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Hormonal changes
related to epilepsy
D. Amado
Disciplina de Neurologia Experimental, Escola Paulista de
Medicina/Universidade
Federal
Pesquisa Albert Einstein, Brazil.
Abstract
Several studies have pointed to a great
influence of hormones in the epileptic phenomena (Scharfman & MacLusky, 2006; Herzog et al., 1986). Gonadal steroids have been shown to
exert both excitatory and inhibitory influences on hippocampal excitability and
plasticity (Joels, 1997; Kokate et al., 1999).
Accordingly to the experimental studies, limbic dysfunction might alter
hypothalamic tropic hormones release inducing ovulatory failure by affecting
the release of pituitary gonadotropins (Herzog et al., 1989, Amado et al.,
1993). In addition, the hormonal treatment is also able to stabilize the mossy
fibers sprouting process, showing the importance of these hormones in the
development of the epilepsy in female rats.
Besides that, with the increasing use of hormone and hormone antagonists
for contraceptives and the controversies about the use of replacement
therapies, it is essential understand of how steroid hormones may alter
hippocampal function.
Another hormone related to epilepsy is the
melatonin, synthesized by the pineal gland with major influence on several
circadian physiological activities (Reiter, 1986). In humans, melatonin has been considered to
act as anticonvulsant following the observation of its ability in reducing the
spiking activity and seizures frequency in patients with intractable epilepsy
(Anton-Tay, 1974). Animal studies indicate that pinealectomy interferes with
the epileptogenesis in the pilocarpine-model of epilepsy and that the pre- or
post-treatment with melatonin have an important neuroprotector effect in the
epileptogenesis and in the control of seizures during the chronic period of
this model (Lima and cols., 2005; 2006).
In resume, hormonal aspects must be considered
in patients with epilepsy.
Key words: epilepsy, hippocampus, reproductive
hormones, melatonin, pilocarpine and hormonal replacement therapy
Resumo
Vários estudos têm apontado para a grande influência dos hormônios no fenômeno epiléptico (Scharfman & MacLusky, 2006; Herzog et al., 1986). Esteróides gonadais exercem influências excitatórias e inibitórias na excitabilidade e plasticidade hipocampal (Joels, 1997; Kokate et al., 1999). De acordo com estudos experimentais, disfunção límbica pode alterar a liberação de hormônios tróficos hipotalâmicos induzindo falência ovariana por afetar a liberação de gonadotrofinas hipofisárias (Herzog et al., 1989, Amado et al., 1993). Além disso, o tratamento hormonal é também capaz de estabilizar o processo de brotamento de fibras musgosas, mostrando a importância destes hormônios no desenvolvimento da epilepsia em ratas fêmeas. Além disso, com o crescente uso de contraceptivos hormonais e as controvérsias sobre o uso de terapia de reposição hormonal, é essencial entender como os hormônios esteróides podem alterar a função hipocampal.
Outro hormônio relacionado com a epilepsia é a melatonina, sintetizada pela glândula pineal com principal influência em várias atividades fisiológicas circadianas (Reiter, 1986). Em humanos, a melatonina tem sido considerada atuar como anticonvulsivante seguindo a observação de sua habilidade em reduzir a atividade espicular e a frequência de crises em pacientes com epilepsia intratável (Anton-Tay, 1974). Estudos experimentais indicam que a pinealectomia interfere com a epileptogênese no modelo de epilepsia induzido por pilocarpina e que o pré- ou pós-tratamento com melatonina tem um importante efeito neuroprotetor na epileptogênese e no controle das crises durante o período crônico deste modelo (Lima and cols., 2005; 2006).
Em resumo, aspectos hormonais devem ser considerados em pacientes com epilepsia.
Unitermos: epilepsia, hipocampo, hormônios reprodutivos, melatonina, pilocarpina e reposição hormonal
Several studies have pointed to a great
influence of hormones in the epileptic phenomena (Scharfman & MacLusky,
2006; Diamantopoulos et al., 1986; Herzog et al., 1986; Wooley et al., 1992).
Endocrine and reproductive dysfunction are
commonly found in women with temporal lobe epilepsy such as, lower fertility
rate (Webber et al., 1986; Cummings et al., 1995), reduction of sexual desire
and arousal (Morrel et al., 1991), high incidence of menstrual abnormalities
(Roscizewska et al., 1986) and gynecological syndromes such as polycystic
ovaries, hypogonadotropic hypogonadism, oligomenorrhea and amenorrhea (Herzog
et al., 1986; Bilo et al.,
1988; Cramer et al., 1991; Isojärvi et al., 1993). Beside that, Morrel et al., (1999) related that
the incidence of sexual dysfunctions occurs in 14-66% of epileptic people and
about 20% of women during menopause present their first seizure.
Gonadal steroids have been shown to exert both
excitatory and inhibitory influences on hippocampal excitability and plasticity
(Joels, 1997; Herzog, 1999; Kokate et al., 1999). Although both biochemical and
physiological evidences exist supporting gonadal hormone modulation of
excitability in the hippocampus, the inconsistency of results obtained in past
studies makes difficult to draw clear conclusions on how the hormones affects
the hippocampal function. Besides that,
with the increasing use of hormone and hormone antagonists for contraceptives
and the controversies about the use of replacement therapies, it is essential
understand of how steroid hormones may alter hippocampal function.
Accordingly to the experimental studies, limbic
dysfunction might alter hypothalamic tropic hormones release inducing ovulatory
failure by affecting the release of pituitary gonadotropins (Herzog et al.,
1989, Amado et al., 1993) based to the fact of limbic cortex and the
hypothalamus are extensively interconnected (Stuenkel, 1991; Van de Poll,
1992). In addition, female rats submitted to different experimental models of
limbic seizures also presented reproductive and endocrine dysfunction (Herzog
et al., 1986; Cramer et al., 1991; Edwards, 1999; Amado et al., 1993,
1998).
It is interesting to observe previous studies
showing that sexual hormones protect the brain of female animals against
noxious conditions during the reproductive life (Mark et al., 1995; Sherwin and
Kaper, 1992; Genazzani et al., 1999; Chen et al, 1999, Abbasi, 1999), but the
mechanisms underlying the neuroprotection offered by sexual hormones are not
completely known. Some possibilities involve the action of ovarian hormones in
brain edema, reduction of free radicals and increase in BDNF mRNA expression
(Scharfman and cols., 2003).
The pilocarpine model of epilepsy was initially
described in male rats by Turski et al. (1983). This epilepsy model is
characterized by three different periods following systemic drug
administration: an acute period, characterized by limbic status epilepticus,
lasting 8-16 h; a silent period (lasting 4 to 44 days), which is characterized
by normal EEG and behavioral data and; by a chronic period, characterized by
the occurrence of spontaneous recurrent seizures. Amado and Cavalheiro (1998)
studying the establishment of this experimental model in female rats observed
that the oestrus cycle was dramatically altered during the acute period of
pilocarpine-induced status epilepticus.
This change was also observed in the other two periods of the
experimental model and was accompanied by decrease in progesterone, LH and FSH
levels and by an increase in the estradiol level (Amado and Cavalheiro, 1998).
When these chronically induced epileptic female rats were mated it was possible
to observe a decrease in the frequency of spontaneous seizures, during
pregnancy and lactation (Amado and Cavalheiro, 1998). These findings indicated that seizure
activity can alter gonadal, hypophyseal and hypothalamic hormone levels, and
thus contribute to alterations in sexual behaviour. It is likely, as well, that changes in
gonadal hormone levels feedback to influence the sequence of epileptic events
induced by
pilocarpine administration. In this sense, it is interesting to know if
the female brain acts in similar way in the pilocarpine model in the absence of
sexual hormones.
As previously described by Valente et al.
(2002) the castration in female rats decrease the latency for
pilocarpine-induced SE, increased the SE-related mortality and decreased the
latent period to spontaneous seizures. Concerning to seizure frequency, Valente
(2000) showed that only castration do not modify the pattern of seizures in the
chronic phase of the model. These
results suggest that female sexual hormones are protective against
pilocarpine-induced SE and that their removal could facilitate the
epileptogenesis in the early stages of this epilepsy model (Valente and cols.,
2002).
In order to understand the effect of sexual
hormones in the development of the epilepsy model induced by pilocarpine,
Valente (2005) studied different hormonal replacement treatment in castrated
epileptic female rats. The animals submitted to 17b -estradiol replacement
therapy did not show differences in seizure frequency. In contraposition, the
treatment with medroxiprogesterone reduced the seizure frequency as well as the
treatment with 17b -estradiol + medroxiprogesterone with a reduction more
expressive. These results are in accordance with previous data with a
anticonvulsant role of the progesterone in the epilepsy could reducing the
neuronal discharges (Smith et al., 1987), reducing the epileptiform discharges
and increasing the seizure threshold in several models of epilepsy (Wooley
& Timiras, 1962; Landgreen et al., 1987).
The mossy fiber sprouting measured by neo-Timm
scale (Tauck & Nadler, 1985) during the chronic period, reached grade 3 for
castrated epileptic rats while the non-castrated epileptic rats showed grade
2. So, conform seem by Valente and cols.
(2002), the castrated epileptic female rats present a more intense grade of
mossy fiber sprouting comparing to intact epileptic animals. However, animals
submitted to 17b- estradiol replacement presented an intermediary grade between
that seem in castrated epileptic female and intact epileptic female. In contraposition, in the groups receiving
17b- estradiol + medroxiprogesterone, the sprouting seems to be stabilized in
the same level observed in intact epileptic female, showing that the
development of sprouting did not progressed.
The same fact could be visualized in female treated with
medroxiprogesterone replacement (Valente, 2005).
These results indicate that castration interferes
with the epileptogenesis in the pilocarpine model of epilepsy suggesting that
female sexual hormones could have protective effects against
pilocarpine-induced SE.
The effect of synaptic sprouting in the
hippocampal function in the epilepsy depends in part, of the balance between
the new innervations of granule cells and inhibitory interneurones (Okasaki et
al., 1995). However, since there is
controversies concerning to hippocampal damage, if it’s a cause or consequence.
This point is interesting because in this study and in that previous study of
Valente et al (2002) we demonstrated that the castrated epileptic animals
presented a more intense grade of sprouting comparing to that showed in
non-castrated epileptic animals and the frequency seizures in both groups did
not show differences. Mattern et al.
(1995; 1996) did not find correlation between the mossy fiber sprouting and
seizure frequency and only correlated the density of sprouting (in animals and
human) with neuronal loss in the hilus of dentate gyrus. This data was confirmed by Pitkänen et al.
(2000) showing that the sprouting density was not associated with epilepsy
severity. Besides that, the sprouting
could be prevented by cicloheximide but the animals developing epilepsy (Longo
et al., 1997; 1998).
In addition to mossy fiber sprouting, the cell
loss in the hippocampus was observed in chronic phase of this model. A visible
cellular loss could be quantified in CA1 and CA3 and morphological changes in
the hippocampus with a cellular disarrangement and dispersion in the hilus of
the dentate gyrus could be visualized.
Although hippocampal cell loss was present in the animals submitted to
hormonal replacement, it was less pronounced (Valente, 2005). So, we could verify that the hormonal
replacement therapy in castrated animals is important in the epileptogenic
process, but its efficiency is dependent of the type reposition that the animal
is submitted.
So, the management of women with epilepsy
requires careful consideration of reproductive aspects can arise during each
phase of life and clinical and animal research with the relevant
endocrinological and neurobiological issues in mind, will help advance in this
field.
Another point related to hormones and epilepsy
is concerning to melatonin.
The occurrence of seizures in certain epileptic
syndromes and the periodicity of interictal epileptiform EEG activity seem to
be influenced by circadian variation (Silva and cols., 1984). Melatonin, a
hormone synthesized by the pineal gland with major influence on several
circadian physiological activities is maximally produced between midnight and
dawn (Reiter, 1986), with low levels during the light period. Furthermore,
melatonin has been described to act as anticonvulsant against chemically (Yehuda,
1993; Lapin, 1998; Yamamoto, 1996) and electrically (Albertson and cols, 1981;
Mevissen, 1998) induced seizures. In humans, melatonin has been considered to
act as anticonvulsant following the observation of its ability in reducing the
spiking activity and seizures frequency in patients with intractable epilepsy
(Anton-Tay, 1974). In addition, Peled et al (2001) observed that the
association of melatonin with antiepileptic drugs (AEDs) could decrease the
severity of tonic-clonic seizures in children.
In patients with temporal lobe epilepsy (Bazil and cols., 2000), low
levels of salivary melatonin were found during the interictal period when
compared to controls. On the other hand, high levels of salivary melatonin were
observed during the postictal period (Bazil and cols., 2000).
In vitro experiments have shown that melatonin
was able to protect neurons from excitotoxicity mediated by kainate-sensitive
glutamate receptors and from oxidative stress-induced DNA damage and apoptosis
(Wu and cols., 1999) and, in vivo, this hormone has been considered
neuroprotective against kainite-induced excitotoxicity (Uz and cols.,, 1996). Taken together, these data are consistent
with the hypothesis that melatonin has an inhibitory function on central
nervous system activity (Molina-Carballo and cols.,, 1994).
In this context, Chung and Han (2003) suggested that melatonin is a
hormone potentially useful in the treatment of acute brain pathologies
associated with oxidative stress-induced neuronal damage such as epilepsy,
stroke and traumatic brain injury. However, this idea is not widely accepted
since several authors did not found evidences that melatonin deficiency could
lead to increased brain vulnerability (Manev and cols., 1996).
One of the main characteristics of rats
submitted to the pilocarpine model of epilepsy (PME; Cavalheiro and cols.,
1991) is that the vast majority of spontaneous seizures observed during the
chronic period of the model occur during the day (Cavalheiro and cols., 1991;
Arida and cols., 1999).
In this context, Lima and cols (2005) clearly
indicate that pinealectomy interferes with the natural course of the
epileptogenesis in the pilocarpine-model of epilepsy (PME) in rats by reducing
the latency for the first spontaneous seizure (latent period) and increasing
the number of spontaneous seizures during the chronic period. Moreover, the
reintroduction
of melatonin during the status epilepticus
(acute) period was able to reduce the number of TUNEL-positive cells in several
limbic areas. In another study, the
pre- or post-treatment with melatonin and N-acetylserotonin showed that these
hormones have an important neuroprotector effect in the epileptogenesis and in
the control of seizures during the chronic period of the pilocarpine model of
epilepsy (Lima and cols., 2006).
These data are in accordance to others in
literature indicating the possibility that in future therapeutic attempts might
be conducted not only toward the use of pharmacological doses of melatonin, but
also to the pharmacological regulation of endogenous melatonin levels in
patients with epilepsy.
In resume, hormonal aspects must be considered
in patients with epilepsy.
Supported by CNPq, FAPESP, FADA and CAPES.
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