Among male epileptic patients, gonadotropic hormone dysregulation, semen parameter impairment, decreased in fertility, and sexual dysfunctions have been reported. From the probable causes was the effect of antiepileptic drugs [12].
In the present study, valproate-treated group (group 1) was examined pre- and post-treatment checkpoint; we found a significant decrease in serum LH and FSH at post-treatment checkpoint. This was in accordance with Xiaotian and colleagues [10]. This decrease in LH and FSH levels credited to negative feedback regulation in the pituitary portal system [13] as well as valproate affects the metabolism of serotonergic and gamma-aminobutyric acid (GABA)-ergic steroids or by a direct effect of VPA on endocrine tissue, in particular in the testis which is supported by studies in dogs, rats, and goats [13, 14].
We found non-significant decrease in serum total testosterone (T) levels at post-treatment checkpoint among valproate-treated group, and this was in accordance with Roste and colleagues [14] and Mikkonen and colleagues [15] who found no significant difference in testosterone level in epileptic patients treated by valproate who compared with the healthy males as a control group.
However, Rattya and colleagues [13] stated that valproate could increase serum androgen concentration involving testosterone in male epileptic patients. Najafi and colleagues [16] showed that valproate-treated males had significantly lower mean testosterone level. Also, Hamed and colleagues [17] in their study found that men with epilepsy had lower serum levels of free testosterone and higher sex hormone-binding globulin (SHBG). Free bioactive testosterone represents 2% of total testosterone, and the majority of plasma testosterone is linked to albumin and SHBG. Increased SHBG would expect to produce sexual dysfunction by decreasing serum levels of free testosterone and/or albumin-bound testosterone. Also, SHBG is the most important regulator for the biologic effect of the testosterone on the target tissue (it decreases the activity of the testosterone on the target cells). Secondary hormonal changes can occur with epilepsy due to a negative feedback loop between testosterone and pituitary hormone. Disturbances may occur at the levels of the hypothalamic, pituitary, and/or gonadal levels [17].
Also, in our research, we found statistical significant increase in serum prolactin (PRL) level in valproate-treated group at post-treatment checkpoint (P < 0.001). This was in agreement with Xiaotian and colleagues [10]. Similarly, in their study, Rabie and colleagues [18] observed that the serum level of prolactin in valproate-treated patients was significantly higher when compared with the control group. Valproate-induced hyperprolactinemia results from altered regulation of GABA-ergic, noradregneric, and serotonergic neurons which in turn modulate dopamine release [10].
Adding to that, seizures induce neuronal discharges which stimulate the hypothalamus and altered prolactin secretion by the pituitary gland [19]. Prolactin levels are further elevated through significantly increased sensitivity to prolactin inhibitory factor and prolactin-releasing factor [10].
Regarding sperm parameters, we found a significant decrease in all measured items at post-treatment checkpoint in the valproate-treated group (group I). This was in going with the results of other studies [14, 10, 20]. Free carnitine to total carnitine ratio decrease in male patients with epilepsy treated by VAP, and this may further affect sperm motility and decrease in fertility rates in these patients [14]. Other studies have confirmed that VAP directly affect sperm motility and marked abnormalities of sperm morphology in rats, dogs, and sheep [20, 21]. In humans treated with VPA, the number of motile sperms is reduced and several morphological changes occurred. These morphological changes increased sperm tail pathology which was suggested to be a cause of decreased of males’ fertility [7]. In in vitro research, it has been proposed that VPA directly affects sperm motility by inducing membrane stabilization [13].
Regarding levetiracetam-treated group (group II), we found non-significant difference between pre- and post-checkpoint of male sex hormones. This result was in agreement with two previous studies [2, 10]. That is, due to the main metabolic pathway of LEV through hydrolase acetyl animation transformation, the main metabolite (UCB 1057) is not transformed by liver cytochromes and LEV and its main metabolites do not affect the activity of hepatic cytochromes p450 [10].
In Svalheim and colleagues’ [22] study, free testosterone and rostenedione levels have been found to be elevated in patients treated with LEV compared with those patients from the control group. However, the same elevation was also recorded in the carbamazepine and lamotrigine groups. The authors have attributed these changes to the disease itself [22]. Harden and colleagues, 2010 [23], found increased testosterone levels in eight men after LEV treatment; however, this study was uncontrolled and was included in a very heterogeneous group of patients.
We found significant decrease in all sperm parameters among LEV-treated group at post-treatment checkpoint. This was according to two previous studies [2, 10]. Sperm parameter changes without alteration of sex hormone levels suggest a possible peripheral mechanism of adverse action [2].
Moreover, in another animal study, LEV adversely affected sperm parameters by reducing sperm concentration and motility, increasing abnormal sperm morphology and sperm DNA damage, and causing damage in the testicular structure of male rats. It is suggested that the mechanism of LEV toxicity in the male reproductive system arises from the promotion of oxidative stress and alterations in hormonal status [24].
Surges and colleagues, 2008 [6], reported that one of the LEV mechanism as antiepileptic drug is its effect on GABA-ergic system as it was associated with GABA-A receptor modification. GABA-A receptors were also found in the testes as well as CNS. It has been shown that GABA-ergic signaling reduced the proliferation of spermatogonial stem cells of the seminiferous tubules [25].
Another explanation of peripheral interference of LEV is the synaptic vesicular protein (SV2A) receptors, which are the most frequently presented form of synaptic vesicles in the glycoprotein family. These receptors were widely present in the CNS and endocrine cells [26]. The peripheral presence of such receptors in the testes could be the cause of reduced sperm parameters among LEV-treated groups.
Our study has some strength, as the pre- and post-antiepileptic drug treatment serum sex hormone assay and semen analysis were done for the same patients (self-control groups). We think that will nullify various external factors. The second strength is that we assessed newly diagnosed epileptic males. Thus, we were able to exclude factors associated with chronicity of the disease and the effects of previously administered AEDs.
Our study has some limitations. First of all, this study group is relatively small. Also, we assessed only the early effects of these drugs on the reproductive function of these epileptic patients.