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Review For reprint orders, please contact [email protected] Epilepsy, sex hormones and antiepileptic drugs in female patients Expert Rev. Neurother. 9(12), 1803–1814 (2009) Alberto Verrotti†, Claudia D’Egidio, Giangennaro Coppola, Pasquale Parisi and Francesco Chiarelli Author for correspondence Department of Pediatrics, University of Chieti, Via dei Vestini 5, 66100 Chieti, Italy Tel.: +39 087 135 8015 Fax: +39 087 157 4831 [email protected] † Women with epilepsy have a higher incidence of reproductive endocrine disorders than the general female population. These alterations include polycystic ovary syndrome, hyperandrogenemia, infertility, hypothalamic amenorrhea and hyperprolactinemia. Reproductive 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 hypothalamic–pituitary axis, thus altering the release of sex steroid hormones, including the production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone and prolactin. AEDs may modulate hormone release from the hypothalamic–pituitary– gonadal axis and they may alter the metabolism of sex hormones and their binding proteins. Hepatic enzyme-inducing AEDs, such as carbamazepine and phenytoin, may be most clearly linked to altered metabolism of sex steroid hormones, but valproic acid, an enzyme inhibitor, has also been associated with a frequent occurrence of polycystic ovary syndrome and 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 affecting women during their reproductive years, and is associated with hormonal disturbances resulting in altered endocrine reproduction and sexual function [1,2] . A possible role for seizure disorder or, alternatively, of the use of antiepileptic drugs (AEDs), have been suggested as the pathogenetic mechanisms. The brain regulates hormonal secretion and is sensitive to hormonal feedback; the neuroendocrine feedback system includes the hypothalamus, pituitary, gonads and amygdala. The amygdala is linked to the hypothalamic– pituitary axis (HPA) [3] , which is involved in the regulation, production and secretion of ovarian steroids. Reproductive endocrine disorders associated with epilepsy can be expected in view of the complex interconnections between the HPA and the limbic system; the involvement of medial temporal lobe regions in epilepsy may cause changes in sex hormone secretion and, consequently, reproductive function [4] . Moreover, AEDs may also alter hormone levels and interfere with reproductive function [5,6] . www.expert-reviews.com 10.1586/ERN.09.112 This review evaluates whether and to what degree epilepsy and its treatment can affect reproductive function. For this purpose, this review is subdivided into two main sections: the effects of epilepsy on reproductive function and the effects of AEDs on sex hormones. Effects of epilepsy on reproductive function Reproductive endocrine disorders, such as menstrual cycle disturbances and ovulatory dysfunctions, have frequently been reported in epileptic women [1–3,5–13] . These abnormalities usually result from abnormal reproductive endocrine function and are associated with lower rates of ovulation and higher rates of infertility [12] . Menstrual disorders are currently estimated to occur in a third of women with epilepsy compared with 12–14% of women in the general population [13] . Anovulation, hypothalamic amenorrhea (HA), hyperandrogenemia, poly cystic ovary syndrome (PCOS), functional hyperprolactinemia, premature menopause and © 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 (Box 1) [1,9,14–20] . Epilepsy itself may have effects on sex hormone levels and reproductive endocrine function [1,5,21–22,23] . Animal studies have demonstrated that reproductive endocrine and sexual dysfunction is more common in partial compared with generalized epilepsy, especially in temporal lobe epilepsy [24–26] ; animal investigations demonstrated that induction of temporo–limbic seizures can cause changes in reproductive hormone levels and reproductive function [24,25,27] . In particular, amygdala seizures in female rodents can cause anovulation, elevated serum testosterone levels and the accumulation of follicular cystis in the ovaries [24] . These findings have also been confirmed in human studies [14,28] . More than a third of cycles in women with localizationrelated epilepsy are anovulatory, compared with 8–10% in controls [11,13,29–33] . Partial epilepsy, mainly when originating in the temporal lobe, is the form most frequently associated with reproductive dysfunction [1,13,19,34] . However, other studies demonstrated that more than 50% of patients with generalized convulsions may develop reproductive and sexual abnormalities [21,29,35] ; in particular, hyperandrogenemia and PCOS are more frequent in women with idiopathic generalized epilepsy than in localization-related epilepsy [14,29,36] . Interestingly, Herzog et al., examined 50 women with tempolimbic epilepsy and found that 28 patients had amenorrhea, oligoamenorrhea, or abnormally long or short menstrual cycle intervals; 19 out of the 28 women with epilepsy and menstrual disorders had readily identifiable reproductive endocrine disorders: PCOS in ten, HA in six, premature menopause in two and hyperprolactinemia in one [1] . Since no significant relationship between the occurrence of menstrual disorders and the use of AEDs has been found, it is suggested that epilepsy may have an independent effect on reproductive function. This is in agreement with a previous study describing a significantly higher frequency of ovulatory dysfunction in female patients, not correlated with the use of any specific AED [35] . Moreover, high levels of luteinizing hormone (LH) and an altered LH-to-follicle-stimulating hormone (FSH) ratio have been reported in women with epilepsy [17–19] . The presence of elevated LH pulse frequency in untreated or epileptic women with regular menstrual cycles supports the notion that epilepsy itself may contribute to reproductive abnormalities [21,35] . Box 1. Frequent reproductive dysfunctions in women with epilepsy. • Hyperandrogenism [29,36,46,94] • High levels of luteinizing hormone and luteinizing hormone-tofollicle-stimulating hormone ratio [16,17,36,55] • Polycystic ovary syndrome [1,13,14,30,31,46,47,92–93] • Menstrual irregularities [1,17,32,35,92] • Premature menopause [1,15,16] • Infertility [7,9,110,149] • Hyperprolactinemia [42,53,150,151] • Sexual dysfunction [14,50,52,152,153] 1804 Interestingly, a recent cross-sectional observational study of Murialdo et al. evaluated the relationships between sex steroids and seizure frequency in women with partial epilepsy on AED treatments [37] . The authors found that estrodiol, free estrodiol and progesterone levels were lower in both ovarian phases in patients, whereas those of sex hormone-binding globulin (SHBG) were higher than in controls. When changes in hormone levels were compared with those in healthy controls, luteal-free estrodiol and progesterone levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures. Furthermore, an inverse relationship was found between free estrodiol levels and seizure frequency scores during the follicular phase, and with disease duration in the luteal phase. However, the authors suggested that these findings may be attributed to the longer duration of AED treatments and the more frequent use of enzyme-inducing AEDs (EIAEDs) in subjects with more severe seizures. Accordingly, a previous retrospective study reported that menstrual disorders were more frequent in patients with high seizure frequency (less than five seizures per year) [38] . The mechanisms underlying the association between epilepsy and reproductive endocrine disorders are still not clear. HPA dysfunction is suggested by observations that pituitary release of LH in women with epilepsy is altered both spontaneously and in response to gonadotropin-releasing hormone (GnRH) [1,30,31] . The brain controls reproductive function primarily through hypothalamic regulation of pituitary secretion [39] . The hypo thalamus receives direct connections from the cerebral hemispheres, especially from temporolimbic structures that are commonly involved in epilepsy and, most notably, from the amygdala [1,40,41] . In the majority of cases, the epileptic activity in the frontal lobe exhibits a propagation towards the temporal lobe and, thereby, influences the hormonal pathway of prolactin (PRL). [42] . Clinically, there is evidence to suggest that epileptiform discharges may disrupt the temporolimbic modulation of hypothalamic–pituitary function [14,26] and, ultimately, lead to changes in ovarian steroidogenesis and morphology [43] . There are also important clinical findings that indicate that the laterality and focality of epilepsy may be important determinants of certain reproductive endocrine disorders [1,14,28,44–46] . In fact, unilateral temporolimbic discharges are associated with laterally differing changes in hormonal secretion at all levels of the neuroendocrine reproductive axis. Consequently, different reproductive disorders may develop in relation to left- and right-sided temporolimbic epilepsy; in particular, left unilateral temporolimbic epilepsy is associated with a higher occurrence of PCOS [14,47] . Indeed, seizures in the left side of the limbic system increase the pulse frequencies of GnRH secretion that, in turn, increases the LH/FSH ratios and testosterone levels. By contrast, right unilateral temporolimbic epilepsy is associated with lower GnRH pulse frequency, which causes a decrease in LH and estrogen levels [1,14] . These hormonal changes are characteristic of HA [9,28,48] . Nevertheless, a recent experiment using the amygdala kindling model in rats demonstrated that, in female rats, seizures that originate in the left or right amygdala do not result in lateralized effects on the reproductive system [27] . Expert Rev. Neurother. 9(12), (2009) Epilepsy, sex hormones & antiepileptic drugs in female patients Epileptic discharges in limbic structures may also contribuite to sexual dysfunction in women, such as lack of sexual interest and high rates of orgasmic dysfunction, including anorgasmia, dyspareunia, vaginism or insuffcient vaginal lubrication [49,50] . Herzog et al. found that right temporal epileptic discharges in women were associated with hypogonadotropic hypogonadism, including decreased sexual interest [1] . Sexuality in people with epilepsy may be adversely affected by alterations in the pituitary gonadotropins, PRL and sex steroid hormones [1,12] . Limbic efferents seem to exhibit an impact on the HPA even in the interictal phase of the disorder, and post-ictally elevated PRL serum concentrations can be detected. In correlation with the type of seizures, evidence of elevated PRL is found in 88% of seizures following generalized tonic–clonic seizures, in 78% of seizures following complex partial seizures and in 22% of seizures following simple partial seizures [51] . The epileptic activity in the frontal lobe exhibits propagation towards the temporal lobe and thereby influences the hormonal pathway of PRL, which can also show tendencies to post-ictal elevation [42] . In women (and men) with epilepsy, reduced genital blood flow during erotic stimulation was found via video. The women with epilepsy who were examined showed a reduced elevation of genital blood flow during the presentation of erotic video movies in comparison with healthy controls [52] . Irrespective of gender, sexual questionnaires revealed reduced libido more commonly in the right- than in the left-sided temporal lobe seizure origin 44] . However, compelling explanation remains to be found. It is possible that the right sided temporal lobe disturbance may have a more pronounced influence on emotions and, therefore, indirectly on libido [53] . Baird et al. reported that a third of their 58 lobectomy patients had an increase in sexual activity after surgery, compared with a quarter of patients having decreased postsurgical sexual activity [45] . Furthermore, Manna et al. recently��������������������� demonstrated �������������������� a relationship between a serotonin transporter genetic polymorphism and temporal lobe epilepsy, suggesting that the serotonin transporter gene may play a role in the development of temporal lobe epilepsy [54] . These findings indicate that some patients with epilepsy may be genetically susceptible to sexual dysfunction through a serotonin transport mechanism. In conclusion, an increased frequency of reproductive endocrine disorders, secondary to pituitary hormone changes, has been reported in women with epilepsy, especially among those with partial epilepsy of temporal lobe origin. Therefore, regular monitoring of reproductive function, including menstrual disorders, infertility, hirsutism and galactorrhea, are recommended. Effects of antiepileptic drugs on sex hormone levels A large body of literature addresses the presence of alterations in sex hormone levels in women taking AEDs [2,5,11,17,18,55–62] . Antiepileptic drugs may have an influence on the metabolism of the central and/or peripheral endocrine hormones and their binding proteins. Hepatic EIAEDs, such as phenobarbital (PB), phenytoin (PHT) and carbamazepine (CBZ), are most clearly linked to altered metabolism of sex steroid hormones. www.expert-reviews.com Review In fact, in the late 1970s and 1980s, serum sex hormone levels were reported to be abnormal in female patients treated with EIAEDs [55,56] . Victor et al. were the first to report elevated serum SHBG concentrations in women treated with PHT [57] , and this finding was later confirmed [55,56] . Low dehydroepiandrosterone sulphate (DHEAS) levels have also been reported in women taking PHT [58] , but its clinical significance is unknown. However, similarly impaired steroid levels have also been shown in women with epilepsy treated with other EIAEDs [60,63] . In particular, Galimberti et al. reported decreased DHEAs levels and increased cortisol levels in women treated with CBZ, PHT, PB in monoor poly-therapy, but not in those treated with non-EIAEDs (NEIAEDs) [63] . The most interesting finding in this study concerned the relation between epilepsy severity, increased cortisol, and decreased DHEAs levels. In fact, cortisol and DHEAS levels were directly and indirectly correlated with seizure frequency, respectively, suggesting that changes in adrenal steroid levels must be ascribed mainly to the frequency of seizures, which are known to activate the hypothalamus–pituitary–adrenal axis [64] . The most recent cross-sectional study showed that women with epilepsy taking EIAED polytherapies had lower levels of estradiol and a lower free estrogen index (FEI) than patients treated with a single EIAED [59] . EIAEDs induce hepatic cytocrome P450dependent steroid hormone breakdown and production of SHBG, thereby reducing biologically active sex hormone serum concentrations, such as estrodiol and testosterone [5,18,60–62] . Galimberti et al. reported that the older patients and those with longer disease duration showed higher levels of SHBG [59] . This can be attributed to the physiologic increase in binding protein levels with aging and to the use of EIAEDs. These changes in serum SHBG levels, and the lowered total estrodiol levels, implied a global decrease in biologically active free estrodiol. Conversely, significant differences in estrodiol levels and in FEI were found between women on different AED regimens. Patients treated with EIAED polytherapies showed estrodiol and FEI values that were lower than those recorded both in patients treated with a single EIAED or NEIAED, or in those on combined (EIAED plus NEIAED) therapies. Recently, Jacobsen et al. reported that PB, PHT, valproic acid (VPA), oxcarbazepine (OXC) and lamotrigine (LTG), but not CBZ, inhibit the aromatase complex (CYP19) activity that converts testosterone into estrodiol in vitro [65] . Accordingly, a more recent study demonstrated that VPA and LTG reduced CYP19 aromatase activity in human ovarian follicular cells, but only in FSH-stimulated cells and at higher concentrations [66] . Additive enzyme inhibition has been observed in combination experiments with multiple AEDs; therefore, aromatase inhibition might explain the decreased production of estrodiol observed in vivo, mainly when combined AED therapies were employed [59] . Many studies that have evaluated the reproductive endocrine effects of CBZ in female patients have consistently reported increased serum SHBG levels and other sex hormone abnormalities [2,62,65,67–71] . Interestingly, Hamed et al. reported elevated levels of LH and FSH in 28.1 and 34.4% of CBZ-treated patients, 1805 Review Verrotti, D’Egidio, Coppola, Parisi & Chiarelli respectively [17] . Dana-Haeri et al. observed that epileptic patients on CBZ had elevated baseline LH levels and a exaggerated LH response to the GnRH and thyrotropin-releasing hormones stimulation [72] . This exaggerated LH response may be related to a positive-feedback mechanism. Furthermore, they reported slightly higher PRL levels 2 h after stimulation with GnRH and thyrotropin-releasing hormone. These changes have not been confirmed by other studies [60,72–74] . Recently, a double-blind, randomized, controlled withdrawal study, reported that CBZ withdrawal was associated with a significant decrease in SHBG levels and a increase in serum testosterone concentrations, free androgen index (FAI) and estrogen/SHBG ratio; these results demonstrated that potential changes in sex steroid levels, induced by CBZ treatment, could be reversible [71] . However, most of the studies have not shown an increased frequency of menstrual disorders or hyperandrogenism and polycystic ovaries (PCO) in women taking CBZ [2,60,67,75,76] , despite alterations in serum sex hormone concentrations. In fact, single abnormal laboratory findings without symptoms may not constitute a clinically relevant endocrine disorder. Among NEIAEDs, VPA appears to be associated with frequent reproductive endocrine disorders, such as polycystic changes in the ovaries, high serum testosterone concentrations and amenorrhea [2,38,77] . These abnormalities are especially common among women who have gained weight during VPA therapy [61] . In 1993, Isojarvi et al. through a cross-sectional study showed that menstrual disorders were common among women taking VPA monotherapy for epilepsy and that they were frequently associated with PCOs and/or hyperandrogenism [2] . PCOs and hyperandrogenism were expecially common if VPA medication was started before the age of 20 years [70] . An increased number of ovarian cysts and PCOS in women on VPA monotherapy was subsequently confirmed [75,78,79] . In another study of women taking VPA currently or within the preceding 3 years, 38.1% had experienced at least one anovulatory cycle in contrast to 10.7% of women not using VPA within the preceding 3 years [11] . Interestingly, women with idiopathic generalized epilepsy receiving VPA were at highest risk for anovulatory cycles, polycystic ovaries, elevated BMI and hyperandrogenism. A more recent prospective study by Morrell et al. reported a higher incidence of hyperandrogenism or ovulatory dysfunction in women taking VPA for epilepsy than in women taking LTG [80] . Moreover, a significant increase in serum testosterone concentration was especially prominent in women initiating treatment before the age of 20 years, suggesting that young women with epilepsy seem to be especially vulnerable to the effects of VPA on ovarian function [70] . By contrast, in two prospective randomized studies by Kwan et al. [81] and Stephen et al. [82] , comparing women receiving VPA and LTG monotherapy, no significant difference in change of testosterone levels from baseline was found between the VPA and LTG groups. This discrepancy is probably owing two main reasons. First, the sample size in these two studies [81,82] were comparatively smaller than in the study by Morrell et al. [80] . Second, the mean age of female subjects in the study by Kwan et al. [81] was more than 10 years older than that of subjects in the study by Morrell et al. [80] . 1806 Alterations in serum androgen levels have even been detected before and during pubertal development in young girls taking VPA [83] . The mean serum testosterone levels and FAI were high in all pubertal phases in girls on VPA, even if the frequency of hyperandrogenism increased with pubertal development. Therefore, it is likely that VPA may affect steroid metabolism during the sensitive period, at the onset of puberty. Accordingly, hyperandrogenism observed in most adult women on VPA therapy can already be induced before the emergence of clinical signs of puberty. A recent cross-sectional study showed that VPA treatment was only associated with higher testosterone levels in girls after menarche, suggesting that the sensitivity to VPA-induced hyperandrogenism is a function of sexual maturation [6] . In postmenarcheal girls, the presence of hyperandrogenemia without clinical hyperandrogenism may reflect the increase in testosterone that precedes the appearance of clinical signs (i.e., hirsutism, acne, menstrual disorders and PCOs). This emphasizes the importance of careful endocrine observation of girls treated with VPA. However, it is encouraging to note that the reproductive endocrine effects of VPA may be reversible after the medication is discontinued; a 5 year follow-up study in young women showed that the 60% of the patients who were administered VPA had PCOS compared with 5.5% of the girls whose medication had been discontinued [82] . The mechanism by which VPA could cause hyperandrogenism and related reproductive disorders is still unclear. It may be that VPA can have a direct effect on ovarian androgen production or that, acting as enzyme inhibitor, VPA may inhibit the metabolism of sex hormones and thereby lead to increased serum androgen levels [53,84,85] . Moreover, obesity (induced by VPA treatment) and associated hyperinsulinemia could be implicated in the development of PCOS and hyperandrogenism (see later) [2,70] . Recently, it has been shown that VPA blocks the androgen and progesterone receptors, but not the estrogen receptor [86] . The strong progesterone receptor antagonism by VPA suggests that some biological effects in women may be at least partly due to impaired progesterone receptor-mediated progesterone action on reproductive tissue (a previously unrecognized factor contri buting to the low fertility of women with epilepsy). In addition, antiprogestin effects may contribute to the higher frequency of anovulation among VPA-treated women with epilepsy [57,77] . The reproductive endocrine effects of the new AEDs have not been widely studied. However, most of the data suggest that OXC therapy is not associated with changes in reproductive function in epileptic patients [83,87] . Only one recent study reported low serum testosterone concentrations, low FAI, elevated levels of androstendione and DHEAS and increased prevalence of PCO in women during OXC treatment [88] . A low prevalence of reproductive disorders has been reported during LTG therapy [5,73] , and replacement of VPA with LTG resulted in normalization of endocrine function in women with previously identified endocrine disorders (PCO, hyperandrogenism and increase in bodyweight), probably related to VPA medication [89] ; serum insulin and testosterone levels returned to normal within 2 months following Expert Rev. Neurother. 9(12), (2009) Epilepsy, sex hormones & antiepileptic drugs in female patients VPA replacement, and the levels remained normal thereafter. Consistent with these findings, Morrell et al. reported that women taking LTG had lower serum testosterone levels than women taking VPA [90] . In conclusion, careful endocrine observation of girls treated with EIAED and VPA is important, while it seems that the new AEDs may offer an alternative if reproductive endocrine problems emerge during treatment with the older AEDs. Ovarian function should be monitored closely as part of the comprehensive care of women with epilepsy to prevent adverse effects of ovarian failure, mainly in patients with more frequent seizures who need AED polytherapies and/or in patients treated with old AEDs. AEDs & PCOS The most common reproductive endocrine disorder in women with epilepsy is PCOS [13,21,75] . PCOS occurs in 10–20% of women with epilepsy compared with 5–6% of women in the general population [9,13,14,75] . Polycystic ovary syndrome 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 FSH, while levels of LH are normal or elevated [61] . These conditions can produce a failure of ovulation and the partially developed follicle is retained in the ovary in the form of a tiny cyst [46,47] . This partially developed follicle is secretory but it is deficient in aromatase, the enzyme that converts testosterone to estrogen and, therefore, this follicle 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, and can result in hyperandrogenism. Testosterone is aromatized in peripheral adipose tissue, generally producing high–normal levels of estrogen [61] . Women with this syndrome frequently have elevated cholesterol with abnormal lipid profiles, elevated insulin and glucose intolerance [90,91] . Although women with epilepsy may already have a higher instance of the PCOS, it has been suggested that treatment with certain AEDs, particularly VPA, increases this risk further [2,70,89] . The role of VPA in the pathogenesis of PCOS has been first raised by Isojärvi et al., who showed that PCOS and hyperandrogenism may be more common in women with epilepsy who were treated with VPA than in women treated with other AEDs [2] . Other studies confirmed these findings [69,70,75,92] . Interestingly, Gorkemli et al. found no statistically significant duration-related rise of risk for patients who developed PCOS; the lack of a duration-related reproductive dysfunction may support the hypothesis of early occurring VPA-associated endocrine changes [93] . However, recent research did not substantiate the role of VPA [60,76,94–96] ; the relationship between PCOS and AED treatment remains controversial [75,95,97] . The pathogenesis of PCOS appears to be multifactorial, including genetic predisposition and the intervention of environmental factors. An important risk factor for PCOS is weight gain [98–101] , which is a common and undesirable effect of certain AEDs, notably VPA and, to a lesser extent, CBZ, vigabatrin and gabapentin [102–107] . Weight www.expert-reviews.com Review gain may lead to the expression or exacerbation of PCOS in some genetically predisposed women, reducing insulin sensitivity. Thus, AED-related weight increases could trigger the manifestation of a clinically relevant endocrine disorder; in particular, VPA-induced weight gain and the related endocrine abnormalities (e.g., hyperinsulinemia and hyperandrogemia) may induce the development of PCOS [18] . The pathogenic mechanisms underlying weight gain during VPA treatment are still unclear [70,108–111] . The observation that VPA-treated epileptic patients who reported weight gain developed increased appetite, thirst and quenching with calorie-rich beverages supports the hypothesis of a stimulating effect of VPA on the hypothalamus [89,109,112,113] . It has been also suggested that VPA-related obesity may be associated with elevated serum leptin levels in women with epilepsy [70,102] , but it is unclear whether leptin behavior in VPAinduced obesity is similar to that in any other obesity situation, as supported by some data [114] . VPA can modify leptin levels through the increase of bodyweight, and this modification is related to BMI. Moreover, it is likely that obesity is the cause of insulin resistance and related hyperinsulinemia [103] , which are often associated with PCOS [115] . By suppressing the synthesis of SHBG, insulin increases free androgen concentrations, subsequently increasing the degree of hirsutism. The positive correlation between insulin resistance and obesity means that in some women with PCO, the clinical manifestation of menstrual irregularity and hirsutism will only become apparent if there is an increase in weight and associated metabolic changes [98] . It has also been proposed that weight gain is associated with low serum IGF-binding protein 1 levels, which may lead to hyperandrogenism and PCO [70] . In addition, a significant weight gain was recorded in a retrospective analysis of hospital records of the women taking VPA who also had PCO and hyperandrogenism; these women had higher insulin and lower IGF-binding protein 1 levels. The specific mechanism by which VPA induces insulin resistance remains to be determined. It is likely that, because VPA is a branched-chain fatty acid, it can compete with free fatty acids for albumin binding, increasing their local availability and thus their physiological modulation of insulin secretion [94] . Moreover, it has been demonstrated that VPA can directly stimulate pancreatic b-cells [116] and inhibit GLUT-1 activity [117] . Finally, in animal experiments VPA has been shown to alter steroidogenesis and increase testosterone-to-estrodiol ratios in porcine ovarian follicles [118] . Continuous treatment with VPA increased the number of follicular cysts and altered sex steroid hormone levels in rats [119] and increased the number of ovarian follicular cysts in rats [120] . It remains to be proven that these direct gonadal VPA effects are clinically relevant in humans. Moreover, VPA is associated with another phenomenon potentially associated with the development of PCOS; it is an AED with an inhibitory effect on the hepatic P450 enzyme system and, therefore, it may inhibit the metabolism of sex steroids, such as testosterone, and thereby lead to increased androgen levels [121] . On the contrary, EIAEDs, such as CBZ, PHT or PB, may exert 1807 Review Verrotti, D’Egidio, Coppola, Parisi & Chiarelli a protective effect against the development of PCOS by reducing biologically active testosterone in the serum and by increasing the binding and metabolism of testosterone. In conclusion, it remains unclear whether VPA is directly responsible for the development of PCOS from otherwise normal ovaries. Although it is possible that weight gain may alter the endocrine and biochemical features to produce PCOS, there is no conclusive evidence to support this hypothesis. For these reasons, to date, VPA remains a first-line option for treatment of many epilepsy types, including in young women. However, since VPA treatment is associated with greater disruption of reproductive endocrine functions than other AEDs, the length of the menstrual cycles and bodyweight should be monitored in women with epilepsy after beginning treatment with VPA. Pregnancy & epilepsy Good seizure control is paramount during pregnancy, especially in the light of the observation that maternal mortality rates are higher in women with epilepsy compared with the general population [122] . Regarding the effects of seizures of the fetus, seizures other than generalized tonic–clonic seizures are unlikely to cause harm. Convulsive seizures, on the other hand, induce lactic acidosis, which is transferred to the fetus and may also cause fetal bradycardia [123,124] . In addition, status epilepticus can result in intrauterine death [125] . The risk for the latter may have been overestimated, since one large prospective study reported only one case of intrauterine death and no maternal mortality among 36 cases with status epilepticus [126] . Furthermore, recent data suggest that the number of stillbirths is not increased among women that are adequately treated for their epilepsy during pregnancy [127,128] . Finally, there is no clear evidence that partial, absence or myoclonic seizures adversely affect a pregnancy or the developing fetus, other than by effects of trauma. In the past, women with epilepsy were considered at greater risk for obstetric complications, including Cesarean delivery, preeclampsia, pregnancy-related hypertension, premature contractions or premature labor and delivery. Most recent studies, however, suggest that with appropriate medical management the incidence of complications in women with epilepsy is similar to that of the general population [128–133] . AED therapy should be optimized at least 6 months before conception. The reduction or withdrawal of AED therapy during pregnancy is pointless because any congenital malformations occur in very early stages of development. The reduction or withdrawal of AED therapy during pregnancy is also hazardous because, although maternal seizures do not seem to increase the risk of congenital malformations [134–138] , they may be harmful to both the mother and the fetus Mothers should be strongly encouraged to maintain adequate compliance with drug therapy [139] . On the other hand, the risk of major congenital malformations is two-to-three-times higher in children of mothers treated for epilepsy during pregnancy than is expected in the general population [124] . The reasons for this increased risk are mainly owing to teratogenic effects of AEDs. In fact, a meta-analysis suggested that the malformation rate among the offspring of women with untreated epilepsy was similar to that of nonepileptic controls [134] . The incidence of 1808 congenital malformations has been reported to increase with the number of AEDs used in polytherapy [140,141] . For some AEDs, notably VPA [127,142,143] and possibly LTG [144] , the risk in monotherapy appears to be dose dependent. Comparative studies suggest that the risk of malformation, in particular of neural tube defects, seems to be greater with VPA compared with other AEDs [144–146] . In conclusion, available information indicates that the risk of congenital malformations is increased among offspring of women with epilepsy, and that this increase may be attributed largely to the effects of AEDs. However, the incidence of congenital malformations varies 20-fold across published studies [147,148] , mainly because of methodological differences. In fact, there are major differences in the populations studied, the diagnostic criteria used to identify abnormalities, exclusion criteria and the denominators used to calculate the risk of malformations. Therefore, although the use of AEDs during pregnancy is associated with an increased risk for birth defects, this risk must be balanced against those associated with uncontrolled seizures. Furthermore, AED-related risks to the fetus could probably be reduced by appropriate treatment adjustments (e.g., a switch from polytherapy to monotherapy, avoidance of VPA when possible and titration to the lowest effective dosage). Expert commentary Sexual dysfunction in women suffering from epilepsy is an important issue and in recent years there has been growing evidence to support the role of both epilepsy per se and different AEDs in the development of this comorbidity. Endocrinologic abnormalities related to epilepsy can reasonably be expected in view of the complex and close interconnections between the HPA and the cortex. Focal epileptic discharges (in particular from the temporal lobe) can affect HPA function. Consequently, the production of LH, FSH, GnRH and PRL and the concentrations and metabolism of their end products (e.g., estrogen, testosterone and DHEAS) appears to be modified in epileptic women. Most of the older AEDs (PB, CBZ and PHT) are known to affect levels of steroid hormones by enhancing their metabolism through activation of the cytochrome P450 oxidative system, thereby also inducing SHBG synthesis in hepatocytes. Moreover, VPA is associated with a frequent occurrence of reproductive endocrine disorders characterized by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. Young women with epilepsy seem to be especially vulnerable to the effects of VPA on serum androgen levels. It is probable that obesity and related hyperinsulinemia may exacerbate the VPA-related reproductive endocrine disorders; in the majority of cases these disorders are reversible. There is a significant lack of data regarding the effects of new AEDs. Physicians should be aware of reproductive endocrine dysfunction that may occur in women with epilepsy during treatment. If a reproductive endocrine disorder is found AEDs should be reviewed in terms of their indication for the particular seizure type and their tolerability vis-à-vis their potential for contributing to these endocrine problems. Expert Rev. Neurother. 9(12), (2009) Epilepsy, sex hormones & antiepileptic drugs in female patients Five-year view It is now clear that both seizures and some old AEDs have detrimental effects on reproductive function in epileptic patients. In the coming years, understanding the underlying mechanisms of these effects will provide more information about the direct influence of the epileptogenic lesion and about the central and peripheral effects on endocrine glands, the metabolism of sex hormones and binding proteins and the secondary endocrine complications of AED-related weight changes. One of the challenges of the next few years is to better define the endocrine and reproductive effects of the new AEDs, especially in long-term therapy. These findings will change our policy toward female patients and enable us to better choose the appropriate AEDs (particularly in subpopulations at risk, e.g., adolescents, Review obese patients and/or patients with previous ovarian dysfunctions). Currently, the concept of ‘personalized’ medicine is receiving much attention; as research in this area advances rapidly, it is probably that the choice of AEDs will be driven by more accurate and complete considerations to optimize the treatment of epilepsy for the individual patients. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. 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 hormonebinding 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. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1 • 2 Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch. Neurol. 43, 341–346 (1986). Shows the lack of a significant relationship between the occurrence of menstrual disorders and the use of antiepileptic drugs (AEDs) in female epileptic patients. Isojärvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllylä VV. 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Self-reported sexual function and sexual arousability in women with epilepsy. Epilepsia 37, 1204–1210 (1996). • • Affiliations • Alberto Verrotti Department of Pediatrics, University of Chieti, Via dei Vestini 5, 66100 Chieti, Italy Tel.: +39 087 135 8015 Fax: +39 087 157 4831 [email protected] 1814 Claudia D’Egidio Department of Pediatrics, University of Chieti, Via dei Vestini 5, 66100 Chieti, Italy Tel.: +39 087 135 8015 Fax: +39 087 157 4831 [email protected] Giangennaro Coppola Clinic of Child Neuropsychiatry, Second University of Naples, Italy Tel.: +39 081 566 6695 Fax: +39 081 566 6694 [email protected] • Pasquale Parisi Department of Child Neurology and Sleep Centre, University of Rome, Italy Tel.: +39 068 213 529 Fax: +39 068 245 556l • Francesco Chiarelli Department of Pediatrics, University of Chieti, Via dei Vestini 5, 66100 Chieti, Italy Tel.: +39 087 135 8015 Fax: +39 087 157 4831 [email protected] Expert Rev. Neurother. 9(12), (2009)