In addition to the effect of epilepsy itself, antiepileptics drugs seem to contribute to hormonal alterations associated with sexual dysfunction. It has been suggested that antiepileptics drugs may have differential influence on the metabolism of sexual hormones and their binding proteins with secondary complications. Moreover, some antiepileptics drugs may adversely affect normal reproductive cycling and sexual function through increasing serotoninergic transmission. Enzyme-inducer antiepileptics drugs, such as carbamazepine, phenytoin and phenobarbital, elevate sex-hormone binding globulin and reduce bioactive testosterone levels. Increased levels of E2, sex-hormone binding globulin, Follicle-stimulating hormone and dehydroepiandrosterone sulfate have been reported in men with erectile dysfunction, while a decrease of dehydroepiandrosterone sulfate is believed to be associated with loss of sexual desire.
Hergoz et al found that men with partial seizures taking phenytoin have raised E2 levels. The author supposed that hepatic microsomial enzyme inducer antiepileptics drugs could lower testosterone by promoting sex-hormone binding globulin synthesis and by inducing aromatase, which converts testosterone in estradiol, the major inhibitor of Luteinizing hormone secretion. Suppression of Luteinizing hormone results in hypogonadotropic hypogonadism and chronically low testosterone to testicular failure and hypergonadotropic hypogonadism.
It has been suggested that phenytoin is associated with reduced sperm motility, semen volume, spermatozoa concentration and sperm count.
Valproate is distinguished from other first-line antiepileptics drugs in that it has enzyme-inhibiting effects. Valproate has been implicated to have only minor effects on the hormonal system in men with epilepsy.
Indeed, while maintaining androgen levels, Valproate seems to increase estrogens levels, perhaps by suppressing enzymatic metabolism of estradiol.
Recent studies in men with epilepsy have shown that both carbamazepine and Valproate are associated with reduced sperm motility and increased frequency of morphologically abnormal sperm; only Valproate was also associated with small testicular size.
Oxcarbazepine, a ketoderivate of carbamazepine, has a different metabolic pathway in the liver since it is mainly metabolized by reduction, and does not appear to induce the oxidative P450-enzyme system to the same extent as carbamazepine. Thus, Oxcarbazepine has been suggested to be a safe antiepileptics drug with regard to endocrine and metabolic effect. However, there is evidence that oxcarbazepine may also induce liver enzyme when used at higher dosage.
A recent study by Rattya et al have demonstrated that Valproate may directly affect steroid synthesis and metabolism, while carbamazepine and oxcarbazepine seem to have different reproductive effects in men with epilepsy whereas oxcarbazepine does not appear to decrease the bioactivity of androgens and carbamazepine does.
Interestingly, it has been shown that more than 80% of patients with enzyme-inducing antiepileptics drug pretreatment experienced an improvement or did not complain about sexual dysfunction after switching to oxcarbazepine. On the other hand, a recent clinical study has demonstrated an association between oxcarbazepine and morphologically abnormal sperm.
Non enzyme-inducing antiepileptics drugs such as lamotrigine may offer a distinct and important advantage in the area of reproductive endocrine function in men as they do not alter sexual hormone. Indeed, it has been demonstrated that lamotrigine use is associated with sexual function, levels of bioactive testosterone and gonadal efficiency values that are comparable to those of normal controls and superior to those found with carbamazepine and phenytoin.
Nevertheless, it has been recently demonstrated that even the new antiepileptics drugs can determine sexual dysfunction through complex and poorly understood mechanisms.
Topiramate, a drug approved for the treatment of both partial and generalized epilepsies and for migraine prophylaxis, has been reported to cause erectile dysfunction (erectile dysfunction) in few cases.
Calabro et al have postulated that topiramate induced-erectile dysfunction might be due to a blockage of AMPA receptors with an inhibition of the glutamatergic pathway, whereas glutamate is considered a candidate neurotransmitter of reflexive erection.
Pregabalin, a new antiepileptics drug structurally related to gabapentin, modulates the release of several neurotransmitters through its binding to voltage-dependent calcium channels and it is commonly used as adjunctive therapy for partial epilepsy. Erectile dysfunction associated with Pregabalin has been recently described in a case series, but pathophysiological mechanisms remains still unclear.
Reversible erectile dysfunction induced by zonisamide has been described so far only in a patient affected by brain tumor. Zonisamide is a sulfonamide derivate and shares with topiramate some common action mechanisms such as blockade of voltage-dependent sodium channels and inhibition of carbonic anhydrase. It has been suggested that zonisamide-related dysfunction could be due to an impairment of the complex interplay between the serotoninergic and nitrergic pathways.
Although oxcarbazepine and lamotrigine are thought to ameliorate sexual function in pre-treated epileptic men, some sexual side effects has been reported. In particular, hypersexuality has been related to lamotrigine-treatment in two patients with epilepsy; anorgasmia has been recently described as a dose-dependent and reversible side effect of oxcarbazepine.
Levetiracetam is a relatively new, broad-spectrum antiepileptics drug that has seen extensive use during recent years. It has recently reported that LEV treatment apparently has no drug specific sexual or endocrine side effects in young-adult epileptic men.
The hormonal effect of the other new antiepileptics drugs (felbamate, gabapentin, tiagabine, tipiramate, vigabatrin) has not been studied, to our knowledge, in men with epilepsy.