Reproductive hormones and epilepsy

Transcription

1 3 rd Congress of the European Academy of Neurology Amsterdam, The Netherlands, June 24 27, 2017 Teaching Course 7 Treatment of women with epilepsy - Level 1-2 Reproductive hormones and epilepsy Gerhard Luef Innsbruck, Austria gerhard.luef@i-med.ac.at

2 Conflict of interest: Not received Reproductive endocrine dysfunction is common among both women and men with epilepsy. The reasons for this are multifactorial and bidirectional; epilepsy can affect hormones, and hormones can affect seizures. Furthermore, several antiepileptic drugs (AEDs) can have endocrine sideeffects, while psychosocial factors and co-morbidity add further complexity. Animal models and experimental models using human tissue or cell lines provide new approaches to investigating the independent effects of the epilepsy itself, hormonal effects, and the effects of AEDs, in isolation and without confounding factors. An understanding of these relationships and their underlying neurological and neuroendocrine mechanisms is important to the comprehensive management of women and men with epilepsy The brain controls reproductive function primarily through the hypothalamic regulation of pituitary secretion. Regions of the hypothalamus that are involved in the regulation, production, and secretion of gonadotropin-releasing hormone (GnRH) receive extensive direct connections from the cerebral hemispheres, especially from temporolimbic structures that are commonly involved in epilepsy, and most notably from the 1

3 amygdala. Significant relationships have been uncovered through which epilepsy may influence the function of this complex neuroendocrine system. Anatomical and neurophysiological studies of tissue from animals and humans have shown that there is a close connection between the temporolimbic system and the hypothalamus, which controls the neuroendocrine system. The amygdala, in particular, has extensive direct reciprocal connections with regions of the hypothalamus that are involved in the regulation, production, and secretion of gonadotropin-releasing hormones (GnRH). In line with this, early studies demonstrated how amygdalakindling in male cats led to hyposexuality. The impact of the epilepsy itself on endocrine function has been recognised and discussed for many years. Clinical studies have shown that epilepsy itself affects the secretion of pituitary hormones, thereby affecting the secretion pattern, rhythmicity, and levels of the peripheral sex steroid hormones. Hospital- and community-based studies have shown that menstrual disorders are more common among women with epilepsy than in the general population The most common reproductive endocrine disorder in women with epilepsy in addition to women in the general population is polycystic ovary syndrome (PCOS). PCOS occurs in 10 to 20 % of women with epilepsy compared with 5 % to 6 % of women in the general population. This increased rate of occurrence may be of considerable medical significance because PCOS is associated with a higher prevalence of migraine, emo- 2

4 tional disorders, diabetes, cardiovascular disease, and female cancers in the general population. Polycystic ovary syndrome is probably not a single nosological entity, but rather the common end point for a number of pathophysiological mechanisms, some of which may be attributable to epilepsy itself or to the use of AEDs, most notably valproate. PCOS represents the failure of the ovarian follicle to complete normal maturation during the menstrual cycle or a series of cycles, a failure that is perhaps related to the presence of inadequate levels of pituitary follicle-stimulating hormone (FSH), while levels of luteinizing hormone (LH) are normal or elevated. These conditions can produce two results. There is a failure of ovulation and the partially developed follicle is retained in the ovary in the form of a tiny cyst. This partially developed follicle is secretory, but deficient in aromatase, the enzyme that converts testosterone to estrogen, and, therefore has testosterone as its principal secretory product. Testosterone may increase the positive feedback of estrogen on pituitary LH secretion, resulting in increased ovarian steroid secretion, which, under these circumstances, may be predominantly testosterone and can result in hyperandrogenism. The testosterone is aromatized in peripheral adipose tissue, generally producing high normal levels of estrogens, which is a major source of the estrogen feedback on the pituitary. The persistent occurrence of such cycles results in hyperandrogenic chronic anovulation, which is currently the simplest and perhaps the most utilitarian definition of PCOS The standard treatment for PCOS in the general population is with the use of oral contraceptive pills. The use of contraceptive hormones, however, requires special precautions in women with epilepsy 3

5 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. This may be attributable to the neuroactive properties of reproductive steroid hormones and the cyclic variation in their serum levels 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 intracellular receptor-genomically-mediated (long latency) effects The potential importance of estradiol in the regulation of temporolimbic function is highlighted by the presence of the estradiol synthesizing enzymes, cytochromes P45017a and P450 aromatases, which are localized in neurons in the hippocampus and the measurement of hippocampal estradiol levels that can surpass serum levels With regard to mechanisms of action, estradiol may act on CA1 hippocampal pyramidal neurons via convergent mechanisms that combine the effects of estradiol priming on hippocampal plasticity with subsequent direct potentiation of excitatory postsynaptic potentials (EPSPs) Progesterone and particularly some of its neuroactive metabolites, most notably allopregnanolone, exert direct membrane-mediated inhibitory effects by potentiating GABA A -mediated chloride conductance. It also 4

6 potentiates the action of the powerful endogenous inhibitory substance adenosine. Progesterone itself also substantially diminishes nicotinic acetylcholine receptor-mediated conductance, which may be relevant to autosomal dominant nocturnal frontal lobe epilepsy. In most adult female animal models, progesterone depresses neuronal firing and lessens spontaneous and induced epileptiform discharges Progestogen treatment 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. 5

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