Sulphates of 3β-hydroxy-5-ene Steroids in Women with Epilepsy

Epilepsy is associated with various reproductive disorders and some antiepileptic drugs also influence the steroid metabolism. There is only limited data concerning the role of steroid sulphates in human epilepsy. Moreover, the substitution treatment with therapeutic substances also improves cognitive functions in humans. Therefore, we evaluated the balance between free and Δ5 sulphated steroids in women with epilepsy on various antiepileptic drugs. The study included 28 patients (17.0–51.0 years), with generalized (n=16) or catamenial epilepsy (n=12) followed in the follicular (FP) and luteal (LP) phases of menstrual cycle. Fifteen patients were on monotherapy and 13 were on polytherapy with 2 or 3 drugs. RIA was used for the steroid analyses. Statistical evaluation was done by Mann-Whitney tests and multivariate regression with reduction of dimensionality (Orthogonal Projections to Latent Structures, O2PLS). The final O2PLS model found a single significant predictive component extracting the variability shared between carbamazepine therapy, age of the subjects, and steroid levels and correlating with the variables as follows pregnenolone sulphate (PregS)-FP: R= –0.844, p<0.01; DHEAS-FP: R= –0.923, p<0.01; PregS-LP: R= –0.876, p<0.01; DHEAS-LP: R= –0.902, p<0.01; carbamazepine therapy: R=0.441, p<0.01; age of the participants (R=0.584, p<0.01). Carbamazepine significantly decreased DHEAS in both FP (p=0.02) and LP (p=0.003) and PregS in LP (p=0.03) and tended to decrease the PregS © Charles University in Prague – Karolinum Press, Prague 2010 This study was supported by grant IGA 1A/8649-5. Mailing Address: Martin Hill, PhD. , DSc. , Institute of Endocrinology, Národní třída 8, 116 94 Prague 1, Czech Republic; Phone: +420 224 905 267; Fax: +420 224 905 325; e-mail: mhill@endo.cz Prague Medical Report / Vol. 111 (2010) No. 2, p. 111–126 Hill M. ; Vrbíková J.; Zárubová J.; Včeláková H. ; Dušková M. ; Kancheva R. ; Kubátová J.; Stárka L. 112) levels in FP (p=0.10), while primidone decreased DHEAS in both FP and LP (both p=0.05) and did not significantly change the levels of PregS. In conclusion, carbamazepine and primidone therapies significantly suppressed the sulphated steroids in serum. Introduction Epilepsy in women is associated with various reproductive disorders like hypogonadotropic hypogonadism (Herzog, 1991a, 1991b; Meo and Bilo, 2003; Morrell, 2003), lower fertility (Morrell, 1999; Pimentel, 2000), abnormalities in luteotropin secretion (Stoffel-Wagner et al., 1998; Morrell, 1999; Tauboll et al., 2003), higher frequency of polycystic ovary syndrome (PCOS) (Herzog, 1991a; Isojarvi, 2003; Meo and Bilo, 2003), higher frequency of anovulatory cycles and with disturbances in the formation of ovarian steroids (Stoffel-Wagner et al., 1998; Morrell, 1999). Some antiepileptic drugs (AED) have also profound impact on steroid metabolism. Carbamazepine, phenytoin and phenobarbitone induce the hepatic P450 cytochrome enzyme system and stimulate steroid clearance. Carbamazepine therapy results in decline of serum TSH, DHEAS and LH in the follicular phase (FP) of menstrual cycle, and estradiol in the LP, otherwise in increase of the cortisol, SHBG and prolactin levels (Isojarvi, 1990; Stoffel-Wagner et al., 1998; Morrell, 2003). Phenytoin treatment lowers circulating adrenal and ovarian steroids as DHEAS and estrogens and mounts circulating cortisol and 5α-reductase activity (Soory and Suchak, 2001; Morrell, 2003). Valproate treatment suppresses cortisol levels (Aydin et al., 2005) and induces a metabolic syndrome with centripetal obesity, hyperinsulinemia, lipid abnormalities, and polycystic ovaries/hyperandrogenism in women with epilepsy. These valproate side effects can be reduced by substituting valproate with lamotrigine (Isojarvi et al., 1998). Testosterone levels and free androgen index are mostly higher in valproate-treated women (Isojarvi et al., 2005). It is probable, that some of these hormonal changes could influence the course of epilepsy. Lamotrigine appeared to have minimum effect on gonadal steroidogenesis, however minor changes in ovarian morphology or alterations in other tissues were observed in lamotrigine treated female rats. Although serum estradiol was significantly reduced, testosterone, FSH, LH, insulin and progesterone remained unchanged in the lamotrigine treated animals (Roste et al., 2003). Concerning hormonal changes after topiramate use, there is no human data available. Various adrenal and gonadal steroids can surpass the blood-brain barrier. Besides the binding to intracellular receptors in brain, some steroids, their metabolites as well as locally produced brain steroids (which are known as neurosteroids) can bind to active sites of neuronal membrane receptors and influence the ion transport and neuronal activity (Bixo et al., 1997; Joels, 1997; Edwards et al., 1999b; Morrell, 1999; Pimentel, 2000; Beyenburg et al., 2001; Rupprecht, 2003). The neurosteroids and steroid neuromodulators of peripheral