Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

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 = 21), CBZ (n = 40), or OXC (n = 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 hormone-binding 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 (< 900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose > or = 900 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.     

Serum androgen levels and testicular structure during pubertal maturation in male subjects with epilepsy

Summary:  Purpose: To evaluate reproductive endocrine function in boys and young men with epilepsy taking an antiepileptic drug in a population-based, controlled study.
Methods: Seventy patients and 70 controls matched for age and pubertal stage participated in this study. Twenty-eight patients were taking carbamazepine (CBZ); five, lamotrigine (LTG); 12, oxcarbazepine (OXC); and 25, valproate (VPA) as monotherapy for epilepsy. All subjects were examined clinically, and their medical histories were obtained. Serum reproductive hormone and sex hormone–binding globulin concentrations were measured, and testicular ultrasonography was performed.
Results: Serum testosterone levels were within the normal range in young male patients with epilepsy. However, the patients taking VPA had high serum androstenedione levels at all pubertal stages. In prepuberty, their serum androstenedione values were already approximately fivefold compared with the values of the controls (8.7 n M ; SD, 4.0 vs. 1.8 n M , SD, 1.0; p < 0.0003), and they were elevated in 64% of the VPA-treated patients compared with none of the other patients, p = 0.0006. Serum sex hormone–binding globulin levels were increased, and serum dehydroepiandrosterone sulfate concentrations decreased in the pubertal patients taking CBZ. The mean testicular volumes did not differ between the patients and the controls.
Conclusions: CBZ and VPA, but not LTG and OXC, are associated with changes in serum sex-hormone levels in boys and young men with epilepsy. However, the long-term health consequences of these reproductive endocrine changes during pubertal development remain to be established.     

Early hormonal changes during valproate or carbamazepine treatment: a 3-month study

BACKGROUND: Long-term treatment with valproate (VPA) or carbamazepine (CBZ) may induce reproductive endocrine disorders in patients with epilepsy. METHODS: Serum concentrations of reproductive hormones were studied in 17 women and 22 men with recently diagnosed epilepsy before they started either VPA or CBZ medication, and 1 and 3 months later. RESULTS: No weight gain or clinical signs of hormonal disorders were observed during the follow-up. The mean serum levels of testosterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin (SHBG) increased, and dehydroepiandrosterone sulfate (DHEAS) decreased, in women starting VPA. Serum testosterone levels increased in half of the women on VPA. Serum concentrations of progesterone and dehydroepiandrosterone increased, and gonadotropins decreased, in men on VPA during the follow-up. Serum SHBG levels increased and DHEAS decreased during the first months of CBZ treatment in both sexes. In addition, the free-androgen index decreased in men after starting CBZ. CONCLUSIONS: Hormonal changes occur after only 1 month's use of VPA or CBZ. VPA-treatment seems to be associated with increased serum androgen levels, but the profile of hormonal changes appears to be different in women than in men. The use of CBZ, in turn, was associated with increased SHBG concentrations and thus with diminished sex steroid function in both sexes. The women with increased serum testosterone levels in the early phase of VPA medication may be at increased risk for VPA-related endocrine disorders later during treatment.     

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug-specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20-40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age-matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C-peptide values compared with controls. Regarding possible drug-specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone-binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C-peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug-specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long-term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C-peptide and carnitine ratio. Long-term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.     

Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication

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 follow‐up 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 (T₄), 70.2; SD, 10.9 nM; and free thyroxine (FT₄), 11.5; SD, 1.8 pM] or OXC (T₄, 74.9; SD, 16.4 nM; and FT₄, 11.3; SD, 1.8 pM) than in the control girls (T₄, 96.6; SD, 15.1 nM, and FT₄, 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 T₄ and/or FT₄ levels below the lower limit of the reference range. The VPA‐treated girls with epilepsy had normal serum T₄ and FT₄ 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.     

Growth and lipid metabolism in girls and young women with epilepsy during pubertal maturation

Summary:  Purpose: To assess growth and the serum lipid profile in girls with epilepsy receiving monotherapy at a mean age of 12.6 years and approximately 6 years later.
Methods: A population-based cohort of 77 girls with epilepsy and 49 healthy controls participated in this follow-up study including two cross-sectional evaluations (age range, 8–18.5 years on the first evaluation, and 12.5–25.8 years on the second evaluation). Forty of the patients were initially taking valproate (VPA), 19, carbamazepine (CBZ), and 18, oxcarbazepine (OXC). Growth data were compiled, body mass index (BMI) was calculated, and serum total (TC), and high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol and triglyceride concentrations were analyzed.
Results: Linear growth and final height did not differ between the patients and the controls. At follow-up, the mean BMI of the patients who were off medication (61%) was similar to that of the controls, whereas the patients initially treated with VPA who were still taking any medication had a higher BMI. On the first evaluation, the patients taking VPA had low serum HDL-C, and those taking CBZ or OXC had high serum TC and LDL-C concentrations. At follow-up, serum lipid levels were similar in the patients off medication and the controls.
Conclusions: Neither epilepsy nor antiepileptic therapy affects linear growth or final height, but they may have unfavorable effects on body weight and serum lipid concentrations. Lipid-profile impairment seems to be transient if the medication is discontinued. Overweight is common in patients treated with VPA during puberty if epilepsy and medication continue into adulthood.     

Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine

PURPOSE: Evidence suggests that enzyme-inducing antiepileptic drugs (AEDs) may decrease serum 25-hydroxyvitamin D (25-OHD) levels and increase bone turnover. We sought to determine whether these are affected by treatment with carbamazepine (CBZ) or oxcarbazepine (OXC). METHODS: We measured serum levels of 25-OHD, parathyroid hormone (PTH), osteocalcin (OCLN), bone alkaline phosphatase (BAP), and urinary N-telopeptides of type I collagen cross-links (NTX) in normal controls (n=24) and in epilepsy patients taking CBZ (n=21) or OXC (n=24) in monotherapy. CBZ patients were subsequently switched overnight to OXC monotherapy, and after 6 weeks, the tests were repeated. RESULTS: 25-OHD levels were lower in each drug-treated group (OXC, 19.4+/-2.3 pg/ml; CBZ, 20.4+/-2.4) than in the controls (27.5+/-2.8) (ANOVA, p=0.052). This difference was significant for the OXC group (p<0.05). PTH, BAP, and NTX did not differ significantly among groups. OCLN levels were somewhat elevated in the OXC group (2.79+/-0.47 ng/ml) and more clearly and significantly elevated in the CBZ group (3.63+/-0.36) compared with controls (2.38+/- 0.41) (p=0.053). Because the data were very similar between OXC and CBZ groups, they were combined to increase statistical power. The combined drug-treatment group had significantly higher BAP (p=0.02) and lower 25-OHD (p=0.015) than did controls. The latter remained significant even after accounting for the confounding effects of age on 25-OHD levels (p<0.05). No significant differences were found after CBZ patients were switched to OXC. CONCLUSIONS: Epilepsy patients taking OXC or CBZ have significantly lower 25-OHD than do normal controls, with a pattern of changes in other bone biomarkers suggestive of secondary hyperparathyroidism. It may be prudent for patients taking CBZ or OXC to be prescribed 25-OHD replacement.     

Objective assessment of neurotoxicity while shifting from carbamazepine to oxcarbazepine

OBJECTIVES: Objective assessment of non-overt neurotoxicity of carbamazepine (CBZ) vs oxcarbazepine (OXC) in patients with difficult-to-treat partial epilepsy, who were resistant to CBZ treatment and were converted from CBZ monotherapy to OXC monotherapy. MATERIAL AND METHODS: Therapeutically equivalent doses (150 mg OXC for every 100 mg CBZ) were compared in 20 adult patients. Neurological investigation, conventional and spectral EEG analysis, brainstem auditory evoked responses (BAER) were carried out in both treatment conditions. EEG and BAER data of 20 age-matched healthy controls helped interpretation. Primary target variables (electrophysiological parameters) were evaluated blindly. RESULTS: There were no significant differences between treatment conditions concerning the neurological condition, lack of clinically evident neurotoxicity, seizure frequency and EEG spike frequency. OXC treatment was characterized by less delta, theta, and alpha power, more beta power, and significantly greater mean alpha frequency (P = 0.03 and 0.05 for the left and right occipital leads, respectively), than CBZ treatment. Interpeak latencies were prolonged in the CBZ condition as compared with normals (P = 0.01) and OXC (P = 0.02). CONCLUSION: In this cohort of patients substitution of OXC for CBZ was associated with significant normalization of electrophysiological parameters, indicating decreasing neurotoxicity while shifting from CBZ to OXC monotherapy.     

Serum Steroid Hormones and Pituitary Function in Female Epileptic Patients During Carbamazepine Therapy

Ten regularly menstruating women with epilepsy were studied in a 12-month prospective follow-up study to evaluate the short-term effects of carbamazepine (CBZ) on serum sex hormone balance and pituitary function. Thirteen female epilepsy patients receiving long-term CBZ monotherapy (mean medication duration 5.3 years) were also studied. Controls were 17 regularly menstruating healthy volunteers. Untreated patients had higher free testosterone (FT) and luteinizing hormone (LH) serum concentrations than control subjects, whereas the other parameters did not differ between these two groups. However, serum sex hormone binding globulin (SHBG) levels increased and dehydroepiandrosterone sulfate (DHEAS) levels decreased during CBZ treatment. Although calculated free androgen index (FAI) decreased during CBZ therapy, the directly measured FT levels remained unaltered. These changes were found after 2 months and continued after 12 months of CBZ treatment. Moreover, patients with long-term CBZ also had high SHBG levels, low serum DHEAS levels, and low FAI values. Basal LH serum levels decreased during the first year of CBZ treatment and luteinizing hormone-releasing hormone (LH-RH)-stimulated LH concentrations were lower after 2 months of CBZ treatment. Although the serum basal follicle-stimulating hormone (FSH) and prolactin (PRL) levels were unaffected during the first year of CBZ therapy, the LH-RH-stimulated FSH concentrations and metoclopramide (MC)-stimulated PRL concentrations were lower after 12 months of CBZ treatment than before CBZ. Both basal and stimulated gonadotropin and PRL serum levels of long-term CBZ patients were unaffected. No changes were found in estradiol (E2), testosterone (T), or cortisol (C) serum concentrations during short or long-term CBZ treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

托吡酯与卡马西平对成年癫痫患者甲状腺激素的影响

目的探讨托吡酯（TPM）及卡马西平（CBZ）对成年癫痫患者甲状腺激素水平的影响。方法选择新确诊的100例成年癫痫患者（50例服用TPM、50例服用CBZ）为试验组,用化学发光法测定用药前甲状腺激素水平并与40例成年健康对照进行比较；再经TPM、CBZ单药治疗3、6个月及1年后检测血中甲状腺激素水平,并与治疗前比较。结果未经治疗的癫痫患者甲状腺激素水平与正常对照组比较无显著性差异（P＞0．05）；与治疗前相比,CBZ治疗3个月、6个月及1年后的游离T4（FT4）、三碘甲状腺原氨酸（TT3）及CBZ治疗6个月及1年后的甲状腺素（TT4）显著降低（P＜0．05）,而CBZ治疗3个月的TT4与服用CBZ后各时点的游离T3（FT3）、促甲状腺素（TSH）无显著性变化（P＞0．05）；经TPM治疗后的不同时段的甲状腺激素水平与治疗前比较均无显著性差异（P＞0．05）。结论CBZ治疗可造成成年癫痫患者甲状腺激素水平的降低。癫痫本身及TPM治疗并不引起成年患者甲状腺激素水平的改变,表明TPM治疗对成年癫痫患者的甲状腺功能更安全。     

Effects of Carbamazepine Therapy on Serum Sex Hormone Levels in Male Patients with Epilepsy

The effects of carbamazepine (CBZ) therapy and epilepsy on sex hormone plasma levels in male patients with epilepsy were evaluated by measuring the levels of testosterone (T), free testosterone (FT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and dehydroepiandrosterone sulfate (DHEAS) and by calculating the free androgen index (FAI) in 23 male patients with epilepsy receiving CBZ medication, in 18 untreated male patients with epilepsy, and in 19 healthy age-matched control subjects. No significant differences in the mean T or FT levels were found between the three groups, but the CBZ-treated patients had significantly higher SHBG levels and their FAI values and DHEAS concentrations were lower. The LH, FSH, PRL, or E2 levels in CBZ-treated and untreated male patients with epilepsy did not differ from the controls. CBZ monotherapy does not significantly change the serum balance of sex hormones; however, CBZ clearly affects the serum levels of SHBG and DHEAS.     

Oxcarbazepine long-term treatment retention in patients switched over from carbamazepine

Abstract We evaluated the long-term outcome of oxcarbazepine (OXC) monotherapy in a population of patients switched over from carbamazepine (CBZ) monotherapy. Subjects of the study were recruited among patients who had successfully completed the PRIMO study, a recent multicentre Italian study that assessed the therapeutic equivalence of immediate (overnight) and more progressive switching from CBZ to OXC monotherapy in patients with partial seizures unsatisfactorily maintained on CBZ monotherapy due to poor tolerability or scant clinical efficacy. Treatment retention rate was chosen as a composite parameter for both efficacy and tolerance of OXC. Twelve months after having completed the PRIMO study, 91 of 105 patients (87%) were still taking OXC, 80 of them (76%) as monotherapy. Mean OXC dose was 1250±459 mg/day. Eighty-four out of 105 patients (80%) rated OXC tolerability as “good” or “very good”. The mean ratio of the last dose of OXC to the last dose of CBZ increased from 1.54 (end of PRIMO study) to 1.69 (end of follow-up). The large majority of a population of patients who were successfully switched from CBZ monotherapy to OXC monotherapy maintained OXC treatment for at least a further 12 months. The 1.5 OXC/CBZ ratio appears to be close to the optimal for the switch from CBZ to OXC, at least in patients treated with CBZ monotherapy. *The Follow-up PRIMO study group comprised the following: L. Antonini, G. De Maria (Brescia), G. Avanzini (Milan), P. Basso, B. Bettini (Gallarate, Varese), P. Benna (Turin), A. Baruzzi, F. Bisulli (Bologna), D. Consoli (Vibo Valentia), P. D’Alessandro (Perugia), P. Garofalo (Vicenza), L. Murri (Pisa), G. Muscas (Firenze), S. Musumeci (Troina, Enna), A. Paggi (Ancona), B. Passarella (Brindisi), S. Striano (Napoli), C. Zucca (Bosisio Parini, Como).     

Differential effects of levetiracetam, carbamazepine, and lamotrigine on reproductive endocrine function in adults

Animal studies have shown endocrine changes after levetiracetam treatment. The present study investigated reproductive and sexual function in patients with epilepsy (aged 18–45) treated with levetiracetam (LEV: 30 men/26 women), carbamazepine (CBZ: 63 men/30 women), or lamotrigine (LTG: 37 men/40 women) monotherapy and in healthy controls (36 men/44 women). In women, no endocrine changes were observed during LEV treatment, whereas steroid hormone-binding globulin levels were greater and progesterone levels lower in women using CBZ. Dehydroepiandrosterone sulfate levels were higher and androstenedione levels lower in LTG-treated women. Arizona Sexual Experience Scale scores, which were significantly lower in females using LTG or LEV, suggesting they have better sexual function than CBZ users and controls. In men, no drug-specific hormonal pattern was observed after LEV treatment. Male patients in all treatment groups had lower androstenedione and free testosterone. Those using CBZ had lower free androgen indices and dehydroepiandrosterone sulfate levels, and higher steroid hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone levels. Arizona Sexual Experience Scale scores for men were similar in all groups. In conclusion, LEV treatment apparently has no drug-specific sexual or endocrine side effects in men or women in this age group.     

Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy

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, gamma-glutamyl-transferase (GGT) and antibody (ab) assays was obtained. RESULTS: Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in men taking CBZ or OCBZ. Forty-five percent of men taking CBZ and 24% of men taking OCBZ had serum T4 and/or FT4 levels below the reference range. However, no correlations were found between T4 or FT4 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.     

Menstrual Disorders in Women with Epilepsy Receiving Carbamazepine

Summary: We measured concentrations of serum sex hormones and sex hormone binding globulin (SHBG) in relation to regularity of the menstrual cycles in 8 women before carbamazepine (CBZ) treatment was initiated and after 1 and 5 years of CBZ therapy. In addition, we evaluated menstrual cycle regularity and related endocrine changes in 56 women receiving CBZ treatment for >5 years. Serum SHBG levels increased, and serum concentrations of 17β-estradiol (estradiol) and estradiol/SHBG ratio decreased during CBZ treatment. Two of the 8 patients (25%) in the prospective study group developed menstrual irregularities during the first 5 years of therapy. In the cross-sectional study group of patients treated with CBZ for >5 years, the frequency of menstrual disturbances was also 25.0% (14 of 56 patients). Concentrations of serum sex hormones and SHBG were measured in 13 women with menstrual disorders and in 11 randomly selected women with regular cycles. In most cases, menstrual disorders were associated with increased serum SHBG and decreased serum estradiol levels and low estradiol/SHBG ratio. Long-term CBZ treatment results in increased serum SHBG levels and decreased estradiol effect, which correlate with the frequency of menstrual disorders in CBZ-treated women with epilepsy.     

Valproate-associated reproductive and metabolic abnormalities: are epileptic women at greater risk than bipolar women?

OBJECTIVE: Evidence indicates that valproate (VPA) may have an adverse impact on reproductive endocrine and metabolic functions in women with epilepsy. This study explores whether the association of VPA with reproductive endocrine abnormalities is applicable to women with bipolar disorder (BD) or is unique to women with epilepsy. METHODS: Thirty female patients aged 18-40 years with a DSM-IV diagnosis of BD (15 on lithium monotherapy and 15 on VPA monotherapy or VPA in combination with lithium therapy) and 15 with idiopathic generalized epilepsy (IGE) on VPA monotherapy were evaluated for reproductive endocrine functioning and metabolic parameters. RESULTS: The menarche age, mean length of menstrual cycle and mean length of menses were not significantly different between groups. None of the bipolar patients on lithium, three (20%) of the bipolar patients on VPA and seven (47%) of the epileptic patients on VPA reported menstrual disturbances. Hirsutism scores of the epilepsy group were significantly higher than those bipolar women, regardless of treatment. Serum total testosterone levels were significantly higher in patients (both with BD and with IGE) treated with VPA than in those treated with lithium. Serum FSH levels were significantly lower and LH-to-FSH ratio was significantly higher in patients with epilepsy than in patients with BD, regardless of treatment. The weight parameters and lipid values investigated did not differ significantly between the groups. CONCLUSION: The study supports the conclusion that VPA may be associated with menstrual abnormalities and increased total testosterone levels in both bipolar and epileptic patients although women with BD did not show clinical features of hyperandrogenism (menstrual abnormalities, hirsutism and truncal obesity) as did frequently as women with epilepsy.     

Increased high-density lipoprotein cholesterol in patients with epilepsy treated with carbamazepine: a gender-related study

PURPOSE: Long-term treatment with carbamazepine (CBZ) may alter serum lipoprotein concentrations. Gender-related examinations, however, are rare and inconsistent in their results. METHODS: To examine possible sex differences, serum lipoproteins were analyzed in 127 clinic outpatients (56 women and 71 men) with epilepsies with focal or secondarily generalized tonic-clonic seizures (or both) treated with a CBZ monotherapy. Results were compared with a control group of 177 blood donors (67 women and 110 men) matched for age and weight. RESULTS: Total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were higher in both male and female patients treated with CBZ compared with controls. The known sex difference in serum lipoprotein concentrations (i.e., higher LDL cholesterol and triglycerides but lower HDL cholesterol in men) was confirmed in controls and patients treated with CBZ, with the exception of LDL cholesterol. The HDL as well as the LDL differences were significantly more pronounced in women treated with CBZ than in men when compared with their controls. These results were independent of the dose of CBZ and plasma concentrations. Lathosterol, a cholesterol precursor, and its ratio to cholesterol, an indicator of cholesterol synthesis, were not different, when compared between gender and different HDL groups. CONCLUSIONS: The observed increase in HDL cholesterol in patients with CBZ, especially in women, might correlate with the previously reported diminished rate of death from coronary heart disease in patients with epilepsy as HDL exerts an antiatherogenic effect.     

Valproate, hyperandrogenism, and polycystic ovaries: a report of 3 cases

BACKGROUND: Reproductive endocrine disorders characterized by menstrual disorders, polycystic ovaries, and hyperandrogenism seem to be common among women treated with sodium valproate for epilepsy. OBJECTIVE: To describe the development of valproate-related reproductive endocrine disorders in women with epilepsy. DESIGN: Case report. PATIENTS: Three patients developed a reproductive endocrine disorder during treatment with valproate. It was characterized by hyperandrogenism and polycystic ovaries in all cases, and it was associated with weight gain and menstrual disorders in 2 of the 3 women. RESULTS: Replacing valproate with lamotrigine resulted in a decrease in serum testosterone concentrations in all 3 women. The polycystic changes disappeared from the ovaries in 2 of the women after valproate therapy was discontinued, and the 2 women who had gained weight and developed amenorrhea while being treated with valproate lost weight and resumed menstruating after the change in medication. CONCLUSIONS: The 3 cases presented here illustrate the development of reproductive endocrine disorders after the initiation of valproate therapy in women with epilepsy. The disorders were characterized by hyperandrogenism and polycystic ovaries in all cases, and were associated with weight gain and menstrual disorders in 2 of the 3 women. An evaluation of ovarian structure and function should be considered in women of reproductive age being treated with valproate for epilepsy, especially if they develop menstrual cycle disturbances during treatment.     

Conversion from carbamazepine or oxcarbazepine to topiramate in adolescents and adults with epilepsy

Objective – To explore effectiveness, tolerability and changes in quality of life in patients with epilepsy converting to topiramate (TPM) from carbamazepine (CBZ) or oxcarbazepine (OXC) due to insufficient effectiveness and/or tolerability. Methods – A multicenter, open‐label, non‐interventional trial was used to examine patients (≥ 12 years) with epilepsy, changing to TPM monotherapy from baseline mono‐ or combination therapy with CBZ or OXC. TPM was added to the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1–2 weeks, until a final dose between 50 and 200 mg/day was reached. On the basis of clinical judgment, the treating physician decided whether or not the existing AED treatment with CBZ or OXC could then be withdrawn. Type and number of seizures, preferred TPM dose, quality of life (QOLIE‐10 questionnaire), subjective perception of improvement and adverse events (AE) were documented. Results – 140 patients (53.5% women, mean age 47 years) decided to switch to TPM due to insufficient effectiveness (75% of patients) and/or poor tolerability (80%) of the CBZ/OXC treatment. Average duration of follow‐up was 24 weeks with an overall discontinuation rate of 19.3%, mainly due to AEs (12.1%). At study endpoint, the intended shift to TPM monotherapy was achieved in 73% of patients at a median TPM dose of 100 mg/day. A seizure reduction of ≥ 50% was achieved in 91% of patients in the last scheduled period (weeks 12–26); 62% of patients entering that period remained seizure free. Quality of life at endpoint improved significantly when compared with baseline for all domains of QOLIE‐10 (P < 0.001). Most frequent AEs (reported by ≥ 5% of patients) were paresthesia (9.3%), weight loss (7.9%), convulsions (5.7%) and memory disorders (5.0%). Conclusion – In patients with epilepsy, previously not satisfactorily treated with CBZ or OXC, conversion to TPM may result in an improvement in seizure control as well as in quality of life.     

Oxcarbazepine-induced hyponatremia and the regulation of serum sodium after replacing carbamazepine with oxcarbazepine in children

While severe hyponatremia is reported to be more frequent in adults treated with oxcarbazepine (OXC) than with carbamazepine (CBZ), there is not sufficient data about the incidence of hyponatremia in childhood during treatment with OXC. We evaluated changes in serum electrolyte balance in 75 children with epilepsy before and during treatment with OXC and after replacing carbamazepine (CBZ) therapy with OXC therapy. All patients had normal sodium serum levels at the onset of OXC. During treatment with OXC we found hyponatremia (Na +< 135 mmol/l) without clinical symptoms in 26.6 % of the children (n = 20), sodium levels below 125 mmol/l were observed in 2 children (2.6 %). Clinically relevant hyponatremia occurred in one girl only (1.3 %). In a subgroup of 27 children, in whom CBZ was directly replaced with OXC, hyponatremia without symptoms was found in one child under CBZ (3.7 %) and in six children under OXC (22.2 %). Dosage of OXC, serum levels of the active metabolite of OXC, antiepileptic comedication or patients' age and gender were of no predictive value for the development of hyponatremia. Electrolytes should be measured before establishing OXC and if clinically relevant side effects occur.