Differential effects of antiepileptic drugs on sexual function and reproductive hormones in men with epilepsy: interim analysis of a comparison between lamotrigine and enzyme-inducing antiepileptic drugs

PURPOSE: We compared sexual function and reproductive hormone levels among men with localization-related epilepsy (LRE) taking various antiepileptic drugs (AEDs) and normal controls (NC). METHODS: Subjects were 63 men with LRE [enzyme-inducing (EI) AEDs, 36; lamotrigine (LTG), 18; no AEDs, 9] and 18 NC. Sexual interest and function (S-score), hormone levels [bioactive testosterone (BAT) and estradiol (BAE)], hormone ratios [BAT/BAE], and gonadal efficiency [BAT/luteinizing hormone (LH)] were compared among the groups. RESULTS: S-scores, BAT levels, BAT/BAE, and BAT/LH were significantly lower in the EIAED group than in NC or LTG groups. Sex hormone-binding globulin (SHBG) was significantly higher in the EIAED group than in all other groups. Of men with LRE, 23.8% had abnormally low S-scores: 33.3% taking EIAEDs, 5.5% taking LTG, and 22.2% taking no AEDs (p < 0.01). BAT was low in 55.6% taking EIAEDs as compared with 33.3% taking LTG and 33.3% taking no AEDs (p < 0.05). Among men with low S-scores, 86.7% had low BAT as compared with 33.3% of men with normal scores (p < 0.01). BAT decline with age was greater among men with LRE than in controls (3.75 vs. 1.80 ng/dl/yr). The slope showed no significant difference among LRE groups. However, 89% of 40- to 50-year-old men taking EIAEDs had low BAT as compared with 33% taking LTG and 33% taking no AED (p < 0.01). CONCLUSIONS: Sexual function, BAT levels, BAT/BAE, and gonadal efficiency are greater with LTG than with EIAED. Abnormally low BAT levels are reached at an earlier age with EIAEDs than with LTG.     

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.     

Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy--a prospective randomized double-blind withdrawal study

PURPOSE: Epilepsy, antiepileptic drugs (AEDs), and reproductive endocrine function have complex interactions. In this study, we wanted to investigate the effects of AEDs on reproductive endocrine function after withdrawal of AEDs and look for reversible endocrine effects. METHODS: The study was prospective, randomized, and double-blinded. A total of 160 patients were included and randomized to withdrawal or not and 150 (80 females, 53%) patients went through the intervention and was included in the study for 12 months. Complete serum samples from before and 4 months after completed withdrawal/no withdrawal were obtained from 130 patients (63 females, 48%). RESULTS: The main finding was that reversible endocrine changes in sex steroid hormone levels could be observed in both sexes after withdrawal of AEDs. For CBZ, which was the drug used by the majority of the patients, withdrawal led to significant increases in serum testosterone concentrations and free androgen index (FAI) in both men (n = 19) and women (n = 19). Mean differences in change in FAI between the withdrawal group and nonwithdrawal group were in men 17.49 (CI 10.16-24.81, p 相似文献   

抗癫药物对内分泌系统及妊娠的影响

疾病状态的药物干预是内科治疗的重要方法之一,药物疗效和安全性在疾病治疗中具有同等重要的作用。对于癫痫这一慢性脑疾病而言,由于患者需要接受长期的药物治疗,故其安全性显得尤为重要。自Isoj(a|¨)rvi报告丙戊酸(VPA)可引起女性癫痫患者生殖内分泌系统功能失调后,有关抗癫痫药物(AEDs)对内分泌系统的影响即成为癫痫药物治疗研究的焦点。     

Seizure type, antiepileptic drugs, and reproductive endocrine dysfunction in Indian women with epilepsy: a cross-sectional study

Background: There is paucity of data regarding occurrence of reproductive endocrine disorders in Asian women with epilepsy (WWE) on antiepileptic drug (AED) therapy. Purpose: To determine the occurrence of reproductive endocrine disorders in Indian WWE, by seizure type and the AED use. Methods: Consecutive 427 reproductive age WWE receiving various AEDs were screened for the occurrence of menstrual abnormalities, weight change, and hirsutism. Of these, 53 WWE with menstrual disturbances and/or hirsutism were further evaluated for ovarian morphology and reproductive hormonal profile. Results: Menstrual abnormalities and/or hirsutism were observed in 83 of 427 (19.4%) WWE irrespective of epileptic seizure type; of these, 50 (60.2%) received valproate, 21 (25.3%) received carbamazepine, 11 (13.3%) received phenytoin, and one (1.2%) received phenobarbitone as the primary AED. Almost half of valproate‐treated women had significant weight gain and obesity. Among 53 of 83 women evaluated further, 23.5% and 63.6% of valproate‐treated women, 25% and 58.3% of carbamazepine‐treated women, and none and 20% of phenytoin‐treated women had polycystic ovaries (PCO) and hyperandrogenemia (HA), respectively. Valproate‐treated women had significantly higher frequency of polycystic ovarian syndrome (PCOS) (11.8% vs. 2.5%, p < 0.0001) and mean serum testrosterone levels (1.78 vs. 1.36 ng/ml, p = 0.03), compared with women treated with other AEDs. Limitations: Limitations include small number of women in antiepileptic subgroups and a high drop out rate in women who underwent ultrasound and endocrinological investigations. Conclusion: Menstrual abnormalities, weight gain, obesity, and PCOS are frequent and significantly higher in WWE receiving valproate, independent of seizure type.     

Differential effects of antiepileptic drugs on neuroactive steroids in men with epilepsy

PURPOSE: To compare serum levels of neuroactive steroids among men with epilepsy who take various antiepileptic drugs, untreated men with epilepsy and normal controls (NC). METHODS: Subjects were 85 men with localization-related epilepsy [unmedicated >6 months (No Rx)-10, carbamazepine (CBZ)-25, phenytoin (PHT)-25, lamotrigine (LTG)-25] and 25 NC. Sexual function scores (S-Score), hormone levels [dehydroepiandrosterone sulfate (DHEAS), bioactive (BA) testosterone (T), estradiol (BAE), and androstanediol (BAL)] and the ratios of inhibitory to excitatory neuroactive metabolites of T, i.e., BAL/BAE, were compared among groups. RESULTS: S-scores, DHEAS, and bioactive testosterone (BAT) were significantly (p < 0.05) lower and BAL and BAL/BAE were significantly higher among CBZ and PHT groups than among NC and LTG groups. LTG did not differ from NC in any of these measures. BAT correlated significantly with BAL/BAE for PHT (r = 0.44, p = 0.02) and CBZ (r = 0.42, p = 0.03) but not for NC (r = 0.03, p = NS) and LTG (r = 0.06, p = NS) groups. CONCLUSIONS: In comparison to LTG, enzyme inducing AEDs (CBZ, PHT) are associated with a more favorable neuroactive steroid balance (lower DHEAS and higher BAL/BAE) for seizure management, but at the expense of reduced serum bioavailable testosterone levels and sexual function.     

Effects of carbamazepine and oxcarbazepine on the reproductive endocrine function in women with epilepsy

PURPOSE: The aim of the study was to compare the effects of carbamazepine (CBZ) and oxcarbazepine (OXC) on the reproductive endocrine function in women with epilepsy. OXC is a novel antiepileptic drug (AED), and the occurrence of reproductive dysfunction in women treated with OXC monotherapy for epilepsy has not been studied previously. METHODS: Thirty-five women with epilepsy were examined in the Department of Neurology at Oulu University Hospital. Sixteen patients were treated with CBZ monotherapy, and nineteen patients were treated with OXC monotherapy. The subjects were clinically examined, vaginal ultrasonography was performed, and serum sex hormone concentrations were measured. RESULTS: The women taking CBZ or OXC had lower serum testosterone (T) levels and lower free androgen indexes (FAIs) than the control subjects. CBZ medication was associated with increased concentrations of serum sex hormone-binding globulin (SHBG). The patients taking OXC had higher concentrations of dehydroepiandrosterone sulfate (DHEAS) and androstendione (A) than did the women taking CBZ. Moreover, the prevalence of polycystic ovaries (PCOs) was high in the OXC-treated women. CONCLUSIONS: CBZ and OXC have different effects on the reproductive endocrine function. Although both drugs were associated with low serum T concentrations and low FAIs, only OXC was associated with a high frequency of elevated levels of A and DHEAS and with an increased prevalence of PCOs. These findings suggest that OXC may be disadvantageous for women with epilepsy and hyperandrogenism, whereas CBZ may be beneficial for these women.     

Sexual and reproductive dysfunction associated with antiepileptic drug use in men with epilepsy

The association between epilepsy and sexual disorders has long been known. However, the etiology remains uncertain, although it is likely to be multifactorial in origin involving neurological, endocrine, iatrogenic, psychiatric and psychosocial factors. Sexual disorders associated with epilepsy can be directly related to seizures (ictal), or unrelated in time to seizure occurrence (interictal). The most common sexual dysfunction is hyposexuality, even if hypersexuality and different paraphilias have been reported in males with epilepsy. Epilepsy and antiepileptic drugs can also alter sex hormone levels to promote the development of reproductive endocrine disorders. This article aims to explore the prevalence and etiology of sexual and reproductive dysfunctions in men with epilepsy, highlighting the pivotal role of antiepileptic drugs in their pathogenesis.     

Effects of topiramate versus other antiepileptic drugs on the cognitive function of patients with epilepsy

BACKGROUND: Only very large dose of topiramate has neurotoxicity, indicating that topiramate has low neurotoxicity and high safety. The residual rate of topiramate is affected by many cognitive-related adverse effects. Patients who take topiramate often accompany with thought slowness, difficulty in finding words, dyscalculia, blunt reaction, attention decreasing, memory deterioration, etc. OBJECTIVE: To compare the effects of topiramate with traditional anti-epileptic drugs (including carbamazepine and Valproic acid (VPA) on cognitive function of patients with epilepsy. DESIGN: Observational experiment, self-control and intergroup comparison. SETTING: Sichuan Academy of Medical Science. PARTICIPANTS: Eighty-seven inpatients and outpatients with newly diagnosed epilepsy who received preliminary diagnosis and follow-up in the Department of Neurology, Sichuan People's Hospital between January 2004 and June 2006 were involved in this survey. They were diagnosed according to disease history and electroencephalogram (EEG). The onset type was diagnosed following the definition of epilepsy and epileptic syndrome in 1989 International Anti-epileptic League. The involved patients and their relatives were informed of detection and therapeutic regimen. The patients were assigned into two groups according to table of random digit: traditional antiepileptic drugs group (AEDs group, n =44) and topiramate (TPM) group (n =43). METHODS: ①Among the patients in AEDs group, carbamazepine was the first choice for 21 patients with partial seizures or partial secondarily generalized seizures, and VPA for 23 patients with generalized seizures. The initial dose of carbamazepine was 300 mg/d, and that of VPA was 500 mg/d. Patients in the TPM group took TPM with the initial dose of 25 mg/d, increased by 25 mg/d each week to target dose 150 mg/d within 8 weeks. ② Curative effect was graded into 4 degrees: markedly effective, effective, ineffective and aggravated. Total effective rate was calculated. ③ Cognitive function of patients was tested before and 6 months after administration by using Wechsler Adult Intelligence Scale(WAIS) or Wechsler Intelligence Scale for Children (WISC, Chinese edition), (Higher scores indicated better cognitive function), Stroop color word interference, test of memory of past numbers, test of telling the names of fruits and vegetables within 1 minute (Shorter time for reading word, telling color and memory of past numbers demonstrated better cognitive function. Less errors in reading words, telling colors and memory of past numbers, numbering and telling the names of fruits and vegetables within 1 minute indicated better cognitive function), etc. totally 22 items. ④ t test and paired t test were used for measurement data. MAIN OUTCOME MEASURES: Clinical curative effects and adverse reactions as well as neurological tests. RESULTS: Eighty-four pationts praticipated final analysis and 3 dropped out. ① Inthe AEDS group and TPM group, total effective rate was 86% and 99%, respectively. ② In the AEDs group, there were no significant changes in the scores of each test of WIS before and after treatment (P > 0.05). In the TPM group, total IQ, word scores, verbal IQ and digit span scores were significantly decreased （t =2.097–4.423，P < 0.05–0.01）.Following treatment, the time for reading word and telling color for patients in the AEDs group was prolonged in Stroop color interference test（t =–2.304，–2.454，P < 0.05）, and time for reading word and memory of past numbers for patients in the topiramate group was significantly prolonged （t =–3.054，2.272，P < 0.01，0.05）. ③There were no significant differences in scores of WIS before and after treatment in AEDs group and TPM group (P > 0.05). Following treatment, verbal IQ, word scores, total IQ, digit span of patients in the TPM group were significantly lower than those in the AEDs group（t =2.052–3.297，P < 0.05–0.01）.There were no significant differences in Stroop color word interference, memory of past numbers and telling the names of fruits and vegetables within 1 minute before and after treatment in AEDs group and TPM group (P > 0.05). CONCLUSION: ① Moderate and small doses of both TPM and AEDs may lead to mild cognitive function impairment of patients, mainly presenting delayed reaction and decreased sensitivity. ②TPM mainly influences attention, language comprehension ability and fluency, while AEDs cause delayed reaction easily, but influence executive function mainly.     

Effects of topiramate versus other antiepileptic drugs on the cognitive function of patients With epilepsy

BACKGROUND： Only very large dose of topiramate has neurotoxicity, indicating that topiramate has low neurotoxicity and high safety. The residual rate of topiramate is affected by many cognitive-related adverse effects. Patients who take topiramate often accompany with thought slowness, difficulty in finding words, dyscalculia, blunt reaction, attention decreasing, memory deterioration, etc. OBJECTIVE： To compare the effects of topiramate with traditional anti-epileptic drugs （including carbamazepine and Valproic acid （VPA） on cognitive function of patients with epilepsy. DESIGN： Observational experiment, self-control and intergroup comparison. SETTING： Sichuan Academy of Medical Science. PARTICIPANTS： Eighty-seven inpatients and outpatients with newly diagnosed epilepsy who received preliminary diagnosis and follow-up in the Department of Neurology, Sichuan People＇s Hospital between January 2004 and June 2006 were involved in this survey. They were diagnosed according to disease history and electroencephalogram （EEG）. The onset type was diagnosed following the definition of epilepsy and epileptic syndrome in 1989 International Anti-epileptic League. The involved patients and their relatives were informed of detection and therapeutic regimen. The patients were assigned into two groups according to table of random digit： traditional antiepileptic drugs group （AEDs group, n =44） and topiramate （TPM） group （n =43）. METHODS： （1）Among the patients in AEDs group, carbamazepine was the first choice for 21 patients with partial seizures or partial secondarily generalized seizures, and VPA for 23 patients with generalized seizures. The initial dose of carbamazepine was 300 mg/d, and that of VPA was 500 mg/d. Patients in the TPM group took TPM with the initial dose of 25 mg/d, increased by 25 mg/d each week to target dose 150 mg/d within 8 weeks. （2） Curative effect was graded into 4 degrees： markedly effective, effective, ineffective and aggravated. Total effective rate was calculated. （3） Cognitive function of patients was tested before and 6 months after administration by using Wechsler Adult Intelligence Scale（WAIS） or Wechsler Intelligence Scale for Children （WISC, Chinese edition）, （Higher scores indicated better cognitive function）, Stroop color word interference, test of memory of past numbers, test of telling the names of fruits and vegetables within 1 minute （Shorter time for reading word, telling color and memory of past numbers demonstrated better cognitive function. Less errors in reading words, telling colors and memory of past numbers, numbering and telling the names of fruits and vegetables within 1 minute indicated better cognitive function）, etc. totally 22 items. （4） t test and paired t test were used for measurement data. MAIN OUTCOME MEASURES： Clinical curative effects and adverse reactions as well as neurological tests. RESULTS： Eighty-four pationts praticipated final analysis and 3 dropped out. （1） Inthe AEDS group and TPM group, total effective rate was 86% and 99%, respectively. （2） In the AEDs group, there were no significant changes in the scores of each test of WIS before and after treatment （P 〉 0.05）. In the TPM group, total IQ, word scores, verbal IQ and digit span scores were significantly decreased （ t =2.097 - 4.423, P 〈 0.05 - 0.01 ） .Following treatment, the time for reading word and telling color for patients in the AEDs group was prolonged in Stroop color interference test （ t = - 2.304, - 2.454, P 〈 0.05 ）, and time for reading word and memory of past numbers for patients in the topiramate group was significantly prolonged （ t = - 3.054, 2.272, P 〈 0.01, 0.05 ）. （3）There were no significant differences in scores of WIS before and after treatment in AEDs group and TPM group （P 〉 0.05）. Following treatment, verbal IQ, word scores, total IQ, digit span of patients in the TPM group were significantly lower than those in the AEDs group （t =2.052 - 3.297, P 〈 0.05- 0.01 ） .There were no significant differences in Stroop color word interference, memory of past numbers and telling the names of fruits and vegetables within 1 minute before and after treatment in AEDs group and TPM group （P 〉 0.05）. CONCLUSION： （1） Moderate and small doses of both TPM and AEDs may lead to mild cognitive function impairment of patients, mainly presenting delayed reaction and decreased sensitivity. （2）TPM mainly influences attention, language comprehension ability and fluency, while AEDs cause delayed reaction easily, but influence executive function mainly.     

Fractures, epilepsy, and antiepileptic drugs

The risk for skeletal fractures in patients with epilepsy is two to six times greater than in the general population. Fractures may be caused by seizures themselves or by falls, with or without seizures. Side effects of antiepileptic drugs (AEDs), such as ataxia, and coexisting neurological deficits contribute to the risk for falls. The effects of older AEDs on bone mineral density probably increase the risk for fractures associated with seizures and falls. Preventive measures include optimal control of seizures and supplementation with calcium and vitamin D. Whether newer AEDs prove to be without adverse effects on bone mineral metabolism remains to be determined.     

Effects of endocrine modulators on sexual differentiation and reproductive function in male Japanese quail

A number of environmental contaminants have been shown to interfere with the endocrine system. Many of these compounds bind to estrogen receptors, thereby potentially disrupting estrogen-regulated functions. In this paper, we review some background data on avian sexual differentiation and present some of the results from our studies on effects of estrogenic chemicals administered during sexual differentiation in the Japanese quail. Initially, our goal was to elucidate whether a decreased male sexual behavior in quail is a suitable endpoint for studying long-term effects of exposure to estrogenic compounds during sexual differentiation in ovo. We thereafter tested some environmental pollutants, suspected to act via mimicking estrogens, using the test system developed. Results from our studies on the synthetic estrogens ethinylestradiol and diethylstilbestrol, as well as the environmental pollutants bisphenol A, tetrabromobisphenol A, and o,p'-DDT are reviewed in this paper. We conclude that the Japanese quail is well suited as an animal model for studying various long-term effects after embryonic exposure to estrogenic compounds. Depressed sexual behavior proved to be the most sensitive of the variables studied in males and we find this endpoint appropriate for studying effects of endocrine modulating chemicals in the adult quail following embryonic exposure.     

Determining the effects of antiepileptic drugs on cognitive function in pediatric patients with epilepsy

The majority of children with epilepsy are of normal intelligence; however, a significant subset suffers from temporary or permanent cognitive impairment. Factors that affect cognitive function are myriad and include the neuropathology underlying the epilepsy, seizures, epileptiform activity, psychosocial problems, and antiepileptic drug side effects. Although cognitive impairment is often wrongly attributed to the effects of antiepileptic drugs, antiepileptic drugs do impair cognition in some children. Clinicians should be aware of the differential cognitive effects of antiepileptic drugs and should monitor cognitive function closely when adding or changing therapy. Based on published data from prospective, chronic dosing studies, phenobarbital and topiramate have the highest potential for causing cognitive dysfunction.     

Premenstrual dysphoric disorder in women with epilepsy: relationships to potential epileptic, antiepileptic drug, and reproductive endocrine factors

The purpose of this prospective observational investigation was to determine whether the frequency of premenstrual dysphoric disorder (PMDD) and the severity of PMDD symptoms differ between women with epilepsy and controls without epilepsy and whether there exists a relationship between the severity of PMDD symptoms and some epileptic, antiepileptic drug, and reproductive endocrine features. The results suggest that epilepsy, antiepileptic drug levels, ovulatory status, and hormone levels and ratios may all influence PMDD in women with epilepsy. PMDD severity scores may be greater in people with right-sided than in those with left-sided epilepsy, and in people with temporal than in those with nontemporal epileptic foci. PMDD severity scores may be greater with anovulatory cycles, and scores may correlate negatively with midluteal serum progesterone levels and positively with midluteal estradiol/progesterone ratios. Mood score may vary with particular antiepileptic drugs, favoring carbamazepine and lamotrigine over levetiracetam. PMDD severity scores may correlate directly with carbamazepine levels, whereas they correlate inversely with lamotrigine levels.     

Effects of the antiepileptic drugs on peripheral nerve function

Objective –  We aimed to compare the effects of antiepileptic drugs and provide findings of peripheral nerve impairment using standard electrophysiological techniques.
Materials and methods –  Young adult outpatients with epilepsy on monotherapy for no less than 6 months with carbamazepine (CBZ), valproic acid (VPA), oxcarbazepine (OXC) and topiramate (TPM) were examined. Patients who had any other disease that could effect nerve conduction studies and who had neuropathic symptoms were excluded.
Results –  Each group contained 15 patients and 20 healthy subjects were examined as the control group. Prolonged latency of median sensory nerve ( P  =   0.004), ulnar sensory nerve ( P  =   0.01) and sural nerve ( P  =   0.003) with a diminished nerve conduction velocity was observed in the CBZ group ( P  =   0.014, P  =   0.002, P  =   0.025, respectively). No correlation was found between VPA, OXC and TPM and the nerve conduction studies ( P  >   0.05).
Conclusions –  Valproic acid, oxcarbazepine and topiramate don't have effects on nerve conduction studies. Mild electrophysiological changes contribute to carbamazepine therapy.