An open study of valproate in subfertile men with epilepsy.

Objectives: The aim of the study was to assess whether, male patients with epilepsy, switching from valproic acid (VPA) to levetiracetam (LEV) or lamotrigine (LMG) critically improves sperm counts and parameters, increasing chance of patients' female partners to spontaneously conceive. Materials and methods: This is an observational prospective study recruiting all consecutive infertile male patients with epilepsy followed up at the outpatient Epilepsy Clinic of University Hospital of Ioannina, Northwest Greece. Infertile couples were referred to the Laboratory of Assisted Reproduction and Treatment of the University Hospital of Ioannina to conduct semen analysis. The first sample was collected while the patients were receiving VPA, and the second semen sample was collected after the patients were switched to LEV or LMG. Results: Seventeen infertile male patients were recruited in the study. Nine patients were switched to LEV, and eight patients were switched to LMG. The mean sperm count increased after VPA withdraw P =.06. Motility was improved with an increase of total motility and non‐progressive motility (P =.02 and P =.03, accordingly), whether sperm defects were decreased, mainly head defects (P =.03). Differences between patients switched to LEV or LMG were minimal and showed no significant findings. Spontaneous pregnancies were reported in three of the patients' partners, without any other clinical intervention offered to the couple. Conclusion: Switching from valproic acid to levetiracetam or lamotrigine improved sperm counts and other sperm parameters in subfertile male patients and increased the chance of spontaneously conceiving in subfertile couples.

Keywords: antiepileptic drugs; epilepsy; fertility; infertility; males; semen; sperm; valproic acid

Epilepsy is quite a common disorder in people of childbearing age. The prevalence of epilepsy is quite high in young men of reproductive age.1

Epilepsy may affect the hypothalamus and pituitary gland through the limbic system and especially by intervening with the pulse pattern of GnRH.2‐5 Literature suggests that antiepileptic drugs (AEDs) may have a significant impact on hormones regulation, affecting peripheral endocrine glands, hormones' protein binding and metabolism and semen quality.6,7

Consequently, epilepsy and antiepileptic drugs may also have an impact on reproductive health, causing infertility related issues and affecting family planning. Infertility, according to the World Health Organization, is a disorder of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.

Valproic acid (VPA) is a commonly used antiepileptic drug with properties involving chromatin conformation and the acetylation of histones.8 The effects of VPA on male reproductive health occur early during treatment with hormonal changes found as early as 1 month after VPA administration.9

The aim of the study was to prospectively assess whether, in male patients with epilepsy, switching from VPA to levetiracetam (LEV) or lamotrigine (LMG) critically improves sperm count and characteristics, increasing the chance of patients' female partners to have spontaneous pregnancies.

This is an observational prospective study recruiting all consecutive male infertile patients with epilepsy followed at the outpatient Epilepsy Clinic of University Hospital of Ioannina, Northwest Greece, for a period of 1 year.

Eligible patients were those who suffer from generalized epilepsy of genetic origin, have epilepsy onset during childhood or adulthood, being on valproic acid monotherapy for at least 2 years and have epilepsy under control with no epileptic seizure for a period of 1‐2 years, since permanent withdrawal of AEDs is considered after two consecutive years of seizure free VPA treatment.

Additional eligibility criterion included failure of their partners to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse and absence of reported sexual dysfunction.

Infertile couples were referred to the Laboratory of Assisted Reproduction at the University Hospital of Ioannina to complete the clinical work‐up for the presence of other causes of male factor infertility and female factor infertility and to conduct semen analysis according to the WHO, 2010. Exclusion criteria included any other possible cause of male infertility, such as varicocele, chromosomal abnormalities and other chronic disease, as well as recognizable female factor infertility.

The age of epilepsy onset, the period on VPA treatment, and the daily VPA dose were recorded. A gradual switch to LEV or LMG was performed by alternating patients either to LEV or to LMG as they entered the study and were assigned a number. Patients with odd numbers were switched to LEV and patients with even numbers to LMG. VPA was withdrawn with a mean rate of 200 mgr/2 weeks.

Drug load for each individual patient was calculated as the sum of the prescribed daily dose (PDD) of VPA/defined daily dose (DDD) ratios for VPA, where DDD corresponds to the assumed average maintenance daily dose of VPA used for its main indication according to the World Health Organization.10 The LEV or LMG final daily dose was collected so that the LEV or LMG PDD/DDD remained the same with VPA PDD/DDD for each patient.

Two semen samples were collected from each participant. The first sample was collected while patients were receiving VPA, and the second semen sample was collected 6 months after permanent VPA withdrawal.

Standard parameters of semen analysis were evaluated (with 3 days of sexual abstinence prior to the collection of each one of the two semen samples). The main quantifiable parameter, the total semen volume, was measured in mL. Sperm concentration and sperm motility characteristics were assessed in undiluted semen, using computer‐assisted semen analysis (CASA) (SCA version 6.4, Microptic). CASA is an automated system with the capability of automatic analysis and assessment of human semen parameters. Sperm motility was assessed in samples with sperm concentrations between 2 × 106 per mL and 50 × 106 per mL.11 The total motility and progressive motility were specified. Spermatozoa morphological defects were categorized as follows: head defects, neck defects, tail defects, and excess residual cytoplasm (ERC), associated with abnormal spermatozoa produced from a defective spermatogenic process were also estimated as percent abnormalities. The teratozoospermia index (TZI) was calculated as a measure for the presence of more than one of the four morphological defects per abnormal spermatozoon: one each for head, neck, and tail defects as well as excess residual cytoplasm.

The sex hormones, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH) levels were measured both times (IU/L).

Any spontaneous pregnancy after the shift from VPA to LEV or LMG for the study period was also recorded, without any other clinical intervention offered to the couple.

Continuous data, such as sperm count, were expressed as mean ± standard deviation (±SD), whereas binary data, such as the presence of defects, were described using percentages. Comparisons of traits of interest between patients on VPA and patients after VPA withdrawal were quantified by a t test for continuous data and an chi‐square test for binary data. Logistic regression analysis was performed to detect any potential association of the age of epilepsy onset, the epilepsy duration, and duration of treatment of VPA and VPA dose with semen parameters.

The study was approved by the Medical Ethical Committee of the University Hospital of Ioannina, and all participants (patients and their partners) gave their informed consent to participate.

Seventeen infertile male patients were recruited in the study, with a mean age of 36.6 (±5.2) years. They all suffered from generalized epilepsy of genetic origin with a mean age of epilepsy onset at 19.2 (±4.2) years. Patients were treated with VPA for a mean period of 16.5 (±3.2) months, on a daily dose of 1390 (±385) and were free from seizures for 15.4 (±2.2) months.

Nine patients were switched to LEV, and eight patients were switched to LMG. The mean period of follow‐up was 9.38 (±0.91) months. No seizure exacerbation was present during switching and after withdrawal, with the exception of one patient on LEV, who had a generalized tonic‐clinic seizure 1 month after VPA withdrawal.

Patients and their epilepsy characteristics are shown in Table 1.

1 TABLEPatients and epilepsy characteristics

1 Abbreviations: LEV, levetiracetam; LMG, lamotrigine; VPA, valproate.

The mean semen volume was 2.4 (±0.8) mL with valproic acid vs 2.5(±0.9) mL, after VPA withdrawal, P = .78, and the mean sperm count was 34.6 (±30.6)106/mL with valproic acid vs 56 (±21) × 106/mL after VPA withdrawal, P = .06 (Table 1). Motility was improved with a statistically significant increase of total motility and non‐progressive motility (P = .02 and P = .03, accordingly), while sperm defects were decreased, mainly head defects (P = .03), as shown in Table 2.

2 TABLESemen characteristics and sex hormones levels of VPA treatment group and LEV/LMG treatment group

• 2 Abbreviations: ERC, excess residual cytoplasm; FSH, follicle‐stimulating hormone; LEV, levetiracetam; LH, luteinizing hormone; LMG, lamotrigine; TZI, teratozoospermia index; VPA, valproate.
• 3 * Statistically significant.

Differences between patients switched to LEV or LMG were minimal and showed no significant findings (Table 3).

3 TABLESemen characteristics and sex hormones levels of LEV treatment group and LMG treatment group

4 Abbreviations: ERC, excess residual cytoplasm; LEV, levetiracetam; LMG, lamotrigine; TZI, teratozoospermia index; VPA, valproate.

There were remarkable differences between the mean values of LH and FSH in the serum of the patients on VPA treatment and after VPA withdrawal (Table 2).

No statistically significant associations of sperm count and semen characteristics with age of epilepsy onset, epilepsy duration, and VPA duration of treatment and dose were found in our study group.

Spontaneous pregnancies were reported in three of the patients' partners. One patient was switched to levetiracetam and two patients to lamotrigine. Two patients were on 2000 mg LEV and 300 mg LMG and were on VPA withdrawal for 2 and 3.5 months at the time of conception accordingly. The third patient was on LMG 200 mg and VPA 500 mg (his daily dose of VPA at the time of recruitment was 1500 mg).

While not all of the results were significant, the overall trend of the present prospective study showed that switching from valproic acid to LEV or LMG improved semen quantitative and quality characteristics in infertile men with epilepsy, with three successful conceptions recorded.

There are certain limitations in our study. It is an observational study with a limited number of participants and any potential effect of epilepsy per se on spermatozoa cannot be explored. Epilepsy itself may have a direct effect on spermatogenesis, with untreated men with epilepsy having low seminal fluid volume, oligospermia and an increased number of abnormal spermatozoa.12‐14 The recruitment of patients with good seizures control was made in order to decrease the effect of epilepsy on spermatozoa on the one hand and to minimize the chance of seizure exacerbation after switching to LEV or LMG on the other. So as to focus on infertility "purely" related to reduction of sperm parameters, males with reported sexual dysfunction were excluded.

Our overall estimation is that VPA was potentially the responsible factor for male infertility, reversed after VPA withdrawal in a group of patients with epilepsy.

It is well known that VPA affects the male reproductive system. Suggested mechanisms include the inhibition of the liver enzymes causing inhibition of the aromatase complex that converts androgens to estrogens and leading to hormone imbalance6 and the impairment of the serotonergic and GABAergic steroid metabolisms, resulting in a negative feedback of LH and FSH, causing their levels to decline.6,9 Another suggested mechanism is associated with oxidative stress with direct damage to DNA, proteins, or lipids and/or by altering signal transduction of gene expression15 VPA acts as a histone deacetylase inhibitor. The histones have multiple post‐translational modifications, critical to the regulation of spermatogenesis16 and especially affect sperm protamine transition and expression. Protamines are important nuclear proteins in sperm cells and abnormal changes of protamine expressions lead to male infertility.15,17,18

There are studies to support that males with epilepsy father fewer children compared to the general population as a result of lower sexual experiences, marital rates, and fertility rates.19‐22 The young age of epilepsy onset and the presence of seizures during adulthood are associated with higher rates of infertility and sexual dysfunction.21,23 The patients enrolled in the present study all had childhood or adulthood epilepsy onset, potentially explaining the absence of association of semen characteristics with the age of epilepsy onset and epilepsy duration.

Men with epilepsy under valproic have, on average, reduced testicular volume when compared to healthy controls6,24 and present a reduced number of spermatozoa, more spermatozoa with abnormal morphology and reduced motility.6,24‐29 Our results, in accordance with the literature, show an improvement in the number of spermatozoa, less spermatozoa with abnormal morphology, less abnormalities per sperm and increased motility after VPA withdrawal.

Comparing the semen from VPA and carbamazepine (CBZ)‐treated patients with controls, a significant reduction of motile spermatozoa and significant differences regarding neck and head abnormalities in patients with epilepsy was reported.24 The influence on motility and head abnormalities was established in our study. A Chinese study comparing VPA and LEV groups with controls showed that the sperm motility rate was significantly lower and sperm morphologic abnormalities were significantly higher in the VPA group, especially with regard to sperm head deformity, in accordance with our findings.28

All the aforementioned studies compared VPA with controls. Only isolated cases for patients switching from VPA to another AED or terminating VPA administration are reported in the literature. In an infertile man with epilepsy, VPA withdrawal and LMG initiation led to semen analysis within normal ranges.27 In two cases of infertile male patients with oligoasthenozoospermia receiving VPA, a complete reversal of the spermatic dysfunction and a successful conception followed VPA discontinuation.25

This is the first study, to our knowledge, to prospectively detect the changes in semen parameters in a population of male infertility patients with epilepsy in Europeans, after switching VPA to LEV or LMG.

In our patients, FSH and LH levels declined in the period of VPA treatment, a finding already known in the literature, as demonstrated in a recent systematic review and meta‐analysis.30 What is not known and also exerts an issue in our study is to what extent the decrease in the serum levels of LH and FSH influence spermatogenesis and sperm maturation6,30 or whether oxidative stress and histone deacetylase inhibition are the main causative factors.

Intriguingly, we found no association of the duration of treatment and the dose of VPA with the sperm parameters in our group. In the literature, there are studies to report dose‐dependent changes in sperm parameters but these studies focus on the semen of the same patient in different VPA doses.27,29 In accordance with these studies, we report a spontaneous pregnancy when VPA dose was decreased.

Levetiracetam does not cause significant sex hormone dysregulation28,31‐33 and does not affect chromatin and histones.34 Wu et al31 found no significant differences in sperm parameters comparing patients receiving LEV and untreated patients while Xiaotian et al28 showed that plasma sex hormone levels in an LEV treatment group were not significant different compared to a control group.

Lamotrigine does not cause significant hormonal changes in men with epilepsy31,33,35 and improvement in semen parameters after initiating lamotrigine in untreated patients with epilepsy has been reported.31

It is clear that many patients are successfully treated with VPA and other AEDs and are not infertile but the intriguing interaction between epilepsy, AEDs, and reproductive disorders suggests that reproductive function should be monitored closely as part of the care given to reproductive‐aged patients with epilepsy. Medically assisted interventions to alleviate infertility may vary according to the primary or secondary issues identified through clinical and laboratory tests.36,37 It is of high clinical impact that fertility specialists be familiarized with issues emerging from chronic diseases and their treatments, such as epilepsy, and to refer their patients for treatment reconsideration.

Regarding physicians, it is important to be cautious when prescribing VPA to reproductive‐aged male patients with epilepsy.30 Physicians should implement strict monitoring of patients taking VPA and proceed to antiepileptic treatment reconsideration in infertile males before referring their patients for further medically assisted interventions.

The adverse reactions of VPA on the reproductive system may cause infertility and thus secondarily affect family planning. The intricate relationship between VPA and reproductive function suggests that reproductive disorders should be monitored closely as part of comprehensive care of men with epilepsy.

Having seizures under control and selecting the appropriate medication, less detrimental to fertility is a decision with a potentially positive influence on reproductive outcomes.

None. No funding to declare.

None of the authors has any conflict of interest to disclose.

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Data available on request from the authors.