• Effects of AEDs
• Reproductive endocrine disorders
• Male infertility
• Male contraception
• Effects of AEDs on male maturation
• Effects on sexual function
• A commentary: the effects of AEDS on male hormones
• References

The effects of enzyme-inducing AEDs on sex steroids has been known for a long time. In 1975, Christensen & Lund3 showed that urinary steroid hormone output was significantly lower in 75 men taking antiepileptic drugs than in a healthy population. They found 50% decreases in androsterone, 75% decreases in etiocholanolone and dihydroepiandrosterone, and 30% higher estrogen levels. Although these data were difficult to interpret, they indicated a profound effect of antiepileptic drugs on the metabolism of sex steroid hormones. A recent report replicated these findings.11 They compared men with partial-onset epilepsy taking carbamazepine or oxcarbazepine with men with generalized epilepsy taking valproate. The findings could be expected based on the enzyme-inducing properties of carbamazepine and oxcarbazepine at higher doses, whereas valproate is an enzyme inhibitor. They also found morphologically abnormal sperm, low sperm motility, and reduced testicular volume among all epilepsy groups compared to healthy controls.

AEDs also might affect spermatogenesis in humans as they do in vitro. Carbamazepine inhibited testosterone synthesis in Leydig cells, phenytoin inhibited testosterone conversion from progestins, and valproate had the least effect on testosterone.5 This in vitro model showed the differential effects of each AED on the metabolic pathway of sex steroid hormones.

Written by: Joyce Cramer, epilepsy.com Editorial Board

Reviewed and revised September 2004 by Steven C. Schachter, MD and Orrin Devinsky MD, epilepsy.com Editorial Board.

Some men taking antiepileptic drugs experience decreased libido and potency, low sperm count, decreased sperm viability, and decreased likelihood of ovum fertilization. Herzog et al4 assessed 20 unselected men with complex partial seizures for comparison with impotent men seen in an endocrine clinic. Hypogonadotropism was found in 20% of men with epilepsy compared to 25% of impotent men, hypergonadotropism in 10% and 7%, respectively, and hyperprolactinemia in 10% and 8%, respectively. They suggested involvement of the temporal lobe discharges because of the similar incidence of endocrine disorders in this small group of men with epilepsy matching the men diagnosed with impotence.

Written by: Joyce Cramer, epilepsy.com Editorial Board

Reviewed and revised September 2004 by Steven C. Schachter, MD and Orrin Devinsky MD, epilepsy.com Editorial Board.

The theory of male contraception is based on suppression of hypothalamic GnRH or decreased pituitary secretion of FSH and LH. Spermatogenesis requires androgen at the initiation phase ands FSH at the terminal phase of spermatid development. FSH and LH levels in the range of 5-20 IU/L are required for normal spermatogenesis. Thus, partial FSH or LH inhibition can reduce or halt sperm production. Christiansen & Lund3 studied the effect of AEDs on sperm in 98 men with epilepsy. When semen samples were requested, only 47 men were able to provide a sample, indicating diminished sexual function in half of these unselected patients. Of the samples received, 50% had low semen volume, 57% had low sperm counts, 89% had abnormal morphology, 9^% had low motility, and 96% showed impaired fertility. These data suggest a direct effect of AEDs on sperm. Further evidence was provided in studies with men taking carbamazepine or phenytoin. Swanson et al8 showed that both drugs are present in higher concentration in semen than plasma, whereas valproate semen levels were lower than in plasma. This probably is based on drug solubility.

Written by: Joyce Cramer, epilepsy.com Editorial Board

Reviewed and revised September 2004 by Steven C. Schachter, MD and Orrin Devinsky MD, epilepsy.com Editorial Board.

El-Khayat et al9 compared 130 boys (ages 8-18) who were taking AEDs with age-matched controls. They found delayed sexual development with lower testicular volume and penile length, delayed pubic hair staging. Boys taking AEDs also had increased total testosterone, lower free testosterone, higher estradiol, and reduced ratios of testosterone to luteinizing hormone. Differences were more pronounced among boys taking multiple AEDS. These differences were unrelated to duration of epilepsy or seizure control, suggesting a drug effect, although they did not evaluate differences among AEDs.

A related report by Mikkonen et al12 described 70 boys taking AEDs (ages 7-21 years) compared to age-matched controls. They found testicular volumes and testosterone levels in the normal range for the boys with epilepsy. Boys taking valproate (N=25) had five-fold higher androstenedione levels, but the clinical implications of this effect are unknown. Sex hormone binding globulin (SHBG) levels were increased while dehydroepiandrosterone (DHEAS) levels decreased in boys taking CBZ (N=28), probably because of enzyme induction. Herzog et al (2004) compared men taking AEDs (ages 30-42 years) who had frequent seizures with a control group. They also found lower testosterone, estradiol and luteinizing hormone levels, as well as reduced sexual desire and performance, among men taking enzyme-inducing AEDs.

Written by: Joyce Cramer, epilepsy.com Editorial Board

Reviewed and revised September 2004 by Steven C. Schachter, MD and Orrin Devinsky MD, epilepsy.com Editorial Board.

Another view of sexual function was presented by Rattya et al13 studying men with epilepsy (ages 18-50 years).The valproate group had enhanced sexual function and increased androstenedione levels, whereas patients taking carbamazepine or oxcarbazepine had the opposite. However, the valproate group had a higher proportion of patients with primary generalized epilepsy than the other groups. This may be an important, unexplored issue. Mattson et al6 noted different responses to progesterone in women with primary or localization-related epilepsy.

Written by: Joyce Cramer, epilepsy.com Editorial Board

Reviewed and revised September 2004 by Steven C. Schachter, MD and Orrin Devinsky MD, epilepsy.com Editorial Board.

As Herzog et al10 noted: "The results confirm some long-held views regarding men with epilepsy." Most of what is being studied currently either replicates old studies or expands into examination of the effects of specific drugs, most of which is predictable based on the pharmacokinetic profiles of the AEDs. The implication is that hormonal changes are related to enzyme induction by AEDs that induced SHBG synthesis, resulting in higher levels of bound testosterone, and lower biologically-active (unbound) testosterone. However, this cycle usually resolves to a steady-state with normal levels of the free compound. However, epilepsy patients may have hypergonadotropic hypogonadism if their hypothalamic-pituitary-gonadal axis is feedback mechanism impaired. The evidence from a variety of studies for a cause of these problems is conflicting. Is it all related to enzyme-inducing AEDs or partly related to the effect of seizures on the hypothalamus and pituitary? A preponderance of the hormone studies on men (and women) were performed in Finland. Are there genetics differences among populations with epilepsy that could affect hormone balance?

Studies of the effects of AEDs on male hormonal function are few, and focused largely on the older, enzyme-inducing drugs. The current attention given to women's issues now is being matched by attention to men's issues. We need to know whether the newer AEDs affect the hypothalamic-pituitary-testicular axis, and what effects this might have on male sexual function. The implications are not limited to libido and potency, but should delve into male fertility, live birth rate, and teratogenic effects when men take AEDs.

Written by: Joyce Cramer, epilepsy.com Editorial Board

Reviewed and revised September 2004 by Steven C. Schachter, MD and Orrin Devinsky MD, epilepsy.com Editorial Board.

1. Cramer JA, Jones EE. Reproductive function in epilepsy. 1991; 32 (Suppl 6): S19-S26.

2. Mattson RH. Cramer JA. Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia 1985; 26 (Suppl 1): S40-S51.

3. Christensen P, Lund M. Sexual potency, testicular function and excretion of sexual hormones in male epileptics. In: Janz D, ed. Advances in Epileptology: VIIth Epilepsy International Symposium. Berlin: Publishing Sciences Group, 1975: 190-191.

4. Herzog AG, et al. Neuroendocrine dysfunction in temporal lobe epilepsy. Arch Neurol 1982; 39: 133-135.

5. Kuhn-Velten WN, et al. Acute effects of anticonvulsant drugs on gonadotropin-stimulated and precursor-supported androgen production in the rat testis. Eur J Pharmacol 1990 ; 181: 151-155.

6. Mattson, RH, Cramer, JA, Caldwell, BV, and Siconolfi, BC. Treatment of seizures with medroxyprogesterone acetate: a preliminary report. Neurology 34:1255-1258, 1984.

7. Mattson, RH, Cramer, JA, Darney, PD, and Naftolin F. Use of oral contraceptives in women with epilepsy. Journal of the American Medicine Association 256:238-240, 1986.

8. Swanson BN, et al. Excretion of valproic acid into semen of rabbits and man. Epilepsia 1978; 19: 541-549.

9. El-Khayat H et al. Physical and hormonal profile of male sexual development in epilepsy. Epilepsia 2003; 44: 447-452.

10. Herzog AG et al. Differential effects of antiepileptic drugs on sexual function and reproductive hormones in men with epilepsy: interim analysis of a comparison between lamotrigine and enzyme-inducing antiepileptic drugs. Epilepsia 2004; 45: 764-768.

11. Isojarvi JIT et al. Effect of epilepsy and antiepileptic drugs onmale reproductive health. Neurol 2004; 62: 247-253.

12. Mikkonen K et al. Serum androgen levels and testicular structure during pubertal maturation in male subjects with epilepsy. Epilepsia 2004; 45: 769-776.

13. Rattya J, et al. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001; 56: 31-36.