Epilepsy, Sex Hormones and Antiepileptic Drugs in Female Patients

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Epilepsy, sex hormones and antiepileptic drugs in female patients

Expert Rev. Neurother. 9(12), 1803–1814 (2009)

Alberto Verrotti†, Women with epilepsy have a higher incidence of reproductive endocrine disorders than the Claudia D’Egidio, general female population. These alterations include polycystic ovary syndrome, Giangennaro Coppola, hyperandrogenemia, infertility, hypothalamic amenorrhea and hyperprolactinemia. Reproductive Pasquale Parisi and dysfunction is attributed both to epilepsy itself and to antiepileptic drugs (AEDs). Focal epileptic discharges from the temporal lobe may have a direct influence on the function of the Francesco Chiarelli hypothalamic–pituitary axis, thus altering the release of sex steroid hormones, including the † Author for correspondence production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing Department of Pediatrics, hormone and prolactin. AEDs may modulate hormone release from the hypothalamic–pituitary– University of Chieti, Via dei gonadal axis and they may alter the metabolism of sex hormones and their binding proteins. Vestini 5, 66100 Chieti, Italy Hepatic enzyme-inducing AEDs, such as carbamazepine and phenytoin, may be most clearly Tel.: +39 087 135 8015 linked to altered metabolism of sex steroid hormones, but valproic acid, an enzyme inhibitor, Fax: +39 087 157 4831 has also been associated with a frequent occurrence of polycystic ovary syndrome and [email protected] hyperandrogenism in women with epilepsy. Therefore, treatment of epilepsy and selection of AEDs are important for reproductive health in female patients. The aim of the present review is to critically evaluate the recently published data concerning the interactions between sex hormones, epilepsy and AEDs.

Keywords: amenorrhea • antiepileptic drug • epilepsy • hyperandrogenemia • hyperprolactinemia • polycystic ovary syndrome • sex hormone dysfunction

Epilepsy is a common neurologic disorder affect- This review evaluates whether and to what ing women during their reproductive years, and degree epilepsy and its treatment can affect is associated with hormonal disturbances result- reproductive function. For this purpose, this ing in altered endocrine reproduction and sexual review is subdivided into two main sections: the function [1,2]. A possible role for seizure disorder effects of epilepsy on reproductive function and or, alternatively, of the use of antiepileptic drugs the effects of AEDs on sex hormones. (AEDs), have been suggested as the pathogenetic­ mechanisms. The brain regulates hormonal Effects of epilepsy on secretion and is sensitive to hormonal feedback; reproductive function the neuroendocrine feedback system includes the Reproductive endocrine disorders, such as men- hypothalamus, pituitary, gonads and amygdala. strual cycle disturbances and ovulatory dysfunc- The amygdala is linked to the hypothalamic– tions, have frequently been reported in epileptic pituitary axis (HPA) [3], which is involved in the women [1–3,5–13]. These abnormalities usually regulation, production and secretion of ovarian result from abnormal reproductive endocrine steroids. Reproductive endocrine disorders asso- function and are associated with lower rates ciated with epilepsy can be expected in view of of ovulation and higher rates of infertility [12]. the complex interconnections between the HPA Menstrual disorders are currently estimated to and the limbic system; the involvement of medial occur in a third of women with epilepsy com- temporal lobe regions in epilepsy may cause pared with 12–14% of women in the general changes in sex hormone secretion and, conse- population [13]. Anovulation, hypothalamic quently, reproductive function [4]. Moreover, amenorrhea (HA), hyperandrogenemia, poly­ AEDs may also alter hormone levels and interfere cystic ovary syndrome (PCOS), functional with reproductive function [5,6]. hyperprolactinemia, premature menopause and www.expert-reviews.com 10.1586/ERN.09.112 © 2009 Expert Reviews Ltd ISSN 1473-7175 1803 Review Verrotti, D’Egidio, Coppola, Parisi & Chiarelli risk of infertility are over-represented in women with epilepsy Interestingly, a recent cross-sectional observational study of (Box 1) [1,9,14–20]. Epilepsy itself may have effects on sex hormone Murialdo et al. evaluated the relationships between sex steroids levels and reproductive endocrine function [1,5,21–22,23]. and seizure frequency in women with partial epilepsy on AED Animal studies have demonstrated that reproductive endo- treatments [37]. The authors found that estrodiol, free estrodiol and crine and sexual dysfunction is more common in partial com- progesterone levels were lower in both ovarian phases in patients, pared with generalized epilepsy, especially in temporal lobe epi- whereas those of sex hormone-binding globulin (SHBG) were lepsy [24–26]; animal investigations demonstrated that induction higher than in controls. When changes in hormone levels were com- of temporo–limbic seizures can cause changes in reproductive pared with those in healthy controls, luteal-free estrodiol and pro- hormone levels and reproductive function [24,25,27]. In particular, gesterone levels were chiefly impaired in women with more frequent amygdala seizures in female rodents can cause anovulation, ele- seizures, mostly undergoing AED polytherapies, but not in those vated serum testosterone levels and the accumulation of follicular with absent or rarer seizures. Furthermore, an inverse relationship cystis in the ovaries [24]. was found between free estrodiol levels and seizure frequency scores These findings have also been confirmed in human studies during the follicular phase, and with disease duration in the luteal [14,28]. More than a third of cycles in women with localization- phase. However, the authors suggested that these findings may be related epilepsy are anovulatory, compared with 8–10% in con- attributed to the longer duration of AED treatments and the more trols [11,13,29–33]. Partial epilepsy, mainly when originating in frequent use of enzyme-inducing AEDs (EIAEDs) in subjects with the temporal lobe, is the form most frequently associated with more severe seizures. Accordingly, a previous retrospective study reproductive dysfunction [1,13,19,34]. However, other studies reported that menstrual disorders were more frequent in patients demonstrated that more than 50% of patients with generalized with high seizure frequency (less than five seizures per year)[38] . convulsions may develop reproductive and sexual abnormali- The mechanisms underlying the association between epilepsy ties [21,29,35]; in particular, hyperandrogenemia and PCOS are and reproductive endocrine disorders are still not clear. HPA dys- more frequent in women with idiopathic generalized epilepsy function is suggested by observations that pituitary release of than in localization-related epilepsy [14,29,36]. Interestingly, LH in women with epilepsy is altered both spontaneously and Herzog et al., examined 50 women with tempolimbic epilepsy in response to gonadotropin-releasing hormone (GnRH) [1,30,31]. and found that 28 patients had amenorrhea, oligoamenorrhea, The brain controls reproductive function primarily through or abnormally long or short menstrual cycle intervals; 19 out of hypothalamic regulation of pituitary secretion [39]. The hypo­ the 28 women with epilepsy and menstrual disorders had readily thalamus receives direct connections from the cerebral hemi- identifiable reproductive endocrine disorders: PCOS in ten, HA spheres, especially from temporolimbic structures that are in six, premature menopause in two and hyperprolactinemia in commonly involved in epilepsy and, most notably, from the one [1]. Since no significant relationship between the occurrence amygdala [1,40,41]. In the majority of cases, the epileptic activity of menstrual disorders and the use of AEDs has been found, it in the frontal lobe exhibits a propagation towards the temporal is suggested that epilepsy may have an independent effect on lobe and, thereby, influences the hormonal pathway of prolactin reproductive function. This is in agreement with a previous (PRL). [42]. Clinically, there is evidence to suggest that epilepti- study describing a significantly higher frequency of ovulatory form discharges may disrupt the temporolimbic modulation of dysfunction in female patients, not correlated with the use of hypothalamic–pituitary function [14,26] and, ultimately, lead to any specific AED [35]. changes in ovarian steroidogenesis and morphology [43]. There are Moreover, high levels of luteinizing hormone (LH) and an also important clinical findings that indicate that the laterality altered LH-to-follicle-stimulating hormone (FSH) ratio have been and focality of epilepsy may be important determinants of certain reported in women with epilepsy [17–19]. The presence of elevated reproductive endocrine disorders [1,14,28,44–46]. In fact, unilateral LH pulse frequency in untreated or epileptic women with regu- temporolimbic discharges are associated with laterally differing lar menstrual cycles supports the notion that epilepsy itself may changes in hormonal secretion at all levels of the neuroendocrine contribute to reproductive abnormalities [21,35]. reproductive axis. Consequently, different reproductive disorders may develop in relation to left- and right-sided temporolimbic epi- Box 1. Frequent reproductive dysfunctions in lepsy; in particular, left unilateral temporolimbic epilepsy is asso- women with epilepsy. ciated with a higher occurrence of PCOS [14,47]. Indeed, seizures in the left side of the limbic system increase the pulse frequencies of • Hyperandrogenism [29,36,46,94] GnRH secretion that, in turn, increases the LH/FSH ratios and • High levels of luteinizing hormone and luteinizing hormone-to- testosterone levels. By contrast, right unilateral temporolimbic follicle-stimulating hormone ratio [16,17,36,55] epilepsy is associated with lower GnRH pulse frequency, which • Polycystic ovary syndrome [1,13,14,30,31,46,47,92–93] causes a decrease in LH and estrogen levels [1,14]. These hormonal • Menstrual irregularities [1,17,32,35,92] changes are characteristic of HA [9,28,48]. • Premature menopause [1,15,16] Nevertheless, a recent experiment using the amygdala kindling • Infertility [7,9,110,149] model in rats demonstrated that, in female rats, seizures that • Hyperprolactinemia [42,53,150,151] originate in the left or right amygdala do not result in lateralized • Sexual dysfunction [14,50,52,152,153] effects on the reproductive system [27].

1804 Expert Rev. Neurother. 9(12), (2009) Epilepsy, sex hormones & antiepileptic drugs in female patients Review

Epileptic discharges in limbic structures may also contribuite In fact, in the late 1970s and 1980s, serum sex hormone levels to sexual dysfunction in women, such as lack of sexual interest were reported to be abnormal in female patients treated with and high rates of orgasmic dysfunction, including anorgasmia, EIAEDs [55,56]. dyspareunia, vaginism or insuffcient vaginal lubrication [49,50]. Victor et al. were the first to report elevated serum SHBG Herzog et al. found that right temporal epileptic discharges in concentrations in women treated with PHT [57], and this find- women were associated with hypogonadotropic hypogonadism, ing was later confirmed[55,56] . Low dehydroepiandrosterone sul- including decreased sexual interest [1]. Sexuality in people with phate (DHEAS) levels have also been reported in women tak- epilepsy may be adversely affected by alterations in the pituitary ing PHT [58], but its clinical significance is unknown. However, gonado­tropins, PRL and sex steroid hormones [1,12]. Limbic effer- similarly impaired steroid levels have also been shown in women ents seem to exhibit an impact on the HPA even in the inter- with epilepsy treated with other EIAEDs [60,63]. In particular, ictal phase of the disorder, and post-ictally elevated PRL serum Galimberti et al. reported decreased DHEAs levels and increased concentrations can be detected. In correlation with the type of cortisol levels in women treated with CBZ, PHT, PB in mono- seizures, evidence of elevated PRL is found in 88% of seizures or poly-therapy, but not in those treated with non-EIAEDs following generalized tonic–clonic seizures, in 78% of seizures (NEIAEDs) [63]. The most interesting finding in this study con- following complex partial seizures and in 22% of seizures follow- cerned the relation between epilepsy severity, increased cortisol, ing simple partial seizures [51]. The epileptic activity in the frontal and decreased DHEAs levels. In fact, cortisol and DHEAS levels lobe exhibits propagation towards the temporal lobe and thereby were directly and indirectly correlated with seizure frequency, influences the hormonal pathway of PRL, which can also show respectively, suggesting that changes in adrenal steroid levels must tendencies to post-ictal elevation [42]. be ascribed mainly to the frequency of seizures, which are known In women (and men) with epilepsy, reduced genital blood to activate the hypothalamus–pituitary–adrenal axis [64]. flow during erotic stimulation was found via video. The women The most recent cross-sectional study showed that women with with epilepsy who were examined showed a reduced elevation of epilepsy taking EIAED polytherapies had lower levels of estradiol genital blood flow during the presentation of erotic video movies and a lower free estrogen index (FEI) than patients treated with in comparison with healthy controls [52]. Irrespective of gender, a single EIAED [59]. EIAEDs induce hepatic cytocrome P450- sexual questionnaires revealed reduced libido more commonly in dependent steroid hormone breakdown and production of SHBG, the right- than in the left-sided temporal lobe seizure origin 44]. thereby reducing biologically active sex hormone serum concen- However, compelling explanation remains to be found. It is pos- trations, such as estrodiol and testosterone [5,18,60–62]. Galimberti sible that the right sided temporal lobe disturbance may have a et al. reported that the older patients and those with longer dis- more pronounced influence on emotions and, therefore, indirectly ease duration showed higher levels of SHBG [59]. This can be on libido [53]. attributed to the physiologic increase in binding protein levels Baird et al. reported that a third of their 58 lobectomy patients with aging and to the use of EIAEDs. These changes in serum had an increase in sexual activity after surgery, compared with SHBG levels, and the lowered total estrodiol levels, implied a a quarter of patients having decreased postsurgical sexual activ- global decrease in biologically active free estrodiol. Conversely, ity [45]. Furthermore, Manna et al. recently��������������������� demonstrated�������������������� a rela- significant differences in estrodiol levels and in FEI were found tionship between a serotonin transporter genetic polymorphism between women on different AED regimens. Patients treated with and temporal lobe epilepsy, suggesting that the serotonin trans- EIAED polytherapies showed estrodiol and FEI values that were porter gene may play a role in the development of temporal lobe lower than those recorded both in patients treated with a single epilepsy [54]. These findings indicate that some patients with epi- EIAED or NEIAED, or in those on combined (EIAED plus lepsy may be genetically susceptible to sexual dysfunction through NEIAED) therapies. a serotonin transport mechanism. Recently, Jacobsen et al. reported that PB, PHT, valproic acid In conclusion, an increased frequency of reproductive endo- (VPA), oxcarbazepine (OXC) and lamotrigine (LTG), but not crine disorders, secondary to pituitary hormone changes, has been CBZ, inhibit the aromatase complex (CYP19) activity that con- reported in women with epilepsy, especially among those with verts testosterone into estrodiol in vitro [65]. Accordingly, a more partial epilepsy of temporal lobe origin. Therefore, regular moni- recent study demonstrated that VPA and LTG reduced CYP19 toring of reproductive function, including menstrual disorders, aromatase activity in human ovarian follicular cells, but only in infertility, hirsutism and galactorrhea, are recommended. FSH-stimulated cells and at higher concentrations [66]. Additive enzyme inhibition has been observed in combination experi- Effects of antiepileptic drugs on sex hormone levels ments with multiple AEDs; therefore, aromatase inhibition might A large body of literature addresses the presence of alterations in explain the decreased production of estrodiol observed in vivo, sex hormone levels in women taking AEDs [2,5,11,17,18,55–62]. mainly when combined AED therapies were employed [59]. Antiepileptic drugs may have an influence on the metabo- Many studies that have evaluated the reproductive endocrine lism of the central and/or peripheral endocrine hormones and effects of CBZ in female patients have consistently reported their binding proteins. Hepatic EIAEDs, such as phenobarbital increased serum SHBG levels and other sex hormone abnormali- (PB), phenytoin (PHT) and carbamazepine (CBZ), are most ties [2,62,65,67–71]. Interestingly, Hamed et al. reported elevated clearly linked to altered metabolism of sex steroid hormones. levels of LH and FSH in 28.1 and 34.4% of CBZ-treated patients, www.expert-reviews.com 1805 Review Verrotti, D’Egidio, Coppola, Parisi & Chiarelli

respectively [17]. Dana-Haeri et al. observed that epileptic patients Alterations in serum androgen levels have even been detected on CBZ had elevated baseline LH levels and a exaggerated LH before and during pubertal development in young girls taking response to the GnRH and thyrotropin-releasing hormones VPA [83]. The mean serum testosterone levels and FAI were high stimulation [72]. This exaggerated LH response may be related in all pubertal phases in girls on VPA, even if the frequency to a positive-feedback mechanism. Furthermore, they reported of hyperandrogenism increased with pubertal development. slightly higher PRL levels 2 h after stimulation with GnRH and Therefore, it is likely that VPA may affect steroid metabolism thyrotropin-releasing hormone. These changes have not been during the sensitive period, at the onset of puberty. Accordingly, confirmed by other studies [60,72–74]. Recently, a double-blind, hyperandrogenism observed in most adult women on VPA ther- randomized, controlled withdrawal study, reported that CBZ apy can already be induced before the emergence of clinical signs withdrawal was associated with a significant decrease in SHBG of puberty. A recent cross-sectional study showed that VPA treat- levels and a increase in serum testosterone concentrations, free ment was only associated with higher testosterone levels in girls androgen index (FAI) and estrogen/SHBG ratio; these results after menarche, suggesting that the sensitivity to VPA-induced demonstrated that potential changes in sex steroid levels, induced hyperandrogenism is a function of sexual maturation [6]. In post- by CBZ treatment, could be reversible [71]. menarcheal girls, the presence of hyperandrogenemia without However, most of the studies have not shown an increased fre- clinical hyperandrogenism may reflect the increase in testoster- quency of menstrual disorders or hyperandrogenism and polycystic one that precedes the appearance of clinical signs (i.e., hirsut- ovaries (PCO) in women taking CBZ [2,60,67,75,76], despite altera- ism, acne, menstrual disorders and PCOs). This emphasizes tions in serum sex hormone concentrations. In fact, single abnor- the importance of careful endocrine observation of girls treated mal laboratory findings without symptoms may not constitute a with VPA. clinically relevant endocrine disorder. However, it is encouraging to note that the reproductive endo- Among NEIAEDs, VPA appears to be associated with frequent crine effects of VPA may be reversible after the medication is reproductive endocrine disorders, such as polycystic changes in discontinued; a 5 year follow-up study in young women showed the ovaries, high serum testosterone concentrations and amenor- that the 60% of the patients who were administered VPA had rhea [2,38,77]. These abnormalities are especially common among PCOS compared with 5.5% of the girls whose medication had women who have gained weight during VPA therapy [61]. In 1993, been discontinued [82]. Isojarvi et al. through a cross-sectional study showed that men- The mechanism by which VPA could cause hyperandrogenism strual disorders were common among women taking VPA mono- and related reproductive disorders is still unclear. It may be that therapy for epilepsy and that they were frequently associated with VPA can have a direct effect on ovarian androgen production or PCOs and/or hyperandrogenism [2]. PCOs and hyperandrogenism that, acting as enzyme inhibitor, VPA may inhibit the metabolism were expecially common if VPA medication was started before of sex hormones and thereby lead to increased serum androgen the age of 20 years [70]. An increased number of ovarian cysts levels [53,84,85]. Moreover, obesity (induced by VPA treatment) and and PCOS in women on VPA monotherapy was subsequently associated hyperinsulinemia could be implicated in the development confirmed [75,78,79]. In another study of women taking VPA cur- of PCOS and hyperandrogenism (see later) [2,70]. rently or within the preceding 3 years, 38.1% had experienced at Recently, it has been shown that VPA blocks the androgen least one anovulatory cycle in contrast to 10.7% of women not and progesterone receptors, but not the estrogen receptor [86]. using VPA within the preceding 3 years [11]. Interestingly, women The strong progesterone receptor antagonism by VPA suggests with idiopathic generalized epilepsy receiving VPA were at highest that some biological effects in women may be at least partly due risk for anovulatory cycles, polycystic ovaries, elevated BMI and to impaired progesterone receptor-mediated progesterone action hyperandrogenism. on reproductive tissue (a previously unrecognized factor contri­ A more recent prospective study by Morrell et al. reported a buting to the low fertility of women with epilepsy). In addition, higher incidence of hyperandrogenism or ovulatory dysfunction in antiprogestin effects may contribute to the higher frequency of women taking VPA for epilepsy than in women taking LTG [80]. anovulation among VPA-treated women with epilepsy [57,77]. Moreover, a significant increase in serum testosterone concentration The reproductive endocrine effects of the new AEDs have not was especially prominent in women initiating treatment before the been widely studied. However, most of the data suggest that OXC age of 20 years, suggesting that young women with epilepsy seem therapy is not associated with changes in reproductive function to be especially vulnerable to the effects of VPA on ovarian func- in epileptic patients [83,87]. Only one recent study reported low tion [70]. By contrast, in two prospective randomized studies by serum testosterone concentrations, low FAI, elevated levels of Kwan et al. [81] and Stephen et al. [82], comparing women receiving androstendione and DHEAS and increased prevalence of PCO in VPA and LTG monotherapy, no significant difference in change of women during OXC treatment [88]. A low prevalence of reproduc- testosterone levels from baseline was found between the VPA and tive disorders has been reported during LTG therapy [5,73], and LTG groups. This discrepancy is probably owing two main reasons. replacement of VPA with LTG resulted in normalization of endo- First, the sample size in these two studies [81,82] were comparatively crine function in women with previously identified endocrine smaller than in the study by Morrell et al. [80]. Second, the mean disorders (PCO, hyperandrogenism and increase in bodyweight), age of female subjects in the study by Kwan et al. [81] was more than probably related to VPA medication [89]; serum insulin and tes- 10 years older than that of subjects in the study by Morrell et al. [80]. tosterone levels returned to normal within 2 months following

1806 Expert Rev. Neurother. 9(12), (2009) Epilepsy, sex hormones & antiepileptic drugs in female patients Review

VPA replacement, and the levels remained normal thereafter. gain may lead to the expression or exacerbation of PCOS in some Consistent with these findings, Morrell et al. reported that genetically predisposed women, reducing insulin sensitivity. Thus, women taking LTG had lower serum testosterone levels than AED-related weight increases could trigger the manifestation of a women taking VPA [90]. clinically relevant endocrine disorder; in particular, VPA-induced In conclusion, careful endocrine observation of girls treated weight gain and the related endocrine abnormalities (e.g., hyper- with EIAED and VPA is important, while it seems that the new insulinemia and hyperandrogemia) may induce the development AEDs may offer an alternative if reproductive endocrine problems of PCOS [18]. emerge during treatment with the older AEDs. Ovarian function The pathogenic mechanisms underlying weight gain during should be monitored closely as part of the comprehensive care of VPA treatment are still unclear [70,108–111]. The observation that women with epilepsy to prevent adverse effects of ovarian failure, VPA-treated epileptic patients who reported weight gain devel- mainly in patients with more frequent seizures who need AED oped increased appetite, thirst and quenching with calorie-rich polytherapies and/or in patients treated with old AEDs. beverages supports the hypothesis of a stimulating effect of VPA on the hypothalamus [89,109,112,113]. AEDs & PCOS It has been also suggested that VPA-related obesity may be The most common reproductive endocrine disorder in women associated with elevated serum leptin levels in women with epi- with epilepsy is PCOS [13,21,75]. PCOS occurs in 10–20% of lepsy [70,102], but it is unclear whether leptin behavior in VPA- women with epilepsy compared with 5–6% of women in the induced obesity is similar to that in any other obesity situation, as general population [9,13,14,75]. supported by some data [114]. VPA can modify leptin levels through Polycystic ovary syndrome represents the failure of the ovar- the increase of bodyweight, and this modification is related to BMI. ian follicle to complete normal maturation during the menstrual Moreover, it is likely that obesity is the cause of insulin resistance cycle or a series of cycles, a failure that is perhaps related to the and related hyperinsulinemia [103], which are often associated presence of inadequate levels of pituitary FSH, while levels of LH with PCOS [115]. By suppressing the synthesis of SHBG, insulin are normal or elevated [61]. These conditions can produce a failure increases free androgen concentrations, subsequently increasing of ovulation and the partially developed follicle is retained in the the degree of hirsutism. The positive correlation between insulin ovary in the form of a tiny cyst [46,47]. This partially developed resistance and obesity means that in some women with PCO, the follicle is secretory but it is deficient in aromatase, the enzyme clinical manifestation of menstrual irregularity and hirsutism that converts testosterone to estrogen and, therefore, this follicle will only become apparent if there is an increase in weight and has testosterone as its principal secretory product. Testosterone associated metabolic changes [98]. may increase the positive feedback of estrogen on pituitary LH It has also been proposed that weight gain is associated with secretion, resulting in increased ovarian steroid secretion, and low serum IGF-binding protein 1 levels, which may lead to can result in hyperandrogenism. Testosterone is aromatized in hyperandrogenism and PCO [70]. In addition, a significant peripheral adipose tissue, generally producing high–normal lev- weight gain was recorded in a retrospective ana­lysis of hospi- els of estrogen [61]. Women with this syndrome frequently have tal records of the women taking VPA who also had PCO and elevated cholesterol with abnormal lipid profiles, elevated insulin hyperandrogenism; these women had higher insulin and lower and glucose intolerance [90,91]. IGF-binding protein 1 levels. Although women with epilepsy may already have a higher The specific mechanism by which VPA induces insulin resis- instance of the PCOS, it has been suggested that treatment with tance remains to be determined. It is likely that, because VPA is a certain AEDs, particularly VPA, increases this risk further [2,70,89]. branched-chain fatty acid, it can compete with free fatty acids for The role of VPA in the pathogenesis of PCOS has been first raised albumin binding, increasing their local availability and thus their by Isojärvi et al., who showed that PCOS and hyper­androgenism physiological modulation of insulin secretion [94]. Moreover, it has may be more common in women with epilepsy who were treated been demonstrated that VPA can directly stimulate pancreatic with VPA than in women treated with other AEDs [2]. Other stud- b-cells [116] and inhibit GLUT-1 activity [117]. ies confirmed these findings [69,70,75,92]. Interestingly, Gorkemli Finally, in animal experiments VPA has been shown to alter et al. found no statistically significant duration-related rise of risk steroidogenesis and increase testosterone-to-estrodiol ratios in for patients who developed PCOS; the lack of a duration-related porcine ovarian follicles [118]. Continuous treatment with VPA reproductive dysfunction may support the hypothesis of early increased the number of follicular cysts and altered sex steroid occurring VPA-associated endocrine changes [93]. hormone levels in rats [119] and increased the number of ovarian However, recent research did not substantiate the role of follicular cysts in rats [120]. It remains to be proven that these VPA [60,76,94–96]; the relationship between PCOS and AED direct gonadal VPA effects are clinically relevant in humans. treatment remains controversial [75,95,97]. Moreover, VPA is associated with another phenomenon poten- The pathogenesis of PCOS appears to be multifactorial, including tially associated with the development of PCOS; it is an AED genetic predisposition and the intervention of environmental factors. with an inhibitory effect on the hepatic P450 enzyme system and, An important risk factor for PCOS is weight gain [98–101], which is a therefore, it may inhibit the metabolism of sex steroids, such as common and undesirable effect of certain AEDs, notably VPA and, testosterone, and thereby lead to increased androgen levels [121]. to a lesser extent, CBZ, vigabatrin and gabapentin [102–107]. Weight On the contrary, EIAEDs, such as CBZ, PHT or PB, may exert www.expert-reviews.com 1807 Review Verrotti, D’Egidio, Coppola, Parisi & Chiarelli a protective effect against the development of PCOS by reducing congenital malformations has been reported to increase with the biologically active testosterone in the serum and by increasing the number of AEDs used in polytherapy [140,141]. For some AEDs, nota- binding and metabolism of testosterone. bly VPA [127,142,143] and possibly LTG [144], the risk in monotherapy In conclusion, it remains unclear whether VPA is directly appears to be dose dependent. Comparative studies suggest that the responsible for the development of PCOS from otherwise nor- risk of malformation, in particular of neural tube defects, seems to mal ovaries. Although it is possible that weight gain may alter be greater with VPA compared with other AEDs [144–146]. the endocrine and biochemical features to produce PCOS, there In conclusion, available information indicates that the risk of is no conclusive evidence to support this hypothesis. For these congenital malformations is increased among offspring of women reasons, to date, VPA remains a first-line option for treatment of with epilepsy, and that this increase may be attributed largely to the many epilepsy types, including in young women. However, since effects of AEDs. However, the incidence of congenital malforma- VPA treatment is associated with greater disruption of reproduc- tions varies 20-fold across published studies [147,148], mainly because tive endocrine functions than other AEDs, the length of the of methodological differences. In fact, there are major differences menstrual cycles and bodyweight should be monitored in women in the populations studied, the diagnostic criteria used to identify with epilepsy after beginning treatment with VPA. abnormalities, exclusion criteria and the denominators used to calculate the risk of malformations. Therefore, although the use Pregnancy & epilepsy of AEDs during pregnancy is associated with an increased risk for Good seizure control is paramount during pregnancy, especially birth defects, this risk must be balanced against those associated in the light of the observation that maternal mortality rates are with uncontrolled seizures. Furthermore, AED-related risks to the higher in women with epilepsy compared with the general popu- fetus could probably be reduced by appropriate treatment adjust- lation [122]. Regarding the effects of seizures of the fetus, seizures ments (e.g., a switch from polytherapy to mono­therapy, avoidance other than generalized tonic–clonic seizures are unlikely to cause of VPA when possible and titration to the lowest effective dosage). harm. Convulsive seizures, on the other hand, induce lactic aci- dosis, which is transferred to the fetus and may also cause fetal Expert commentary bradycardia [123,124]. In addition, status epilepticus can result in Sexual dysfunction in women suffering from epilepsy is an impor- intrauterine death [125]. The risk for the latter may have been over- tant issue and in recent years there has been growing evidence to estimated, since one large prospective study reported only one case support the role of both epilepsy per se and different AEDs in the of intrauterine death and no maternal mortality among 36 cases development of this comorbidity. with status epilepticus [126]. Furthermore, recent data suggest Endocrinologic abnormalities related to epilepsy can reason- that the number of stillbirths is not increased among women ably be expected in view of the complex and close intercon- that are adequately treated for their epilepsy during pregnancy nections between the HPA and the cortex. Focal epileptic dis- [127,128]. Finally, there is no clear evidence that partial, absence or charges (in particular from the temporal lobe) can affect HPA myoclonic seizures adversely affect a pregnancy or the developing function. Consequently, the production of LH, FSH, GnRH fetus, other than by effects of trauma. and PRL and the concentrations and metabolism of their end In the past, women with epilepsy were considered at greater products (e.g., estrogen, testosterone and DHEAS) appears to risk for obstetric complications, including Cesarean delivery, pre- be modified in epileptic women. Most of the older AEDs (PB, eclampsia, pregnancy-related hypertension, premature contractions CBZ and PHT) are known to affect levels of steroid hormones or premature labor and delivery. Most recent studies, however, sug- by enhancing their metabolism through activation of the cyto- gest that with appropriate medical management the incidence of chrome P450 oxidative system, thereby also inducing SHBG complications in women with epilepsy is similar to that of the gen- synthesis in hepatocytes. eral population [128–133]. AED therapy should be optimized at least Moreover, VPA is associated with a frequent occurrence of 6 months before conception. The reduction or withdrawal of AED reproductive endocrine disorders characterized by polycystic therapy during pregnancy is pointless because any congenital mal- changes in the ovaries, high serum testosterone concentrations formations occur in very early stages of develop­ment. The reduction (hyperandrogenism) and menstrual disorders. Young women with or withdrawal of AED therapy during pregnancy is also hazardous epilepsy seem to be especially vulnerable to the effects of VPA because, although maternal seizures do not seem to increase the risk on serum androgen levels. It is probable that obesity and related of congenital malformations [134–138], they may be harmful to both hyperinsulinemia may exacerbate the VPA-related reproductive the mother and the fetus Mothers should be strongly encouraged to endocrine disorders; in the majority of cases these disorders are maintain adequate compliance with drug therapy [139]. reversible. There is a significant lack of data regarding the effects On the other hand, the risk of major congenital malformations is of new AEDs. two-to-three-times higher in children of mothers treated for epilepsy Physicians should be aware of reproductive endocrine dys- during pregnancy than is expected in the general population [124]. function that may occur in women with epilepsy during treat- The reasons for this increased risk are mainly owing to teratogenic ment. If a reproductive endocrine disorder is found AEDs effects of AEDs. In fact, a meta-ana­lysis suggested that the malfor- should be reviewed in terms of their indication for the par- mation rate among the offspring of women with untreated epilepsy ticular seizure type and their tolerability vis-à-vis their potential was similar to that of nonepileptic controls [134]. The incidence of for contributing to these endocrine problems.

1808 Expert Rev. Neurother. 9(12), (2009) Epilepsy, sex hormones & antiepileptic drugs in female patients Review

Five-year view obese patients and/or patients with previous ovarian dysfunc- It is now clear that both seizures and some old AEDs have det- tions). Currently, the concept of ‘personalized’ medicine is receiv- rimental effects on reproductive function in epileptic patients. ing much attention; as research in this area advances rapidly, it is In the coming years, understanding the underlying mechanisms probably that the choice of AEDs will be driven by more accurate of these effects will provide more information about the direct and complete considerations to optimize the treatment of epilepsy influence of the epileptogenic lesion and about the central and for the individual patients. peri­pheral effects on endocrine glands, the metabolism of sex hormones and binding proteins and the secondary endocrine Financial & competing interests disclosure complications of AED-related weight changes. The authors have no relevant affiliations or financial involvement with any One of the challenges of the next few years is to better define the organization or entity with a financial interest in or financial conflict with endocrine and reproductive effects of the new AEDs, especially in the subject matter or materials discussed in the manuscript. This includes long-term therapy. These findings will change our policy toward employment, consultancies, honoraria, stock ownership or options, expert female patients and enable us to better choose the appropriate testimony, grants or patents received or pending, or royalties. AEDs (particularly in subpopulations at risk, e.g., adolescents, No writing assistance was utilized in the production of this manuscript.

Key issues • Reproductive endocrine disorders, including polycystic ovary syndrome (PCOS), have been associated with epilepsy and the incidence of menstrual irregularities appears to be more common among women with epilepsy than among women without epilepsy. • Epilepsy itself may directly influence the endocrine control centers in the brain by altering the release of sex steroid hormones including the production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone and prolactin and the concentrations and metabolism of its end products such as estrogen and testosterone. • In localization-related epilepsy, clinical investigations indicate a close relationship between the occurrence of temporolimbic discharges and pituitary hormone changes, and an association between epilepsy laterality in temporolimbic epilepsy and the occurrence of certain reproductive endocrine disorders. • Left unilateral temporolimbic epilepsy is associated with a higher occurrence of PCOS, while right unilateral temporolimbic epilepsy is associated with hypothalamic amenorrhea. • A possible role for the use of antiepileptic drugs as an alternative pathogenic mechanism has been suggested. • The use of enzyme-inducing antieplileptic drugs, such as phenobarbital, phenytoin and carbamazepine, increases serum sex hormone- binding globulin concentrations leading to diminished bioactivity of estrodiol, which may result in menstrual disorders in some women, and thus to reduced fertility. • The inhibition of the aromatase complex (CYP19) activity, induced by phenobarbital, phenytoin, valproic acid (VPA), oxcarbazepine and lamotrigine, may explain the decreased production of estrodiol observed in vivo. • In women, the use of valproic acid (VPA), a non-enzyme-inducing antiepileptic drug, appears to be associated with a frequent occurrence of menstrual disorders, hyperandrogenisn and polycystic changes. These disorders are especially common among women who have gained weight during VPA treatment. • The mechanism of VPA-associated hyperandrogenism may result from inhibition of the conversion of testosterone to estrogen induced by VPA. • The mechanisms of VPA-induced PCOS are still controversial. VPA-induced weight gain or obesity and the resultant insulin resistance have been suggested to predispose patients to PCOS.

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152 Duncan S, Blacklaw J, Beastall GH, • Claudia D’Egidio • Pasquale Parisi Brodie MJ. Sexual function in women with Department of Pediatrics, University of Department of Child Neurology and Sleep epilepsy. Epilepsia 38, 1074–1081 (1997). Chieti, Via dei Vestini 5, 66100 Chieti, Centre, University of Rome, Italy 153 Morrell MJ, Guldner GT. Self-reported Italy Tel.: +39 068 213 529 sexual function and sexual arousability in Tel.: +39 087 135 8015 Fax: +39 068 245 556l women with epilepsy. Epilepsia 37, Fax: +39 087 157 4831 • Francesco Chiarelli 1204–1210 (1996). [email protected] Department of Pediatrics, University of • Giangennaro Coppola Chieti, Via dei Vestini 5, 66100 Chieti, Clinic of Child Neuropsychiatry, Second Italy Affiliations University of Naples, Italy Tel.: +39 087 135 8015 • Alberto Verrotti Tel.: +39 081 566 6695 Fax: +39 087 157 4831 Department of Pediatrics, University of Fax: +39 081 566 6694 [email protected] Chieti, Via dei Vestini 5, 66100 Chieti, [email protected] Italy Tel.: +39 087 135 8015 Fax: +39 087 157 4831 [email protected]

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