Epilepsy and antiepileptic drugs have complex effects on male reproduction. Men with epilepsy are susceptible to reproductive endocrine disorders, sexual dysfunction, and fertility disorders, and these effects may be related to epilepsy itself or to the use of antiepileptic drugs. It has long been known that epilepsy itself and the use of traditional antiepileptic drugs can lead to reproductive dysfunction in men with epilepsy. Research related to newer antiepileptic drugs, on the other hand, has lagged relatively behind. We review the effects of antiepileptic drugs, especially newer antiepileptic drugs, on reproductive endocrinology, sexual function, and fertility in men with epilepsy. I. Effects of epilepsy on reproduction in men with epilepsy Epilepsy itself can affect the secretion of sex hormones. Evidence from preclinical studies has shown that abnormalities in sex hormone levels can be monitored in animals after induction of partial or full-blown epileptic seizures, and that repeated seizures can cause changes in gonad size and decreased sexual function. Evidence from clinical studies also shows a close relationship between epileptic discharges in the brain and altered sex hormones, especially in temporal lobe epilepsy, where disturbances in hormone levels are more likely to be detected, and the mechanism may be that the epileptic discharges interfere with the hypothalamic pituitary gonadal axis. Ramesha et al. followed 50 male patients with epilepsy after resection of the epileptogenic focus and showed that sexual function was improved in most of them. In addition, one study found that a greater proportion of spermatozoa in untreated epilepsy showed morphological abnormalities than in healthy controls, suggesting that epilepsy itself may affect the quality of sperm leading to infertility. Second, the effect of antiepileptic drugs on reproduction in men with epilepsy Antiepileptic drugs can lead to endocrine disruption in men with epilepsy. In addition, epidemiological data clearly show that men with epilepsy have a higher rate of sexual dysfunction, up to 20%-50%; the fertility rate is reduced to 1/2-3/4 of the healthy population . (i) Traditional antiepileptic drugs 1. Liver enzyme inducers (carbamazepine, phenytoin sodium, phenobarbital): the use of liver enzyme inducers can cause endocrine disorders in men, probably due to the drug-induced hepatic P450 enzyme system, resulting in an increase in sex hormone-binding globulin and a significant decrease in free androgens available in the tissues, which ultimately leads to severe sexual dysfunction in some men with epilepsy. This ultimately leads to severe sexual dysfunction in some men with epilepsy. Studies have shown that erectile function and sexual intercourse in men with epilepsy in the carbamazepine-treated group were significantly lower than in healthy controls. Carbamazepine may also cause infertility in men with epilepsy. Hayashi et al. reported a case of a male patient with epilepsy who was diagnosed with infertility and weak spermatozoa due to long-term carbamazepine at a dose of 400 mg/d. After switching to phenytoin sodium for 1 month, sperm motility improved by 65% and his wife was successfully conceived 5 months later. A clinical study also found that carbamazepine reduced sperm motility and increased the number of abnormally morphologic sperm in men with epilepsy. According to one study, sexual function was significantly lower in men with epilepsy in the phenytoin sodium treatment group than in the healthy population group and the epilepsy unmedicated group. In a study by Owoeye et al, phenytoin sodium reduced sperm motility and sperm volume in men with epilepsy after long-term phenytoin sodium administration for more than 6 years, and sperm quality returned to normal after 3 months of treatment with sodium valproate. Further studies by Bhattacharjee et al. found that male rats given phenobarbital had a higher frequency of abnormal sperm head shape and that this was more pronounced as the duration of administration increased. 2. Enzyme inhibitors (sodium valproate): Valproic acid can cause a decrease in serum luteinizing hormone (LH) and follicle producing hormone (FSH) levels and an increase in dehydroepiandrosterone sulfate and androstenedione concentrations in male patients. In contrast, Xiaotian et al. showed that only blood LH and FSH levels were reduced in the valproate group, and the rest of the sex hormone levels were normal. The mechanism by which sodium valproate affects reproductive function may be that GABAergic neurons regulate the input of norepinephrinergic neurons to gonadotropin-releasing hormoneergic neurons. Alternatively, valproic acid may act directly on GABAergic neurotransmission and thus alter gonadotropin release. In one study, the International Index of Erectile Function Questionnaire (IIEF-5) scores for sexual function were significantly lower in the valproate treated group. Valproic acid can also cause infertility, and Hayashi et al. reported two patients diagnosed with oligospermia and azoospermia as a result of valproate sodium, who recovered completely from sperm abnormalities after stopping the drug, suggesting a reproductive toxic effect of valproic acid. Several studies on the effects of valproic acid on gonads and sperm in men with epilepsy found that valproic acid caused reversible changes in sperm quality and gonadal cell structure in patients, and was positively correlated with dose. （Malatkova reported that in 12 patients treated with oxcarbazepine instead of carbamazepine, the sex hormone disorder caused by carbamazepine returned to normal. However, the effect was dose-dependent, with an increase in serum testosterone and sex hormone binding protein and gonadotropin levels in patients at doses <900 mg >900 mg/d. Oxcarbazepine had no significant negative effect on male sexual function. One study investigated 228 male patients with epilepsy who had below-baseline sexual function impairment, and after 12 weeks of initial or replacement with oxcarbazepine monotherapy, 79, 4% showed an improvement in sexual function and no deterioration in sexual function. However, several cases of oxcarbazepine induceable erectile dysfunction in men have been reported, characterized by dose dependence and reversibility. In addition, oxcarbazepine can cause infertility, and Calabro et al. reported a case of infertility in a male patient with epilepsy, who was diagnosed with infertility and a significant decrease in sperm quality, and after 3 months of replacement with lamotrigine treatment, the sperm count increased 2, 7-fold and sperm motility improved by 68%, and the wife was successfully conceived after 5 months. Previous studies have suggested that oxcarbazepine causes a significant increase in the rate of abnormal sperm morphology. Cansu et al. also found in animal experiments that oxcarbazepine caused a decrease in the number of spermatocytes at all stages of development, but the difference was not statistically significant. 2. Lamotrigine: The effect of lamotrigine on sex hormones in male patients with epilepsy is controversial. Several studies have shown that lamotrigine does not cause changes in sex hormone levels in men with epilepsy; some studies have also shown that lamotrigine can cause a decrease in testosterone levels, but the degree of decrease is significantly lower than in the carbamazepine and sodium valproate groups. A clinical study by Gil-Nagel et al. followed 79 men with epilepsy who were treated with lamotrigine as an initial drug or as a replacement drug for 4 months and significantly improved sexual function in men compared to before the drug. This may be the result of improvement in seizures, elimination of adverse effects of other antiepileptic drugs, and the mood-stabilizing effects of lamotrigine. The effect of lamotrigine on male fertility has not been studied, but Roste et al. found through animal experiments that no significant testicular morphological and weight abnormalities were seen in rats given long-term therapeutic doses of lamotrigine. 3, gabapentin: Daoud et al.’s experiments on rats showed that the administration of gabapentin (100 mg/kg per day for 60 d) caused a decrease in serum testosterone and FSH levels in rats. There are no clinical trials of this type for this drug. Cases of reversible sexual dysfunction have been reported with gabapentin, and sexual dysfunction was gradually restored after dose reduction and completely relieved after complete discontinuation of the drug.Shetty’s study showed that gabapentin given to rats at different doses (16, 25, and 32 mg/d), and no spermatozoa were detected on day 14 and at the time points set for testing after day 35 Significant abnormalities in morphology. 4. Topiramate: Rats given topiramate showed a widespread reduction in plasma testosterone levels and a significant decrease in FSH levels. However, the results of a clinical study by Civardi et al. showed that topiramate did not affect sex hormone levels in patients. Topiramate has been reported in the literature to cause erectile dysfunction, and sexual function returned to normal after discontinuation of the drug, with no abnormalities in sex hormone levels monitored during any of this process. Topiramate is a carbonic anhydrase inhibitor, and carbonic anhydrase inhibitors interfere with the production of vasoactive intestinal peptides and nitric oxide, resulting in decreased blood flow to the genitals, so the patient’s erectile dysfunction may be vascular in origin. Topiramate may have reproductive toxicity. Animal experiments by Otoom et al. showed that sperm motility, density and testicular weight of rats were significantly decreased after administration of topiramate (100 mg/kg daily for 60 d). 5. Levetiracetam: Harden et al. mentioned in their article that compared to patients before taking the drug, after taking levetiracetam, patients had a 16% increase in total testosterone, a 19% increase in free testosterone, and a 29% increase in the mean free testosterone index. Several studies have shown that treatment with levetiracetam at therapeutic doses did not result in abnormal sex hormone levels. One study showed that patients with levetiracetam had lower IIEF-5 scores than healthy controls, and Calabro et al. also reported two cases of young men with epilepsy who experienced severe deficits in libido and sexual pleasure after taking levetiracetam. In addition, one study showed that therapeutic doses of levetiracetam caused a significant decrease in sperm viability but did not cause significant abnormalities in sperm morphology in men with epilepsy, whereas valproic acid caused significant abnormalities in both sperm viability and morphology. III. Discussion and outlook Epilepsy, especially temporal lobe epilepsy, can lead to abnormal secretion of sex hormones in men with epilepsy, and the mechanism may be that epileptic discharges interfere with the hypothalamic pituitary gonadal axis, thus affecting the release of hormones and leading to male reproductive disorders. Carbamazepine, phenobarbital, and phenytoin sodium can promote the synthesis of biologically inactive sex hormone-binding globulin and correspondingly reduce testosterone activity; the enzyme inhibitor sodium valproate can also lead to abnormal secretion of sex hormones in men with epilepsy; in addition, all traditional antiepileptic drugs may lead to male sexual dysfunction and cause a decrease in sperm quality, increasing the risk of male infertility. Research on newer antiepileptic drugs has lagged behind, and current studies suggest that newer antiepileptic drugs have less overall effect on male epileptic patients’ sex hormones at therapeutic doses. However, with the exception of lamotrigine and oxcarbazepine, which do not affect or can improve sexual function in male patients after initial or replacement therapy, newer antiepileptic drugs can still have a negative impact on male sexual function. In addition, except for lamotrigine and gabapentin, which have no significant effect on sperm, other new antiepileptic drugs can still cause a significant decrease in sperm quality. Currently, phenytoin sodium, carbamazepine, valproate sodium, and oxcarbazepine have been successively reported to cause infertility in male patients. There is no comprehensive cross-sectional comparison and meta-analysis of the effects of various antiepileptic drugs on reproductive endocrine, sexual function and fertility in men with epilepsy, and the mechanisms of their effects are unclear. More studies are needed in the future to give better advice on the use of medications in men with epilepsy who have sexual and reproductive needs.