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Onset of late posttraumatic seizure after dehydroepiandrosterone treatment
CASE REPORT Onset of late posttraumatic seizure after dehydroepiandrosterone treatment Galia Karp, M.D.,a Yaakov Bentov, M.D.,b Rafik Masalha, M.D.,c and Gal Ifergane, M.D.c a
Internal Medicine Department, Soroka University Medical Center, Beer-Sheva, Israel; b Department of Obstetrics and Gynecology and the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada; and c Department of Neurology, Soroka University Medical Center, Beer-Sheva, Israel
Objective: To describe the first reported case of a seizure in a patient using the dietary supplement DHEA in an attempt to improve ovarian oocyte production. Design: Case report. Setting: University-affiliated teaching hospital, neurologic department. Patient(s): A 30-year-old woman with fragile X syndrome and no history of any convulsive disorder who was receiving IVF treatment. Intervention(s): Daily treatment with the dietary supplement DHEA. Main Outcome Measure(s): Generalized seizure. Result(s): After 1 month of DHEA treatment, the patient was admitted with a generalized seizure. Conclusion(s): A generalized seizure, associated with concurrent intake of DHEA. (Fertil Steril 2009;91:931.e1–e2. 2009 by American Society for Reproductive Medicine.) Key Words: DHEA, seizure, low ovarian reserve, IVF
There is growing interest in the use of DHEA, following recent reports by Barad and Gleicher on the improved ovarian response to gonadotropin stimulation (1, 2). Dehydroepiandrosterone is a precursor of human sex steroids, with a central role in the reproductive period. Importantly, accumulating data from animal studies have shown DHEA to have proconvulsant effects. In addition to its role as a sex steroid, DHEA readily crosses the blood-brain barrier and functions as a neuroactive steroid (3). Its influence on neuronal excitability is mediated via g-aminobutyric acid A (GABAA) and N-methyl-D-aspartate (NMDA) receptors (4). In this report we present a 30-year-old nulligravida woman, 5 years after head injury, who had a generalized seizure after 1 month of treatment with DHEA. CASE HISTORY A 30-year-old woman was admitted to the neurologic department because of a first generalized seizure. Five years before that, the patient had a severe head injury during a car accident, after which she was unconscious for several days. She had contusions in the left frontal lobe, from which she recovered with a sequel of mild short-term memory loss and a learning disability. She never had seizures and never was treated with anticonvulsants. Received July 18, 2008; revised and accepted August 25, 2008. G.K. has nothing to disclose. Y.B. has nothing to disclose. R.M. has nothing to disclose. G.I. has nothing to disclose. Reprint requests: Galia Karp, M.D., Internal Medicine Department D, Soroka University Medical Center, POB 151, Beer-Sheva 84101, Israel (FAX: 972-8-9911472; E-mail: [email protected]).
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.08.115
A reduced ovarian reserve was diagnosed in the patient and was attributed to her being a fragile X carrier. She underwent several IVF cycles. During the month before the convulsive attack she began supplementary treatment with DHEA, 75 mg/d. After recovery from the seizure, results of her neurologic examination were normal except for very mild right hemiparesis. Computed tomographic scan of the brain disclosed a hypodense area in the left frontal lobe, consistent with focal posttraumatic gliosis.
DISCUSSION One of the major problems of infertility treatment that still remains unanswered is reduced ovarian response. Despite major developments in this field in recent years, no effective treatment can be suggested to those patients aside from oocyte donation. In 2000, Casson et al. (5) reported that patients with poor ovarian response may show an improved response with the addition of adjuvant DHEA treatment. A few years later, Barad and Gleicher brought DHEA back into the spotlight. They presented a case of a 42-year-old woman who independently self-administered 75 mg DHEA per day while being treated by ovulation stimulation for egg cryopreservation. The concurrent use of DHEA resulted in a gradual increase in the number of oocytes retrieved in every consecutive cycle (1). After this case report, they presented a small study of patients treated with controlled ovarian stimulation before and after the addition of DHEA supplementation. In this study they were able to show
Fertility and Sterility Vol. 91, No. 3, March 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
931.e1
a significant improvement in both the number of oocytes retrieved and their quality (2). Dehydroepiandrosterone is a mild androgen and an essential precursor of human sex steroid biosynthesis in males and females (6) and is the most abundant steroid in the serum of young adults (7). About one half of the daily production of DHEA is secreted by the adrenal gland, and the rest is divided equally between the ovary and peripheral tissues (8). Dehydroepiandrosterone also is produced by the central nervous system (1). Dehydroepiandrosterone levels are reduced progressively with age (5). After menopause the circulating levels of DHEA are approximately 70% less than those in young adult life (8). The association of a reduction in the rate of DHEA secretion with ovarian function suggested a potential role for DHEA deficiency in the pathogenesis of reduced ovarian function. The brain is a known target organ for steroid hormones, which easily cross the blood-brain barrier and act as neuroactive hormones (9). Both DHEA and DHEAS cross the bloodbrain barrier, are detectable in cerebrospinal fluid, and function as neurosteroids. Neurosteroids exert a direct effect on neuronal membrane permeability and thus affect CNS excitability and seizures via several receptors, among them the GABAA receptor complex and NMDA receptors (3, 4). Dysfunction of GABAA receptor–mediated inhibition is implicated in the pathophysiology of several neurologic and psychiatric conditions, among them epilepsy. Some of these conditions have been associated with abnormal levels of certain neurosteroids, which may mediate the function of the brain’s major inhibitory receptor, the GABAA receptor (10). Interaction of DHEAS with excitatory amino acid transmission is rather complex and may result in both neuroprotective effects and proconvulsive effects (11). Several lines of evidence suggest that DHEAS can act as a proconvulsant agent by acting as a negative modulator of GABAA receptor and a positive modulator of the NMDA subtype of glutamate receptor (3, 4). Intracerebroventricular injection of DHEAS induced clonic-tonic seizures in a dose-dependent manner (3). Reddy and Kulkarni (4) investigated the potential neurotoxic and proconvulsive effect of long-term treatment with DHEAS. Although short-term administration of DHEA did not modify seizure reactivity, mice treated for 4 weeks with DHEA exhibited increased sensitivity to tonic convulsions (4). Although human information is lacking, it has been demonstrated that serum levels of DHEA were modified significantly in the presence of a convulsive disorder (9). The patient had an intracerebral lesion due to head injury. Traumatic brain injury is associated with increased risk of seizures, brain contusions acting as strong risk factors for late seizures. Posttraumatic epilepsy is caused by injury to the brain after trauma. The disorder is classified as immediate seizures (<24 hours after injury), early seizures (<1 week after injury), and late seizures (>8 days after injury). The incidence of late posttraumatic seizures is up to 42% in civilian head injuries, and they may persist for up to 20 years (12). 931.e2
Karp et al.
Although this patient had no prior seizures, the existence of a brain lesion increases her tendency for convulsion. One month after DHEA treatment was initiated, a first seizure occurred. One can assume that a proconvulsant drug rarely will affect a healthy brain; however, in a patient with an increased potential for seizures, there is a lower threshold and seizures may occur. CONCLUSIONS To the best of our knowledge this is the first published case of an association between a new onset of epilepsy and the use of DHEA. Despite the circumstantial nature of the evidence we presented, there is a significant body of direct and indirect evidence to support a potential role for DHEA in inducing a seizure in a high-risk patient. The findings that DHEA and DHEAS act as neurosteroids, modulating neuronal excitability, are of importance to caregivers who advise use of this ‘‘dietary supplement.’’ Physicians advising use of this product should be aware of potential neurologic adverse effects and advise their patients to report any irregular neurologic event. Special attention should be given to women prone to convulsive activity, such as our patient. Further investigation is needed to expand our knowledge and understanding of DHEA’s neurosteroidal activities. REFERENCES 1. Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril 2005;84:756. 2. Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod 2006;21:2845–9. 3. Czionkowska AI, Krzascik P, Sienkiewicz-Jarosz H, Siemiatkowski M, Szyndler J, Bidzinski A, et al. The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol. Pharmacol Biochem Behav 2000;67:345–53. 4. Reddy DS, Kulkarni SK. Proconvulsant effects of neurosteroids pregnenolone sulfate and dehydroepiandrosterone sulfate in mice. Eur J Pharmacol 1998;345:55–9. 5. Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000;15:2129–32. 6. Arlt W. Androgen therapy in women. Eur J Endocrinol 2006;154:1–11. 7. Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert J. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid–induced neurotoxicity. Proc Natl Acad Sci USA 1998;95:1852–7. 8. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. Philadelphia, PA: Lippincott Williams & Wilkins, 2004. 9. Galimberti CA, Magri F, Copello F, Arbasino C, Cravello L, Casu M, et al. Seizure frequency and cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in women with epilepsy receiving antiepileptic drug treatment. Epilepsia 2005;46:517–23. 10. Belelli D, Herd MB, Mitchell EA, Peden DR, Vardy AW, Gentet L, et al. Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance. Neuroscience 2006;138:821–9. 11. Lesskiewicz M, Budziszewska B, Jaworska-Feil L, Kubera M, BastaKaim A, Lason W. Inhibitory effect of some neuroactive steroids on cocaine-induced kindling in mice. Pol J Pharmacol 2003;55:1131–6. 12. Agrawal A, Timothy J, Pandit L, Manja M. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg 2006;108:433–9.
Seizure associated with DHEA supplementation
Vol. 91, No. 3, March 2009
Internal Medicine Department, Soroka University Medical Center, Beer-Sheva, Israel; b Department of Obstetrics and Gynecology and the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada; and c Department of Neurology, Soroka University Medical Center, Beer-Sheva, Israel
Objective: To describe the first reported case of a seizure in a patient using the dietary supplement DHEA in an attempt to improve ovarian oocyte production. Design: Case report. Setting: University-affiliated teaching hospital, neurologic department. Patient(s): A 30-year-old woman with fragile X syndrome and no history of any convulsive disorder who was receiving IVF treatment. Intervention(s): Daily treatment with the dietary supplement DHEA. Main Outcome Measure(s): Generalized seizure. Result(s): After 1 month of DHEA treatment, the patient was admitted with a generalized seizure. Conclusion(s): A generalized seizure, associated with concurrent intake of DHEA. (Fertil Steril 2009;91:931.e1–e2. 2009 by American Society for Reproductive Medicine.) Key Words: DHEA, seizure, low ovarian reserve, IVF
There is growing interest in the use of DHEA, following recent reports by Barad and Gleicher on the improved ovarian response to gonadotropin stimulation (1, 2). Dehydroepiandrosterone is a precursor of human sex steroids, with a central role in the reproductive period. Importantly, accumulating data from animal studies have shown DHEA to have proconvulsant effects. In addition to its role as a sex steroid, DHEA readily crosses the blood-brain barrier and functions as a neuroactive steroid (3). Its influence on neuronal excitability is mediated via g-aminobutyric acid A (GABAA) and N-methyl-D-aspartate (NMDA) receptors (4). In this report we present a 30-year-old nulligravida woman, 5 years after head injury, who had a generalized seizure after 1 month of treatment with DHEA. CASE HISTORY A 30-year-old woman was admitted to the neurologic department because of a first generalized seizure. Five years before that, the patient had a severe head injury during a car accident, after which she was unconscious for several days. She had contusions in the left frontal lobe, from which she recovered with a sequel of mild short-term memory loss and a learning disability. She never had seizures and never was treated with anticonvulsants. Received July 18, 2008; revised and accepted August 25, 2008. G.K. has nothing to disclose. Y.B. has nothing to disclose. R.M. has nothing to disclose. G.I. has nothing to disclose. Reprint requests: Galia Karp, M.D., Internal Medicine Department D, Soroka University Medical Center, POB 151, Beer-Sheva 84101, Israel (FAX: 972-8-9911472; E-mail: [email protected]).
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.08.115
A reduced ovarian reserve was diagnosed in the patient and was attributed to her being a fragile X carrier. She underwent several IVF cycles. During the month before the convulsive attack she began supplementary treatment with DHEA, 75 mg/d. After recovery from the seizure, results of her neurologic examination were normal except for very mild right hemiparesis. Computed tomographic scan of the brain disclosed a hypodense area in the left frontal lobe, consistent with focal posttraumatic gliosis.
DISCUSSION One of the major problems of infertility treatment that still remains unanswered is reduced ovarian response. Despite major developments in this field in recent years, no effective treatment can be suggested to those patients aside from oocyte donation. In 2000, Casson et al. (5) reported that patients with poor ovarian response may show an improved response with the addition of adjuvant DHEA treatment. A few years later, Barad and Gleicher brought DHEA back into the spotlight. They presented a case of a 42-year-old woman who independently self-administered 75 mg DHEA per day while being treated by ovulation stimulation for egg cryopreservation. The concurrent use of DHEA resulted in a gradual increase in the number of oocytes retrieved in every consecutive cycle (1). After this case report, they presented a small study of patients treated with controlled ovarian stimulation before and after the addition of DHEA supplementation. In this study they were able to show
Fertility and Sterility Vol. 91, No. 3, March 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
931.e1
a significant improvement in both the number of oocytes retrieved and their quality (2). Dehydroepiandrosterone is a mild androgen and an essential precursor of human sex steroid biosynthesis in males and females (6) and is the most abundant steroid in the serum of young adults (7). About one half of the daily production of DHEA is secreted by the adrenal gland, and the rest is divided equally between the ovary and peripheral tissues (8). Dehydroepiandrosterone also is produced by the central nervous system (1). Dehydroepiandrosterone levels are reduced progressively with age (5). After menopause the circulating levels of DHEA are approximately 70% less than those in young adult life (8). The association of a reduction in the rate of DHEA secretion with ovarian function suggested a potential role for DHEA deficiency in the pathogenesis of reduced ovarian function. The brain is a known target organ for steroid hormones, which easily cross the blood-brain barrier and act as neuroactive hormones (9). Both DHEA and DHEAS cross the bloodbrain barrier, are detectable in cerebrospinal fluid, and function as neurosteroids. Neurosteroids exert a direct effect on neuronal membrane permeability and thus affect CNS excitability and seizures via several receptors, among them the GABAA receptor complex and NMDA receptors (3, 4). Dysfunction of GABAA receptor–mediated inhibition is implicated in the pathophysiology of several neurologic and psychiatric conditions, among them epilepsy. Some of these conditions have been associated with abnormal levels of certain neurosteroids, which may mediate the function of the brain’s major inhibitory receptor, the GABAA receptor (10). Interaction of DHEAS with excitatory amino acid transmission is rather complex and may result in both neuroprotective effects and proconvulsive effects (11). Several lines of evidence suggest that DHEAS can act as a proconvulsant agent by acting as a negative modulator of GABAA receptor and a positive modulator of the NMDA subtype of glutamate receptor (3, 4). Intracerebroventricular injection of DHEAS induced clonic-tonic seizures in a dose-dependent manner (3). Reddy and Kulkarni (4) investigated the potential neurotoxic and proconvulsive effect of long-term treatment with DHEAS. Although short-term administration of DHEA did not modify seizure reactivity, mice treated for 4 weeks with DHEA exhibited increased sensitivity to tonic convulsions (4). Although human information is lacking, it has been demonstrated that serum levels of DHEA were modified significantly in the presence of a convulsive disorder (9). The patient had an intracerebral lesion due to head injury. Traumatic brain injury is associated with increased risk of seizures, brain contusions acting as strong risk factors for late seizures. Posttraumatic epilepsy is caused by injury to the brain after trauma. The disorder is classified as immediate seizures (<24 hours after injury), early seizures (<1 week after injury), and late seizures (>8 days after injury). The incidence of late posttraumatic seizures is up to 42% in civilian head injuries, and they may persist for up to 20 years (12). 931.e2
Karp et al.
Although this patient had no prior seizures, the existence of a brain lesion increases her tendency for convulsion. One month after DHEA treatment was initiated, a first seizure occurred. One can assume that a proconvulsant drug rarely will affect a healthy brain; however, in a patient with an increased potential for seizures, there is a lower threshold and seizures may occur. CONCLUSIONS To the best of our knowledge this is the first published case of an association between a new onset of epilepsy and the use of DHEA. Despite the circumstantial nature of the evidence we presented, there is a significant body of direct and indirect evidence to support a potential role for DHEA in inducing a seizure in a high-risk patient. The findings that DHEA and DHEAS act as neurosteroids, modulating neuronal excitability, are of importance to caregivers who advise use of this ‘‘dietary supplement.’’ Physicians advising use of this product should be aware of potential neurologic adverse effects and advise their patients to report any irregular neurologic event. Special attention should be given to women prone to convulsive activity, such as our patient. Further investigation is needed to expand our knowledge and understanding of DHEA’s neurosteroidal activities. REFERENCES 1. Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril 2005;84:756. 2. Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod 2006;21:2845–9. 3. Czionkowska AI, Krzascik P, Sienkiewicz-Jarosz H, Siemiatkowski M, Szyndler J, Bidzinski A, et al. The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol. Pharmacol Biochem Behav 2000;67:345–53. 4. Reddy DS, Kulkarni SK. Proconvulsant effects of neurosteroids pregnenolone sulfate and dehydroepiandrosterone sulfate in mice. Eur J Pharmacol 1998;345:55–9. 5. Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000;15:2129–32. 6. Arlt W. Androgen therapy in women. Eur J Endocrinol 2006;154:1–11. 7. Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert J. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid–induced neurotoxicity. Proc Natl Acad Sci USA 1998;95:1852–7. 8. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. Philadelphia, PA: Lippincott Williams & Wilkins, 2004. 9. Galimberti CA, Magri F, Copello F, Arbasino C, Cravello L, Casu M, et al. Seizure frequency and cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in women with epilepsy receiving antiepileptic drug treatment. Epilepsia 2005;46:517–23. 10. Belelli D, Herd MB, Mitchell EA, Peden DR, Vardy AW, Gentet L, et al. Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance. Neuroscience 2006;138:821–9. 11. Lesskiewicz M, Budziszewska B, Jaworska-Feil L, Kubera M, BastaKaim A, Lason W. Inhibitory effect of some neuroactive steroids on cocaine-induced kindling in mice. Pol J Pharmacol 2003;55:1131–6. 12. Agrawal A, Timothy J, Pandit L, Manja M. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg 2006;108:433–9.
Seizure associated with DHEA supplementation
Vol. 91, No. 3, March 2009