- Email: [email protected]
Aromatase inhibition, testosterone, and seizures
Epilepsy & Behavior Epilepsy & Behavior 5 (2004) 260–263 www.elsevier.com/locate/yebeh
Case Report
Aromatase inhibition, testosterone, and seizures Cynthia Hardena,* and Neil J. MacLuskyb a
Department of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College of Cornell University, New York, NY, USA b Department of Obstetrics and Gynecology, Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, NY, USA Received 18 September 2003; revised 5 December 2003; accepted 9 December 2003
Abstract The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosteroneÕs action in the brain may be due to its conversion to estrogen via aromatase. We report herein a 61-year-old man with temporal lobe epilepsy and sexual dysfunction due to low testosterone levels. Use of an aromatase inhibitor, letrozole, normalized his testosterone level and improved his sexual functioning. Letrozole, in addition to standard antiseizure medication, was also associated with improved seizure control. This was sustained and, further, was associated with seizure exacerbation after withdrawing letrozole, and subsequent seizure improvement after restarting it. During the course of treatment, his serum testosterone level increased, sex hormone-binding globulin decreased (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels increased, while serum estradiol levels remained undetectable. Letrozole may, therefore, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. This experience suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy. 2004 Elsevier Inc. All rights reserved. Keywords: Aromatase inhibitor; Letrozole; Testosterone; Seizures
1. Introduction The effects of the principal male sex steroid, testosterone, on neuronal excitability and seizures remain unclear. In experimental models of epilepsy, testosteroneÕs influence has been reported to be mixed, excitatory in some circumstances, inhibitory in others [1–3]. This may be a consequence of the fact that in the brain, testosterone is converted to metabolites having a range of biological activities. Aromatization of testosterone results in the formation of estradiol, a hormone that promotes seizures [4,5]. Conversely, testosterone itself, and its 5a-reduced metabolites, may inhibit seizures, raising discharge thresholds in the limbic system [2] inhibiting NMDA receptor-mediated neuronal excitation [6], and exerting antiseizure effects, possibly via direct effects on GABAA receptors [1,7].
* Corresponding author. Fax: 1-212-746-8984. E-mail address: [email protected] (C. Harden).
1525-5050/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2003.12.001
We report herein a male patient with intractable complex partial seizures who was also symptomatic from a low serum testosterone level. Changing his standard antiseizure medication achieved an improvement in seizure frequency. Seizure control was further improved by the addition of an aromatase inhibitor, letrozole, which inhibits the conversion of testosterone to estradiol.
2. Case description The patient is a 61-year-old right-handed man diagnosed at age 60 years as having a partial seizure disorder manifested by complex partial seizures. His seizures were characterized by a feeling of anxiety and a sensation in the lower abdomen, followed by brief disorientation. These occurred several times per week. After the diagnosis was made, he was told by acquaintances that he had been having brief episodes of disorientation for the previous 4 years. His interictal EEG showed
Case Report / Epilepsy & Behavior 5 (2004) 260–263
independent left and right temporal spikes, as well as intermittent slowing in the temporal areas, both independently and synchronously. A brain MRI was normal. A PET scan of the brain was also normal. Past medical history reveals that he was born prematurely, due to maternal pre-eclampsia, with a birth weight of 2 lb 10 oz. The patient miraculously (for the time) survived prematurity without complications. There was no history of febrile seizures, head trauma, or central nervous system infection and no family history of epilepsy. Review of systems includes a history of hypertension since age 25 years, which is under good control with medical treatment. He had pyelonephritis at age 12 years. Additionally, he had complaints of lack of energy over the past several years, as well as decreased libido. At age 60 years, he developed chronic neck pain with degenerative bone changes present on imaging of the cervical spine, which was managed with a cervical collar, nonsteroidal anti-inflammatory agents, and physical therapy. Physical examination revealed a well-developed male of average height and body habitus. General examination and neurological examination were normal. He was started on carbamazepine at the time of diagnosis, with improvement in the seizure frequency, but he noted cognitive slowing and worsened lack of energy since starting the treatment. The patient underwent neuropsychological testing, which showed very mild cognitive dysfunction but superior intellectual function in general, and the results further indicated an antiseizure medication effect contributing to cognitive impairment. Because of the persistence of seizures occurring several times per week, and the adverse effects of carbamazepine, levetiracetam was added to his regimen. The dose of levetiracetam was increased to 3000 mg per day and then carbamazepine was tapered off within 6 weeks of starting levetiracetam. The patient felt that he was much improved and seizures decreased to occurring only with exhaustion or lack of sleep, about one every 2 weeks. He then self-decreased levetiracetam to 1500 mg per day, but had a recurrence of seizures to several times
261
per week, including nocturnally. He then raised the dose back to 3000 mg per day and the improvement in seizure frequency was restored. However, he still complained of lack of energy and decreased libido, which were present before levitiracetam treatment. Laboratory results on levetiracetam monotherapy revealed a low serum testosterone level of 187 ng/dL. Sex hormone-binding globulin (SHBG) was normal at 25 ng/ L and estradiol was normal at <10 ng/L. Follicle-stimulating hormone (FSH) was 3.8 U/L and luteinizing hormone (LH) was 3.7 U/L, which are also normal (see Table 1 for ranges of normal values). The patient was then started on an aromatase inhibitor, letrozole, after being fully informed that this medication is indicated for the treatment of advanced breast cancer in women only and is not approved by FDA for use in men. He was informed that the off-label uses for letrozole include the treatment of delayed puberty in boys. He was advised that this treatment was being suggested to him because it could potentially improve his libido and energy level, and that there was preliminary information it may also improve seizure control. The patient is a board-certified neurologist, and stated his understanding. He was begun on a dose of 2.5 mg per day. Within 10 days, the patient noticed a marked increase in energy level and sexual functioning and a further reduction in seizure frequency. Testosterone level was normalized at 458 ng/dL, 6 weeks after starting letrozole. FSH had increased to 16.9 U/L and LH had increased to 16.7 U/L, which are elevated values for males. Levetiracetam was then gradually decreased from 3000 to 1500 mg per day over the course of 2 months to minimize any cognitive adverse effects of the drug, and there was no recurrence of seizures. Eight weeks later, however, testosterone had increased to 754 ng/dL, which is at the upper range of normal values for a male in this age group. The free fraction was normal at 2.6%. FSH was 18.8 and LH was 17.2, which again are elevated. The SHBG was also normal at 18, but was decreased from the previous value of 25. The continued rise in serum testosterone was a source of concern, so the letrozole was decreased to
Table 1 Laboratory values in relationship to letrozole dosea Laboratory values
ÆTime 1æ Before letrozole
ÆTime 2æ 6 weeks since Time 1: 2.5 mg/day
ÆTime 3æ 8 weeks since Time 1: 2.5 mg/day
ÆTime 4æ 9 weeks since Time 1: 33 h post dose of 2.5 mg/ 36 h
ÆTime 5æ 1 day since Time 4: 9 h post dose of 2.5 mg/ 36 h
ÆTime 6æ 3 weeks since Time 4: 13 h post dose of 2.5 mg/36 h
Testosterone (ng/dL) 17b-Estradiol (ng/L) LH (U/L) FSH (U/L) SHBG (nmol/L)
187 <10 3.7 3.8 25
458
754
16.7 16.9
17.2 18.8 18
452 <10 14.5 17.3 17
502 <10 18.5 17.6 15
488 <10 13.1 14.9 17
a Normative values for levels for men: testosterone, 212–755 ng/dL for men > 50 years of age; 17 b-estradiol, <60 ng/L; luteinizing hormone (LH) 0.4–8 U/L; follicle-stimulating hormone (FSH), 0.4–8 U/L; sex hormone—binding globulin (SHBG), 7–50 nmol/L.
262
Case Report / Epilepsy & Behavior 5 (2004) 260–263
2.5 mg every other day. The patient then noted seizure auras late in the day on the alternate days when he did not take letrozole. The letrozole regimen was changed to a dose every 36 h and testosterone levels were obtained at various times after the dose to determine stability of the levels (see Table 1, Times 4–6). The levels were stable in the midrange of expected values. FSH and LH remained elevated but unchanged and SHBG declined slightly. Estradiol levels remained <10 ng/L throughout the medication adjustments. On this regimen of letrozole taken every 36 hours and levetiracetam 1500 mg per day, seizures recurred. Levetiracetam was then increased to 2000 mg per day with subsequent stability of seizure control. The patient remained stable with rare seizures and normalized energy levels and sexual functioning on the above doses of letrozole and levetiracetam for the subsequent 6 months of follow-up. At this point, the patient ran out of letrozole and failed to refill his prescription for a week, while continuing to take levetiracetam 2000 mg per day. Within 4 days of stopping letrozole, seizures recurred (one or two a day) and continued until the letrozole treatment was reinstated. During the subsequent 2 months of follow-up, he has maintained good seizure control on letrozole 2.5 mg/36 h combined with levetiracetam 2000 mg daily.
3. Discussion Diminished sexual function is common in men with epilepsy [8–10]. Previous studies have suggested that in hypogonadal male epileptics treated with testosterone, it may be possible to enhance seizure control as well as reproductive function via addition of an aromatase inhibitor, to limit estradiol biosynthesis [8,11]. Since the negative feedback effects of testosterone on gonadotropin release reflect contributions from both androgen and estrogen action [12–14] we hypothesized that it might be possible, in cases of epilepsy associated with mild hypogonadism, to elevate endogenous testosterone secretion simply by blocking aromatase. Estrogen is known to potentiate neuronal excitability and to increase seizure frequency and severity [4,5,15]. However, estrogen is not essential for either normal male sexual function or the expression of male secondary sexual characteristics [16]. Therefore, an increase in endogenous testosterone under conditions of aromatase blockade should theoretically improve seizure control, while simultaneously ameliorating the symptoms of testosterone insufficiency. Previous studies have provided evidence consistent with the hypothesis that low androgen levels, in the absence of estrogen, may enhance the risk of seizures as well as other neurological problems. In rodents, 5a-reduced androgens, which are not substrates for estrogen biosynthesis, raise amygdala afterdischarge thresholds
[2], and suppress pentylenetetrazole-induced seizures [1,7]. Low androgen levels have also been associated with diminished cognitive performance in man [17,18], whereas in animals, cognitive deficits observed following castration can be reversed by androgen replacement [19,20]. This combination of effects may reflect the ability of androgens to simultaneously potentiate GABAergic neurotransmission [1] while inducing neurotrophic and neuroprotective responses similar to those elicited by estradiol [21,22]. In this case, we did not find evidence of a change in serum estradiol levels throughout the course of treatment because the peripheral levels were always below the limits of detection. Letrozole may, however, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. The consequent increase in androgen levels appears to have favorably influenced seizure frequency, in that the patient was able on letrozole to reduce his dose of levetiracetam. When letrozole was discontinued, the same dose of levetiracetam was not sufficient to maintain good seizure control. However, seizure control was restored without increasing levetiracetam, when letrozole treatment was reinstated. As levetiracetam is metabolized extrahepatically and has no potential for inducing or inhibiting hepatic enzymes, endogenous testosterone or other hormone levels would not be altered by its use or by changes in levetiracetam dose. While this single case does not prove the benefit of aromatase inhibition, the potential for enhancement of sensitivity to conventional antiepileptic drug medication, while simultaneously improving gonadal and sexual function, suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy. This treatment approach would expand the disciplines involved to produce optimal seizure treatment to include urology and reproductive endocrinology, as well as neurology.
References [1] Frye CA, Rhodes ME, Walf AA, Harney JP. Testosterone reduces pentylenetetrazole-induced ictal activity of wildtype mice but not those deficient in type I 5 alpha-reductase. Brain Res 2001;918:182–6. [2] Edwards HE, Burnham WM, MacLusky NJ. Testosterone and its metabolites affect afterdischarge thresholds and the development of amygdala kindled seizures. Brain Res 1999;838:151–7. [3] Mejias-Aponte CA, Jimenez-Rivera CA, Segarra AC. Sex differences in models of temporal lobe epilepsy: role of testosterone. Brain Res 2002;944:210–8. [4] Backstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 1976;54:321–47.
Case Report / Epilepsy & Behavior 5 (2004) 260–263 [5] Edwards HE, Burnham WM, Mendonca A, Bowlby DA, MacLusky NJ. Steroid hormones affect limbic after discharge thresholds and kindling rates in adult female rats. Brain Res 1999;838:136–50. [6] Pouliot WA, Handa RJ, Beck SG. Androgen modulates Nmethyl-D -aspartate-mediated depolarization in CA1 hippocampal pyramidal cells. Synapse 1996;23:10–9. [7] Frye CA. The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Res Brain Res Rev 2001;37:201–22. [8] Herzog AG. Reproductive endocrine considerations and hormonal therapy for men with epilepsy. (review). Epilepsia 1991;32(Suppl. 6):S34–7. [9] Morrell MJ. Sexual dysfunction in epilepsy. Epilepsia 1991;32(Suppl. 6):S38–45. [10] Harden CL. Treatment of sexual disorders in people with epilepsy. Epilepsy Behav 2002;3:38–41. [11] Herzog AG, Klein P, Jacobs AR. Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism. Neurology 1998;50:782–4. [12] DÕAgata R, Vicari E, Aliffi A, Gulizia S, Palumbo G. Direct evidence in men for a role of endogenous oestrogens on gonadotrophin release. Acta Endocrinol (Copenh) 1981;97:145–9. [13] Urban RJ, Davis MR, Rogol AD, Johnson ML, Veldhuis JD. Acute androgen receptor blockade increases luteinizing hormone secretory activity in men. J Clin Endocrinol Metab 1988;67:1149–55.
263
[14] Gooren L. Androgens and estrogens in their negative feedback action in the hypothalamo–pituitary–testis axis: site of action and evidence of their interaction. J Steroid Biochem 1989; 33:757–61. [15] Woolley DE, Timiras PS. The gonad–brain relationship: effects of female sex hormones on electroshock convulsions in the rat. Endocrinology 1962;70:196–209. [16] Gooren LJ. Human male sexual functions do not require aromatization of testosterone: a study using tamoxifen, testolactone, and dihydrotestosterone. Arch Sex Behav 1985;14:539–48. [17] Howell S, Shalet S. Testosterone deficiency and replacement. Horm Res 2001;56(Suppl. 1):86–92. [18] Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50:707–12. [19] Frye CA, Lacey EH. Posttraining androgensÕ enhancement of cognitive performance is temporally distinct from androgensÕ increases in affective behavior. Cogn Affect Behav Neurosci 2001;1:172–82. [20] Kritzer MF, McLaughlin PJ, Smirlis T, Robinson JK. Gonadectomy impairs T-maze acquisition in adult male rats. Horm Behav 2001;39:167–74. [21] Pike CJ. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res 2001;919:160–5. [22] Leranth C, Petnehazy O, MacLusky NJ. Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 2003;23:1588–92.
Case Report
Aromatase inhibition, testosterone, and seizures Cynthia Hardena,* and Neil J. MacLuskyb a
Department of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College of Cornell University, New York, NY, USA b Department of Obstetrics and Gynecology, Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, NY, USA Received 18 September 2003; revised 5 December 2003; accepted 9 December 2003
Abstract The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosteroneÕs action in the brain may be due to its conversion to estrogen via aromatase. We report herein a 61-year-old man with temporal lobe epilepsy and sexual dysfunction due to low testosterone levels. Use of an aromatase inhibitor, letrozole, normalized his testosterone level and improved his sexual functioning. Letrozole, in addition to standard antiseizure medication, was also associated with improved seizure control. This was sustained and, further, was associated with seizure exacerbation after withdrawing letrozole, and subsequent seizure improvement after restarting it. During the course of treatment, his serum testosterone level increased, sex hormone-binding globulin decreased (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels increased, while serum estradiol levels remained undetectable. Letrozole may, therefore, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. This experience suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy. 2004 Elsevier Inc. All rights reserved. Keywords: Aromatase inhibitor; Letrozole; Testosterone; Seizures
1. Introduction The effects of the principal male sex steroid, testosterone, on neuronal excitability and seizures remain unclear. In experimental models of epilepsy, testosteroneÕs influence has been reported to be mixed, excitatory in some circumstances, inhibitory in others [1–3]. This may be a consequence of the fact that in the brain, testosterone is converted to metabolites having a range of biological activities. Aromatization of testosterone results in the formation of estradiol, a hormone that promotes seizures [4,5]. Conversely, testosterone itself, and its 5a-reduced metabolites, may inhibit seizures, raising discharge thresholds in the limbic system [2] inhibiting NMDA receptor-mediated neuronal excitation [6], and exerting antiseizure effects, possibly via direct effects on GABAA receptors [1,7].
* Corresponding author. Fax: 1-212-746-8984. E-mail address: [email protected] (C. Harden).
1525-5050/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2003.12.001
We report herein a male patient with intractable complex partial seizures who was also symptomatic from a low serum testosterone level. Changing his standard antiseizure medication achieved an improvement in seizure frequency. Seizure control was further improved by the addition of an aromatase inhibitor, letrozole, which inhibits the conversion of testosterone to estradiol.
2. Case description The patient is a 61-year-old right-handed man diagnosed at age 60 years as having a partial seizure disorder manifested by complex partial seizures. His seizures were characterized by a feeling of anxiety and a sensation in the lower abdomen, followed by brief disorientation. These occurred several times per week. After the diagnosis was made, he was told by acquaintances that he had been having brief episodes of disorientation for the previous 4 years. His interictal EEG showed
Case Report / Epilepsy & Behavior 5 (2004) 260–263
independent left and right temporal spikes, as well as intermittent slowing in the temporal areas, both independently and synchronously. A brain MRI was normal. A PET scan of the brain was also normal. Past medical history reveals that he was born prematurely, due to maternal pre-eclampsia, with a birth weight of 2 lb 10 oz. The patient miraculously (for the time) survived prematurity without complications. There was no history of febrile seizures, head trauma, or central nervous system infection and no family history of epilepsy. Review of systems includes a history of hypertension since age 25 years, which is under good control with medical treatment. He had pyelonephritis at age 12 years. Additionally, he had complaints of lack of energy over the past several years, as well as decreased libido. At age 60 years, he developed chronic neck pain with degenerative bone changes present on imaging of the cervical spine, which was managed with a cervical collar, nonsteroidal anti-inflammatory agents, and physical therapy. Physical examination revealed a well-developed male of average height and body habitus. General examination and neurological examination were normal. He was started on carbamazepine at the time of diagnosis, with improvement in the seizure frequency, but he noted cognitive slowing and worsened lack of energy since starting the treatment. The patient underwent neuropsychological testing, which showed very mild cognitive dysfunction but superior intellectual function in general, and the results further indicated an antiseizure medication effect contributing to cognitive impairment. Because of the persistence of seizures occurring several times per week, and the adverse effects of carbamazepine, levetiracetam was added to his regimen. The dose of levetiracetam was increased to 3000 mg per day and then carbamazepine was tapered off within 6 weeks of starting levetiracetam. The patient felt that he was much improved and seizures decreased to occurring only with exhaustion or lack of sleep, about one every 2 weeks. He then self-decreased levetiracetam to 1500 mg per day, but had a recurrence of seizures to several times
261
per week, including nocturnally. He then raised the dose back to 3000 mg per day and the improvement in seizure frequency was restored. However, he still complained of lack of energy and decreased libido, which were present before levitiracetam treatment. Laboratory results on levetiracetam monotherapy revealed a low serum testosterone level of 187 ng/dL. Sex hormone-binding globulin (SHBG) was normal at 25 ng/ L and estradiol was normal at <10 ng/L. Follicle-stimulating hormone (FSH) was 3.8 U/L and luteinizing hormone (LH) was 3.7 U/L, which are also normal (see Table 1 for ranges of normal values). The patient was then started on an aromatase inhibitor, letrozole, after being fully informed that this medication is indicated for the treatment of advanced breast cancer in women only and is not approved by FDA for use in men. He was informed that the off-label uses for letrozole include the treatment of delayed puberty in boys. He was advised that this treatment was being suggested to him because it could potentially improve his libido and energy level, and that there was preliminary information it may also improve seizure control. The patient is a board-certified neurologist, and stated his understanding. He was begun on a dose of 2.5 mg per day. Within 10 days, the patient noticed a marked increase in energy level and sexual functioning and a further reduction in seizure frequency. Testosterone level was normalized at 458 ng/dL, 6 weeks after starting letrozole. FSH had increased to 16.9 U/L and LH had increased to 16.7 U/L, which are elevated values for males. Levetiracetam was then gradually decreased from 3000 to 1500 mg per day over the course of 2 months to minimize any cognitive adverse effects of the drug, and there was no recurrence of seizures. Eight weeks later, however, testosterone had increased to 754 ng/dL, which is at the upper range of normal values for a male in this age group. The free fraction was normal at 2.6%. FSH was 18.8 and LH was 17.2, which again are elevated. The SHBG was also normal at 18, but was decreased from the previous value of 25. The continued rise in serum testosterone was a source of concern, so the letrozole was decreased to
Table 1 Laboratory values in relationship to letrozole dosea Laboratory values
ÆTime 1æ Before letrozole
ÆTime 2æ 6 weeks since Time 1: 2.5 mg/day
ÆTime 3æ 8 weeks since Time 1: 2.5 mg/day
ÆTime 4æ 9 weeks since Time 1: 33 h post dose of 2.5 mg/ 36 h
ÆTime 5æ 1 day since Time 4: 9 h post dose of 2.5 mg/ 36 h
ÆTime 6æ 3 weeks since Time 4: 13 h post dose of 2.5 mg/36 h
Testosterone (ng/dL) 17b-Estradiol (ng/L) LH (U/L) FSH (U/L) SHBG (nmol/L)
187 <10 3.7 3.8 25
458
754
16.7 16.9
17.2 18.8 18
452 <10 14.5 17.3 17
502 <10 18.5 17.6 15
488 <10 13.1 14.9 17
a Normative values for levels for men: testosterone, 212–755 ng/dL for men > 50 years of age; 17 b-estradiol, <60 ng/L; luteinizing hormone (LH) 0.4–8 U/L; follicle-stimulating hormone (FSH), 0.4–8 U/L; sex hormone—binding globulin (SHBG), 7–50 nmol/L.
262
Case Report / Epilepsy & Behavior 5 (2004) 260–263
2.5 mg every other day. The patient then noted seizure auras late in the day on the alternate days when he did not take letrozole. The letrozole regimen was changed to a dose every 36 h and testosterone levels were obtained at various times after the dose to determine stability of the levels (see Table 1, Times 4–6). The levels were stable in the midrange of expected values. FSH and LH remained elevated but unchanged and SHBG declined slightly. Estradiol levels remained <10 ng/L throughout the medication adjustments. On this regimen of letrozole taken every 36 hours and levetiracetam 1500 mg per day, seizures recurred. Levetiracetam was then increased to 2000 mg per day with subsequent stability of seizure control. The patient remained stable with rare seizures and normalized energy levels and sexual functioning on the above doses of letrozole and levetiracetam for the subsequent 6 months of follow-up. At this point, the patient ran out of letrozole and failed to refill his prescription for a week, while continuing to take levetiracetam 2000 mg per day. Within 4 days of stopping letrozole, seizures recurred (one or two a day) and continued until the letrozole treatment was reinstated. During the subsequent 2 months of follow-up, he has maintained good seizure control on letrozole 2.5 mg/36 h combined with levetiracetam 2000 mg daily.
3. Discussion Diminished sexual function is common in men with epilepsy [8–10]. Previous studies have suggested that in hypogonadal male epileptics treated with testosterone, it may be possible to enhance seizure control as well as reproductive function via addition of an aromatase inhibitor, to limit estradiol biosynthesis [8,11]. Since the negative feedback effects of testosterone on gonadotropin release reflect contributions from both androgen and estrogen action [12–14] we hypothesized that it might be possible, in cases of epilepsy associated with mild hypogonadism, to elevate endogenous testosterone secretion simply by blocking aromatase. Estrogen is known to potentiate neuronal excitability and to increase seizure frequency and severity [4,5,15]. However, estrogen is not essential for either normal male sexual function or the expression of male secondary sexual characteristics [16]. Therefore, an increase in endogenous testosterone under conditions of aromatase blockade should theoretically improve seizure control, while simultaneously ameliorating the symptoms of testosterone insufficiency. Previous studies have provided evidence consistent with the hypothesis that low androgen levels, in the absence of estrogen, may enhance the risk of seizures as well as other neurological problems. In rodents, 5a-reduced androgens, which are not substrates for estrogen biosynthesis, raise amygdala afterdischarge thresholds
[2], and suppress pentylenetetrazole-induced seizures [1,7]. Low androgen levels have also been associated with diminished cognitive performance in man [17,18], whereas in animals, cognitive deficits observed following castration can be reversed by androgen replacement [19,20]. This combination of effects may reflect the ability of androgens to simultaneously potentiate GABAergic neurotransmission [1] while inducing neurotrophic and neuroprotective responses similar to those elicited by estradiol [21,22]. In this case, we did not find evidence of a change in serum estradiol levels throughout the course of treatment because the peripheral levels were always below the limits of detection. Letrozole may, however, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. The consequent increase in androgen levels appears to have favorably influenced seizure frequency, in that the patient was able on letrozole to reduce his dose of levetiracetam. When letrozole was discontinued, the same dose of levetiracetam was not sufficient to maintain good seizure control. However, seizure control was restored without increasing levetiracetam, when letrozole treatment was reinstated. As levetiracetam is metabolized extrahepatically and has no potential for inducing or inhibiting hepatic enzymes, endogenous testosterone or other hormone levels would not be altered by its use or by changes in levetiracetam dose. While this single case does not prove the benefit of aromatase inhibition, the potential for enhancement of sensitivity to conventional antiepileptic drug medication, while simultaneously improving gonadal and sexual function, suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy. This treatment approach would expand the disciplines involved to produce optimal seizure treatment to include urology and reproductive endocrinology, as well as neurology.
References [1] Frye CA, Rhodes ME, Walf AA, Harney JP. Testosterone reduces pentylenetetrazole-induced ictal activity of wildtype mice but not those deficient in type I 5 alpha-reductase. Brain Res 2001;918:182–6. [2] Edwards HE, Burnham WM, MacLusky NJ. Testosterone and its metabolites affect afterdischarge thresholds and the development of amygdala kindled seizures. Brain Res 1999;838:151–7. [3] Mejias-Aponte CA, Jimenez-Rivera CA, Segarra AC. Sex differences in models of temporal lobe epilepsy: role of testosterone. Brain Res 2002;944:210–8. [4] Backstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 1976;54:321–47.
Case Report / Epilepsy & Behavior 5 (2004) 260–263 [5] Edwards HE, Burnham WM, Mendonca A, Bowlby DA, MacLusky NJ. Steroid hormones affect limbic after discharge thresholds and kindling rates in adult female rats. Brain Res 1999;838:136–50. [6] Pouliot WA, Handa RJ, Beck SG. Androgen modulates Nmethyl-D -aspartate-mediated depolarization in CA1 hippocampal pyramidal cells. Synapse 1996;23:10–9. [7] Frye CA. The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Res Brain Res Rev 2001;37:201–22. [8] Herzog AG. Reproductive endocrine considerations and hormonal therapy for men with epilepsy. (review). Epilepsia 1991;32(Suppl. 6):S34–7. [9] Morrell MJ. Sexual dysfunction in epilepsy. Epilepsia 1991;32(Suppl. 6):S38–45. [10] Harden CL. Treatment of sexual disorders in people with epilepsy. Epilepsy Behav 2002;3:38–41. [11] Herzog AG, Klein P, Jacobs AR. Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism. Neurology 1998;50:782–4. [12] DÕAgata R, Vicari E, Aliffi A, Gulizia S, Palumbo G. Direct evidence in men for a role of endogenous oestrogens on gonadotrophin release. Acta Endocrinol (Copenh) 1981;97:145–9. [13] Urban RJ, Davis MR, Rogol AD, Johnson ML, Veldhuis JD. Acute androgen receptor blockade increases luteinizing hormone secretory activity in men. J Clin Endocrinol Metab 1988;67:1149–55.
263
[14] Gooren L. Androgens and estrogens in their negative feedback action in the hypothalamo–pituitary–testis axis: site of action and evidence of their interaction. J Steroid Biochem 1989; 33:757–61. [15] Woolley DE, Timiras PS. The gonad–brain relationship: effects of female sex hormones on electroshock convulsions in the rat. Endocrinology 1962;70:196–209. [16] Gooren LJ. Human male sexual functions do not require aromatization of testosterone: a study using tamoxifen, testolactone, and dihydrotestosterone. Arch Sex Behav 1985;14:539–48. [17] Howell S, Shalet S. Testosterone deficiency and replacement. Horm Res 2001;56(Suppl. 1):86–92. [18] Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50:707–12. [19] Frye CA, Lacey EH. Posttraining androgensÕ enhancement of cognitive performance is temporally distinct from androgensÕ increases in affective behavior. Cogn Affect Behav Neurosci 2001;1:172–82. [20] Kritzer MF, McLaughlin PJ, Smirlis T, Robinson JK. Gonadectomy impairs T-maze acquisition in adult male rats. Horm Behav 2001;39:167–74. [21] Pike CJ. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res 2001;919:160–5. [22] Leranth C, Petnehazy O, MacLusky NJ. Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 2003;23:1588–92.