GnRH-immunoreactive fiber changes with unilateral amygdala-kindled seizures

doi:10.1016/S0920-1211(02)00196-1

Epilepsy Research

Volume 52, Issue 2, December 2002, Pages 73-77

https://doi.org/10.1016/S0920-1211(02)00196-1 Get rights and content

Abstract

Purpose: To assess whether unilateral amygdala seizures are associated with a change in the number and lateral distribution of gonadotropin releasing hormone (GnRH)-staining fibers in the ventromedial hypothalamus of female rats. Methods: The study compared three groups of female rats: (1) amygdala seizures induced by focal injection of kainic acid (KA); (2) saline injected controls; and (3) naı̈ve controls. The animals were sacrificed at 4 weeks in the diestrus phase. GnRH fibers were counted in the ventromedial hypothalamus and compared among groups. Results: GnRH fiber counts were significantly lower in KA than saline and naı̈ve animals ipsilaterally but not contralaterally. Conclusions: This finding may support a potential mechanism by which (1) temporolimbic epilepsy may promote the development of reproductive endocrine disorders and (2) the laterality of the epilepsy may influence the particular nature of the reproductive endocrine disorder.

Introduction

Reproductive dysfunction is unusually common among women with temporolimbic epilepsy (TLE) (Herzog and Friedman, 2002) and can usually be related to reproductive endocrine disorders (Herzog et al., 1986; Herzog, 1989, Herzog, 1997). Involvement of mesial temporolimbic structures with epileptiform discharges may disrupt the orderly pulsatile secretion of gonadotropin releasing hormone (GnRH) (Drislane et al., 1994; Herzog et al., 2000; Quigg et al., 2002). Altered hypothalamopituitary regulation of ovarian secretion may promote the development of reproductive endocrine disorders. Different reproductive endocrine disorders may be associated with unilateral left and right-sided foci (Herzog, 1993). Specifically, polycystic ovarian syndrome (PCOS) may occur more frequently with left lateral discharges. Hypothalamic amenorrhea (HA) may be more common with right lateral discharges.

The amygdala, a common site of involvement in TLE, has massive direct reciprocal anatomic connections with the ventromedial hypothalamus that is involved in the regulation, production and secretion of GnRH (Zolovick, 1972). Amygdala kindling can produce reproductive endocrine changes and disruption of the estrus cycle in female rats (Edwards et al., 1999). Disruption of the GnRH system may be a factor. Hypothalamic GnRH fiber staining is diminished in a pilocarpine model (Amado et al., 1993). Furthermore, unilateral amygdala kindling activates reproductive endocrine hypothalamic nuclei ipsilaterally more than contralaterally as suggested by fos staining in the female rat (Silveira et al., 2000). Since GnRH content and regulation of reproductive and sexual function differs between the left and right sides of the hypothalamus (Gerendai et al., 1978), laterally asymmetric activation of the reproductive neuroendocrine system by seizures may be a factor in the development of different reproductive endocrine disorders with left and right sided temprolimbic epilepsy.

The purpose of this investigation was to carry out a preliminary evaluation of this postulated mechanism. Specifically, this investigation assessed whether unilateral amygdala-induced seizures are associated with a change in the number and lateral distribution of GnRH-staining fibers in the ventromedial hypothalamus using a focal kainic acid (KA) injection female rat model of epilepsy. We chose to focus on the ventrolateral part of the ventromedial hypothalamic nucleus (VMHVL), a sexually dimorphic region that is known to be important in the regulation of reproductive function.

Section snippets

Methods

Twenty-two Sprague–Dawley adult female rats, weighing 220–300 g, were used in this study. Four microliters unilateral injections of kainic acid (0.5 μg/μl, ten animals) or saline (seven animals) were placed in the amygdala using the following stereotaxic coordinates (Paxinos and Watson, 1986): 2.8 mm posterior to the bregma, 5.0 mm lateral to the midline, and 8.2 mm below the skull.

Animals were observed for up to 4 h after the injection, and then periodically for 4 weeks. In the experimental

Results

Generalized convulsive seizures occurred in all experimental animals following KA injection but in none of the saline injected or naı̈ve control animals. Spontaneous recurrent seizures, consisting of motor arrest and staring episodes, were occasionally seen in the KA animals over the 4-week observation period. Unilateral amygdaloid lesions developed in all KA animals (Fig. 1, Fig. 2). There was no evidence on cresyl violet staining that the lesions in the KA animals were bilateral or

Discussion

Amado et al. reported a generalized yet selective reduction in the density of hypothalamic GnRH-immunoreactive fibers following intraperitoneal pilocarpine administration in a female rat epilepsy model. The density reduction was noted at two time intervals, 10–15 days and 60–90 days. Their study showed that GnRH fiber staining loss was quite selective following pilocarpine-induced seizures since galanin staining did not show a significant difference in the number and size of perikarya between

Acknowledgements

Supported by a Winokur Foundation Grant.

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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.
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It is noteworthy that both primary generalized [15] and focal onset [16] epilepsy can alter gonadotropin releasing hormone (GnRH) pulsatility. In focal onset epilepsy, moreover, there is a lateralized asymmetry in this modulation such that the directional change in pulse frequency relates to the laterality of the epileptic focus [16–18]. Since the development of normal GnRH pulsatility is a prerequisite for the establishment of menarche and ovulatory cycles, it is then possible that epilepsy may alter these processes.
To determine whether there is a relationship between the age of seizure onset and the age of menarche.
1144 women with epilepsy (WWE) in the community, ages 18–47 years, provided web-based survey data. We compared the frequencies of the individual differences between their ages of seizure onset and menarche to each other and chance. We determined whether the age of menarche is a predictor of the age of seizure onset and the percentage of the variance that menarche explains. We used two-step cluster analysis to auto-identify a cluster of years relative to the age of menarche that showed the greatest predilection for seizure onset.
Average age of menarche was 12.55 [95% CI: 12.45–12.65]. It was greater in WWE who developed seizures before versus after menarche (12.70 [12.54–12.86] v 12.42 [12.30–12.54], p = 0.006). More WWE had seizure onset during the year of menarche than during any other year (8.3% v expected 2.1%; p < 0.0001). Menarche, however, explained only 1% of the variance. Seizure onset frequencies were greatest for an auto-identified cluster that spanned 2 years before to 6 years after menarche and subsumed 49.3% of seizure onset.
Although the results indicate a significant relationship between the age of seizure onset and the age of menarche, the broader auto-identified perimenarchal cluster that subsumes 49.3% of seizure onset suggests that research target the potential role of the great increase in adrenarchal, as well as gonadarchal, neuroactive steroids that modulate neuronal excitability and seizures during that span.
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Sexuality is an important and private aspect of life and sexuality and epilepsy have been intimately linked since ancient time. Disturbances of reproductive and sexual health are common in men and women with epilepsy. Multiple causes may lead to sexual dysfunction. The basis for hyposexuality has been attributed to both epilepsy and antiepileptic drug use, making it difficult to distinguish between the illness-specific and pharmacologic impacts on sexual functioning. Low levels of androgens are associated with sexual arousal insufficiency and sexual dysfunction. Data from animal studies support the hypothesis that hyposexuality occurs as a result of epileptiform activity in the temporal lobe, but not in the motor cortex. Enzyme-inducing antiepileptic drugs are metabolized in the hepatic P 450 system (e.g., 3A4, 2C9, 2C19), induce hepatic enzymes, increase the hepatic synthesis of sex hormone-binding globulin (SHBG), and increase the metabolism of sex hormones that might have an additional influence on sexuality in patients with epilepsy. When examining sexual dysfunction in men and women with epilepsy, the Arizona Sexual Experience Scale may be helpful in evaluating sexual function. Laboratory tests for estrogen, free and total testosterone, and serum SHBG may also be useful in evaluating sexual health.
Neuroendocrine considerations in the treatment of men and women with epilepsy
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The GnRH-cell population is vulnerable to injury by seizures. In female rats with seizures induced by local injection of kainic acid into the amygdala, ipsilateral loss of GnRH-staining fibres in the hypothalamus was noted.27,28 Lateralisation of temporal lobe epilepsy seems to be associated with specific types of reproductive dysfunction.
Complex, multidirectional interactions between hormones, seizures, and the medications used to control them can present a challenge for clinicians treating patients with epilepsy. Many hormones act as neurosteroids, modulating brain excitability via direct binding sites. Thus, changes in endogenous or exogenous hormone levels can affect the occurrence of seizures directly as well as indirectly through pharmacokinetic effects that alter the concentrations of antiepileptic drugs. The underlying structural and physiological brain abnormalities of epilepsy and the metabolic activity of antiepileptic drugs can adversely affect hypothalamic and gonadal functioning. Knowledge of these complex interactions has increased and can now be incorporated in meaningful treatment approaches for men and women with epilepsy.
Pilocarpine-induced status epilepticus and subsequent spontaneous seizures: Lack of effect on the number of gonadotropin-releasing hormone-positive neurons in a mouse model of temporal lobe epilepsy
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The discrepancy in the data of the present study with those of Amado et al. (1993) and Friedman et al. (2002) may reflect methodological differences including, but not limited to, the procedures for preparation of the animal model of epilepsy, the GnRH antibody, the nature of the histopathological observations (e.g. axonal fibers vs. cell bodies), and the procedures for quantification of the data. For example, Friedman et al. (2002) quantified GnRH-positive fibers from two sections in one area of GnRH distribution (ventromedial hypothalamus), and Amado et al. (1993) quantified fibers from every third section. The focus on GnRH fibers and the lower sample numbers in the previous studies, compared with the present studies aimed primarily at counting neuronal cell bodies, may have resulted in false positives by Amado et al. (1993) and Friedman et al. (2002), owing to intra- and inter-animal variations in the distribution of GnRH neurons and fibers.
Women with temporal lobe epilepsy have a higher incidence of reproductive disorders, which have been linked to alterations in the pulsatile release of gonadotropin-releasing hormone (GnRH). These experiments tested the hypothesis that the number of GnRH neurons is reduced in an animal model of temporal lobe epilepsy. The effects of pilocarpine-induced status epilepticus (SE) and the subsequent spontaneous recurrent eizures on the number of GnRH-positive neurons were studied in adult female mice. Systemic injections of pilocarpine were used to induce SE, and diazepam was administered 90 min after the first seizure. Control mice received all drugs except pilocarpine. The mice were euthanized either 1 week or 3 months after SE (i.e. after spontaneous recurrent seizures were observed). Even though the estrous cycle was disrupted after SE, and hippocampal damage was detected in both the CA1 and CA3 regions, pilocarpine-treated mice did not show a significant decrease in total or regional numbers of GnRH-immunopositive neurons. Therefore, these data do not support the hypothesis that a reduction in the number of GnRH neurons is responsible for the disruption of the estrous cycle after pilocarpine-induced epilepsy, which suggests that other mechanisms contribute to female reproductive disorders associated with chronic epilepsy.
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Postictal increases in prolactin (PRL), luteinizing hormone, and follicle-stimulating hormone have been recorded in patients with both generalized tonic–clonic and partial seizures. Elevations of PRL and luteinizing hormone were seen immediately and at 20 minutes after generalized tonic–clonic seizures in male and female patients. Usually, PRL blood levels return to normal values within 1 hour. Previous studies have evaluated the utility of the transient increases in PRL, neuron-specific enolase, and S-100 protein as markers of epileptic seizures in children and adults. The conclusion was that measurement of serum PRL is a reliable confirmatory test in the presence of a seizure, but only modestly effective as a screening test for suspected seizures. Temporal lobe epilepsy is associated with abnormalities of reproductive physiology, but the mechanisms of hormonal dysregulation are not clear. A direct influence of epilepsy on the reproductive endocrine system is suggested by acute changes in PRL and gonadotropin levels following generalized and partial seizures, pointing to a possible relationship between temporolimbic epileptiform discharges and particular reproductive endocrine disorders. Chronic effects of the epileptic state and the acute impact of seizures could alter hypothalamic function, as indicated by downstream pulsatile secretion of luteinizing hormone. The brain controls reproductive function primarily through hypothalamic regulation of pituitary secretion regions of the hypothalamus. These are areas that are involved in the regulation, production, and secretion of gonadotropin-releasing hormone and receive extensive direct connections from the cerebral hemispheres, especially from temporolimbic structures, most notably from the amygdala, that are commonly involved in temporal lobe epilepsy. Significant relationships have been uncovered through which ictal and postictal effects of seizures and epilepsy may influence the function of this complex neuroendocrine system.

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GnRH-immunoreactive fiber changes with unilateral amygdala-kindled seizures

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

Epilepsy Res.

Brain Res.

Neurosci. Lett.

Neuroscience

Epilepsy Res.

Altered pulsatile secretion of luteinizing hormone in women with epilepsy

Neurology

A relationship between particular reproductive endocrine disorders and the laterality of epileptiform discharges in women with epilepsy

Neurology

Disorders of reproduction and fertility