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The effects of oxcarbazepine, levetiracetam, and lamotrigine on semen quality, sexual function, and sex hormones in male adults with epilepsy. Department of Neurology, Southwest Medical University, Luzhou, China.

Department of Neurology, Southwest Medical University, Luzhou, China. Department of Orthopedics, Zizhong People's Hospital, Neijiang, China.

Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China. Hongbin Sun, Department of Neurology, Southwest Medical University, Luzhou, China.

Yang Si, Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China.

Department of Neurology, Southwest Medical University, Luzhou, China. Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China.

Hongbin Sun, Department of Neurology, Southwest Medical University, Luzhou, China.

Yang Si, Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China.

Department of Neurology, Southwest Medical University, Luzhou, China. Department of Neurology, Southwest Medical University, Luzhou, China. Department of Orthopedics, Zizhong People's Hospital, Neijiang, China. Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China.

Hongbin Sun, Department of Neurology, Southwest Medical University, Luzhou, China.

Yang Si, Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China. Department of Neurology, Southwest Medical University, Luzhou, China. Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China. Hongbin Sun, Department of Neurology, Southwest Medical University, Luzhou, China. Yang Si, Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, China. To investigate the effects of antiepileptic drugs (AEDs; oxcarbazepine [OXC], levetiracetam [LEV], and lamotrigine [LTG]) on semen quality, sexual function, and sex hormones in male adults with epilepsy.

Individual treatment with OXC, LEV, or LTG was randomly assigned to 38 newly diagnosed male adult patients with epilepsy.

Semen quality and sex hormones were measured before treatment and 6 months after taking the medicine.

A questionnaire was administered using the International Index of Erectile Function Scale?5 and the Premature Ejaculation Diagnostic Tool Self?Assessment Scale to evaluate sexual function, followed by an analysis of the comparison between the treated patients and healthy volunteers (sildenafil 50 mg tablet coupon healthy controls) as well as the changes and differences between the patients themselves before and after treatment. The total sperm count, fast forward movement rate (FFMR), survival rate, and normal sperm rate in the group with epilepsy were lower than those in healthy controls best sildenafil coupon ( P.

The semen quality of males with epilepsy is decreased even before treatment. The AEDs (OXC, LEV, and LTG) have no significant effect on sexual function and sex hormones, and OXC can improve the sperm FFMR and survival rate. The semen quality of males with epilepsy is decreased even before treatment The antiepileptic drugs oxcarbazepine, levetiracetam, and lamotrigine have no significant effect on sexual function and sex hormones Oxcarbazepine can improve the sperm quality in fast forward movement rate and survival rate.

Epilepsy is a common disease of the nervous system. Epidemiological surveys show that the prevalence of epilepsy is higher in males than in females. 1 About 38%?71% of men with epilepsy have sexual dysfunction, and fertility rates are only one?third to one?half of the rate in healthy people. 2 Studies have investigated the effects of seizures themselves and some older antiepileptic drugs (AEDs; carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT], and valproic acid [VPA]) on the reproductive and sexual function of male patients with epilepsy. 3-5 There have been relatively few studies of newer AEDs (oxcarbazepine [OXC], levetiracetam [LEV], or lamotrigine [LTG]), and some of

them

are controversial.

6, 7 In this study, newly diagnosed male adult patients with epilepsy were randomized to receive OXC, LEV, or LTG monotherapy to observe the quality of semen, sexual function, and sex hormones before and after treatment, and to explore the effects of these AEDs on the reproductive and sexual functions of male adult patients with epilepsy.

Thirty?eight newly diagnosed male adult patients with epilepsy were enrolled at the Epilepsy Center Sichuan Provincial People's Hospital from April 2015 to November 2016. The diagnosis was in line with the classification of epilepsy defined by the International League Against Epilepsy (1981).

Only patients with generalized or focal epilepsy, with generalized or secondary generalized tonic–clonic seizures, were recruited into the present study.

Patients with genital organic or functional lesions were excluded; patients were also required to be free of serious psychosis, diabetes, malignant neoplasm, and other progressive neurological diseases. Patients signed informed consent and agreed to enter the study before recruitment.

Twenty?six volunteers in the same period were recruited as the healthy control group.

The institutional ethics committee of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital provided ethical approval for this study.

The AED group was randomly divided into 3 subgroups and given OXC (300?900 mg/d), LEV (1000?1500 mg/d), or LTG (100?150 mg/d).

Each subgroup was administered monotherapy for ?6 months.

The semen samples were collected from the healthy control group and from the AED group.

In the AED group, semen samples were collected both before and 6 months after medication. All semen samples were obtained by masturbation 3?7 days after abstinence and quantified by a pipette.

The semen was kept at a constant temperature of 37°C for 30 minutes (or until liquefaction).

The total number, the pH value, the fast forward movement rate (FFMR), and the survival rate of the sperm from all participants were evaluated by the same researchers, who were unaware of the group allocations. All operations were conducted in accordance with World Health Organization standards.

The sexual function of the patients was evaluated using the International Index of Erectile Function Scale?5 and the Premature Ejaculation Diagnostic Tool Self?Assessment Scale.

8, 9 The 2 questionnaires were completed by those who had had a sexual experience. Six patients did not complete the questionnaire because they had no sexual experience. Five?milliliter samples of blood after early morning fasting was collected from study patients diagnosed with epilepsy before or after medication treatment.

The levels of sex hormones, estradiol, testosterone, luteinizing hormone (LH), follicle?stimulating hormone (FSH), and prolactin, were determined by chemiluminescence analysis. The chemiluminescence analyzer (serial number iSR05848) and detection kit were purchased from Abbott Laboratories (Abbott Park, IL, USA). The analyses were performed in strict accordance with the company's instructions. SPSS v17.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. The data were expressed as mean ± standard deviation when the quantitative data were consistent with the normal distribution, and Student?Newman?Keuls or Dunnett t test was conducted for the analysis. Kruskal?Wallis and Mann?Whitney tests were used for quantitative data that did not fit the normal distribution, and the constituent ratios of the rates were determined using the Pearson chi?square or Fisher's exact test. There was no significant difference in the basic demographic data between the groups of controls and patients with epilepsy in terms of age and educational level, but the patients’ marriage rate and birth rate were significantly lower than those of the healthy control group (57.7% vs 26.3%, P Table 1.

Demographic data, marriage status, and fertility rate of male patients with epilepsy and the healthy control group. Age, y Disease course, y Marriage rate, % Birth rate, % Education levels, n Elementary or under Middle school College or above Pre?AEDs 38 28.09 ± 3.08 4.61 ± 5.48 26.32a a Pearson chi?square test for comparison of male epilepsy patients and control participants regarding marriage rate and fertility rate, P 15.79a a Pearson chi?square test for comparison of male epilepsy patients and control participants regarding marriage rate and fertility rate, P 0 20 18 Control 26 28.00 ± 4.68 – 57.69 46.15 0 8 18 P .99 .012 .008 – – .14 OXC 16 28.30 ± 4.65 7.69 ± 7.18 37.50 18.75 0 9 7 LEV 11 29.00 ± 6.12 3.42 ± 5.53 18.18 18.18 0 5 6 LTG 11 27.00 ± 3.21 5.57 ± 2.37 18.18 9.10 0 6 5 P .85 .08 .46 .87 – – .92. AED, antiepileptic drug; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine. a Pearson chi?square test for comparison of male epilepsy patients and control participants regarding marriage rate and fertility rate, P.

The total number of sperm, FFMR, survival rate, and normal sperm rate in male adult patients with epilepsy before treatment were lower than those in healthy controls ( P .05; Table 2). AED, antiepileptic drug; CON, control; FFMR, fast forward movement rate; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine. a Mann?Whitney test showed that the total sperm count, FFMR, survival rate, and normal sperm count of male patients with epilepsy before treatment were significantly lower than after treatment ( P b Before and after treatment with OXC, P. 3.3 Comparison of sexual function among the groups.

The erectile function scale scores and premature ejaculation index scores of male adult patients with epilepsy before treatment were lower than those of the healthy control group, but there was no statistically significant difference. The erectile function before and after AED treatment had a trend toward improvement, whereas premature ejaculation did not improve, although both were not significantly different ( P > .05; Table 3). Erectile function score Premature ejaculation index score Pre?AEDs 38 19.36 ± 1.57 4.14 ± 2.19 CON 26 21.50 ± 3.73 4.26 ± 3.01 P .09 .90 Pre?OXC 16 19.31 ± 1.08 4.10 ± 1.89 OXC 16 20.09 ± 1.87 6.30 ± 3.65 P , before/after .30 .53 Pre?LEV 11 19.36 ± 2.03 4.20 ± 3.08 LEV 11 20.27 ± 2.61 7.00 ± 3.90 P , before/after .17 .40 Pre?LTG 11 19.43 ± 1.97 4.18 ± 1.50 LTG 11 20.82 ± 2.18 8.00 ± 5.73 P , before/after .22 .17. AED, antiepileptic drug; CON, control; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine. Compared with the healthy control group, the male adult patients with epilepsy before treatment, and the patients with epilepsy in the 3 different drug treatment subgroups before and after treatment, sex hormone levels were not significantly different ( P > .05; Table 4).

E2, pmol/L T, nmol/L LH, mIU/mL FSH, mIU/mL PRL, mIU/L Pre?AEDs 38 110.84 ± 42.63 19.41 ± 4.41 3.36 ± 1.72 3.68 ± 2.40 265.14 ± 97.38 CON 26 106.58 ± 31.52 17.18 ± 6.26 2.61 ± 1.17 2.93 ± 1.50 224.01 ± 59.73 P .99 .86 .22 .51 .40 Pre?OXC 16 108.12 ± 35.23 19.45 ± 3.41 3.40 ± 2.07 3.67 ± 1.96 266.35 ± 95.34 OXC 16 119.33 ± 25.90 17.02 ± 6.69 3.66 ± 1.41 3.98 ± 2.46 209.06 ± 86.35 P , before/after .93 .74 .91 .98 .27 Pre?LEV 11 112.81 ± 43.18 19.38 ± 5.87 3.31 ± 1.46 3.64 ± 2.01 263.57 ± 117.87 LEV 11 133.91 ± 48.20 18.46 ± 6.05 2.44 ± 1.06 3.37 ± 1.17 208.29 ± 61.61 P , before/after .32 .99 .20 .97 .27 Pre?LTG 11 111.56 ± 42.75 19.50 ± 4.67 3.42 ± 1.34 3.70 ± 3.21 266.36 ± 67.27 LTG 11 120.10 ± 16.73 22.39 ± 6.43 3.67 ± 2.49 4.70 ± 1.60 285.22 ± 109.54 P , before/after .92 .61 .91 .42 .94.

AED, sildenafil 50 mg tablet coupon antiepileptic drug; CON, control; E2, estradiol; FSH, follicle?stimulating hormone; LEV, levetiracetam; LH, luteinizing hormone; LTG, lamotrigine; OXC, oxcarbazepine; PRL, prolactin; T, testosterone. It has been reported that the incidence of sexual dysfunction in male patients with epilepsy is 5 times higher than that in healthy people, and the incidence of sexual hyperactivity is about 2.9%. 10 A number of studies have shown that epilepsy and AEDs (especially older AEDs) have a complex effect on male sex hormones, reproductive organs, and sexual function, leading to a decrease in fertility in male patients with epilepsy. 4, 5 In this study, the marriage rate and birth rate of the male adult patients with epilepsy were significantly lower than those of the healthy group, which may be related to the patients’ anxiety caused by seizures and different degrees of social discrimination.

That the fertility rate of the adult male epilepsy patients was lower than that of the healthy controls may be related to the low occurrence of marriage and the impact of seizures on reproductive function. In this study, we only recruited those patients with generalized and secondary generalized tonic–clonic seizures; patients with focal seizures (except for secondary generalized tonic–clonic seizures) were excluded, because they rarely seek medical care and show poor medical compliance. It has been reported in both animal and clinical studies that an epileptic seizure itself can affect the secretion of sex hormones. In animal experiments, a partial or generalized seizure can lead to abnormal sex hormone levels; repeated seizure attacks can cause gonadal size changes and decreased sexual function. 10 Clinical studies have also observed that abnormal brain epileptiform discharges may directly interfere with the function of the hypothalamic?pituitary?gonadal axis, especially in temporal lobe epilepsy, which may cause abnormalities in the secretion of sex hormones and lead to reproductive endocrine disorders.

10 It is known that AEDs can cause endocrine disorders in male patients with epilepsy, which is particularly common in older AEDs such as the enzyme inducer classes (CBZ, PHT, PB, etc) and liver enzyme inhibitors (VPA).

This class of drugs induces hepatic cytochrome P450 to increase the synthesis of sex hormone–binding globulin, decreases the level of free androgens, or promotes the conversion of testosterone to estradiol by aromatase. This affects the function of the hypothalamic?pituitary?gonadal axis and causes sex hormone disorders.

11 Enzyme inhibitory AEDs can affect the output of gonadotrophin?releasing hormone neurons by affecting serotonin and ??aminobutyric acid (GABA) neurons, thereby increasing the concentration of dehydroepiandrosterone sulfate, causing negative feedback

regulation

and a reduction of LH and FSH.

The study on the impact of AEDs on the level of sex hormones in male patients with epilepsy has yielded differing results.

Malatkova et al 13 reported that sex hormone disorders in 12 patients returned to normal after CBZ was replaced by OXC. Verrotti et al 14 showed that OXC can have a dose?dependent effect on reproductive endocrine function, and serum testosterone, sex hormone–binding protein, and gonadotropin levels all increased when OXC doses were >900 mg/d.



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