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Catamenial epilepsy: Definition, prevalence pathophysiology and treatment

Open ArchivePublished:January 03, 2008DOI:https://doi.org/10.1016/j.seizure.2007.11.014

      Summary

      Seizures do not occur randomly. They tend to cluster in the majority of men and women with epilepsy. Seizure clusters, in turn, often show a periodicity. When the periodicity of seizure exacerbation aligns itself with that of the menstrual cycle, it is designated as catamenial epilepsy. The neuroactive properties of reproductive steroids and the cyclic variation in their serum concentrations are important pathophysiologic factors. Recent investigations have demonstrated and confirmed the existence of at least three patterns of catamenial seizure exacerbation: perimenstrual and periovulatory in ovulatory cycles and entire luteal phase in anovulatory cycles. A rational mathematical basis for the categorization of seizure exacerbation as catamenial epilepsy has been developed. It identifies approximately one third of women as having catamenial epilepsy. If seizures show hormonal sensitivity in their occurrence, they may also respond to hormonal treatment. Successful open label trials using cyclic natural progesterone supplement, depomedroxyprogesterone and gonadotropin-releasing hormone analogues in women and using testosterone with or without aromatase inhibitor in men have been reported. Prospective, randomized, placebo-controlled, double-blind investigations are warranted and under way.

      Keywords

      Definition, patterns and prevalence

      Seizures do not occur randomly in the majority of men and women with epilepsy.
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      • Lundervold A.
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      Temporal distribution of seizures in epilepsy.
      They tend to cluster in over 50% of cases.
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      Temporal distribution of seizures in epilepsy.
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      Distribution of seizure occurrence in women with epilepsy: preliminary data analysis in a prospective multicenter investigation.
      Seizure clusters, in turn, may occur with temporal rhythmicity in a significant proportion of men (29%) and women (35%) with epilepsy.
      • Almqvist R.
      The rhythm of epileptic attacks and its relationship to the menstrual cycle.
      When the periodicity of seizure exacerbation aligns with the menstrual cycle, it is commonly known as catamenial epilepsy.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      This may be attributable to (1) the neuroactive properties of steroid hormones and (2) the cyclic variation in their serum levels.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      Physiological endocrine secretion during the menstrual cycle influences the occurrence of seizures (Fig. 1). In ovulatory cycles, seizure frequency shows a statistically significant positive correlation with the serum estradiol/progesterone ratio.
      • Backstrom T.
      Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle.
      This ratio is highest during the days prior to ovulation and menstruation and is lowest during the early- and mid-luteal phase.
      • Backstrom T.
      Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle.
      The premenstrual exacerbation of seizures has been attributed to the rapid withdrawal of the antiseizure effects of progesterone.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      • Backstrom T.
      Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle.
      Mid cycle exacerbations may be due to the preovulatory surge of estrogen, unaccompanied by any rise in progesterone until ovulation occurs.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      • Backstrom T.
      Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle.
      • Laidlaw J.
      Catamenial epilepsy.
      Seizures are least common during the mid-luteal phase when progesterone levels are highest
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      • Backstrom T.
      Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle.
      • Laidlaw J.
      Catamenial epilepsy.
      except in anovulatory cycles in which the mid cycle surge in estrogen still occurs, albeit not as high as in ovulatory cycles, but unaccompanied by any substantial increase in progesterone levels.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      Figure thumbnail gr1
      Figure 1Three patterns of catamenial epilepsy: perimenstrual (C1) and periovulatory (C2) exacerbations during normal ovulatory cycles and entire second half of the cycle (C3) exacerbation during inadequate luteal phase cycles where Day 1 is the first day of menstrual flow and Day 14 is the day of ovulation.
      Herzog et al.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      • Herzog A.G.
      • Harden C.L.
      • Liporace J.
      • Pennell P.
      • Schomer D.L.
      • Sperling M.
      • et al.
      Frequency of catamenial seizure exacerbation in women with localization-related epilepsy.
      have presented statistical evidence to support the concept of catamenial epilepsy and the existence of at least three distinct patterns of seizure exacerbation in relation to the menstrual cycle (Fig. 1): (1) perimenstrual (C1: Days −3 to 3) and (2) periovulatory (C2: Days 10 to −13) in normal cycles, and (3) luteal (C3: Days 10–3) in inadequate luteal phase cycles. In these cycles, Day 1 is the first day of menstrual flow and ovulation is presumed to occur 14 days before the subsequent onset of menses (Day −14). These three patterns can be demonstrated simply by (1) charting menses and seizures and (2) obtaining a mid-luteal phase serum progesterone level to distinguish between normal and inadequate luteal phase cycles (<5 ng/ml).
      While the precise definition of catamenial epilepsy remains arbitrary, one may maximize the efficiency of distinguishing between women whose seizure occurrence shows a high versus low degree of hormonal sensitivity by using the points of inflection of the S-shaped distribution curves that define the relationship between the severity of seizure exacerbation and the number of women who have exacerbation.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      • Herzog A.G.
      • Harden C.L.
      • Liporace J.
      • Pennell P.
      • Schomer D.L.
      • Sperling M.
      • et al.
      Frequency of catamenial seizure exacerbation in women with localization-related epilepsy.
      These points are calculated to be in the vicinity of a twofold increase in average daily seizure frequency during the phases of exacerbation relative to the baseline phases for all three types of catamenial exacerbation. We propose the use of these points of inflection values in seizure frequency for the designation of catamenial epilepsy. By this criterion, approximately one third of women with intractable partial epilepsy would qualify for the designation of having catamenial epilepsy.
      • Herzog A.G.
      • Klein P.
      • Ransil B.J.
      Three patterns of catamenial epilepsy.
      • Herzog A.G.
      • Harden C.L.
      • Liporace J.
      • Pennell P.
      • Schomer D.L.
      • Sperling M.
      • et al.
      Frequency of catamenial seizure exacerbation in women with localization-related epilepsy.
      Adoption of a standard albeit arbitrary nomenclature may provide greater uniformity to study designs for the investigation of the pathogenesis and treatment of catamenial seizure exacerbation.

      Pathophysiology

      There is considerable scientific evidence at molecular biological, neuronal, experimental animal and clinical levels to indicate that reproductive steroids have neuroactive properties that play an important role in the pathophysiology of epilepsy and the pattern of seizure occurrence. Steroids act in the brain by direct membrane-mediated (short latency) effects as well as receptor-mediated genomically mediated (long latency) effects.
      • McEwen B.S.
      How do sex and stress hormones affect nerve cells?.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Klein P.
      • Herzog A.G.
      Endocrine aspects of epilepsy.

      Reproductive hormonal effects on epilepsy

      Estradiol

      Estradiol exerts direct excitatory effects at the neuronal membrane, where it augments N-methyl-d-aspartate (NMDA) mediated glutamate receptor activity.
      • Smith S.S.
      Estrogen administration increases neuronal responses to excitatory amino acids as a long term effect.
      • Wong M.
      • Moss R.
      Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons.
      This enhances the resting discharge rates of neurons in a number of brain areas, including the hippocampus
      • Smith S.S.
      Estrogen administration increases neuronal responses to excitatory amino acids as a long term effect.
      • Wong M.
      • Moss R.
      Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons.
      • Kawakami M.
      • Teresawa E.
      • Ibuki T.
      Changes in multiple unit activity in the brain during the estrous cycle.
      where estradiol increases excitability of the hippocampal CA1 pyramidal neurons and induces repetitive firing in response to Schaffer collateral stimulation.
      • Wong M.
      • Moss R.
      Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons.
      Estradiol potentiates neuronal excitability by regulating neuronal plasticity. It increases the density of spines and excitatory, NMDA receptor-containing synapses on the apical dendrites of hippocampal CA1 pyramidal neurons via a post-transcriptional mechanism.
      • Woolley C.S.
      • McEwen B.S.
      Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.
      • Woolley C.S.
      • McEwen B.S.
      Estradiol regulates hippocampal dendritic spine density via an N-methyl-d-aspartate receptor-dependent mechanism.
      The dendritic spine density on these neurons correlates positively with the levels of circulating estradiol during the estrous cycle of the rat and is decreased by oophorectomy.
      • Woolley C.S.
      • McEwen B.S.
      Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.
      • Woolley C.S.
      • McEwen B.S.
      Estradiol regulates hippocampal dendritic spine density via an N-methyl-d-aspartate receptor-dependent mechanism.
      Estradiol may thus further increase excitatory input to the CA1 neurons.
      Estradiol may affect neuronal excitability by cytosolic neuronal estrogen receptor-mediated, genomically dependent mechanisms. Receptors are particularly abundant in the temporolimbic system, especially in the medial and cortical amygdaloid nuclei, and occur in much fewer numbers in the hippocampal pyramidal cell layer and the subiculum.
      • Pfaff D.W.
      • Keiner M.
      Estradiol-concentrating cells in the rat amygdala as part of a limbic-hypothalamic hormone-sensitive system.
      • Simerly R.B.
      • Chang C.
      • Muramatsu M.
      • Swanson L.W.
      Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study.
      Estrogen receptor-containing neurons co-localize with other neurotransmitters, including gamma-amino-butyric acid (GABA).
      • McEwen B.S.
      Nongenomic and genomic effects of steroids on neural activity.
      • Finn D.A.
      • Gee K.W.
      The influence of estrus cycle phase on neurosteroid potency at the GABAA receptor complex.
      By regulating the expression of genes affecting the activity, release and post-synaptic action of different neurotransmitters and neuromodulators, estrogens may act to increase the excitability of neurons, which concentrate estradiol. For instance, estradiol lessens inhibitory neurotransmission by decreasing GABA synthesis in the corticomedial amygdala by reducing the activity of glutamic acid decarboxylase,
      • Wallis C.J.
      • Luttge W.G.
      Influence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain.
      and enhances brain epileptogenic muscarinic neurotransmission by increasing choline acetyl transferase and acetylcholine.
      • Luine V.N.
      • Renner K.J.
      • McEwen B.S.
      Sex-dependent differences in estrogen regulation of choline acetyltransferase are altered by neonatal treatments.
      In adult experimental animals, the thresholds of limbic seizures in female rats fluctuate during the estrus cycle inversely to estradiol levels.
      • Teresawa E.
      • Timiras P.
      Electrical activity during the estrous cycle of the rat; cyclic changes in limbic structures.
      Physiological doses of estradiol activate spike discharges
      • Wong M.
      • Moss R.
      Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons.
      • Kawakami M.
      • Teresawa E.
      • Ibuki T.
      Changes in multiple unit activity in the brain during the estrous cycle.
      • Logothetis J.
      • Harner R.
      Electrocortical activation by estrogens.
      • Marcus E.M.
      • Watson C.W.
      • Goodman P.L.
      Effects of steroids on cerebral electrical activity.
      and lower the thresholds of seizures induced by electroshock, kindling, pentylenetetrazol, kainic acid, ethyl chloride and other agents and procedures.
      • Logothetis J.
      • Harner R.
      Electrocortical activation by estrogens.
      • Marcus E.M.
      • Watson C.W.
      • Goodman P.L.
      Effects of steroids on cerebral electrical activity.
      • Hom A.C.
      • Buterbaugh G.G.
      Estrogen alters the acquisition of seizures kindled by repeated amygdala stimulation or pentylenetetrazol administration in ovariectomized female rats.
      • Nicoletti F.
      • Speciale C.
      • Sortino M.A.
      • Summa G.
      • Caruso G.
      • Patti F.
      • et al.
      Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats.
      • Spiegel E.
      • Wycis H.
      Anticonvulsant effects of steroids.
      • Woolley D.E.
      • Timiras P.S.
      The gonad–brain relationship: effects of female sex hormones on electroshock convulsions in the rat.
      In fact, topical brain application, as well as intravenous systemic administration, of estradiol in rabbits produces a significant increase in spontaneous electrically recorded paroxysmal spike discharges.
      • Marcus E.M.
      • Watson C.W.
      • Goodman P.L.
      Effects of steroids on cerebral electrical activity.
      The increase is seen within a few seconds of application to suggest a direct membrane rather than a genomic effect and is more dramatic in animals with preexistent cortical lesions.
      • Logothetis J.
      • Harner R.
      Electrocortical activation by estrogens.
      • Marcus E.M.
      • Watson C.W.
      • Goodman P.L.
      Effects of steroids on cerebral electrical activity.
      The role of estrogen, however, may be more complex since there is also evidence in some models that estradiol can raise seizure thresholds in the hippocampal region and provide neuroprotection against seizure-induced injury.
      • Veliskova J.
      • Velisek L.
      • Galanopoulou A.S.
      • Sperber E.F.
      Neuroprotective effects of estrogens on hippocampal cells in adult female rats after status epilepticus.
      Clinically, Logothetis et al.
      • Logothetis J.
      • Harner R.
      • Morrell F.
      • Torres F.
      The role of estrogens in catamenial exacerbation of epilepsy.
      showed that intravenously administered conjugated estrogen clearly activated epileptiform in 11 of 16 women and was associated with clinical seizures in four.

      Progesterone

      Progesterone and particularly some of its neuroactive metabolites, most notably allopregnanolone, exert direct membrane-mediated inhibitory effects by potentiating GABAA-mediated chloride conductance.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Majewska M.D.
      • Harrison N.L.
      • Schwartz R.D.
      • Barker J.L.
      • Paul S.M.
      Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      It also potentiates the action of the powerful endogenous inhibitory substance adenosine.
      • Phyllis J.W.
      Potentiation of the depression by adenosine of rat cerebral cortex neurones by progestational agents.
      Progesterone itself also substantially diminishes nicotinic acetylcholine receptor-mediated conductance, which may be relevant to autosomal dominant nocturnal frontal lobe epilepsy.
      • Valera S.
      • Ballivet M.
      • Bertrand D.
      Progesterone modulates a neuronal nicotinic acetylcholine receptor.
      Progesterone may act via genomic mechanisms to influence the enzymatic activity controlling the synthesis and release of various neurotransmitters and neuromodulators produced by progesterone receptor-containing neurons.
      • McEwen B.S.
      Nongenomic and genomic effects of steroids on neural activity.
      Progesterone binds specific cytosolic receptors not only to produce its own characteristic effects but also to lower estrogen receptor numbers and thereby antagonize estrogen actions.
      • Hsueh A.J.W.
      • Peck E.J.
      • Clark J.H.
      Control of uterine estrogen receptor levels by progesterone.
      Chronic progesterone decreases the number of hippocampal CA1 dendritic spines and excitatory synapses faster than the simple withdrawal of estrogen, counteracting the stimulatory effects of estradiol.
      • Woolley C.S.
      • McEwen B.S.
      Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.
      Progesterone and allopregnanolone have also been shown to have neuroprotective effects on hippocampal neurons in kainic acid-induced seizure models.
      • Frye C.A.
      The neurosteroid 3a-5a-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy.
      In most adult female animal models, progesterone depresses neuronal firing,
      • Smith S.S.
      • Waterhouse B.D.
      • Woodward D.J.
      Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters.
      and lessens spontaneous and induced epileptiform discharges.
      • Nicoletti F.
      • Speciale C.
      • Sortino M.A.
      • Summa G.
      • Caruso G.
      • Patti F.
      • et al.
      Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats.
      • Spiegel E.
      • Wycis H.
      Anticonvulsant effects of steroids.
      • Woolley D.E.
      • Timiras P.S.
      The gonad–brain relationship: effects of female sex hormones on electroshock convulsions in the rat.
      • Frye C.A.
      The neurosteroid 3a-5a-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy.
      • Smith S.S.
      • Waterhouse B.D.
      • Woodward D.J.
      Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters.
      • Landgren S.
      • Backstrom T.
      • Kalistratov G.
      The effect of progesterone on the spontaneous interictal spike evoked by the application of penicillin to the cat's cerebral cortex.
      It retards kindling and decreases seizure occurrence.
      • Nicoletti F.
      • Speciale C.
      • Sortino M.A.
      • Summa G.
      • Caruso G.
      • Patti F.
      • et al.
      Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats.
      • Spiegel E.
      • Wycis H.
      Anticonvulsant effects of steroids.
      • Woolley D.E.
      • Timiras P.S.
      The gonad–brain relationship: effects of female sex hormones on electroshock convulsions in the rat.
      • Frye C.A.
      The neurosteroid 3a-5a-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy.
      • Smith S.S.
      • Waterhouse B.D.
      • Woodward D.J.
      Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters.
      • Landgren S.
      • Backstrom T.
      • Kalistratov G.
      The effect of progesterone on the spontaneous interictal spike evoked by the application of penicillin to the cat's cerebral cortex.
      Backstrom et al.
      • Backstrom T.
      • Zetterlund B.
      • Blom S.
      • Romano M.
      Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy.
      found that intravenous infusion of progesterone, sufficient to produce luteal phase serum levels, was associated with a significant decrease in interictal spike frequency in four of seven women with partial epilepsy.

      Neurosteroids

      Most of the membrane effect of progesterone is due to the action of its 3α-hydroxylated (i.e. A-ring-reduced) metabolite, 3α-hydroxy-5α-pregnane-20-one or allopregnanolone (AP).
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      AP and the 3,5-hydroxylated natural metabolite of the mineralocorticoid deoxycorticosterone, allotetrahydro-deoxycorticosterone (allo-THDOC), are among the most potent of a number of endogenous neuroactive steroids with a direct membrane effect on neuronal excitability.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Majewska M.D.
      • Harrison N.L.
      • Schwartz R.D.
      • Barker J.L.
      • Paul S.M.
      Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      AP, but not allo-THDOC, is devoid of hormonal effects and may, together with other related neuroactive steroids, be thought of as an endogenous regulator of brain excitability with anxiolytic, sedative-hypnotic and anticonvulsant properties.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Majewska M.D.
      • Harrison N.L.
      • Schwartz R.D.
      • Barker J.L.
      • Paul S.M.
      Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      AP and allo-THDOC hyperpolarize hippocampal and other neurons by potentiating GABAA-mediated inhibition.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      At physiological (nanogram) with an extrasynaptic steroid-specific site near the synaptic receptor to facilitate chloride channel opening and prolong the inhibitory action of GABA on neurons.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Majewska M.D.
      • Harrison N.L.
      • Schwartz R.D.
      • Barker J.L.
      • Paul S.M.
      Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      • Maguire J.L.
      • Stell B.M.
      • Rafizadeh M.
      • Mody I.
      Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety.
      • Wu F.S.
      • Gibbs T.T.
      • Farb D.H.
      Inverse modulation of g-aminobutyric acid- and glycine-induced currents by progesterone.
      At higher pharmacological (micromolar) concentrations, AP also has a direct effect at the synaptic GABAA receptor to induce chloride currents.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      AP is one of the most potent ligands of GABAA receptors in the CNS, with affinities similar to those of the potent benzodiazepine, flunitrazepam, and approximately a thousand times higher than pentobarbital.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Gee K.W.
      • McCauley L.D.
      • Lan N.C.
      A putative receptor for neurosteroids on the GABA receptor complex: the pharmacological properties and therapeutic potential of epalons.
      The parent steroid, progesterone, enhances GABA-induced chloride currents only weakly and only in high concentrations.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      • Wu F.S.
      • Gibbs T.T.
      • Farb D.H.
      Inverse modulation of g-aminobutyric acid- and glycine-induced currents by progesterone.
      Plasma and brain levels of AP parallel those of progesterone in rats. In women, plasma levels of AP correlate with progesterone levels during the menstrual cycle and pregnancy.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      However, brain activity of progesterone and AP is not dependent solely on ovarian and adrenal production, as they are both synthesized de novo in the brain.
      • Cheney D.L.
      • Uzunov D.
      • Costa E.
      • Guidotti A.
      Gas chromatographic-mass fragmentographic quantitation of 3a-hydroxy-5a-pragnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats.
      Their synthesis is region-specific and includes the cortex and the hippocampus.
      • Cheney D.L.
      • Uzunov D.
      • Costa E.
      • Guidotti A.
      Gas chromatographic-mass fragmentographic quantitation of 3a-hydroxy-5a-pragnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats.
      By contrast, allo-THDOC is only synthesized by the adrenal gland and not in the brain.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      AP, allo-THDOC and a number of other endogenous and synthetic pregnane steroids have a potent anticonvulsant effect in bicuculine-, metrazol-, picrotoxin-, pentylenetetrazol-, pilocarpine- and kainic acid-induced seizures and against status epilepticus, but are ineffective against electroshock and strychnine-induced seizures.
      • Majewska M.D.
      • Harrison N.L.
      • Schwartz R.D.
      • Barker J.L.
      • Paul S.M.
      Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
      • Belleli D.
      • Bolger M.B.
      • Gee K.W.
      Anticonvulsant profile of the progesterone metabolite 5a-pregnan-3a-ol-20-one.
      • Kokate T.G.
      • Svensson B.E.
      • Rogawski M.A.
      Anticonvulsant activity of neurosteroids: correlation with g-aminobutyric acid-evoked chloride current potentiation.
      • Kokate T.G.
      • Cohen A.L.
      • Karp E.
      • Rogawski M.A.
      Neuroactive steroids protect against pilocarpine-and kainic acid-induced limbic seizures and status epilepticus in mice.
      The anticonvulsant properties of allopregnanolone resemble those of the benzodiazepine and clonazepam.
      • Finn D.A.
      • Gee K.W.
      The influence of estrus cycle phase on neurosteroid potency at the GABAA receptor complex.
      • Majewska M.D.
      • Harrison N.L.
      • Schwartz R.D.
      • Barker J.L.
      • Paul S.M.
      Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
      • Kokate T.G.
      • Cohen A.L.
      • Karp E.
      • Rogawski M.A.
      Neuroactive steroids protect against pilocarpine-and kainic acid-induced limbic seizures and status epilepticus in mice.
      AP is less potent than clonazepam but may have lower relative toxicity.
      • Kokate T.G.
      • Svensson B.E.
      • Rogawski M.A.
      Anticonvulsant activity of neurosteroids: correlation with g-aminobutyric acid-evoked chloride current potentiation.
      • Kokate T.G.
      • Cohen A.L.
      • Karp E.
      • Rogawski M.A.
      Neuroactive steroids protect against pilocarpine-and kainic acid-induced limbic seizures and status epilepticus in mice.
      The anticonvulsant effect of AP is greater in female rats in the diestrus 1 part of the ovulatory cycle (equivalent to human mid-luteal phase when progesterone levels are high) than in estrus (equivalent to ovulation when estrogen levels are high) or in the male.
      • Maguire J.L.
      • Stell B.M.
      • Rafizadeh M.
      • Mody I.
      Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety.
      Enhanced mid-luteal efficacy at the GABAA receptor may be related to a progesterone-induced enhanced formation of the δ GABAA receptor subtype.
      • Maguire J.L.
      • Stell B.M.
      • Rafizadeh M.
      • Mody I.
      Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety.
      Rapid withdrawal of progesterone in late diestrus makes the GABAA receptor insensitive to benzodiazepine, but not AP, perhaps as the result of a decrease in the benzodiazepine-sensitive synaptic GABAA receptors.
      • Smith S.S.
      • Gong Q.H.
      • Hau F.-C.
      • Markowitz R.S.
      • ffrench-Mullen J.M.H.
      • Li X.
      GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid.
      This effect can be blocked by inhibiting the formation of the α4 subunit of the GABAA receptor.
      • Maguire J.L.
      • Stell B.M.
      • Rafizadeh M.
      • Mody I.
      Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety.
      • Smith S.S.
      • Gong Q.H.
      • Hau F.-C.
      • Markowitz R.S.
      • ffrench-Mullen J.M.H.
      • Li X.
      GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid.
      By contrast, some of the sulfated neuroactive steroids have excitatory neuronal effects. They include pregnenolone sulfate and dehydroepiandrosterone sulfate (DHEAS), the naturally occurring sulfated esters of the progesterone precursor pregnenolone and progesterone metabolite DHEA.
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      They increase neuronal firing when directly applied to neurons by negatively modulating the GABAA receptor
      • Paul S.M.
      • Purdy R.H.
      Neuroactive steroids.
      and by facilitating glutamate-induced excitation at the NMDA receptor.
      • Irwin R.P.
      • Maragakis N.J.
      • Rogawski M.A.
      • Purdy R.H.
      • Farb D.H.
      • Paul S.M.
      Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons.
      In animal seizure models, pregnenolone sulfate and DHEAS have proconvulsant effect.
      • Heuser G.
      • Ling G.M.
      • Buchwald N.A.
      Sedation or seizures as dose-dependent effects of steroids.
      Of note, serum DHEAS levels are substantially reduced by enzyme-inducing antiepileptic drugs such as phenytoin and carbamazepine.
      • Levesque L.A.
      • Herzog A.G.
      • Seibel M.M.
      The effect of phenytoin and carbamazepine on dehydroepiandrosterone sulfate in men and women who have partial seizures with temporal lobe involvement.
      • Herzog A.G.
      • Drislane F.W.
      • Schomer D.L.
      • Pennell P.B.
      • Bromfield E.B.
      • Kelly K.M.
      • et al.
      Differential antiepileptic drug effects on sexual function and reproductive hormones: interim analysis of a comparison between lamotrigine and enzyme-inducing antiepileptic drugs.

      Hormonal treatment

      Progestogen therapy

      The term “progestogen” refers to the broad class of progestational agents. These include progesterone (i.e. naturally occurring progesterone), and progestins (i.e. synthetic progestational agents). Progestogen treatment (Table 1, Table 2) has taken two forms: (1) cyclic progesterone therapy that supplements progesterone during the luteal phase and withdraws it gradually premenstrually and (2) suppressive therapy in which the goal is to suppress the menstrual cycle which is generally accomplished using injectable progestins or gonadotropin-releasing hormone analogues.
      Table 1Investigational sex hormone treatments of women with epilepsy
      Investigational treatmentsDosagePotential adverse effects
      Progesterone lozengesDays 14–25: 1/2–1 lozenge t.i.d. Days 26–27: 1/4–1/2 lozenge t.i.d. Day 28: 1/4 lozenge t.i.d.Sedation, depression, breast tenderness, vaginal bleeding, constipation, exacerbation of asthma, weight gain
      Depomedroxyprogesterone150–250 mg I.M. q 1–3 monthsAs above plus delay of months to 2 years in recovery of ovulatory cycles during which time seizure numbers may increase sometimes beyond baseline
      GnRH analogueLeuprolide: 3.75 mg I.M. q 4 weeks 11.25 mg I.M. q 12 weeksMenopausal symptoms unless concomitant estradiol and progesterone supplement is administered
      ClomipheneDays 5–9: 25–50 mg dailyOvarian overstimulation syndrome (N.B. distention of ovaries can be very painful)
      Table 2Adjunctive cyclic progestogen therapy
      Medroxy-progesterone (Herzog, 1983)
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      Progesterone suppositories
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      Progesterone lozenges
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      Progesterone lozenges (Herzog 3-year follow-up)
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      Regimen5–10 mg q.d. Days 15–28 of cycle100–200 mg t.i.d. Days 15–28 of cycle100–200 mg t.i.d. Days 15–28 of cycle100–200 mg t.i.d. Days 15–28 of cycle
      Assessmentat 3 monthsat 3 monthsat 3 monthsat 3 years
      Subjects2482515 of original 25
      Number improved10 (42%)6 (75%)18 (72%)15 (100%/60% overall)
      Seizure frequency−10%−68%
      p<.05.
      −54%
      p<.01.
      CPS, −58%
      p<.05.
      SGMS
      −62%
      p<.01.
      CPS, −74%
      p<.01.
      SGMS
      * p < .05.
      ** p < .01.

      Cyclic progesterone therapy

      In contrast to published cyclic oral progestin investigations that did not result in significant reduction of seizure frequency,
      • Dana Haeri J.
      • Richens A.
      Effect of norethistrone on seizures associated with menstruation.
      • Mattson R.H.
      • Cramer J.A.
      • Caldwell B.V.
      • Siconolfi B.C.
      Treatment of seizures with medroxyprogesterone acetate: preliminary report.
      two open label trials of adjunctive progesterone therapy for women with catamenial epilepsy did result in clinically important and statistically significant reductions in seizure occurrence (Table 2).
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      In one investigation of women who had inadequate luteal phase cycles with catamenial exacerbation of intractable complex partial seizures, six of eight women experienced improved seizure control with a 68% decline in average monthly seizure frequency over 3 months for the whole group.
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      In a subsequent open trial of adjunctive cyclic progesterone versus the optimal antiseizure medication alone in 25 women (14 with inadequate luteal phase or anovulatory cycles and 11 with normal cycles and perimenstrual seizure exacerbation), 19 (72%) experienced fewer seizures with an overall average monthly decline of 54% for complex partial and 58% for secondary generalized seizures over 3 months.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      Progesterone was more efficacious when administered during the entire second half of the cycle, rather than just premenstrually, and then tapered and discontinued gradually over 3 or 4 days at the end of the cycle.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      Failure to taper gradually premenstrually can result in rebound seizure exacerbation. At 3 years, the average daily seizure frequency per patient showed that the 15 women who remained on cyclic progesterone therapy and their original antiepileptic drugs continued to show improved seizure control in comparison to their own baseline (Table 2, 3-year follow-up).
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      Three women were entirely seizure-free. Four had total seizure reductions of 75–99%. Eight had reductions of 50–74%. Complex partial seizures in these 15 were lower by a statistically significant 62% (baseline: 0.328, 3-year follow-up: 0.125; p < .01); secondary generalized motor seizures, by 74% (baseline: 0.148, 3-year follow-up: 0.038; p < .01). Antiepileptic drug serum levels continued to show no significant change. The three remaining women who continued on progesterone therapy had 10–50% improvement at the end of the original investigation at 3 months and were not considered further because they changed antiepileptic drugs.
      By way of critique, the weakness of these preliminary progesterone investigations is that they were not placebo-controlled or blinded. The favorable 3-year follow-up results are biased by analysis of only 15 of the original 25 subjects. These 15 who remained on the original treatment regimen are more likely to represent those who had the most favorable response. There are reasons, however, to consider that the results of the present investigation may represent more than placebo effects: (1) few placebo studies, including our own progestin trial that used a similar methodology, and could be used, therefore, as a retrospective control, show favorable response in more than 50% of subjects; (2) few placebo treatments have resulted in greater than 50% seizure reduction; (3) while placebo effects generally wear off over a few months, substantial and statistically significant improvements in the present investigation persisted after 3 years in the majority of subjects.
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      Another argument against the placebo explanation is that the beneficial effect of progesterone can be eliminated by the concomitant use of a reductase inhibitor that presumably blocks the reduction of progesterone to its potent GABAergic metabolite allopregnanolone.
      • Herzog A.G.
      • Frye C.A.
      Seizure exacerbation associated with inhibition of progesterone metabolism.
      Finally, there is transcranial magnetic stimulation evidence that progesterone may increase inhibition in the brain premenstrually.
      • Herzog A.G.
      • Friedman M.N.
      • Freund S.
      • Pascual-Leone A.
      Transcranial magnetic stimulation evidence of a potential role for progesterone in the modulation of premenstrual cortico-cortical inhibition in a woman with catamenial seizure exacerbation.
      A prospective multicenter, randomized, double-blind, placebo-controlled investigation of cyclic, adjunctive progesterone therapy in the management of women with catamenially exacerbated, intractable localization-related epilepsy is now under way.
      • Fowler K.
      • Massaro J.
      • Harden C.
      • Liporace J.
      • Pennell P.
      • Schomer D.
      • et al.
      Distribution of seizure occurrence in women with epilepsy: preliminary data analysis in a prospective multicenter investigation.
      • Herzog A.G.
      • Harden C.L.
      • Liporace J.
      • Pennell P.
      • Schomer D.L.
      • Sperling M.
      • et al.
      Frequency of catamenial seizure exacerbation in women with localization-related epilepsy.
      Natural progesterone is available as an extract of yams or soy in lozenge form in variable dosages ranging from 25 to 200 mg and should be administered three times daily because of its brief half-life of about 4–6 h.
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      The daily regimen to achieve physiological luteal range serum levels measured 4 h after administration ranges from 50 to 200 mg, taken three times daily, with the usual optimal daily dose ranging from 300 to 600 mg.
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      The maintenance dosage and regimen should be individualized and based on a combination of clinical response and serum progesterone levels between 20 and 40 ng/ml. Progesterone is also available in micronized form in an oral capsule preparation that may also exert similar antiseizure effects although formal investigations to this effect are lacking. Theoretically, it is possible that first pass through the liver using the oral micronized form may result in the delivery of different concentrations of progesterone and its neuroactive metabolite to the brain.
      Adverse effects occur with overdosage and include sedation, emotional depression and asthenia.
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      Progesterone use may also occasionally be associated with breast tenderness, weight gain, and irregular vaginal bleeding and sometimes constipation. The vehicle used to dissolve progesterone for suppository use may rarely be responsible for the development of an allergic rash. Discontinuation of the hormone or lowering of the dosage resolves these side effects.
      • Herzog A.G.
      Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.
      • Herzog A.G.
      Progesterone therapy in complex partial and secondary generalized seizures.
      • Herzog A.G.
      Progesterone therapy in women with epilepsy: a 3-year follow-up.
      Drug interactions are an important consideration. Higher progesterone dosages may be required to achieve luteal range levels in women who take antiseizure medications because carbamazepine, phenytoin and barbiturates are known to enhance the hepatic metabolism of gonadal and adrenal steroid hormones as well as to increase hormonal binding to serum proteins.
      • Herzog A.G.
      • Frye C.A.
      Seizure exacerbation associated with inhibition of progesterone metabolism.
      Progesterone use has been associated with changes in antiseizure medication levels in some cases but this effect has been sporadic and not in a predictable direction. Therefore, total and possibly free serum antiseizure medication levels should be checked regularly during concomitant hormonal therapy.

      Progestin therapy

      Parenteral depomedroxyprogesterone may lower seizure frequency when it is given in sufficient dosage to induce amenorrhea.
      • Mattson R.H.
      • Cramer J.A.
      • Caldwell B.V.
      • Siconolfi B.C.
      Treatment of seizures with medroxyprogesterone acetate: preliminary report.
      • Zimmerman A.W.
      • Holden K.R.
      • Reiter E.O.
      • Dekaban A.S.
      Medroxyprogesterone acetate in the treatment of seizures associated with menstruation.
      In one open label study of 14 women with refractory partial seizures and normal ovulatory cycles, parenteral depomedroxyprogesterone administration in doses large enough to induce amenorrhea (i.e. 120–150 mg every 6–12 weeks) resulted in a 39% seizure reduction.
      • Mattson R.H.
      • Cramer J.A.
      • Caldwell B.V.
      • Siconolfi B.C.
      Treatment of seizures with medroxyprogesterone acetate: preliminary report.
      It was unclear whether the effect was due to direct anticonvulsant activity of medroxyprogesterone or to the hormonal consequences of the induced amenorrhea. One patient who had absence rather than partial seizures did not improve. Side effects included those encountered with natural progesterone. Depot administration, however, is also commonly associated with hot flashes, irregular breakthrough vaginal bleeding and a lengthy delay of 6–12 months in the return of regular ovulatory cycles.
      • Mattson R.H.
      • Cramer J.A.
      • Caldwell B.V.
      • Siconolfi B.C.
      Treatment of seizures with medroxyprogesterone acetate: preliminary report.
      Long-term hypoestrogenic effects on cardiovascular and emotional status need to be considered with chronic use. Bone density is only partially maintained.
      Oral synthetic progestins administered cyclically or continuously have not proven to be an effective therapy for seizures in clinical investigations
      • Dana Haeri J.
      • Richens A.
      Effect of norethistrone on seizures associated with menstruation.
      • Mattson R.H.
      • Cramer J.A.
      • Caldwell B.V.
      • Siconolfi B.C.
      Treatment of seizures with medroxyprogesterone acetate: preliminary report.
      although individual successes with continuous daily oral use of norethistrone and combination pills have been reported.
      • Hall S.M.
      Treatment of menstrual epilepsy with a progesterone-only oral contraceptive.

      Gonadotrophin-releasing hormone analogue therapy

      Bauer et al.
      • Bauer J.
      • Wildt L.
      • Flugel D.
      • Stefan H.
      The effect of a synthetic GnRH analogue on catamenial epilepsy: a study in ten patients.
      used triptorelin, a synthetic gonadotrophin-releasing hormone (GnRH) analogue (3.75 mg) in a controlled release depot form intramuscularly every 4 weeks for an average of 11.8 months in 10 women (aged 20–50) with catamenial seizures intractable to high therapeutic doses of carbamazepine, diphenylhydantoin, phenobarbital and valproic acid in monotherapy or combined. They remained on a stable dose of the anticonvulsant throughout the period of treatment with triptorelin. They reported that three patients became seizure-free; four showed a decrease in seizure frequency of up to 50%. In one the duration of seizures was shortened; two had no therapeutic effect. These results were attained within the first 2 months of starting triptorelin. The study was not a controlled study and longer term follow-up was not available for some of the patients. Serum LH and estrogen were measured in one patient before and during the second month of triptorelin treatment; and as expected showed marked inhibition of LH and estrogen production. All the women became amenorrheic. Eight of the ten patients experienced hot flushes, headache or weight gain.
      Haider and Barnett
      • Haider Y.
      • Barnett D.B.
      Catamenial epilepsy and goserelin.
      reported on their use of goserelin 3.6 mg subcutaneously every 4 weeks in a 41-year-old woman who had had frequent catamenial status epilepticus despite therapeutic anticonvulsant drug levels which also did not respond to levonorgestrel/ethinyl estradiol. They reported a decrease in frequency from 10 admissions for status to three over a similar period.
      GnRH analogues basically create a medical oophorectomy. Common side effects are flushing, vaginal dryness and dyspareunia. Serious long-term risks include osteoporosis and cardiovascular disease. Reid and Gangar
      • Reid B.
      • Gangar K.F.
      Catamenial epilepsy and goserelin.
      suggested the addition of medroxyprogesterone acetate and conjugated estrogens to goserelin to prevent this while still abolishing most of the cyclical fluctuations of ovarian hormones. Finkelstein et al.
      • Finkelstein J.S.
      • Klibenski A.
      • Schaefer E.H.
      • Hornstein M.D.
      • Schiff I.
      • Neer R.M.
      Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency.
      recently discussed the use of parathyroid hormone to prevent bone loss in women treated with GnRH analogues. Although neither Bauer et al.
      • Haider Y.
      • Barnett D.B.
      Catamenial epilepsy and goserelin.
      nor Haider and Barrett
      • Reid B.
      • Gangar K.F.
      Catamenial epilepsy and goserelin.
      reported exacerbation of seizures with GnRH analogues, Herzog
      • Herzog A.G.
      Reproductive endocrine considerations and hormonal therapy for women with epilepsy.
      found that during the first 3 weeks, when there is an initial stimulation of estrogen before its production is inhibited, some women experienced such a marked exacerbation of their seizures and auras that they could not tolerate further use of GnRH analogue.

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