Maximizing the Health of Women with Epilepsy: Science and Ethics in New Drug Development

Abstract

Summary:Issues of unique concern to women with epilepsy largely arise from gender-based physiological differences. Female sex steroid hormones may alter the expression of epilepsy and the efficacy of antiepileptic drugs (AEDs). Seizures and AEDs in turn affect the hypothalamic-pituitary axis and can adversely impact reproductive function and bone health. Maternal seizures and exposure to AEDs may compromise fetal development. At this time, women with epilepsy and their medical caretakers do not have access to all the information necessary to formulate a treatment plan that will have the least impact on reproductive and general health. In part, this is because reproductive aged women are excluded from the earliest phases of drug testing and pregnant and lactating women are excluded from all aspects of new drug development. Therefore, as new AEDs enter the marketplace, women with epilepsy must decide whether a new AED is appropriate for therapy based on very limited information. Postmarketing surveillance of gender-specific adverse effects, as with all adverse effects, depends on voluntary reporting. Only a small percentage of significant adverse events are believed to be captured by the present system. Consumers, ethicists, and some physician groups are now arguing that women should be included in all aspects of the development of drugs they will ultimately use-even pregnant and lactating women. Some of the issues of concern for women with epilepsy regarding epilepsy treatment, reproductive function and general health will be reviewed, followed by a discussion of the drug development process and how it does, and could better, address the concerns of women. Key Words: Epilepsy-Women-Anticonvulsant drugs-HormonesDrug therapy-Drug toxicity-Reproduction-Clinical drug evaluation-Clinical trials-Fertility-Teratogens. EFFECT OF HORMONES ON SEIZURES AND ON AED EFFICACYSteroid hormones are active in the central nervous system (CNS) and may alter the seizure threshold to a clinically significant extent (1). The ovarian sex steroid hormones, estrogen and progesterone, appear to act in an opposing fashion to modulate excitability of neurons of the cerebral cortex ( 2 ) . Estrogen has a seizure activating effect in experimental models of epilepsy such as the electroshock seizure threshold and after creation of a new seizure focus. Progesterone has an inhibitory effect in these same models. In human females, estrogen appears to activate interictal epileptiform activity whereas progesterone and its reduced metabolites reduce epileptiform activity.Both estrogen and progesterone exert their opposing effects, at least in part, at the GABA-A receptor complex (3). A recognition site for these neuroactive steroids has been identified on the GABA-A receptor complex (43). When k strogen occupies the receptor site, chloride conductance through the receptor is reduced, whereas progesterone has the opposite effect. Estrogen and progesterone also alter RNA encoding the synthesis of the GABA-A receptor complex and of GABA itselfprobably thr...

Psychosocial adjustment of epilepsy patients in Cyprus

“…Concerns and psychopathology reflect social as well as biological differences. Female patients in general exhibit more illness behavior than males [44], whereas issues unique to women with epilepsy largely arise from gender-based physiological differences affecting the hypothalamicpituitary axis, which can adversely impact endogenous reproductive hormones as well as affective health [45,46].…”

Updates on the Treatment of Epilepsy in Women

“…Most WWE appear to have normal sex lives, although approximately 33% to 50% of them may experience some degree of sexual dysfunction. 2,24,40,41 Greater levels of anxiety and apathy related to sexual performance as well as reduced vaginal lubrication and genital blood flow and increased dyspareunia and anorgasmia during intercourse have been reported. 3,40 A multifactorial cause appears operational.…”

“…[3][4][5][6]13,31,36,40 Seizures arising from limbic structures disrupt function in the neighboring hypothalamus and medial frontal lobe, which are important in regulating expression of libido and arousal. 40,41 Also, seizures electrically alter hormonal function 14 via pituitary secretion, creating sexual dysfunction. 40 It has been reported that AEDs can interfere with circulating sex steroid concentrations 2,3,6 and directly influence mood and behavior, thereby affecting sexual desire.…”

Current Issues on Epileptic Women

“…In particular, this condition is associated with VPA treatment, suggesting inibition of steroid hormones by this AED [30]. Other studies report polycystic ovaries associated to other AEDs [33]. This entity includes also hirsutism, acne, obesity, elevated androgens, an elevated LH: FSH ratio, chronic anovolution, and insulin resistance [34], and can be associated, among other disturbances, with infertility, an elevated risk for cardiovascular disease and dyslipidemia, and endometrial and breast cancer [35].…”