Pharmacological Reports Copyright © 2013 2013, 65, 8998 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Progesterone therapy in women with epilepsy
Ewa Motta1, Anna Golba1, Zofia Ostrowska1, Arkadiusz Steposz1, Maciej Huc1, Justyna Kotas-Rusnak2, Jarogniew J. £uszczki3,4, Stanis³aw J. Czuczwar3,5, W³adys³aw Lasoñ6
1Department of Neurology, Silesian Medical University, Zio³owa 45/47, PL 40-635 Katowice, Poland
2Regional Specialist Hospital, Energetyków 46, PL 44-200 Rybnik, Poland
3Department of Pathophysiology, Medical University, Aleje Rac³awickie 1, PL 20-059 Lublin, Poland
4Isobolographic Analysis Laboratory, 5Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, PL 20-090 Lublin, Poland
6Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
Correspondence: Ewa Motta, e-mail: [email protected]
Abstract: Background: Progesterone with its anti-seizure effect plays a role in the pathophysiology of catamenial epilepsy which affects 31–60% of epileptic women. In this study, an attempt to treat women suffering from catamenial epilepsy with progesterone, as an adjuvant drug, was made. Methods: The treatment was given to 36 women aged 20–40 years (mean age: 30.75 ± 6.05) with seizures in the entire second half of the menstrual cycle, who were found to have low serum levels of progesterone on days 22, 27, 28 of the cycle in comparison with a control group of healthy women. The patients were administered progesterone in a daily dose of 50 mg on days 16–25 of each cycle. The serum levels of antiepileptic drugs were assayed. The period of progesterone therapy ranged from 3 to 45 months (17.7 on average). Results: Three patients were free of secondary generalized seizures, and one – of simple partial seizures. A decline in the frequency of primary and secondary generalized seizures by 20–96% (55.9% on average) was accomplished in 18 patients (primary general- ized by 20–96% – 54.7% on average, and secondarily generalized by 38–85% – 59% on average). Adecline in the frequency of com- plex partial seizures by 38–87% (63.1% on average) was achieved in 15 women. In 1 patient, the frequency of myoclonic seizures decreased by 46%. There was no improvement in 5 women (3 patients with generalized, 1 with complex partial and 1 with simple partial seizures). An exacerbation of seizure frequency occurred in 5 patients. Adverse effects were not found in any of the subjects. The average concentrations of antiepileptic drugs during hormonal therapy were in the therapeutic range. Conclusion: Progesterone combined with antiepileptic therapy was well tolerated and resulted in a significant reduction of seizure frequency in majority of patients with catamenial epilepsy.
Key words: catamenial epilepsy, progesterone therapy, menstrual cycle
Pharmacological Reports, 2013, 65, 8998 89 Introduction tor of GABAA receptor function [24]. Indeed, proges- terone suppressed the pentetrazole-induced convul- sions in male mice and this effect was reversed by Both experimental and clinical evidence indicates that finasteride, a 5a-reductase inhibitor, which prevents ovarian hormones exert a profound effect on neuronal conversion of progesterone to allopregnanolone. In- excitability, though in a complex manner. The effects terestingly, a progesterone receptor antagonist, mife- of estrogens on brain function are mediated by two pristone, remained without any significant action different nuclear estradiol receptors: ERa and ERb upon the convulsive threshold in female mice against [12, 42]. The ERa are involved in regulation of repro- electroconvulsions or pentetrazole-induced seizures ductive neuroendocrine and several behavioral func- [4]. Further evidence that antiseizure effects of pro- tions, whereas the role of ERb in the brain is rather gesterone result from its conversion to allopreg- modulatory [12]. These receptors are ligand-dependent nanolone and do not require progesterone receptors transcription factors, however, nonnuclear estrogen was provided by Reddy et al. [31]. These investiga- receptors coupled to second messenger systems can tors conducted adequate experiments in progesterone also be found e.g., in dendrites, presynaptic terminals receptor knockout mice of both sexes using pentetra- and glia cells [28]. zole, maximal electroshock and amygdala-kindling Estradiol exerts generally proconvulsant activity. seizure models. However, subsequent study per- Specifically, estrogen per se was documented to pro- formed by these authors suggested that the kindling- duce epileptic foci in the feline sensory motor cortex retarding effects of progesterone may partly involve [23] or to shorten the acquisition of kindled seizures the progesterone-receptor-dependent mechanism [32]. by electric stimulation of the amygdala or pentetra- In contrast to convulsive seizure models, progesterone zole injections in ovariectomized rats [22]. Further, aggravates spike-wave discharges in a genetic model estradiol replacement in ovariectomized rats led to of absence epilepsy, and this effect also depends on its a significant enhancement of postictal events – for in- conversion to allopregnanolone [40]. Collectively, the stance, myoclonic jerks [5]. Estradiol also aggravates experimental data suggest that modulation of seizure seizures evoked by bicuculline, picrotoxin and kai- activity by ovary hormones engages both genomic nate, but not those induced by flurothyl [30, 37, 41]. and non-genomic mechanisms and depends on animal On the other hand, in juvenile rats ERb was shown to model of seizures. mediate antiseizure effects of testosterone metabolites The cyclical occurrence of epileptic seizures was [8]. In contrast to estrogens, progesterone is recog- already observed in antiquity. In 1857, Locock no- nized as an anticonvulsant, however, its mechanism of ticed that seizures in women were often associated action in the central nervous system has been only with hysteria or menstruation [29]. Their connection partially unravelled. Progesterone receptor belongs to with the menstrual cycle was described for the first a family of nuclear transcription factors and consists time by Gowers in 1885 [29]. The term “catamenial of two isoforms, PR-A and PR-B, derived from the epilepsy” comes from the Greek word “katomenios”, same gene. These isoforms are abundant in brain tis- meaning “monthly”. Catamenial epilepsy is a particu- sue and appear to differentially regulate expression of lar disease in which there is a cyclical increase in the neurotransmitter synthesizing enzymes and their re- number of seizures during menses or in other phases ceptors [9]. Recent data point to a crucial involvement of the menstrual cycle. Herzog defined catamenial of progesterone nuclear receptors in the development epilepsy as a greater than average seizure frequency and persistence of experimental epileptogenesis. To during perimenstrual or periovulatory periods in nor- this end, it has been reported that mice which lack mal ovulatory cycles and during the luteal phase in both PR-A and PR-B isoforms were more resistant to anovulatory cycles [20]. Cyclical changes in the con- hippocampal and amygdalar kindling than the wild- centrations of circulating estrogens and progesterone type mice [33]. Progesterone also prevented generali- are now accepted to play a role in the development of zation in kindled seizures in rats, this effect being, catamenial epilepsy. The fluctuations in concentra- however, observed in sexually immature rats [21]. tions of antiepileptic drug and changes in water and Other data indicate that the anticonvulsant effects of electrolyte balance have been also proposed as causes progesterone may be mainly mediated by its metabo- for the occurrence of catamenial epilepsy [1, 13, 15, lite allopregnanolone, a neurosteroid positive modula- 25, 27, 35, 36, 38, 39]. Progesterone with its antisei-
90 Pharmacological Reports, 2013, 65, 8998 Progesterone therapy in women with epilepsy Ewa Motta et al.
Tab. 1. Mean serum progesterone concentration during menstrual cycle in 36 women with catamenial epilepsy before progesterone treatment and in the control group
Progesterone Day of menstrual cycle [nmol/l] 5 6 12 13 14 15 22 27 28 Women with catamenial epilepsy (n = 36) Mean (± SD) 1.012 0.872 1.417 1.750 2.263 2.454 26.959 6.801 3.375 (± 0.246) (± 0.198) (± 0.321) (± 0.315) (± 0.535) (± 0.311) (± 2.735) (± 1.123) (± 0.409) Significance <