Aromatase inhibition, testosterone, and seizures

doi:10.1016/j.yebeh.2003.12.001

Epilepsy & Behavior

Volume 5, Issue 2, April 2004, Pages 260-263

https://doi.org/10.1016/j.yebeh.2003.12.001 Get rights and content

Abstract

The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosterone's 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.

Introduction

The effects of the principal male sex steroid, testosterone, on neuronal excitability and seizures remain unclear. In experimental models of epilepsy, testosterone's influence has been reported to be mixed, excitatory in some circumstances, inhibitory in others [1], [2], [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 5α-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 GABA_A receptors [1], [7].

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.

Section snippets

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 independent

Discussion

Diminished sexual function is common in men with epilepsy [8], [9], [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], [13], [14] we

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Cited by (43)

Mechanisms linking neurological disorders with reproductive endocrine dysfunction: Insights from epilepsy research
2023, Frontiers in Neuroendocrinology
Gonadal hormone actions in the brain can both worsen and alleviate symptoms of neurological disorders. Although neurological conditions and reproductive endocrine function are seemingly disparate, compelling evidence indicates that reciprocal interactions exist between certain disorders and hypothalamic-pituitary–gonadal (HPG) axis irregularities. Epilepsy is a neurological disorder that shows significant reproductive endocrine dysfunction (RED) in clinical populations. Seizures, particularly those arising from temporal lobe structures, can drive HPG axis alterations, and hormones produced in the HPG axis can reciprocally modulate seizure activity. Despite this relationship, mechanistic links between seizures and RED, and vice versa, are still largely unknown. Here, we review clinical evidence alongside recent investigations in preclinical animal models into the contributions of seizures to HPG axis malfunction, describe the effects of HPG axis hormonal feedback on seizure activity, and discuss how epilepsy research can offer insight into mechanisms linking neurological disorders to HPG axis dysfunction, an understudied area of neuroendocrinology.
Sex and gender differences in epilepsy
2022, International Review of Neurobiology
Citation Excerpt :
Its effects are mainly through its metabolites including estradiol with its predominantly proconvulsant effect, as well as androsterone and 5α-androstane-3α,17β-diol with mainly anticonvulsant effects (Harden & Pennell, 2013). Aromatase inhibition has been proposed as a possible adjunct treatment for men with epilepsy as it reduces the conversion of testosterone to estradiol, but additional research is needed to further understand this relationship (Harden & MacLusky, 2004, 2005). The synthesis of sex hormones is regulated by the hypothalamic-pituitary-gonadal axis.
Sex and gender differences in epilepsy are important influencing factors in epilepsy care. In epilepsy, the hormonal differences between the sexes are important as they impact specific treatment considerations for patients at various life stages particularly during early adulthood with establishment of the menstrual cycle, pregnancy, perimenopause and menopause. Choice of antiseizure medication may have direct consequences on hormonal cycles, hormonal contraception, pregnancy and fetal risk of major congenital malformation. Conversely hormones whether intrinsic or extrinsically administered may have direct impact on antiseizure medications and seizure control. This chapter explores these important influences on the management of persons with epilepsy.
Efficacy of Non-Testosterone–Based Treatment in Hypogonadal Men: A Review
2021, Sexual Medicine Reviews
Although testosterone replacement therapy is an effective treatment for hypogonadism, there are safety concerns regarding potential cardiovascular risks and fertility preservation.
To assess the effect of selective estrogen receptor modulator (SERM), aromatase inhibitor, and human chorionic gonadotropin (hCG) on total testosterone (TT) levels and hypogonadism.
We performed a systematic literature review from 1987 to 2019 via PubMed, Cochrane review, and Web of Science. Terms used were infertility, hypogonadism, alternative to testosterone therapy, selective estrogen receptor modulator, aromatase inhibitor, and human chorionic gonadotropin. Studies that reported an effect of TT and hypogonadism after treatment of each medication were selected. Hypogonadal symptoms were assessed by the Androgen Deficiency of The Aging Male (ADAM) questionnaire. Aggregated data were analyzed via Chi-squared analysis.
From literature, 25 studies were selected; of which, 12 evaluated efficacy of aromatase inhibitor, 8 evaluated SERMs, and 5 evaluated hCG effects. For SERMs, 512 patients with mean age 42.3 ± 1.94 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5–216.1 95% confidence interval {CI}]). For aromatase inhibitor, 375 patients with mean age 54.1 ± 0.67 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5–216.1 95% CI]). SERMs also showed ADAM before treatment vs after treatment (4.95 ± 0.28 vs 5.50 ± 0.19, P < .0001 [0.523–0.581 95% CI]). For hCG, 196 patients with mean age 41.7 ± 1.5 years showed mean TT before treatment vs after treatment (284.5 ± 13.6 [ng/dl] vs 565.6 ± 39.7 [ng/dl], P < .0001 [275.2–287.0 95% CI]). In addition, hCG also showed ADAM before treatment vs after treatment (28.1 ± 2.0 vs 30.9 ± 2.3, P < .0001 [2.313 95% CI]).
Non-testosterone therapies are efficacious in hypogonadal men. Our results show statistically significant improvement in TT and ADAM scores in all 3 medications after treatment. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone–based treatment.
Raheem OA, Chen TT, Le TV, et al. Efficacy of Non-Testosterone–Based Treatment in Hypogonadal Men: A Review. Sex Med Rev 2021;9:381–392.
Design and development of letrozole nanoemulsion: A comparative evaluation of brain targeted nanoemulsion with free letrozole against status epilepticus and neurodegeneration in mice
2019, International Journal of Pharmaceutics
The target of the current study is to formulate letrozole loaded nanoemulsion (LET-NE) for the direct nose to brain delivery to reduce peripheral effects of letrozole (LET). LET-NE is compared against intraperitoneally administered free LET in kainic acid (KA) induced status epilepticus (SE) in mice. LET loaded nanoemulsion (LET-NE) was prepared by aqueous microtitration method using Triacetin, Tween 80 and PEG-400 as the oil phase, surfactant, and co-surfactant. Nanoemulsion was studied for droplet size, polydispersity index (PDI), zeta potential, percentage transmittance, drug content, surface morphology. TEM images of developed formulation demonstrated spherical droplets with a mean diameter of 95.59 ± 2.34 nm, PDI of 0.162 ± 0.012 and zeta potential of −7.12 ± 0.12 mV respectively. In in-vitro and ex-vivo drug release, LET-NE showed prolonged drug release profile as compared to suspension. SE was induced by KA (10 mg/kg, i.p.) in Swiss albino mice. Behavioral seizure monitoring, biochemical estimations, and histopathological examination were performed. The onset time of SE was significantly enhanced and % incidence of SE was reduced by intranasal administration of LET-NE as compared to KA and LET administered intraperitoneally. Biochemical estimations revealed that LET-NE effectively decreased levels of 17-β estradiol while the levels of 5α-Dihydrotestosterone (5α-DHT) and 3α-androstanediol (3α-Diol) were significantly increased in the hippocampus. In cresyl violet staining LET-NE showed better protection of the hippocampus from neurotoxicity induced by KA as compared to LET. Also, in gamma scintigraphy of mouse brain, intranasal administration of nanoemulsion exhibited the presence of high concentration of LET. The study demonstrates the anticonvulsant and neuroprotective effect of LET-NE probably by inhibition of aromatization of testosterone into 17-β estradiol, proconvulsant, and diverting the pathway into the synthesis of testosterone metabolites, 3α-Diol with known anticonvulsant and neuroprotective action. Brain targeting of LET-NE showed better anticonvulsant and neuroprotective action than LET.
Effects of androsterone on the protective action of various antiepileptic drugs against maximal electroshock-induced seizures in mice
2019, Psychoneuroendocrinology
This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg⁻¹) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg⁻¹) failed to change the threshold. AND at a subthreshold dose of 40 mg kg⁻¹ significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED₅₀) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg⁻¹ (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg⁻¹ (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg⁻¹ (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg⁻¹) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg⁻¹ failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.
Aromatase inhibition by letrozole attenuates kainic acid-induced seizures but not neurotoxicity in mice
2018, Epilepsy Research
Citation Excerpt :
Also, letrozole was previously reported inhibiting the testosterone-induced increase in PTZ seizure activity in mice (Reddy, 2004b). Clinically, letrozole has been shown to improve seizure control in a 61-year-old man with temporal lobe epilepsy (Harden and MacLusky, 2004, 2005). It suggests that letrozole should be further investigated as a beneficial treatment for male patients with epilepsy.
Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-β estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABA_A receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5α-reductase and indomethacin, a selective inhibitor of 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-β estradiol and elevated the levels of 5α-dihydrotestosterone (DHT) and 3α-Diol in the hippocampus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5α-DHT and 3α-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17β-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5α-DHT and 3α-Diol. Acute aromatase inhibition, thus, might be used as an adjuvant in the treatment of status epilepticus and can be pursued further.

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Case ReportAromatase inhibition, testosterone, and seizures

Abstract

Introduction

Section snippets

Case description

Discussion

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res. Brain Res. Rev.

Epilepsy Behav.

J. Steroid Biochem.

Horm. Behav.

Brain Res.

Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle

Acta Neurol. Scand.

Androgen modulates N-methyl-d-aspartate-mediated depolarization in CA1 hippocampal pyramidal cells

Synapse

Case Report
Aromatase inhibition, testosterone, and seizures