Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy L. S. Røste a , E. Taubøll a , L. Mørkrid b , T. Bjørnenak a , E. R. Sætre c , T. Mørland d and L. Gjerstad a a Department of Neurology, Rikshospitalet, University of Oslo, Oslo, Norway; b Department of Clinical Chemistry, Rikshospitalet, University of Oslo, Oslo, Norway; c Department of Neurology, Ulleva ˚l University hospital, Oslo, Norway; and d Department of Neurology, Telemark Hospital, Skien, Norway Keywords: carbamazepine, epilepsy, human, reproductive hormones, valproate Received 5 January 2004 Accepted 11 April 2004 Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug- specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20–40 years old, having used either VPA (n ¼ 16) or CBZ (n ¼ 19) as monotherapy for >2 years were included and compared with age-matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C-peptide values compared with controls. Regarding possible drug-specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone-binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C-peptide concentrations. The CBZ treated patients had significantly lower testos- terone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carni- tine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug-specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long-term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C-peptide and carnitine ratio. Long-term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men. Introduction Men with epilepsy experience problems that are con- sistent with disturbances of reproductive endocrine hormones. Reduced fertility (Alstrom, 1950; Dansky et al., 1980; Webber et al., 1986) and sexual dysfunc- tion are common (Herzog et al., 1986; Morrell et al., 1994). Schupf and Ottman (1996) found reduced fer- tility after, but not before, onset of epilepsy and studies of semen of men with epilepsy have disclosed abnor- malities in morphology, motility and sperm count (Christensen et al., 1975; Chen et al., 1992; Schechter- Amir et al., 1993; Taneja et al., 1994; Røste et al., 2003). The epilepsy itself may cause these changes, and temporal lobe epilepsy has been associated with abnormalities of male reproductive physiology (Herzog et al., 1986; Quigg et al., 2002). However, there is an ongoing debate over the impact of antiepileptic drugs on reproductive endocrine func- tion and gonadal morphology in women (Isoja¨rvi et al., 2001a; Bauer et al., 2002). In men, enzyme inducing antiepileptic drugs may increase the hepatic synthesis of SHBG, thereby decreasing the bioactive portion of total testosterone (MacPhee et al., 1988; Isoja¨rvi et al., 1995; Stoffel-Wagner et al., 1998). Less is known of the impact of non-enzyme-inducing antiepileptic drugs. In a recent study by Ra¨ttya¨ et al. (2001), men taking valproate (VPA) were found to have increased serum androsten- edione levels. Also, two case studies have pointed out the possibility of VPA-induced reduction in fertility in men (Curtis et al., 1994; Yerby and McCoy, 1999). Correspondence: Line Sveberg Røste, Department of Neurology, Rikshospitalet, 0027 Oslo, Norway (tel.: +47 230 70281; fax: +47 230 74891; e-mail: line.sveberg.roste@rikshospitalet.no). 118 Ó 2005 EFNS European Journal of Neurology 2005, 12: 118–124