This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition. To date, there are no specific drug treatments for catamenial epilepsy however, non-hormonal and hormonal therapies have been proposed. The aim of this review is to report preclinical and clinical evidences about the relationship between female reproductive steroids and epileptic seizures, and to describe treatment approaches for catamenial epilepsy. Keywords: catamenial epilepsy, estrogens, progesterone, neurosteroids Introduction Women with epilepsy may have seizure patterns associated with changes in estrogen and progesterone levels.
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This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition.
To date, there are no specific drug treatments for catamenial epilepsy however, non-hormonal and hormonal therapies have been proposed. The aim of this review is to report preclinical and clinical evidences about the relationship between female reproductive steroids and epileptic seizures, and to describe treatment approaches for catamenial epilepsy.
Keywords: catamenial epilepsy, estrogens, progesterone, neurosteroids Introduction Women with epilepsy may have seizure patterns associated with changes in estrogen and progesterone levels. Relationship between epilepsy and the menstrual cycle Catamenial epilepsy is believed to occur secondarily to the neuroactive properties of endogenous steroid hormones and the natural cyclic variation in their serum levels throughout the menstrual cycle.
Probably, the sudden withdrawal of progesterone, analogous to a benzodiazepine withdrawal, could be the cause of the premenstrual rise in seizure frequency, while, during the days preceding ovulation, the rapid and steep rise in serum estradiol concentration is believed to be responsible for the increase of seizures at that time. Furthermore, Quigg et al 19 also reported that age affects overall seizure rate: youth increases seizure occurrence across the day cycle.
Because this factor is phase-independent, the modulatory effect of age may arise from factors outside the cyclic effects of the hypothalamic-pituitary- gonadal axis. Pathophysiology of catamenial epilepsy It is known that estrogen and progesterone have important effects on neuronal development and plasticity in widespread cerebral and brainstem regions, 20 through their capacity to regulate synthesis, release, and transport of neurotransmitters.
There are also studies that support protective effects of estrogen and that suggest that it may also be anticonvulsant under some circumstances. Logothetis et al 28 have demonstrated that intravenous infusions of estrogen were associated with rapid interictal epileptiform activity in women with epilepsy, and that seizures were exacerbated when estrogen was given premenstrually.
Therefore, it is hypothesized that estrogens may facilitate some forms of catamenial seizures observed during these phases. The periovulatory catamenial exacerbation has been attributed to the midcycle surge of estrogen that is relatively unopposed by progesterone until early luteal phase. They also reported that in many patients with catamenial epilepsy, a marked increase in spike and wave discharges are observed during menstruation.
In contrast, there are several studies of chronic estrogen administration in females that show either anticonvulsant or no effect of estrogen on seizures. The neuroprotective activity of estrogens was then confirmed by several subsequent studies. In animal models, progesterone has been found to reduce neuronal firing and decrease spontaneous and induced epileptiform discharges. The rise in progesterone levels during the luteal phase of the ovulatory cycles and the progesterone withdrawal during menstruation did not induce significant changes in any of the transcranial magnetic stimulation parameters.
Furthermore, there was no correlation between progesterone levels and intracortical inhibition. Physiological actions of progesterone are mediated by progesterone receptors PR , a member of the nuclear receptor superfamily of transcription factors. However, there is strong evidence that the antiseizure effects of progesterone are not related to interactions with classical PR; in fact, the antiseizure activity of progesterone was undiminished in PR knockout mice, 1 which are generated by a null mutation of the PR gene.
Thus, the role of the PR in seizure susceptibility has not been fully explained. To date, a rapid effect of progesterone has been reported in the hippocampus slice excitability, that was blocked by the PR antagonist RU It causes a transient increase in dendritic spines over the first 6 hours of exposure, followed by a decrease in the number of CA1 dendritic spines and excitatory synapses.
Progesterone also antagonizes estrogen actions, lowering estrogen receptor number. Women with catamenial epilepsy may experience an increase in seizure frequency in perimenopause and a decrease after menopause, which is consistent with the high estrogen levels in perimenopause, and low estrogen levels in postmenopause.
In fact, both estradiol and progesterone affect the GABA function; therefore, the simultaneous decrease of estrogen and progesterone may lead to a decrease in GABAergic inhibition, facilitating seizures. The brain hormonal milieu in which exogenous hormones are introduced is markedly different in menopause from that in menstruating women. Some women with epilepsy appear to be at increased risk of ovulatory dysfunction. However, in another investigation of women with focal epilepsy, 39 had anovulatory cycles.
However, evidence for the effectiveness of these treatments is not well established. Large multicenter trials are needed to identify the most effective treatment for women with catamenial epilepsy. Hormonal therapy Because progesterone has mainly been shown to have anticonvulsant effects, and because women with catamenial epilepsy under study often had inadequate luteal-phase or anovulatory cycles, it can be hypothesized that progesterone, progesterone metabolites, or estrogen antagonists may be used in conjunction with current antiepileptic medications, to treat these patients.
Natural progesterone, is a treatment option for patients with catamenial epilepsy and impaired luteal phase cycles. It is usually given in cyclic form during the luteal phase, taken orally at a dose of — mg, twice a day or three times a day. In fact, progesterone is poorly absorbed orally and has a short half-life, so that it must be administered multiple times per day.
Even though estrogen is a proconvulsant, combined oral contraceptives have not been associated with an increase in seizures. They may be used in women with epilepsy also to prevent unwanted pregnancies. Gonadotropin releasing hormone analog, was studied in women with refractory perimenstrual seizures.
The action mechanism of gonadotropin releasing hormone analog is the decreased luteinizing hormone and estrogen production with consequent amenorrhea. In one study, this was given intramuscularly in a controlled-release depot preparation every 28 days. Clomiphene is an ovulatory stimulant that is used to treat infertility in women with oligoanovulation or anovulation.
Ganaxolone, a synthetic analog of allopregnanolone, is able to modulate most GABA-A receptors and is under investigation for the treatment of epilepsy.
Laxer et al 70 completed a multicenter, double-blind, randomized, placebo-controlled, monotherapy clinical trial that evaluated the safety, tolerability, and antiepileptic activity of ganaxolone.
The study population consisted of 52 inpatients with medically- refractory, complex, partial seizures. Each patient was studied for up to 8 days, with patients receiving placebo or ganaxolone. The primary measure of antiepileptic activity was the duration of treatment prior to withdrawal from the study. Patients were withdrawn from the study at the occurrence of one of the following: four seizures of any type with the exception of simple, partial seizures ; three generalized tonic-clonic seizures; or status epilepticus.
Tolerability of ganaxolone was similar to that of placebo. Ganaxolone may provide an effective approach for catamenial epilepsy therapy that is reliable, and that does not expose patients to the risk of hormonal side effects. New oral formulations of ganaxolone are going to be developed with enhanced bioavailability and more consistent absorption.
It is clear, however, that tolerance develops, which results in diminishing efficacy over time. Therefore, this drug can only be administered on an intermittent basis, which is appropriate for catamenial epilepsy but not for ordinary seizure prophylaxis.
Benzodiazepines are of limited utility in seizure prophylaxis however, they could theoretically be used on an intermittent basis for the treatment of catamenial seizures. In fact, 1,5-benzodiazepine clobazam, administered intermittently, has been used to treat catamenial seizure exacerbations over long periods of time with good results. References 1. Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice.
J Pharmacol Exp Ther. Females, their estrogens, and seizures. Reddy DS. Role of neurosteroids in catamenial epilepsy. Epilepsy Res. Herzog AG. Catamenial epilepsy: definition, prevalence, pathophysiology and treatment. The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy.
How common is catamenial epilepsy? Occurrence of menstrual cycle related seizure patterns among epileptic women attending the tertiary neurology clinics of the National Hospital of Sri Lanka.
Menstrual cycle worsening of epileptic seizures in women with symptomatic focal epilepsy. Arq Neuropsiquiatr. Frequency of catamenial seizure exacerbation in women with localization-related epilepsy.
Ann Neurol. Reproductive hormonal changes and catamenial pattern in adolescent females with epilepsy. Three patterns of catamenial epilepsy. Studies on the pattern of circulating steroids in the normal menstrual cycle.
Simultaneous assays of progesterone, pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone, androstenedione, oestradiol and oestrone. Acta Endocrinol Copenh ;81 1 — Redei E, Freeman EW. Daily plasma estradiol and progesterone levels over the menstrual cycle and their relation to premenstrual symptoms.
Variation of seizure frequency with ovulatory status of menstrual cycles. Circalunar and ultralunar periodicities in women with partial seizures. Menstrual cycle interval and ovulation in women with localization-related epilepsy. Ovulatory function in epilepsy. Chronology and evolution of temporal lobe epilepsy and endocrine reproductive dysfunction in women: relationships to side of focus and catameniality. Epilepsy Behav. Laterality and location influence catamenial seizure expression in women with partial epilepsy.
Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol. Neuroactive properties of reproductive steroids. Terasawa E, Timiras PS. Electrical activity during the estrous cycle of the rat: cyclic changes in limbic structures. Effects of steroids on cerebral electrical activity. Epileptogenic effects of conjugated estrogens and related compounds in the cat and rabbit.
Arch Neurol. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J Neurosci. The effects of estrogen, progesterone, and ionized calcium on seizures during the menstrual cycle of epileptic women. Morrell MJ.
Progesterone Our understanding of the major gonadal hormones , estrogen , progesterone , and testosterone , has significantly increased in the last century. These hormones are synthesized in various locations in the body, including the ovaries, adrenal gland, liver, subcutaneous fat, and brain. Estrone E1 , estradiol E2 , and estriol E3 are the three principal circulating estrogens in the body. In normally menstruating women, serum estradiol levels are typically present by day 10 of the menstrual cycle, and persist until ovulation. Estrone is the major estrogen after menopause, and this hormone may be very influential in seizure control of the catamenial woman if she is severely overweight or obese. Estradiol represents the most prolific estrogen ligand receptor in the female body, particularly in non-pregnant females, and is a more effective activator of estrogen receptor function than estrone or estriol.
Diagnosis and management of catamenial seizures: a review