We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism associated with weight gain and hyperinsulinemia in women taking valproate for epilepsy. The purpose of this study was to evaluate the risks related to valproate-induced hyperinsulinemia and their reversibility after discontinuing the medication. Sixteen women with valproate-related polycystic ovaries or hyperandrogenism participated in the study. Vaginal ultrasonography was performed, and endocrine and lipid parameters were measured. Thereafter, lamotrigine was substituted for valproate and the patients were observed for 12 months. Twenty-four healthy age-matched women served as control subjects. Twelve women completed the 12-month follow-up. While still on valproate they had centripetal obesity with associated hyperinsulinemia and unfavorable serum lipid profiles. The body-mass index and fasting serum insulin and testosterone concentrations decreased during the first year after replacing valproate with lamotrigine whereas the HDL-cholesterol/total cholesterol ratios increased from 0.17 +/- 0.06 to 0.26 +/- 0.05. The total number of polycystic ovaries in these women decreased from 20 during valproate medication to 11 one year after replacing valproate with lamotrigine. Valproate induces a metabolic syndrome with centripetal obesity, hyperinsulinemia, lipid abnormalities, and polycystic ovaries/hyperandrogenism in women with epilepsy. These valproate-related risks can be reduced by substituting lamotrigine for valproate.

Summary:Purpose: Antiepileptic drugs may affect the serum thyroid hormone concentrations. The aim of this study was to evaluate thyroid function in 78 girls taking carbamazepine (CBZ), oxcarbazepine (OXC), or valproate (VPA) monotherapy for epilepsy and after withdrawal of the treatment.Methods: Forty-one girls taking VPA, 19 taking CBZ, and 18 taking OXC for epilepsy, as well as 54 healthy age-matched controls, aged 8 to 18 years, participated in the study. All the girls were examined clinically, and their pubertal stage was assessed. Blood samples were obtained for thyroid hormone and antibody assays. These examinations were repeated after a mean followup of 5.8 years to assess thyroid function, and 64 (82%) of 78 patients and 42 (78%) of 54 controls agreed to participate in the second evaluation.Results: In the first evaluation, the mean serum thyroid hormone concentrations were lower in the girls taking CBZ [thyroxine (T 4 ), 70.2; SD, 10.9 nM; and free thyroxine (FT 4 ), 11.5; SD, 1.8 pM] or OXC (T 4 , 74.9; SD, 16.4 nM; and FT 4 , 11.3; SD, 1.8 pM) than in the control girls (T 4 , 96.6; SD, 15.1 nM, and FT 4 , 14.4; SD, 1.5 pM; p < 0.001, all comparisons). However, thyrotropin (TSH) concentrations were normal in the girls taking CBZ or OXC. Sixty-three% of the girls taking CBZ and 67% of the girls taking OXC had serum T 4 and/or FT 4 levels below the lower limit of the reference range. The VPA-treated girls with epilepsy had normal serum T 4 and FT 4 concentrations, but slightly increased TSH levels (3.3; SD, 1.5 mU/L; p < 0.01) compared with the control girls (2.5; SD, 1.0 mU/L). Normal serum hormone concentrations were restored in the patients who discontinued the medication.Conclusions: Both CBZ and OXC reduce serum thyroid hormone concentrations in girls with epilepsy. Conversely, VPA is associated with normal serum thyroid hormone and increased thyrotropin levels. However, our results suggest that the changes in serum thyroid hormone and thyrotropin levels are reversible after withdrawal of the medication. Key Words: Epilepsy-Children-Thyroid functionCarbamazepine-Oxcarbazepine-Valproate.It is well known that the traditionally used antiepileptic drugs (AEDs) may affect thyroid function (1-5). The effects of AEDs on thyroid function in children with epilepsy have been investigated less extensively, however. Moreover, no data exist on thyroid function in children treated with oxcarbazepine (OXC).Carbamazepine (CBZ) is the most widely used first-line AED in partial-onset epilepsy of both adults and children (6). OXC is the 10-keto analogue of CBZ and has anticonvulsant efficacy comparable to that of CBZ in partial seizures with or without generalization (7). Despite this, CBZ and OXC have different metabolic pathways in the liver: CBZ is oxidized and OXC is metabolized mainly by reduction to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine.CBZ therapy has certain effects on thyroid function: it decreases the serum thyroid hormone levels, but allows the serum thyrotropin (TSH) concentrations ...

Summary:Purpose: Antiepileptic drugs (AEDs) may affect serum thyroid hormone concentrations. This study aimed to evaluate thyroid function in men taking carbamazepine (CBZ), oxcarbazepine (OCBZ), or valproate (VPA) for epilepsy.Methods: Ninety men with epilepsy (40 taking CBZ, 29 taking OCBZ, and 21 taking VPA monotherapy) and 25 control subjects participated in the study. After clinical examination, a blood sample for hormone, ␥-glutamyl-transferase (GGT) and antibody (ab) assays was obtained.Results: Serum thyroxine (T 4 ) and free thyroxine (FT 4 ) concentrations were low in men taking CBZ or OCBZ. Forty-five percent of men taking CBZ and 24% of men taking OCBZ had serum T 4 and/or FT 4 levels below the reference range. However, no correlations were found between T 4 or FT 4 and GGT concentrations in men taking CBZ or OCBZ. Thirteen percent of men taking CBZ, 17% of men taking OCBZ, and 6% of control men had increased levels of thyroid peroxidase (TPO)-ab and/or thyroglobulin (TG)-ab, but these were not associated with altered serum thyroid hormone concentrations. Serum triiodothyronine and thyrotropin levels in men taking CBZ or OCBZ were normal. In men taking VPA, the concentrations of thyroid hormones, thyrotropin, and antithyroid ab were normal.Conclusions: Serum thyroid hormone concentrations are low in CBZ-or OCBZ-treated men. However, these low levels do not seem to be due to liver enzyme induction or activation of immunologic mechanisms. Therefore, interference with hypothalamic regulation of thyroid function by CBZ and OCBZ seems possible. VPA does not have any significant effects on thyroid function. Key Words: Epilepsy-Thyroid hormonesCarbamazepine-Oxcarbazepine-Valproate.The endocrine effects of carbamazepine (CBZ) have been well documented. A decrease in serum thyroid hormone levels can already be detected in patients 2 months after starting CBZ (1). However, serum thyrotropin concentrations do not change, and the clinical significance of low serum thyroid hormone concentrations is unclear (1-8). The altered thyroid function during CBZ medication has been attributed to induction of the hepatic P-450 enzyme system and the consequent increase in the metabolism of thyroid hormones (9,10).Oxcarbazepine (OCBZ) is a novel antiepileptic drug (AED) that structurally resembles CBZ. However, the metabolic pathway of OCBZ in the liver is different from that of CBZ. OCBZ is mainly reduced, instead of being oxidized. Consequently, OCBZ does not appear to induce the hepatic P-450 enzyme system (11). Therefore, it has been suggested that OCBZ may not have effects on endocrine function equivalent to those of CBZ, and replacing CBZ with OCBZ resulted in deinduction of liver enzyme levels and short-term restoration of normal endocrine function in men with epilepsy (10,12). However, OCBZ may induce the hepatic P-450 enzyme system when given in high doses, and recent studies have shown that high doses of OCBZ may also affect sex hormone metabolism in men with epilepsy (13). Furthermore, OCBZ is well known to decreas...

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Article abstract-Background: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. Methods: Reproductive endocrine function was evaluated in 90 men taking VPA (n ϭ 21), CBZ (n ϭ 40), or OXC (n ϭ 29) as monotherapy for epilepsy and in 25 healthy control men. Results: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormonebinding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (Ͻ900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose Ն900 mg. Conclusions: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not. NEUROLOGY 2001;56:31-36 Reproductive endocrine disorders and sexual dysfunction have frequently been attributed to epilepsy itself, but antiepileptic drugs (AED) also have various effects on endocrine function.1-7 Valproate (VPA) has been implicated to have only minor effects on the hormonal system in men with epilepsy.3,4 However, there is growing evidence that VPA therapy induces endocrine disorders in women with epilepsy, which are characterized by hyperandrogenism and hyperinsulinemia that are related to obesity. 5,6 Carbamazepine (CBZ) is one of the most widely used first-line AED. The use of CBZ is associated with a progressive increase in circulating levels of sex hormone-binding globulin (SHBG) and, consequently, in a decreased proportion of free, bioactive testosterone, which may result in sexual dysfunction in some men with epilepsy after long-term CBZ treatment.8 CBZ-related endocrine changes have been attributed to the induction of the hepatic P450-enzyme system by the drug. 9,10Oxcarbazepine (OXC), a keto-derivative of CBZ, is a new AED that closely resembles CBZ in structure.11 However, it has a different metabolic pathway in the liver; instead of by oxidation, it is mainly metabolized by reduction, and does not appear to induce the oxidative P450-enzyme system to the same extent as CBZ.12 Previous studies have shown that the CBZ-induced changes in endocrine and metabolic function equilibrate after CBZ is replaced with OXC.13,14 Thus, OXC has been suggested to be a safe AED with regard to endocrine and metabolic effects. However, there is evidence that OXC may also induce liver enzymes when prescribed at higher doses. 15 Endocrine effects of OXC have not been previously assessed...