The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: Implications for diagnosis and treatment

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Epilepsy & Behavior (Impact Factor: 2.06). 08/2008; 13(1):12-24. DOI: 10.1016/j.yebeh.2008.02.004
Source: PubMed

ABSTRACT Despite our understanding of hormonal influences on central nervous system (CNS) function, there is still much to learn about the pathogenesis of menstrual cycle-linked disorders. A growing literature suggests that the influence of sex steroids on neurological and psychiatric disorders is in part mediated by an aberrant CNS response to neuroactive steroids. Although sex steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO) influence numerous neurotransmitter systems, it is their potent effect on the brain's primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate that links the study of premenstrual dysphoric disorder (PMDD) and catamenial epilepsy (CE). After providing an overview of these menstrual cycle-linked disorders, this article focuses on the preclinical and clinical research investigating the role of estradiol and progesterone (via ALLO) in the etiology of PMDD and CE. Through exploration of the phenomenological and neurobiological overlap between CE and PMDD, we aim to highlight areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders.

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    • "Also, a mutual relation is reported between serum estradiol/P 4 ratio and seizure incidence in ovulatory cycles. So, the lowest seizure activity was detected with high levels of P 4 compared to the estradiol levels (Juline et al. 1975; Holmes and Weber 1984; Mattson and Cramer 1985; Frye and Bayon 1999; Kokate et al. 1999; Borowicz et al. 2003; Guille et al. 2008). In Sprague-Dawley rats, estrous cycle includes a 4-day cycle: proestrus begins with a rapid increase in the estradiol concentration followed by P 4 surge in the afternoon and evening, which summits during the ovulation in the late evening and then declines rapidly. "
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    ABSTRACT: Catamenial epilepsy is a special form of epi-lepsy in women whom seizure aggravation is arranged with menstrual cycle that may affect up to 70 % of epileptic women. Antiepileptic effect of Ghrelin hormone has been proved recently. Due to effects of Ghrelin on GABA and LH concentration and periodic variation in the level of estrogen (E 2) and progesterone (P 4) during menstrual cycle, it seems that antiepileptic effect of Ghrelin can be different during various phases of estrous cycle. So this study was conducted to survey antiepileptic effect of Ghrelin during various phases of estrous cycle in rats. 72 adult female Wistar rats in three groups (control, 40 and 80 lg/kg of Ghrelin), each with four subgroups (proestrus, estrus, metestrus and diestrus) were used (n = 6). Then, intra-cerebroventricular (ICV) injection of Ghrelin (40 and 80 lg/kg) followed by intraperitoneal injection of 80 lg/kg pentylenetetrazole in control and treatment groups were done. Initiation time of myoclonic seizures (ITMS), initi-ation time of tonic–clonic seizures (ITTS), seizures dura-tion and mortality rate were monitored and recorded for 30 min. Results showed that, ICV injection of Ghrelin significantly increased ITMS and ITTS during luteal phase than follicular phase compared to control group (P \ 0.05). Also, seizure duration significantly decreased after ICV injection of Ghrelin during luteal phase and follicular phase compared to control group (P \ 0.05). Furthermore, there was no mortality after ICV injection of Ghrelin (40 and 80 lg/kg) during luteal and follicular phases compared to control group (P \ 0.05). These results suggest that Ghrelin has antiepileptic effects which are more prominent during luteal phase than follicular phase.
    International Journal of Peptide Research and Therapeutics 07/2014; 20(4). DOI:10.1007/s10989-014-9418-8 · 0.83 Impact Factor
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    • "Comparing the levels, distribution, and function of each step in the pathways(s) leading from E2 activation of extranuclear ERα to modulation of GABA release in both males and females may point to which of the many signaling pathways acutely activated by E2 are relevant to acute suppression of inhibitory synaptic transmission. E2 is well known to influence hippocampal functions such as memory and affective behaviors that differ between the sexes (Gillies and McArthur 2010), as well as neurological disorders that involve the hippocampus such as temporal lobe epilepsy (Guille et al., 2008). Most behavioral studies have examined effects of E2 in females and on a time scale corresponding to ovarian E2 fluctuations, which is much slower than the acute suppression of inhibition we report here. "
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    ABSTRACT: The steroid 17β-estradiol (E2) is well known to influence hippocampal functions such as memory, affective behaviors, and epilepsy. There is growing awareness that in addition to responding to ovarian E2, the hippocampus of both males and females synthesizes E2 as a neurosteroid that could acutely modulate synaptic function. Previous work on acute E2 actions in the hippocampus has focused on excitatory synapses. Here, we show that E2 rapidly suppresses inhibitory synaptic transmission in hippocampal CA1. E2 acts through the α form of the estrogen receptor to stimulate postsynaptic mGluR1-dependent mobilization of the endocannabinoid anandamide, which retrogradely suppresses GABA release from CB1 receptor-containing inhibitory presynaptic boutons. Remarkably, this effect of E2 is sex specific, occurring in females but not in males. Acute E2 modulation of endocannabinoid tone and consequent suppression of inhibition provide a mechanism by which neurosteroid E2 could modulate hippocampus-dependent behaviors in a sex-specific manner.
    Neuron 06/2012; 74(5):801-8. DOI:10.1016/j.neuron.2012.03.035 · 15.98 Impact Factor
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    • "However, consensus regarding steroid-induced changes in GABA receptors has been complicated by difficulties in distinguishing effects due to changes in sensitivity to GABAergic drugs from effects due to changes in circulating hormone levels (reviewed in N-Wihlback et al., 2006). In addition, studies examining relationships between neuroactive steroid levels and premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) have yielded discordant results (reviewed in Guille et al., 2008). In light of physiological differences between primates and species typically used to study GABAergic system regulation, primate models may be most appropriate for elucidating effects of hormone cyclicity or hormone-replacement therapy on neurological changes in women. "
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    ABSTRACT: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and the responsiveness of neurons to GABA can be modulated by sex steroids. To better understand how ovarian steroids influence the GABAergic system in the primate brain, we evaluated the expression of genes encoding GABA receptor subunits, glutamic acid decarboxylase (GAD) and a GABA transporter in the brains of female rhesus macaques. Ovariectomized adults were subjected to a hormone replacement paradigm involving either 17beta-estradiol (E), or E plus progesterone (E+P). Untreated animals served as controls. Using GeneChip microarray analysis and real-time RT-PCR (qPCR), we examined gene expression differences within and between the amygdala (AMD), hippocampus (HPC) and arcuate nuclei of the medial basal hypothalamus (MBH). The results from PCR corresponded with results from representative GeneChip probesets, and showed similar effects of sex steroids on GABA receptor subunit gene expression in the AMD and HPC, and a more pronounced expression than in the MBH. Exposure to E+P attenuated GAD1, GAD2 and SLC32A1 gene expression in the AMD and HPC, but not in the MBH. GABA receptor subunit gene expression was generally higher in the AMD and HPC than in the MBH, with the exception of receptor subunits epsilon and gamma 2. Taken together, the data demonstrate differential regulation of GABA receptor subunits and GABAergic system components in the MBH compared to the AMD and HPC of rhesus macaques. Elevated epsilon and reduced delta subunit expression in the MBH supports the hypothesis that the hypothalamic GABAergic system is resistant to the modulatory effects of sex steroids.
    Brain research 10/2009; 1307:28-42. DOI:10.1016/j.brainres.2009.10.011 · 2.83 Impact Factor
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