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Infertility secondary to valproate
J Epilepsy 1994;7:259-261 © 1994 Butterworth-Heinemann
Infertility Secondary to Valproate 1Valerie L. Curtis, 2David G. Oelberg, and 1L. James Willmore
Valproic acid (VPA) is generally thought to be more benign in terms of fertility effects in patients with epilepsy than carbamazepine (CBZ) or phenytoin (PHT) due to its lack of liver-enzyme-inducing properties. We report a patient treated with VPA for partial seizures, previously fertile on CBZ. When conception failed while taking VPA, semen analysis revealed a decreased number of sperm, reduced motility, and altered morphology. Endocrinologic studies and evaluation of the patient's wife were all normal. Successful pregnancy was achieved and abnormal sperm indices reverted to normal when VPA was discontinued and CBZ reinstituted. It is probable that a direct gonadal or sperm membrane effect of VPA is the responsible mechanism for this rare phenomenon. Key Words: Infertility-Valproate--Spermatogenesis.
Reproductive dysfunction is a well-recognized problem for patients with epilepsy. Fertility is reduced by 15% in w o m e n with partial seizures and by 20% in men. However, reduced fertility is not observed in patients with generalized epilepsy (1). Hence, medication effects alone may not account for the altered fecundity. The greater reduction in fertility for men may indicate a preferential adverse influence of antiepileptic drugs (AEDs) (1). Several factors may account for impaired reproductive success in men. Sexual dysfunction will have an indirect effect on reproductive success. Epileptiform discharges in the limbic system may disrupt the function of those structures mediating sexual behavior or alter the release of hypothalamic or pituitary hormones (2-7). Endocrine dysfunction is found in 50% of men with temporal lobe epilepsy, indepenReceived January 28,. 1994; accepted April 15, 1994. From the 1Department of Neurology, University of Texas, Health Science Center at Houston, Houston, TX, and the 2Center for Pediatric Research, Division of Neonatal-Perinatal Medicine, Eastern Virginia Medical School Norfolk, VA, U.S.A. Address correspondence and reprint requests to Dr. V. L. Curtis at Department of Neurology, University of Texas, Health Science Center at Houston, 6431 Fannin, Suite 7.044, Houston, TX 77030, U.S.A.
dent of AED treatment (4). Possible causes of this endocrine change include central neuroendocrine abnormalities from hypothalamic dysfunction directly related to temporal lobe epilepsy (2-6), altered psychosocial and psychophysiologic function (8,9), and effects of AEDs. As shown by this case, complete infertility evaluation with endocrine assessment may identify reasons for reproductive failure in some patients, but the role of AEDs is significant and should be considered. Several mechanisms may be operant in altered fertility caused by AEDs. Enzyme-inducing drugs such as carbamazepine, phenytoin, and phenobarbital cause increased levels of sex h o r m o n e binding globulin via hepatic induction. Consequently, levels of bound testosterone increase, with subsequent decrease in the active free fraction (7,10,11). Decreases in free testosterone alter libido (11). AEDs such as phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) mixed with h u m a n semen in vitro have acute effects on sperm motility (12). Valproate (VPA) alters male reproductive function due to oligospermia (2). VPA, however, is considered less harmful to endocrine function than AEDs that cause hepatic e n z y m e induction (13)..Since VPA is known not to affect steroid h o r m o n e levels (13), if altered spermatogenesis were to occur, it might not be a J EPILF2SY, V O L 7, NO. 4, 1994
259
V. L. CURTIS ET AL.
direct effect of the drug. VPA is highly lipophilic and has membrane-stabilizing properties. These attributes are conducive to inhibiting sperm motility through direct action on testicular germinal cell and mature sperm membrane (12). Although sperm morphology and count are factors in fertility, adequate motility correlates highly with reproductive success. Motility is essential for penetrating the zona pellucida of the ovum (12). Since acute exposure of rabbit sperm to VPA does not alter motility in concentrations comparable to those obtained in human semen, it is probable that altered sperm motility requires chronic exposure to the drug (14). Chronic animal toxicity studies, more reflective of human therapeutic drug exposure, show VPA will cause testicular damage, including degeneration of the interstitial cells (14).
for 3 years. An infertility evaluation was done when pregnancy failed to occur after repeated attempts over a 1-year period. The patient had a complete infertility assessment, and his wife had screening infertility studies. Gynecologic examination of the patient's wife was normal. The patient's serum folliclestimulating hormone, leutinizing hormone, testosterone, and prolactin levels were within normal limits. His physical examination was normal except for a small, clinically insignificant varicocele. Two separate semen analyses revealed borderline low sperm counts with decreased motility and abnormal morphology (Table 1). VPA was discontinued and CBZ was added. Serum abnormalities ameliorated over several months of CBZ monotherapy. Pregnancy was subsequently successfully achieved, and a healthy, full-term male child resulted.
Case Report A 39-year-old male had childhood onset of simple partial seizures characterized by aphasic episodes. Accurate diagnosis was made and treatment initiated at 24 years of age. He failed phenytoin but had good seizure control with CBZ monotherapy at 1,200 mg/day. An average trough level of 10 pg/ml was observed at age 30. On this regimen, he and his wife successfully achieved pregnancy, even though she had an intrauterine device in place and thus subsequently aborted. The patient's wife then took oral contraceptive pills for 6-7 years, discontinuing them when pregnancy was planned. Prior to her discontinuation of contraceptive pills, the patient was switched from CBZ therapy to VPA because of deteriorating seizure control. The VPA dose was titrated gradually over 2 years to 2,250 mg/day, with trough levels of at least 96 pg/ml, and treatment continued Table 1.
Sperm characteristic
On valproate 18.4 X 106 sperm/ ml (normal >20 X 106 sperm/
Motility
4-8.4% motile (normal >50% motile) Abnormal: only 4-5% oval sperm (normal >60% oval sperm)
After valproate 157.5X 106 sperm/ml
ml)
260
In our patient, spermatozoal function was impaired without effect on endocrine function. It is likely that VPA, because of its lipophilicity, crosses the bloodtesticle barrier into the seminiferous tubules and genital tract, similar to its transport from blood to cerebrospinal fluid. Its chronic presence in the geni'tal tract ultimately results in impaired sperm motility, possibly through interference with sperm membrane function. Deficient energy utilization by the altered spermatozoa may be the mechanism underlying reduced motility, as evidenced by faster sperm motility decay rates in patients on long-term AED therapy (13). The resultant impaired fertility appears to be reversible, as exemplified by our patient's case. This case underscores the importance of assessment of drug effect as a cause of infertility, and the need to suspect agents not commonly known to have such adverse properties.
Valproate-induced sperm alterations
Count
Morphology
Discussion
] EPILEPSY, VOL. 7, NO. 4, 1994
65% motile Improved, with 34% oval sperm
References 1. WebberMP, Hauser WA, Ottman R, Annegers JF. Fertility in persons with epilepsy. Epilepsia 1986;27:74652. 2. Falker G, Krause W. Oligoasthenoteratozoospermia in valproic acid therapy. Med Zentrum fur Hautkrankheiten am Kliniku~n der Philipps Marburg, Abt Dermatologie SP Andrologie 1988;63:142-3. 3. Herzog A, Seibel M, Schomer D, VaitukaitisJ, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341-6. 4. Herzog A, Seibel M, Schomer D, VaitukaitisJ, Geschwind N. Reproductive endocrine disorders in men with partial seizures of temporal !obe origin. Arch Neurol 1986;43:347-50.
INFERTILITY SECONDARY TO VALPROATE 5. Horowitz J, Goble A. Drugs and impaired male sexual function. Drugs 1979;18:206-17. 6. Herzog A, Russell V, Vaitukaitis J, Geschwind N. Neuroendorcrine dysfunction in temporal lobe epilepsy. Arch Neurol 1982;39:133-5. 7. Morrell M. Sexual dysfunction in epilepsy. Epilepsia 1991;32(Suppl 6):$38-45. 8. Cramer J, Jones E. Reproductive function in epilepsy. Epilepsia 1991;32(Suppl 6):$19-26. 9. Mattson R, Cramer J. Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia 1985;26(Suppl 1):$40-51. 10. Tartara A, Manni R, Delodovici M, Bonura M, Murialdo G. Pituitary function, testosterone, and SHBG levels in treated epileptic male subjects. In: Porter RJ, Mattson RH, Ward AA, Dam M, eds. The XVth Epilepsy lnterna-
tional Symposium. New York: Raven Press, 1984:20914. (Advances in epileptology; vol 15.) 11. Toone B, Wheeler M, Fenwick P. Sex hormone changes in male epileptics. Clin Endocrinol 1980;12:391-5. 12. Chen S, Shen M, Chen R, Lai S. Effects of antiepileptic drugs on sperm motility of normal controls and epileptic patients with long-term therapy. Epilepsia 1992;33: 149-53. 13. Isojarvi J, Pakarinen A, Ylipslosaari P, MyUyla V. Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol 1990;47:6706. 14. Swanson B, Harland R, Dickinson R, Gerber N. Excertion of valproic acid into semen of rabbits and man. Epilepsia 1978;19:541-6.
J F_~ILEPSY,VOL. 7, NO. 4, 1994 261
Infertility Secondary to Valproate 1Valerie L. Curtis, 2David G. Oelberg, and 1L. James Willmore
Valproic acid (VPA) is generally thought to be more benign in terms of fertility effects in patients with epilepsy than carbamazepine (CBZ) or phenytoin (PHT) due to its lack of liver-enzyme-inducing properties. We report a patient treated with VPA for partial seizures, previously fertile on CBZ. When conception failed while taking VPA, semen analysis revealed a decreased number of sperm, reduced motility, and altered morphology. Endocrinologic studies and evaluation of the patient's wife were all normal. Successful pregnancy was achieved and abnormal sperm indices reverted to normal when VPA was discontinued and CBZ reinstituted. It is probable that a direct gonadal or sperm membrane effect of VPA is the responsible mechanism for this rare phenomenon. Key Words: Infertility-Valproate--Spermatogenesis.
Reproductive dysfunction is a well-recognized problem for patients with epilepsy. Fertility is reduced by 15% in w o m e n with partial seizures and by 20% in men. However, reduced fertility is not observed in patients with generalized epilepsy (1). Hence, medication effects alone may not account for the altered fecundity. The greater reduction in fertility for men may indicate a preferential adverse influence of antiepileptic drugs (AEDs) (1). Several factors may account for impaired reproductive success in men. Sexual dysfunction will have an indirect effect on reproductive success. Epileptiform discharges in the limbic system may disrupt the function of those structures mediating sexual behavior or alter the release of hypothalamic or pituitary hormones (2-7). Endocrine dysfunction is found in 50% of men with temporal lobe epilepsy, indepenReceived January 28,. 1994; accepted April 15, 1994. From the 1Department of Neurology, University of Texas, Health Science Center at Houston, Houston, TX, and the 2Center for Pediatric Research, Division of Neonatal-Perinatal Medicine, Eastern Virginia Medical School Norfolk, VA, U.S.A. Address correspondence and reprint requests to Dr. V. L. Curtis at Department of Neurology, University of Texas, Health Science Center at Houston, 6431 Fannin, Suite 7.044, Houston, TX 77030, U.S.A.
dent of AED treatment (4). Possible causes of this endocrine change include central neuroendocrine abnormalities from hypothalamic dysfunction directly related to temporal lobe epilepsy (2-6), altered psychosocial and psychophysiologic function (8,9), and effects of AEDs. As shown by this case, complete infertility evaluation with endocrine assessment may identify reasons for reproductive failure in some patients, but the role of AEDs is significant and should be considered. Several mechanisms may be operant in altered fertility caused by AEDs. Enzyme-inducing drugs such as carbamazepine, phenytoin, and phenobarbital cause increased levels of sex h o r m o n e binding globulin via hepatic induction. Consequently, levels of bound testosterone increase, with subsequent decrease in the active free fraction (7,10,11). Decreases in free testosterone alter libido (11). AEDs such as phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) mixed with h u m a n semen in vitro have acute effects on sperm motility (12). Valproate (VPA) alters male reproductive function due to oligospermia (2). VPA, however, is considered less harmful to endocrine function than AEDs that cause hepatic e n z y m e induction (13)..Since VPA is known not to affect steroid h o r m o n e levels (13), if altered spermatogenesis were to occur, it might not be a J EPILF2SY, V O L 7, NO. 4, 1994
259
V. L. CURTIS ET AL.
direct effect of the drug. VPA is highly lipophilic and has membrane-stabilizing properties. These attributes are conducive to inhibiting sperm motility through direct action on testicular germinal cell and mature sperm membrane (12). Although sperm morphology and count are factors in fertility, adequate motility correlates highly with reproductive success. Motility is essential for penetrating the zona pellucida of the ovum (12). Since acute exposure of rabbit sperm to VPA does not alter motility in concentrations comparable to those obtained in human semen, it is probable that altered sperm motility requires chronic exposure to the drug (14). Chronic animal toxicity studies, more reflective of human therapeutic drug exposure, show VPA will cause testicular damage, including degeneration of the interstitial cells (14).
for 3 years. An infertility evaluation was done when pregnancy failed to occur after repeated attempts over a 1-year period. The patient had a complete infertility assessment, and his wife had screening infertility studies. Gynecologic examination of the patient's wife was normal. The patient's serum folliclestimulating hormone, leutinizing hormone, testosterone, and prolactin levels were within normal limits. His physical examination was normal except for a small, clinically insignificant varicocele. Two separate semen analyses revealed borderline low sperm counts with decreased motility and abnormal morphology (Table 1). VPA was discontinued and CBZ was added. Serum abnormalities ameliorated over several months of CBZ monotherapy. Pregnancy was subsequently successfully achieved, and a healthy, full-term male child resulted.
Case Report A 39-year-old male had childhood onset of simple partial seizures characterized by aphasic episodes. Accurate diagnosis was made and treatment initiated at 24 years of age. He failed phenytoin but had good seizure control with CBZ monotherapy at 1,200 mg/day. An average trough level of 10 pg/ml was observed at age 30. On this regimen, he and his wife successfully achieved pregnancy, even though she had an intrauterine device in place and thus subsequently aborted. The patient's wife then took oral contraceptive pills for 6-7 years, discontinuing them when pregnancy was planned. Prior to her discontinuation of contraceptive pills, the patient was switched from CBZ therapy to VPA because of deteriorating seizure control. The VPA dose was titrated gradually over 2 years to 2,250 mg/day, with trough levels of at least 96 pg/ml, and treatment continued Table 1.
Sperm characteristic
On valproate 18.4 X 106 sperm/ ml (normal >20 X 106 sperm/
Motility
4-8.4% motile (normal >50% motile) Abnormal: only 4-5% oval sperm (normal >60% oval sperm)
After valproate 157.5X 106 sperm/ml
ml)
260
In our patient, spermatozoal function was impaired without effect on endocrine function. It is likely that VPA, because of its lipophilicity, crosses the bloodtesticle barrier into the seminiferous tubules and genital tract, similar to its transport from blood to cerebrospinal fluid. Its chronic presence in the geni'tal tract ultimately results in impaired sperm motility, possibly through interference with sperm membrane function. Deficient energy utilization by the altered spermatozoa may be the mechanism underlying reduced motility, as evidenced by faster sperm motility decay rates in patients on long-term AED therapy (13). The resultant impaired fertility appears to be reversible, as exemplified by our patient's case. This case underscores the importance of assessment of drug effect as a cause of infertility, and the need to suspect agents not commonly known to have such adverse properties.
Valproate-induced sperm alterations
Count
Morphology
Discussion
] EPILEPSY, VOL. 7, NO. 4, 1994
65% motile Improved, with 34% oval sperm
References 1. WebberMP, Hauser WA, Ottman R, Annegers JF. Fertility in persons with epilepsy. Epilepsia 1986;27:74652. 2. Falker G, Krause W. Oligoasthenoteratozoospermia in valproic acid therapy. Med Zentrum fur Hautkrankheiten am Kliniku~n der Philipps Marburg, Abt Dermatologie SP Andrologie 1988;63:142-3. 3. Herzog A, Seibel M, Schomer D, VaitukaitisJ, Geschwind N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986;43:341-6. 4. Herzog A, Seibel M, Schomer D, VaitukaitisJ, Geschwind N. Reproductive endocrine disorders in men with partial seizures of temporal !obe origin. Arch Neurol 1986;43:347-50.
INFERTILITY SECONDARY TO VALPROATE 5. Horowitz J, Goble A. Drugs and impaired male sexual function. Drugs 1979;18:206-17. 6. Herzog A, Russell V, Vaitukaitis J, Geschwind N. Neuroendorcrine dysfunction in temporal lobe epilepsy. Arch Neurol 1982;39:133-5. 7. Morrell M. Sexual dysfunction in epilepsy. Epilepsia 1991;32(Suppl 6):$38-45. 8. Cramer J, Jones E. Reproductive function in epilepsy. Epilepsia 1991;32(Suppl 6):$19-26. 9. Mattson R, Cramer J. Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia 1985;26(Suppl 1):$40-51. 10. Tartara A, Manni R, Delodovici M, Bonura M, Murialdo G. Pituitary function, testosterone, and SHBG levels in treated epileptic male subjects. In: Porter RJ, Mattson RH, Ward AA, Dam M, eds. The XVth Epilepsy lnterna-
tional Symposium. New York: Raven Press, 1984:20914. (Advances in epileptology; vol 15.) 11. Toone B, Wheeler M, Fenwick P. Sex hormone changes in male epileptics. Clin Endocrinol 1980;12:391-5. 12. Chen S, Shen M, Chen R, Lai S. Effects of antiepileptic drugs on sperm motility of normal controls and epileptic patients with long-term therapy. Epilepsia 1992;33: 149-53. 13. Isojarvi J, Pakarinen A, Ylipslosaari P, MyUyla V. Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol 1990;47:6706. 14. Swanson B, Harland R, Dickinson R, Gerber N. Excertion of valproic acid into semen of rabbits and man. Epilepsia 1978;19:541-6.
J F_~ILEPSY,VOL. 7, NO. 4, 1994 261