Hormonal Therapy for Epilepsy

In 2011, there are greater than 20 antiepileptic medications available. These medications work by modulating neuronal excitability. Reproductive hormones have been found to have a role in the pathogenesis and treatment of seizures by also altering neuronal excitability, especially in women with catamenial epilepsy. The female reproductive hormones have in general opposing effects on neuronal excitability; estrogens generally impart a proconvulsant neurophysiologic tone, whereas the progestogens have anticonvulsant effects. It follows then that fluctuations in the levels of serum progesterone and estrogen throughout a normal reproductive cycle bring about an increased or decreased risk of seizure occurrence based upon the serum estradiol/progesterone ratio. Therefore, using progesterone, its metabolite allopregnanolone, or other hormonal therapies have been explored in the treatment of patients with epilepsy.     

Hormones and Epilepsy Through the Lifetime

Summary: Hormones influence brain function from gestation throughout life and may affect the seizure threshold by altering neuronal excitability. Estrogen enhances and progesterone diminishes neuronal excitability experimentally, whereas testosterone and corticosteroids have less consistent effects. Hormonal effects in the CNS also depend on the region of brain in which the hormone acts. Sites of action for most steroid hormones include the hypothalamus and limbic cortex, providing a mechanism for modulating behavior and endocrine function. Seizure patterns may change at certain life stages, perhaps as a result of alterations in hormones. At puberty, epilepsy and benign rolandic epilepsy often remit, while juvenile myoclonic and photosensitive epilepsy may arise. Other types of epilepsy do not respond predictably to events in the reproductive life or to advancing age. In some women, fluctuations in hormones over the menstrual cycle appear to increase seizure vulnerability, probably reflecting changes in relative amounts of estrogen and progesterone. Seizure patterns can be altered, for better or worse, during pregnancy. Whether this reflects the effects of hormones or changes in levels of antiepileptic drugs is not resolved. More information is needed about changes in established epilepsy at menopause and in the elderly. Better understanding of endocrine effects on seizures over a lifetime should lead to more effective epilepsy therapies.     

Hormonal considerations in women with seizures

The relationships between seizures in epileptic women and the hormones estrogen and progesterone are under increasing study. Serum concentrations of estrogen and progesterone parallel cerebrospinal concentrations, and circulating sex hormones are concentrated in specific areas of the brain that regulate sexual behavior. These centers include two potentially epileptogenic regions--the amygdala and hippocampus. Many of these structures are physiologically affected in vitro by estrogen and progesterone. Exogenous sex hormones change the seizure threshold in animal models of epilepsy. Cyclical hormonal variations may influence electroencephalographic activity and affect seizure frequency in women with epilepsy. Hormonal therapy may be appropriate adjunctive anticonvulsant treatment, particularly for women with seizures that are catamenial or associated with a menstrual or reproductive endocrine disorder.     

Neuroactive steroids and seizure susceptibility

There is increasing clinical and experimental evidence that hormones, in particular sex steroid hormones, influence neuronal excitability and other brain functions. The term 'neuroactive steroids' has been coined for steroids that interact with neurotransmitter receptors. One of the best characterized actions of neuroactive steroids is the allosteric modulation of GABA(A)-receptor function via binding to a putative steroid-binding site. Since neuroactive steroids may interact with a variety of other membrane receptors, excitatory as well as inhibitory, they may have an impact on the excitability of specific brain regions. Neuronal excitability is enhanced by estrogen, whereas progesterone and its metabolites exert anticonvulsant effects. Testosterone and corticosteroids have less consistent effects on seizure susceptibility. Apart from these particular properties, neuroactive steroids may regulate gene expression via progesterone receptors. Based on their molecular properties, these compounds appear to have a promising therapeutical profile for the treatment of different neuropsychiatric diseases including epilepsy. This review focuses on the effects of neuroactive steroids on neuronal excitability and their putative impact on the physiology of epileptic disorders.     

Changes in sex steroid levels in women with epilepsy on treatment: Relationship with antiepileptic therapies and seizure frequency

Purpose:   Reproductive dysfunction in epilepsy is attributed to the seizures themselves and also to antiepileptic drugs (AEDs), which affect steroid production, binding, and metabolism. In turn, neuroactive steroids may influence neuronal excitability. A previous study in this cohort of consecutive women with epilepsy showed that patients with more frequent seizures had higher cortisol and lower dehydroepiandrosterone sulfate levels than those with rare or absent seizures. The present study was aimed at evaluating, in these same women, the possible relationship between some clinical parameters, seizure frequency, AED therapies, and sex hormone levels.
Methods:   Estradiol (E2), progesterone (Pg), sex hormone-binding globulin (SHBG), and free estrogen index (FEI) were measured during the luteal phase in 113 consecutive females, 16–47 years old, with different epilepsy syndromes on enzyme-inducing AED (EIAED) and/or non–enzyme-inducing AED (NEIAED) treatments, and in 30 age-matched healthy women. Hormonal data were correlated with clinical parameters (age, epilepsy syndrome, disease onset, and duration), seizure frequency assessed on the basis of a seizure frequency score (SFS), and AED therapies.
Results:   E2, Pg, and FEI were lower, whereas SHBG levels were higher in the epilepsy patients than in the controls. However, sex steroid and SHBG levels were not different between groups of patients categorized according to SFS. Therapies with EIAEDs accounted for changes in E2 levels and FEI.
Conclusions:   Despite globally decreased sex steroid levels in serum, actual hormone titers were not significantly correlated with SFS in consecutive epilepsy women; rather, these hormonal changes were explained by AED treatments, mainly when EIAED polytherapies were given.     

Epilepsy, Sex Hormones, and Antiepileptic Drugs

Summary: Many factors associated with hormone function have an impact on the course of epilepsy. Patients with epilepsy may have disturbances in sexual function such as anovulatory cycles in women and decreased libido and potency in men. Data indicate seizures, especially those arising in the limbic system, may influence the hypothalamic pituitary axis. Antiepileptic drugs also influence sexual function through direct brain effects as well as through induced changes in pharmacokinetics of the sex steroid hormones. Pregnancy has been reported to be a time of increased seizures; however, this has often been associated with low drug levels, for reasons that include inadequate drug dose, possible changes in pharmacokinetics, and noncompliance. Some evidence suggests that hormones affect seizure frequency. Changes in seizures during the menstrual cycle (catamenial epilepsy) have been found in some women: seizures were fewer during the luteal phase but increased when progesterone levels declined. Some improvement in seizure frequency has been shown in pilot studies using medroxyprogesterone acetate, a synthetic progesterone. Current concepts of the interrelationship among epilepsy, sex hormones, and antiepileptic drugs are discussed.     

Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase

PURPOSE: Several lines of evidence indicate that there exists a relation between ovarian hormones and epilepsy. Estrogens decrease seizure threshold and increase brain excitability, whereas progesterone has an inhibitory effect and reduces epileptiform activity. Recently considerable interest has turned to neuroactive steroids, a group of progesterone metabolites, as endogenous modulators of excitability of the central nervous system (CNS). Their ability to alter neuronal firing rapidly occurs through interaction with gamma-aminobutyric acid (GABA) A receptor complex. In a previous experience, serum allopregnanolone (3alpha-OH-5alpha-pregnan-20-one) levels were measured in 15 women with partial epilepsy in the intercritical phase, and no significant differences were found between patients and control subjects. METHODS: To find out if there are changes in serum allopregnanolone levels after epileptic seizure, blood samples were drawn immediately, 15 min, and 6 h after a seizure in seven fertile females with partial epilepsy. RESULTS: The most interesting finding is that allopregnanolone increases in serum during the first 15 min after partial seizures (p < 0.05) and decreases after 6 h. CONCLUSIONS: These data are consistent with a role for allopregnanolone in the control of neuronal excitability and seizures.     

Role of neurosteroids in catamenial epilepsy

Catamenial epilepsy is a menstrual cycle-related seizure disorder that affects up to 70% of women with epilepsy. Catamenial epilepsy is characterized by an increase in seizures during particular phases of the menstrual cycle. Three distinct patterns of catamenial epilepsy - perimenstrual, periovulatory, and inadequate luteal phase - have been described. Currently, there is no specific treatment for catamenial epilepsy. The molecular mechanisms involved in the pathophysiology of catamenial epilepsy are not well understood. Recent studies suggest that cyclical changes of ovarian hormones estrogens (proconvulsant) and progesterone (anticonvulsant) appear to play a key role in the genesis of catamenial seizures. Progesterone reduces seizure susceptibility partly through conversion to neurosteroids such as allopregnanolone, which enhances GABA(A) receptor function and thereby inhibits neuronal excitability. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy has proven effective in women with epilepsy. Moreover, neurosteroids have been shown to be very effective inhibitors of catamenial seizures in animal models. Thus, synthetic neuroactive steroids, such as ganaxolone, which are orally active and devoid of hormonal side effects, represent a novel treatment strategy for catamenial epilepsy. However, their clinical efficacy in catamenial epilepsy has yet to be explored. A greater understanding of the molecular mechanisms is clearly needed for designing effective treatment and prevention strategies of catamenial epilepsy in women at risk.     

Hormonal Effects on Epilepsy in Women

Summary: Some female gonadal and adrenal steroid hor-mones and their related pituitary peptides have neuroactive effects that can influence seizures. These effects may play a significant role in the pathophysiology of epilepsy, the pattern of seizure occurrence, therapeutic interventions using naturally occurring hormones, and the development of hormone-based neuroactive synthetic analogues with potent antiepileptic properties.     

Seizure frequency and sex steroids in women with partial epilepsy on antiepileptic therapy

Purpose:   Neuroactive sex steroids influence neuron excitability, which is enhanced by estradiol (E2) and decreased by progesterone (Pg). In epilepsy, the production, metabolism, biologic availability, and activity of sex hormones may be affected by seizures themselves or by antiepileptic drugs (AEDs). This cross-sectional observational study was aimed at evaluating the relationships between sex steroids, seizure frequency, and other clinical parameters in women with partial epilepsy (PE) on AED treatments.
Methods:   Serum E2, Pg, sex hormone binding globulin (SHBG) levels, free E2 (fE2), and E2/Pg ratios were determined during the follicular and luteal phases in 72 adult women with PE, and in 30 healthy controls. Hormonal data were correlated with seizure frequency, age, body weight, body mass index (BMI), disease onset and duration, and AED therapies.
Results:   In patients, E2, fE2, and Pg levels were lower in both ovarian phases, whereas those of SHBG were higher than in controls. No significant changes in hormone levels and in prevalence of anovulatory cycles were observed between patients grouped according to their seizure frequency. However, when compared with those in healthy controls, luteal fE2 and Pg levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures.
Conclusions:   The actual changes in sex steroid levels and E2/Pg ratios did not explain an increased seizure frequency in adult women with AED-treated PE, but patients with more severe disease showed more relevant changes in their sex hormone profile and impaired Pg levels during the luteal phase.     

Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine

Despite numerous neuroendocrinological studies of seizures, the influence of estrogen and progesterone on seizures and epilepsy remains unclear. This may be due to the fact that previous studies have not systematically compared distinct endocrine conditions and included all relevant controls. The goal of the present study was to conduct such a study using pilocarpine as chemoconvulsant. Thus, age and weight-matched, intact or ovariectomized rats were tested to determine incidence of status epilepticus and to study events leading to status. Intact female rats were sampled at each cycle stage (proestrus, estrus, metestrus, or diestrus 2). Convulsant was administered at the same time of day, 10:00-10:30 a.m. Statistical analysis showed that there was a significantly lower incidence of status on the morning of estrus, but differences were attenuated in older animals. Ovariectomized rats were distinct in their rapid progression to status. These results show that the incidence of status in female rats following pilocarpine injection, and the progression to pilocarpine-induced status, are influenced by reproductive state as well as age. The hormonal milieu present specifically on the morning of estrus appears to decrease susceptibility to pilocarpine-induced status, particularly at young ages. In contrast, the chronic absence of reproductive steroids that characterizes the ovariectomized rat leads to a more rapid progression to status. This dissociation between incidence vs. progression provides new insight into the influence of estrogen and progesterone on seizures.     

Treatment of women with epilepsy

Epilepsy is equally prevalent in men and women. However, for women there are unique concerns related to hormone effects on seizures and the effects of seizures and antiepileptic drugs (AEDs) on reproductive health. Steroid hormones affect neuronal excitability and seizure frequency. Some AEDs reduce the efficacy of oral contraceptive agents, increasing the probability of unplanned pregnancies. AEDs affect bone density. AEDs may alter reproductive hormones resulting in polycystic-appearing ovaries, anovulatory cycles, and infertility. Seizure frequency may change during pregnancy, seizures may cause pregnancy complications, some AEDs are teratogenic, and many cross into breast milk. The treatment of a woman with epilepsy must consider all these issues.     

The role of progesterone in memory: An overview of three decades

Memory comprises acquisition, consolidation and retrieval of information. Many substances can influence these different phases. It is well demonstrated that sex hormones, mainly estrogen, impact cognitive function. More recently, progesterone has also been documented as playing an important role in cognition, since it influences brain regions involved in memory. Currently, many women are under hormone treatment, which contain progesterone to decrease the risk of development of endometrial cancer. This affords the opportunity to study the real effects of this hormonal replacement on cognition. There are many contradictory results regarding the role of progesterone in memory. Therefore, the aim of this review was to synthesize these studies using the new perspective of the influence of hormone replacement on cognition in women.     

Investigating the effects of estradiol or estradiol/progesterone treatment on mood, depressive symptoms, menopausal symptoms and subjective sleep quality in older healthy hysterectomized women: a questionnaire study

Clinical studies have documented that estrogen treatment often ameliorates mood disturbances and depressive symptoms occurring during the menopausal transition. The relevance of gonadal hormones for mood and well-being in healthy older nondepressed women is less well understood. Fifty-one healthy hysterectomized women (mean age 64) participated in a placebo-controlled double-blind study on the effects of gonadal hormones on cognition. They received either estradiol (2 mg estradiol valerate), estradiol plus progesterone (100 mg micronized progesterone) or placebo. Mood, well being, menopausal symptoms, depressive symptoms and subjective sleep quality were measured at baseline and after 4 and 24 weeks of treatment using three questionnaires. Thirty-five women could be included into the final analysis. Strong increases in estradiol and progesterone levels occurred in response to the treatment. The two hormones, however, had no effects on mood, well-being, menopausal symptoms, sleep quality and depressive symptoms. The current small study suggests that older healthy nondepressed hysterectomized women do not react with positive or negative mood changes to estradiol or estradiol/progesterone treatment.     

Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons

Changes in gonadal steroid hormone levels during the menstrual cycle affect seizure frequency in women with catamenial epilepsy. Since GABA(A) receptors (GABARs) contribute to the prevention and termination of seizures by reducing neuronal excitability, we hypothesized that fluctuating gonadal steroid levels might affect GABAR subunit expression, which could alter inhibitory tone leading to increased seizure activity. To address this question in a simplified environment in vitro, we examined the effects of gonadal steroids on NT2-N neuronal cells. We have previously shown that NT2-N cells express functional GABARs, and that the expression pattern of GABAR subunits is regulated by chronic benzodiazepine exposure and hypoxia. NT2-N neurons were exposed to progesterone (0.1 microM), beta-estradiol (3 nM), or vehicle (DMSO) for 2 days or 7 days prior to RNA harvesting. GABAR subunit mRNA levels were assessed by semiquantitative RT-PCR normalized to actin levels. Progesterone exposure for 7 days increased alpha2 and gamma3 and decreased alpha5 subunit mRNAs, while beta-estradiol caused significant increases in alpha3, beta3 and epsilon expression. Further analysis revealed differential regulation of alpha4, alpha5, epsilon and pi subunit expression. Plots of relative PCR density in progesterone-treated cells for alpha2 vs. alpha5, alpha5 vs. gamma3 and alpha2 vs. gamma3 showed correlation between samples, suggesting coordinate regulation. Both progesterone and estrogen nuclear receptor mRNAs were detected by RT-PCR, and 2 days but not 7 days estrogen exposure upregulated progesterone receptor mRNA. Gonadal steroid fluctuations regulate GABA(A) receptor subunit expression in NT2-N cells. Such changes, if observed in vivo, could affect seizure frequency.     

The importance of translationally evaluating steroid hormone contributions to substance use

Clinically, women appear to be more susceptible to certain aspects of substance use disorders (SUDs). The steroid hormones 17β-estradiol (E2) and progesterone (Pg) have been linked to women-specific drug behaviors. Here, we review clinical and preclinical studies investigating how cycling ovarian hormones affect nicotine-, cocaine-, and opioid-related behaviors. We also highlight gaps in the literature regarding how synthetic steroid hormone use may influence drug-related behaviors. In addition, we explore how E2 and Pg are known to interact in brain reward pathways and provide evidence of how these interactions may influence drug-related behaviors. The synthesis of this review demonstrates the critical need to study women-specific factors that may influence aspects of SUDs, which may play important roles in addiction processes in a sex-specific fashion. It is important to understand factors that impact women’s health and may be key to moving the field forward toward more efficacious and individualized treatment strategies.     

Aromatase inhibitors as add-on treatment for men with epilepsy

Manipulation of neurosteroids to treat epilepsy has been an area of active research. The effect of testosterone on brain excitability and seizure threshold has been mixed; the estradiol metabolite of testosterone increases brain excitability, while the reduced metabolite of testosterone, 3alpha-androstanediol, decreases brain excitability, likely through an action at the gamma-amino butyric acid A receptor. Therefore, the metabolites of testosterone produce opposite effects on brain excitability in seizure models. Aromatase is the enzyme for the conversion of testosterone to 17beta-estradiol. Aromatase inhibitors could decrease brain excitability by decreasing local estradiol levels and therefore, could be beneficial for the treatment of epilepsy. Aromatase inhibitors are US Food and Drug Administration-approved and have a long history of safe use in menopausal women with breast cancer. This review presents the results of using anastrazole in an open-label, add-on manner in a small group of men with epilepsy in order to improve seizures. The results suggested some effect on reduction of seizures and no side effects. Testosterone levels did increase, but not to above the normal range. Letrozole used in a single case was also beneficial for seizures. It was concluded that aromatase inhibitors may be a useful adjunct to the treatment of epilepsy, but habituation to the treatment may be limiting. Many men with epilepsy have low testosterone, and aromatase inhibition may be helpful in restoring levels to normal. Modulation of reproductive hormones by aromatase inhibition as well as enhancement of the 3alpha-androstanediol pathway may be an avenue of epilepsy treatment that would not produce sedative side effects, which is often a limiting factor with standard antiseizure medications. A further interesting result is that elevated follicle stimulating hormone and luteal stimulating hormone levels were associated with seizure reduction, suggesting that they may be a biomarker for a beneficial effect of aromatase inhibition on brain excitability.     

Seizure occurrence during ovulatory and anovulatory cycles in patients with temporal lobe epilepsy: a prospective study

We investigated the influence of ovulatory and anovulatory menstrual cycles on seizure occurrence in female patients with complex partial seizures. We prospectively documented seizures in relation to menstrual cycles (defined by measurement of basal body temperature and progesterone serum concentrations) in 39 female patients. One hundred and thirty-two cycles of 35 patients entered final analysis. Only eight patients had anovulatory cycles, in 18 patients all cycles were ovulatory. In the remaining nine patients anovulatory as well as ovulatory cycles were documented. In ovulatory cycles the mean frequency of seizures during the days of menstruation was significantly higher as compared to the periovulatory or the luteal phase of the cycles. During anovulatory cycles seizure frequency was significantly lower during menstruation than in the remaining days of the cycles. Since progesterone is known to exhibit anticonvulsant effects, seizure occurrence during menstruation seems to be related to ovulatory cycles, possibly due to the premenstrual decrease of progesterone. Therapeutic recommendations for the treatment of seizures related to the menstrual cycle (catamenial seizures) include the administration of hormones, as progesterone (recommended especially for women with catamenial epilepsy who have a documented inadequate luteal phase) or the suppression of the menstrual hormonal cycle by synthetic gonadotropin releasing hormone analogs.     

Reproductive Endocrine Considerations and Hormonal Therapy for Women with Epilepsy

Summary: Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotro-pic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomi-phene, constitute rational and effective adjuncts to therapy.     

Seizures, hormones and sexuality.

Sexual disorders (both hyposexuality and sexual dysfunction) are common in people with epilepsy, occurring in up to two-thirds of patients. However, characteristically, patients do not spontaneously report these problems. Nocturnal penile tumescence testing suggests that the erectile dysfunction has a neurophysiological component. The aetiology remains uncertain but is likely to be multifactorial, involving neurological, endocrine, iatrogenic, cognitive, psychiatric and psychosocial factors. Epilepsy-related factors include the age of onset/duration of epilepsy along with the seizure type and focus. In addition, seizure frequency might be relevant as successful epilepsy surgery can result in an improvement in sexual functioning despite remaining on anticonvulsant medication. Endocrine changes (raised sex hormone binding globulin and reduced free testosterone) have been reported in men with epilepsy, especially when treated with hepatic-enzyme inducing antiepileptic drugs. Studies have not been performed evaluating anticonvulsants that do not induce hepatic enzymes such as lamotrigine. The association between these endocrine changes and hyposexuality is not known. The relationship between seizures, hormones and anticonvulsant medication in women is explored, focusing on issues such as catamenial epilepsy, the menopause, hormone replacement therapy and the polycystic ovarian syndrome. Suggestions for future research and treatment issues are discussed.