence)
    WAG/Rij♀ = ♂
    GAERS♀ = ♂
    Focal
    Kainic acidRats: ♀ < sensitivity
    Mouse: ♀ > sensitivity
    PilocarpineRats: ♀ < sensitivity
    Mice: mixed reports
    KindlingAmygdala kindling: ♀ = ♂
    Hippocampus kindling: ♀ < sensitivity
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    TABLE 2

    Summary of observed changes in circulating sex steroid levels in various rodent models of TLE

    TLE modelSpeciesEstradiolProgesteroneTestosterone
    Amygdala kindling
    MaleRats––↑ Edwards et al., 1999a
    FemaleRats↑ Edwards et al., 1999c––
    Systemic pilocarpine
    FemaleRats↑ Amado and Cavalheiro, 1998↓ Amado and Cavalheiro, 1998↑ Scharfman et al., 2008
    ↔ Scharfman et al., 2008↔ Scharfman et al., 2008
    Intrahippocampal KA
    MaleMice––↔ Li et al., 2018
    FemaleRats–↓ Amado et al., 1987–
    Mice↑ (Estrus) Li et al., 2018↓ (Diestrus and estrus) Li et al., 2018–
    • View popup
    TABLE 3

    Effects of sex steroid treatment on seizure susceptibility in preclinical rodent models

    EstrogenProgesteroneTestosterone
    Generalized (Motor)
    Picrotoxin♀ = Anticonvulsant♂ = Increased sensitivity♀ = Proconvulsant
    ♂ = Anticonvulsant
    PentlyenetetrazoleRats, ♀ = proepileptogenicRat: anticonvulsantRat: anticonvulsant
    NMDASensitivity: OVX > controlMice, ♂ = anticonvulsant
    ♀ = Anticonvulsant
    ElectroshockProconvulsantAnticonvulsantBoth pro- and anticonvulsant effects
    Generalized (Absence)
    WAG/RijMore seizures during proestrus
    Focal
    Kainic acidRat: proconvulsantRat: castration is anticonvulsant
    PilocarpineRats, ♀: agonists increase seizure frequency
    KindlingRats: proepileptogenicRats, ♀ = proepileptogenicProepileptogenic
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Pharmacological Reviews: 72 (4)
Pharmacological Reviews
Vol. 72, Issue 4
1 Oct 2020
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Review ArticleReview Article

Sex Differences in Epilepsy and Comorbidities

Catherine A. Christian, Doodipala Samba Reddy, Jamie Maguire and Patrick A. Forcelli
Pharmacological Reviews October 1, 2020, 72 (4) 767-800; DOI: https://doi.org/10.1124/pr.119.017392

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Review ArticleReview Article

Sex Differences in Epilepsy and Comorbidities

Catherine A. Christian, Doodipala Samba Reddy, Jamie Maguire and Patrick A. Forcelli
Pharmacological Reviews October 1, 2020, 72 (4) 767-800; DOI: https://doi.org/10.1124/pr.119.017392
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  • Article
    • Abstract
    • I. Introduction to Epilepsy, Seizures, and the Importance of Investigating Sex Differences
    • II. Sex Differences in Epilepsies and Comorbidities: Clinical Conditions and Animal Models
    • III. Catamenial Epilepsy: Fluctuations in Seizure Occurrence across the Menstrual Cycle
    • IV. Potential Neurobiological Bases for Sex Differences in Seizure Susceptibility and Epilepsy
    • V. Considerations for Antiseizure Pharmacotherapies, Drug Screening, and Development
    • VI. Concluding Remarks and Future Directions
    • Acknowledgments
    • Authorship Contributions
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