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, 47 (9), 1423-40

The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the Female


The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the Female

Helen E Scharfman et al. Epilepsia.


It is clear from both clinical observations of women, and research in laboratory animals, that gonadal hormones exert a profound influence on neuronal excitability, seizures, and epilepsy. These studies have led to a focus on two of the primary ovarian steroid hormones, estrogen and progesterone, to clarify how gonadal hormones influence seizures in women with epilepsy. The prevailing view is that estrogen is proconvulsant, whereas progesterone is anticonvulsant. However, estrogen and progesterone may not be the only reproductive hormones to consider in evaluating excitability, seizures, or epilepsy in the female. It seems unlikely that estrogen and progesterone would exert single, uniform actions given our current understanding of their complex pharmacological and physiological relationships. Their modulatory effects are likely to depend on endocrine state, relative concentration, metabolism, and many other factors. Despite the challenges these issues raise to future research, some recent advances have helped clarify past confusion in the literature. In addition, testable hypotheses have developed for complex clinical problems such as "catamenial epilepsy." Clinical and animal research, designed with the relevant endocrinological and neurobiological issues in mind, will help advance this field in the future.


FIG. 1
FIG. 1
Comparison of the ovarian cycle of women (the menstrual cycle) and the rat (the estrous cycle). A. A diagram of the menstrual cycle of the normal adult woman (from 183). The follicular phase is the first half of the 28-day cycle. Ovulation occurs at mid-cycle, and is followed by the luteal phase, which is the second half of the cycle. Menstruation (menses) begins at the end of the luteal phase. LH, luteinizing hormone; FSH, follicle-stimulating hormone. B. A diagram of the 4-day estrous cycle of the normal adult Sprague-Dawley rat (modified from 184). The estradiol surge that precedes ovulation occurs during the morning of proestrus. Progesterone begins to rise in the afternoon of proestrus and has fallen by the morning of the next day, which is called estrus. The day “estrus” is distinct from “behavioral estrus”; the latter refers to the evening of proestrus, when sexual behavior peaks. Following proestrus and estrus is a 2-day period termed diestrus: the first day is diestrus 1 (also called metestrus), and it is followed by diestrus 2. Dark bars on the X axis indicate night, dashed lines denote midnight. Days 1–4 are numbered arbitrarily on the X axis for clarification of the timing of events.
FIG. 2
FIG. 2
Estrogen and progesterone biosynthesis and the influence of anticonvulsant drugs. Major steps in the synthesis of progesterone and estrogen are shown. Anticonvulsants that induce enzymes are shown in green, and those that inhibit enzyme activity are shown in red. Regarding the effects of anticonvulsants, most information has been derived from studies of hepatic enzymes, nonhuman species, and reduced preparations, using varied concentrations and times of exposure to drugs. Therefore, generalizations (i.e., to patients with epilepsy) should be made with caution. Asterisks indicate enzymes that have been shown to be present in human tissue from patients with epilepsy (22). HSD, hydroxysteroid dehydrogenase; AROM P450, aromatase P450.
FIG. 3
FIG. 3
Estrogen and progesterone receptor action. Cellular actions of estrogen and progesterone are depicted schematically for a generic neuron. Both steroids easily cross the plasma membrane to bind to cytoplasmic receptors; after receptor dimerization and activation (which may involve steroid coactivators and other accessory proteins), the receptor complexes bind to steroid response elements on target genes. Dimerization may involve identical or different subunits (homo- or hetero-dimerization). In addition, membrane receptors exist which potentially activate various signal transduction pathways. MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide-3 kinase; PLC γ, phospholipase-C γ.
FIG. 4
FIG. 4
Effects of 17β-estradiol in area CA1 of rat hippocampus. A summary of potential actions of 17β-estradiol in area CA1 of rat hippocampus. Estradiol activates target genes by nuclear hormone receptors that act as transcription factors. Estradiol also acts by nongenomic mechanisms that involve membrane receptors. Its effects are not only on pyramidal cells but also on GABAergic neurons, cholinergic input, glia, and blood vessels. Glutamatergic transmission may be influenced in a number of ways, by pre- and postsynaptic mechanisms. In addition, ion channels on pyramidal cells are modulated by estradiol, influencing neuronal firing behavior. For further description and references, see text.
FIG. 5
FIG. 5
Catamenial epilepsy subtypes and associated mechanistic hypotheses. The subtypes of catamenial epilepsy proposed by Herzog and colleagues (149) are shown schematically, using a diagram of the fluctuations in estradiol and progesterone during the menstrual cycle of a normal adult woman (modified from 184). Note that the normal menstrual cycle is assumed to occur in women with epilepsy. However, irregular fluctuations in serum levels of estrogen and progesterone have been reported (148), so the assumption may not be true in all cases. Double-headed arrows with adjacent asterisks are placed over the schematic to reflect the time of the menstrual cycle when seizures increase (in frequency or severity) for each subtype. It has also been reported that seizures may change in nature (7). Hypotheses that have been suggested to explain the seizure patterns are listed below the diagram of each subtype (see text).

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