The interactions between reproductive hormones and epilepsy.

There are complex interactions between hormones, epilepsy, and antiepileptic drugs (AEDs). While there is ample evidence that hormones influence epilepsy, it is also apparent that epileptic activity influences hormones in both women and men. In addition, AEDs may disturb endocrine function. The clinical importance of these interactions is primarily related to the effects on reproductive hormones, which is the focus of this article. Reproductive endocrine dysfunction is common among women and men with epilepsy. Menstrual disorders, polycystic ovaries, and infertility have been described among women with epilepsy, while reduced potency and sperm abnormalities have been found in men. Sexual problems and endocrine changes have been frequently described in both sexes. Epilepsy and AEDs can target a number of substrates to impact hormone levels. These include the limbic system, hypothalamus, pituitary, peripheral endocrine glands, liver, and adipose tissue. AEDs may also alter the synthesis of steroids and binding proteins, as well as hormone metabolism, and produce direct gonadal effects.

Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial.

PURPOSE: To extend our knowledge and practical application of the concept of catamenial epilepsy. METHODS: The review focuses on the impact of the NIH Progesterone Trial on our understanding of the pathophysiology and treatment of catamenial epilepsy. RESULTS: Catamenial epilepsy refers to the cyclic exacerbation of seizures in relation to the menstrual cycle. An interaction between seizures and the menstrual cycle is suggested by variations in seizure frequency according to the day, phase and ovulatory status of the menstrual cycle. There are three commonly recognized patterns: perimenstrual (C1: Day -3 to +3), peri-ovulatory (C2: Day 10 to 3) and entire luteal phase in anovulatory cycles (C3: Day 10 to 3). Pathophysiological determinants include 1) the neuroactive properties of reproductive steroids, 2) the variation of neuroactive steroid levels across the menstrual cycle and 3) the differential susceptibility of epileptic substrates to neuroactive steroid effects. Perimenstrual seizure exacerbation may result from the premenstrual withdrawal of progesterone which is accompanied by withdrawal of allopregnanolone, a potent positive allosteric modulator of the GABAA receptor, and changes in the subunit composition of the GABAA receptor to the α4 subtype which is insensitive to benzodiazepine and GABA. Bioidentical progesterone supplement is no better than placebo in the treatment of women with focal onset epilepsy overall but shows superior efficacy in women whose seizures show robust perimenstrual exacerbation. CONCLUSION: There is sound evidence for the existence of catamenial epilepsy and class 3 evidence for adjunctive progesterone treatment of the perimenstrually exacerbated subtype.

Allopregnanolone levels and seizure frequency in progesterone-treated women with epilepsy.

OBJECTIVE: To determine whether allopregnanolone (AP) may mediate seizure reduction in progesterone-treated women with epilepsy. METHODS: The NIH Progesterone Trial compared the efficacy of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects, randomized 2:1 to progesterone or placebo, stratified by catamenial vs noncatamenial designation. Treatments were compared on proportions of 50% responders, and changes in seizure frequency from 3 baseline to 3 treatment cycles. Serum AP levels were measured by radioimmunoassay from 155 women with intractable focal-onset seizures who had baseline and treatment-phase midluteal serum samples drawn each cycle for hormone measurements. RESULTS: There was no significant correlation between percentage changes in AP levels and seizure frequencies from baseline to treatment for either the catamenial or noncatamenial stratum. There was a significant correlation for the subset of subjects who showed a significantly greater responder rate in the post hoc analysis of the trial, i.e., subjects who had a 3-fold or greater increase in average daily seizure frequency perimenstrually compared with the midfollicular and midluteal phases (C1 ≥ 3: r = -0.442, p = 0.013, and specifically for C1 ≥ 3 progesterone-treated subjects [r = -0.452, p = 0.035], but not other groups [C1 ≥ 3 placebo: r = -0.367; C1 <3 progesterone: r = 0.099; C1 <3 placebo: r = 0.131; p = not significant]). CONCLUSIONS: The findings support AP as a mediator of seizure reduction in progesterone-treated women who have a substantial level of perimenstrually exacerbated seizures.

Premenstrual dysphoric disorder in women with epilepsy: relationships to potential epileptic, antiepileptic drug, and reproductive endocrine factors.

The purpose of this prospective observational investigation was to determine whether the frequency of premenstrual dysphoric disorder (PMDD) and the severity of PMDD symptoms differ between women with epilepsy and controls without epilepsy and whether there exists a relationship between the severity of PMDD symptoms and some epileptic, antiepileptic drug, and reproductive endocrine features. The results suggest that epilepsy, antiepileptic drug levels, ovulatory status, and hormone levels and ratios may all influence PMDD in women with epilepsy. PMDD severity scores may be greater in people with right-sided than in those with left-sided epilepsy, and in people with temporal than in those with nontemporal epileptic foci. PMDD severity scores may be greater with anovulatory cycles, and scores may correlate negatively with midluteal serum progesterone levels and positively with midluteal estradiol/progesterone ratios. Mood score may vary with particular antiepileptic drugs, favoring carbamazepine and lamotrigine over levetiracetam. PMDD severity scores may correlate directly with carbamazepine levels, whereas they correlate inversely with lamotrigine levels.

Variation of seizure frequency with ovulatory status of menstrual cycles.

PURPOSE: To determine if seizure frequency differs between anovulatory and ovulatory cycles. METHODS: The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic-clonic seizures - 2°GTCS, complex partial seizures - CPS, simple partial seizures - SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis. KEY FINDINGS: ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only. SIGNIFICANCE: Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.

Hormonal therapies: progesterone.

Seizures do not occur randomly in the majority of people with epilepsy. They tend to cluster. Seizure clusters, in turn, commonly occur with a temporal rhythmicity that shows a readily identifiable and predictable periodicity. When the periodicity of seizure exacerbation in women conforms to that of the menstrual cycle, it is commonly known as catamenial epilepsy. This may be attributable to 1) the neuroactive properties of steroid hormones and 2) the cyclic variation in their serum levels. If hormones play a role in seizure occurrence, hormones may also have a role in treatment. Progesterone has potent GABAergic metabolites that may provide safe and effective seizure control in women who have catamenial epilepsy.

Sleep spindle alterations in patients with malformations of cortical development.

Malformations of cortical development are disorders of altered brain anatomy and architecture that arise from abnormalities in the usual processes of cerebral cortical development. Although they often lead to epilepsy, cognitive delay, and motor impairment, little is known about their effect on sleep. Since malformations may anatomically or functionally disrupt the cerebral circuits that mediate sleep spindles, we hypothesized that these disorders would be associated with abnormal spindle characteristics. We analyzed the density, maximum frequency, laterality and distribution of sleep spindles seen in routine and long-term electroencephalographic recordings performed in ten brain malformation subjects and ten matched controls. There were no significant differences in spindle density or maximum frequency between the two groups, but malformation subjects had a significantly lower proportion of bilateral spindles and a significantly higher proportion of anterior and diffuse spindles compared to controls. In addition, unilateral malformations appeared to be associated with a skewing of unilateral spindles toward the contralateral side. Our findings suggest that brain malformations disrupt the thalamocortical circuits responsible for sleep spindle generation, and support the need for further studies on the relationships between cortical maldevelopment and sleep.

Circalunar and ultralunar periodicities in women with partial seizures.

PURPOSE: Little consensus exists for the definition of catamenial epilepsy. Few studies have evaluated the periodicity of seizures to test the hypothesis that seizures in women have periodic patterns of occurrence independent of a priori hormonal considerations. In the present study, we determined seizure periodicity according to a "menstrual clock" provided by a common phase marker of the onset of menses. METHODS: Seizure and menstrual diaries of approximately 3 months duration were obtained from women enrolled in a trial of hormonal therapy for localization-related epilepsy. Midluteal progesterone levels identified ovulatory (>or=5 ng/ml, OC) from anovulatory cycles (AC). Individual cycles were normalized to a common phase and period (day 0 = menses onset, intervening days = 28 bins). Periodicity of combined data was estimated with cosinor-nonlinear least squares analysis. Best-fit rhythms were estimated with 95% confidence limits. RESULTS: 100 patients provided 3344 seizures within 293 cycles (77% OC, 20% AC, indeterminate 3%). OC seizures displayed a circalunar rhythm with peak phase of occurrence at onset of menses. AC seizures also featured a circalunar rhythm that peaked at menses onset but also had ultralunar rhythms of approximately 14 and approximately 9 days. DISCUSSION: Seizures in women with epilepsy occur in circalunar rhythms. OC and AC seizures differ in seizure timing with the latter occurring in ultralunar rhythms in addition to the predominant circalunar rhythm. This finding supports the existence of catamenial epilepsy and differences in patterns of seizure occurrence between OC and AC.

Neuroactive properties of reproductive steroids.

Migraine is 3 times more common in postpubertal women than in men. Migraine is frequently exacerbated perimenstrually and commonly occurs exclusively at that time. It is often benefited by pregnancy and menopause. Estrogen withdrawal has been implicated as a mechanism for triggering migraines. The mechanism, however, is not well understood. Reproductive steroids have neuroactive properties that can modulate neuronal morphology and physiology. Increasing evidence suggests that circulating reproductive steroid levels regulate the balance of neuroexcitatory and neuroinhibitory activities in some brain regions by influencing synaptic plasticity. Estrogen has neuroexcitatory, whereas progesterone has neuroinhibitory, effects in most preclinical and clinical models. Several neurotransmitter systems that are implicated in migraine vary with reproductive steroid levels during the reproductive cycle. Estrogen stabilization may provide effective treatment in susceptible women, especially for catamenially exacerbated migraine.

Differential effects of antiepileptic drugs on neuroactive steroids in men with epilepsy.

PURPOSE: To compare serum levels of neuroactive steroids among men with epilepsy who take various antiepileptic drugs, untreated men with epilepsy and normal controls (NC). METHODS: Subjects were 85 men with localization-related epilepsy [unmedicated >6 months (No Rx)-10, carbamazepine (CBZ)-25, phenytoin (PHT)-25, lamotrigine (LTG)-25] and 25 NC. Sexual function scores (S-Score), hormone levels [dehydroepiandrosterone sulfate (DHEAS), bioactive (BA) testosterone (T), estradiol (BAE), and androstanediol (BAL)] and the ratios of inhibitory to excitatory neuroactive metabolites of T, i.e., BAL/BAE, were compared among groups. RESULTS: S-scores, DHEAS, and bioactive testosterone (BAT) were significantly (p < 0.05) lower and BAL and BAL/BAE were significantly higher among CBZ and PHT groups than among NC and LTG groups. LTG did not differ from NC in any of these measures. BAT correlated significantly with BAL/BAE for PHT (r = 0.44, p = 0.02) and CBZ (r = 0.42, p = 0.03) but not for NC (r = 0.03, p = NS) and LTG (r = 0.06, p = NS) groups. CONCLUSIONS: In comparison to LTG, enzyme inducing AEDs (CBZ, PHT) are associated with a more favorable neuroactive steroid balance (lower DHEAS and higher BAL/BAE) for seizure management, but at the expense of reduced serum bioavailable testosterone levels and sexual function.

Menstrual disorders in women with epilepsy.

Women with epilepsy are more likely to have menstrual disorders than women in the general population. Estimates vary because of different definitions of menstrual disorder. Our best estimate is that perhaps one of every three women with epilepsy may be affected compared with one of seven in the general population. Menstrual disorders are significant because they are associated with anovulatory cycles that may increase the risks for infertility, migraine, emotional disorders, and female cancers. They are neurologically important because they are associated with greater seizure frequency. Increasing evidence implicates both epilepsy itself and antiepileptic drug (AED) use as causal or contributory factors. These factors can alter reproductive hormone levels and promote the development of reproductive endocrine disorders, especially polycystic ovarian syndrome (PCOS). Among AEDs, valproate has been associated with the development of characteristic PCOS features. The risk appears to be particularly high when valproate use is started in childhood or adolescence. Menopause tends to occur earlier in women with epilepsy, especially in the setting of a high lifetime number of seizures and lifetime use of multiple enzyme-inducing AEDs. The intricate relationship between reproductive disorders and epilepsy suggests that reproductive function should be monitored closely as part of the comprehensive care of women with epilepsy.

Differential effects of antiepileptic drugs on sexual function and reproductive hormones in men with epilepsy: interim analysis of a comparison between lamotrigine and enzyme-inducing antiepileptic drugs.

PURPOSE: We compared sexual function and reproductive hormone levels among men with localization-related epilepsy (LRE) taking various antiepileptic drugs (AEDs) and normal controls (NC). METHODS: Subjects were 63 men with LRE [enzyme-inducing (EI) AEDs, 36; lamotrigine (LTG), 18; no AEDs, 9] and 18 NC. Sexual interest and function (S-score), hormone levels [bioactive testosterone (BAT) and estradiol (BAE)], hormone ratios [BAT/BAE], and gonadal efficiency [BAT/luteinizing hormone (LH)] were compared among the groups. RESULTS: S-scores, BAT levels, BAT/BAE, and BAT/LH were significantly lower in the EIAED group than in NC or LTG groups. Sex hormone-binding globulin (SHBG) was significantly higher in the EIAED group than in all other groups. Of men with LRE, 23.8% had abnormally low S-scores: 33.3% taking EIAEDs, 5.5% taking LTG, and 22.2% taking no AEDs (p < 0.01). BAT was low in 55.6% taking EIAEDs as compared with 33.3% taking LTG and 33.3% taking no AEDs (p < 0.05). Among men with low S-scores, 86.7% had low BAT as compared with 33.3% of men with normal scores (p < 0.01). BAT decline with age was greater among men with LRE than in controls (3.75 vs. 1.80 ng/dl/yr). The slope showed no significant difference among LRE groups. However, 89% of 40- to 50-year-old men taking EIAEDs had low BAT as compared with 33% taking LTG and 33% taking no AED (p < 0.01). CONCLUSIONS: Sexual function, BAT levels, BAT/BAE, and gonadal efficiency are greater with LTG than with EIAED. Abnormally low BAT levels are reached at an earlier age with EIAEDs than with LTG.

Seizure exacerbation associated with inhibition of progesterone metabolism.

The reduced progesterone metabolite tetrahydroprogesterone is a potent positive modulator of GABA(A) chloride conductance that exerts powerful neuroinhibitiory and anti-seizure effects in animal models. Cyclic natural progesterone use may lessen seizure frequency in women with catamenial seizure exacerbation. We report a case in which efficacy was eliminated during concomitant treatment with a reductase inhibitor. The observation suggests that a reduced metabolite, rather than progesterone itself, was responsible for improved seizure control.