The effect of seizures and kindling on reproductive hormones in the rat
Section snippets
Introduction: reproductive dysfunction in women and men with epilepsy
Reproductive dysfunction and endocrine disorders are unusually common among both women and men who have epilepsy, and in particular, temporal lobe epilepsy. Reduced fertility [94], diminished sexual desire [65] and diminished sexual responsiveness [66] have all been described.
In women with epilepsy, menstrual disorders are common. Clinical studies indicate that more than 50% of women with temporal lobe epilepsy have anovulatory cycles, irregular menstrual cycle length, amenorrhea,
The neural substrate of reproductive function—temporolimbic pathways
Reproductive dysfunction is more common in patients with temporal lobe epilepsy than in patients with generalized seizures or focal seizures originating in other parts of the brain [44]. This may relate to the extensive interconnections between the limbic structures of the temporal lobe and the hypothalamic nuclei, which govern the production and secretion of gonadotrophin releasing hormone (GnRH; [54]). The pulsatile release of GnRH secondarily controls the production and release of the
Reproductive dysfunction in women and men with temporal-lobe seizures—clinical studies
It is known that repeated seizures can induce long-lasting hyperactivity in neural pathways [2], [14], [76]. If so, repeated temporal-lobe seizures might be expected to produce changes in limbic-hypothalamic pathways, and, secondarily, in hormonal status.
The available clinical studies suggest that temporal-lobe seizures do alter gonadotropin secretion and that the effect may depend on drug therapy. Bilo et al. [11], for instance, have reported that drug-free epileptic women have higher LH pulse
Problems with clinical studies: drug effects
Medications in particular are known to have complex effects on reproductive hormones. Some drugs (e.g. phenytoin, barbiturates) increase the metabolic clearance of the gonadal steroids through induction of hepatic microsomal oxidative enzyme activity [73]. These drugs also increase concentrations of sex hormone-binding globulin, which binds circulating gonadal steroids [60], [82], [93]. The net result is a lower amount of free, biologically active hormone in the circulation which, in turn,
Effect of seizures on reproductive hormones in animals—ECS experiments
To date, most animal studies have involved electroconvulsive shock (ECS) seizures, which are primary generalized seizures, or kindled seizures, which are initially focal.
In female rats, studies with ECS have provided evidence that generalized seizures may interfere with reproductive hormones. In juvenile female rats, repeated ECS seizures delay the onset of puberty and the initiation of ovarian cyclicity [16]. They also attenuate the responsiveness of LH and FSH secretion to gonadal steroid
Effects of seizures on reproductive hormones—kindling experiments
Recent studies in our laboratory have also investigated the effects of repeated limbic seizures on reproductive function using the amygdala-kindling model. The kindling model is the best-known animal model of complex partial seizures, and involves repeated, brief electrical stimulations of the brain, usually limbic sites, via chronically implanted bipolar electrodes [55], [80]. At first, epileptiform afterdischarges are localized to the site of stimulation [80]. With repeated stimulations,
Could changes in reproductive hormones alter subsequent seizure susceptibility?
The above data suggest that repeated seizures may change reproductive hormone function. In turn, changes in sex steroid levels might enhance subsequent seizure susceptibility.
High-affinity receptors for sex steroids have been identified in many regions of the limbic system, including the amygdala and hippocampus [17], [88]. Estrogen and androgen receptors are highly concentrated in the amygdala, while progesterone and mineralocorticoid receptors are highly localized in the hippocampus [17], [79]
Could changes in reproductive hormones alter subsequent emotional status?
Since the reproductive hormones are known to affect mood and emotional behavior, seizure-induced alterations in hormonal status may also have an effect on emotion and mood [45].
Estrogen is generally considered to elevate mood. Depression, for instance, has been related to estrogen deficiency and has been effectively treated in some women with hormone replacement [53]. Excessive estrogen exposure, however, may also cause agitated depression or promote the development of anxiety syndromes (e.g.
Conclusions
Studies in animals support the hypothesis that seizures per se—independent of anticonvulsant medications—can induce abnormalities in the reproductive hormones. They suggest that reproductive dysfunction in patients with epilepsy—and in particular temporal lobe epilepsy—may reflect seizure-induced changes in the neuroendocrine regulation of gonadal function. Changes in hormone levels may also have effects on subsequent seizure susceptibility and on emotion and mood.
In the future, a better
Acknowledgements
The ECS and kindling studies were supported by grants from the Bloorview Childrens Hospital Foundation and the Bahen Family Foundation. We would like to acknowledge the assistance of Ms Alla Vilner and Mr David Bahn in the preparation of the manuscript.
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