hormonal therapy for epilepsy
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Hormonal Therapy for Epilepsy
Abstract In 2011, there are greater than 20 antiepileptic medications available. Thesemedications wor by mod!lating ne!ronal e"citability. #eprod!ctive hormones have
been fo!nd to have a role in the pathogenesis and treatment of sei$!res by also altering
ne!ronal e"citability, especially in women with catamenial epilepsy. The female
reprod!ctive hormones have in general opposing effects on ne!ronal e"citability%
estrogens generally impart a proconv!lsant ne!rophysiologic tone, whereas the
progestogens have anticonv!lsant effects. It follows then that fl!ct!ations in the levels of
ser!m progesterone and estrogen thro!gho!t a normal reprod!ctive cycle bring abo!t an
increased or decreased ris of sei$!re occ!rrence based !pon the ser!m
estradiol&progesterone ratio. Therefore, !sing progesterone, its metabolite
allopregnanolone, or other hormonal therapies have been e"plored in the treatment of
patients with epilepsy.
Introd!ction
'ver the past two decades, many antiepileptic dr!gs (AE)s* have been released for the
treatment of patients with epilepsy. Altho!gh these medications do not afford a c!re to
the patient with epilepsy or prevent epileptogenesis, they remain the most important
means of preventing sei$!res in the lives of the nearly + million people with epilepsy in
the nited -tates 1/. These medications attempt to mod!late ne!ronal e"citability to
prevent the rec!rrence of sei$!res in patients diagnosed with epilepsy.
It is important to note that endogeno!s reprod!ctive steroids have also been fo!nd to have
ne!roactive properties. This is especially tr!e in catamenial epilepsy, characteri$ed by
sei$!res that cl!ster at different times thro!gho!t the menstr!al cycle. Therefore, if
endogeno!s hormones can alter the occ!rrence of sei$!res, e"ogeno!s hormones may
also have the ability to alter ne!ronal e"citability and have a role in the treatment of
epilepsy. Altho!gh antiepileptic medications remain the mainstay of sei$!re therapy,
m!ch research has been cond!cted on the !tility of hormonal therapy for treating the
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patient with epilepsy.
atamenial Epilepsy and the enstr!al ycle
It is well nown that fl!ct!ations of the primary female reprod!ctive hormones, estrogen
and progesterone, over the co!rse of a normal menstr!al cycle change sei$!re
s!sceptibility in e"perimental models of epilepsy 2/. This cl!stering of sei$!res in
alignment with the female reprod!ctive cycle is nown as catamenial epilepsy. This
phenomenon is believed to occ!r secondary to the ne!roactive properties of endogeno!s
steroid hormones in combination with the nat!ral cyclic variation in their ser!m levels
thro!gho!t the menstr!al cycle +/.
The average menstr!al cycle is 23 days, with some fl!ct!ation being normal, and beginson the first day of menses. 'v!lation occ!rs on day 14, preceded by the follic!lar phase
d!ring days 1 thro!gh 1+. After the oocyte is released, the l!teal phase begins which has
a fairly invariant d!ration of 14 days, in which the dominant follicle forms the corp!s
l!te!m which releases progesterone. Th!s, ser!m progesterone, in a normal menstr!al
cycle, is higher d!ring the l!teal phase than the follic!lar phase, prior to rapidly
decreasing several days before menses.
The ratio of ser!m estradiol&progesterone has been shown to be lined to sei$!re
fre5!ency, with higher ratios leading to the cl!stering of sei$!res 4/. In the normal cycle,
this ratio is greatest d!ring the premenstr!al period and the days preceding ov!lation, and
is lowest d!ring the mid6l!teal phase. Two other st!dies have fo!nd a positive
relationship between sei$!re occ!rrence and a higher estrogen&progesterone ratio 7, 8/.
The premenstr!al rise in sei$!re fre5!ency has been tho!ght to be secondary to the rapid
withdrawal of progesterone, analogo!s to a ben$odia$epine withdrawal 4, 9/. The
increase in sei$!res d!ring the days preceding ov!lation is tho!ght to be secondary to the
rapid and steep rise in ser!m estradiol concentration, prior to the increase in ser!m
progesterone concentration that occ!rs at ov!lation 4, 9/. -ei$!res are least liely to
occ!r d!ring the mid6l!teal phase, d!ring which the ser!m progesterone levels are higher
than those of ser!m estradiol. The e"ception to this is anov!latory cycles, in which there
is still a rise in ser!m estrogen witho!t an increase in ser!m progesterone 9/. These
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relationships are shown in :ig. 1.
In women with abnormal follicle6stim!lating hormone (:-H* secretion, there is poor
development of the follicle with a poorly developed and f!nctioning corp!s l!te!m,
leading to a decreased prod!ction of progesterone. This phenomenon is nown as
inade5!ate l!teal phase (I;<*. Altho!gh I;< cycles may occ!r occasionally in normal
women, they may be ca!sed secondary to problems with the hypothalamic pit!itary a"is,
ovarian defects, or defects in l!teal cell steroidogenesis 3/. It has been shown that I;<
cycles occ!r more in women with epilepsy than in healthy control women =, 10/, which
is liely related to dysf!nction of inp!ts to the hypothalam!s from ictal and interictal
discharges. Estrogen prod!ction in not affected, leading to an increase in the estradiol&
progesterone ratio, and therefore increased sei$!re occ!r6 rence from days 10 to + of the
menstr!al cycle 9/.
Hormones and >e!ronal E"citability
There has been m!ch research on the role of hormones on ne!ronal e"citability in
molec!lar, animal, and clinical levels. Hormones can mod!late ne!ronal e"citability
thro!gh nongenomic direct membrane6mediated effects or receptor6mediated effects
thro!gh the indirect genomic pathway that reg!lates protein synthesis.
Estrogen wors thro!gh both nongenomic and genomic pathways, by binding to estrogen
receptors that are widely spread thro!gho!t the brain 11/. The nongenomic direct
pathway has on onset of effect within seconds with a short d!ration of action, whereas the
genomic pathway has a more prolonged onset with a long d!ration of action 11/. In
animal e"periments on rats, estrogens have been shown to have e"citatory ne!ronal
effects by facilitating indling and red!cing the threshold to electroconv!lsive shoc
12/, as well as increasing the severity of chemically ind!ced sei$!res 1+/. This is
tho!ght to be secondary to decreasing chloride cond!ction thro!gh the ?6aminob!tyric
acid (@AA*A6receptor comple" and the inhibition of @AA synthesis, an inhibitory
central ne!rotransmitter 14/. Estradiol also increases the ne!ronal response to gl!tamate,
an e"citatory central ne!rotransmitter 17/.
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Altho!gh estrogen has been fo!nd to have proconv!lsant properties, it has also been
fo!nd to have an anticonv!lsant effect as well. The dose, ro!te of administration, chronic
vers!s ac!te administration, and species of estrogen can determine if estrogen is
proconv!lsant or anticonv!lsant 18/. This data may be !sef!l in determining if estrogen
can be !sed as therapy in treating patients with epilepsy.
<rogesterone, the other maBor female reprod!ctive hormone, has also been shown to
effect ne!ronal e"citabil6 ity. nlie estrogen, which may decrease the cond!ction of
chloride at the @AAA6receptor comple", progesterone has been fo!nd to increased
chloride cond!ctance. This ca!ses a direct ne!ronal inhibitory effect 19/. ost of this
is a res!lt of the action of allopregnanolone, a ne!roactive metabolite of progesterone
19/. Allopregnanolone has a strong effect !pon @AAA receptors in the central
nervo!s system, similar to that of a potent ben$odia$epine and a tho!sand times stronger
than that of phenobarbital 19/. However, it has been fo!nd to bind to sites on @AA A
receptors, which are different than those for @AA, ben$odia$epines, and barbit!rates.
It is therefore believed that progesterone, mainly thro!gh its metabolites, has
anticonv!lsant properties. In contrast to estrogen, progesterone s!ppresses indling and
increases the sei$!re threshold 13/. In animals, progesterone has been fo!nd to increase
the electroconv!lsive shoc threshold and increase the threshold for chemically ind!ced
sei$!res 18/. It has also been shown that women with catamenial epilepsy have lower
ser!m levels of progesterone than healthy control patients d!ring similarly timed phases
of the menstr!al cycle 1=/. In fact, inhibition of progesterone metabolism has even been
shown in a case report to e"acerbate sei$!res in a patient with catamenial epilepsy 20/,
s!ggesting that the ac!te decrease of allopregnanolone in the premenstr!al phase may
decrease the inhibitory action of this metabolite and increase the chance of having a
sei$!re or cl!ster of sei$!res. The maBor effects of progesterone and estrogen within the
central nervo!s system are listed on Table 1.
Hormonal Therapy for the Treatment of Epilepsy
eca!se progesterone has mainly been shown to have anticonv!lsant effects, and
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estrogen for the most part has proconv!lsive actions, it can be hypothesi$ed that
progesterone, progesterone metabolites, or estrogen antagonists may be !sed in
conB!nction with c!rrent antiepileptic medications to treat patients with refractory
epilepsy.
<rogestogen Therapy
<rogestogen therapy incl!des both nat!rally occ!rring progesterone and synthetic
progestational agents. It can be !sed in two waysC 1* cyclically, in which it s!pplements
endogeno!s progesterone d!ring the l!teal phase and is withdrawn grad!ally prior to
menses, and 2* s!ppressive therapy, in which it is !sed to s!ppress the menstr!al cycle
19/. Her$og 21/ was the first to describe the !se of nat!ral progesterone as cyclic
therapy in the treatment of sei$!res. A pilot st!dy treated eight women with temporal
lobe epilepsy and I;< with vaginal s!ppositories of nat!ral progesterone d!ring the phase
of highest sei$!re fre5!ency. )oses were adB!sted to obtain ser!m progesterone levels
ranging from 7 to 27 ng&m; 2 to 8 h after dosing. This st!dy showed that monthly sei$!re
fre5!ency decreased by 83D d!ring the +6month treatment, and 97D of the women had
fewer sei$!res. -imilarly, a 1==7 st!dy by Her$og 22/ eval!ated 27 women with
temporal lobe epilepsy and a diagnosis of catamenial epilepsy treated with progesterone
lo$enges. Eleven of the women s!ffered from perimenstr!al sei$!re e"acerbation and 14women had inade5!ate l!teal6 phase or anov!latory cycles. 'ver a +6month period, 92D
of the women reported a decrease in sei$!re fre5!ency% the average daily fre5!ency
decreased by 77D. :ive women reported no change in the fre5!ency of their sei$!res, and
women with I;< were shown to have a slightly higher decrease in sei$!re fre5!ency
compared to those with perimenstr!al catamenial epilepsy. A +6year follow6!p showed a
mean focal sei$!re red!ction of 74D, with three of the women remaining sei$!re free
2+/. It was shown that progesterone was more effective when !sed from days 17 to 23 of
the menstr!al cycle with a grad!al taper at the end of the cycle, rather than B!st !sing it
premenstr!ally 22/. 'f note, these st!dies were not placebo6controlled or blinded and
had a small sample si$e, leaving room for f!rther investigation.
>at!ral progesterone, brand6name <rometri!m (Abbott ;aboratories, Abbott <ar, I;*, is
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available by prescription in 1006 and 2006mg tablets for gynecologic and obstetric !ses.
Altho!gh progesterone is not yet approved for !se in the treatment of sei$!res, it is clear
that nat!ral progesterone co!ld play an important role in women with catamenial
epilepsy. It has been !sed as on off6label treatment option for patients with catamenial
epilepsy, partic!larly in women with impaired l!teal phase cycles. It is !s!ally given
d!ring the l!teal phase at 1006 to 200 mg twice a day or three times a day, depending on
both the clinical response and&or the achievement of a midl!teal ser!m progesterone level
of 2040 ng&m;. It is grad!ally tapered off near the end of the reprod!ctive cycle.
An ongoing - >ational Instit!tes of Healthsponsored m!lticenter, prospective, do!ble6
blinded, randomi$ed, placebo6controlled investigation of the !se of progesterone
treatment for medically intractable sei$!res is !nderway. In this trial, patients were given
+ months of progesterone therapy after baseline, with open6label e"tension offered to all
patients. -everal h!ndred patients were enrolled at centers thro!gho!t the nation to
determine the effect of progesterone on sei$!re fre5!ency. The st!dy is still !ndergoing
analysis at this time, and the res!lts are not yet available.
-edation, weaness, and depression have been fo!nd to be the most common side effects
of progesterone therapy when st!died for !se in epileptic patients 21 2+/. However,
breast tenderness, vaginal bleeding, weight gain, and e"acerbation of asthma have also been reported. ;owering the dose or discontin!ing the therapy has been fo!nd to resolve
these iss!es 21 2+/. 'ther nown common side effects of progesterone in general
incl!de diarrhea, dry mo!th, edema, headache, gastroesophageal refl!" disease,
irritability, m!sc!lar pain, na!sea, cramping, acne, hirs!tism, and decreased libido.
-erio!s, rare side effects of progesterone therapy incl!de !rticaria, anaphyla"is, stroe,
retinal thrombosis, hyperlipidemia, and p!lmonary embolism.
edro"yprogesterone acetate (<A* is a synthetic contraceptive agent, containing only
progestin with an !nnown mechanism of action toward the red!ction of sei$!re
fre5!ency. It is inBected intram!sc!larly every 12 wees at a dose of 170 mg and inhibits
normal menstr!ation. Fhen given in doses large eno!gh to ca!se amenorrhea, st!dies
have shown that <A can red!ce sei$!re fre5!ency by +=D at a 16year follow6!p 24/.
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-t!died epileptic patients given intram!sc!lar <A were fo!nd to have side effects
similar to those enco!ntered with progesterone therapy, with the addition of increased
breathro!gh vaginal bleeding, delayed ret!rn to normal menses ranging from months to
years, and hot flashes 24/. to be performed prior to maing a B!dgment as to the benefits
and riss of !sing a @n#H analog!e in the treatment of patients with refractory epilepsy.
lomiphene and 'ral ontraceptive <ills
lomiphene is an ov!latory stim!lant that is !sed to treat infertility in women with
oligoanov!lation or anov!lation. It is an agonist&antagonist at the estrogen receptor that is
taen for 7 days beginning on the 7th day of the reprod!ctive cycle. A 1=33 st!dy by
Her$og 29/ fo!nd that in 10 of 12 women with refractory comple" partial epilepsy and
menstr!al disorders, the !se of clomiphene decreased sei$!res by 70D. The two women
who showed no improvement contin!ed to have prolonged irreg!lar cycles. Adverse side
effects have limited the !se of clomiphene for the treatment of women with epilepsy. It is
associated with the ovarian hyperstim!lation syndrome, which can present with
symptoms of na!sea, weight gain, bloating, and abdominal pain.
'ral contraceptive pills have been fo!nd in case reports to decrease sei$!re fre5!ency,
b!t have not yet been systemically st!died. However, they may be !sed in women with
epilepsy to prevent !nwanted high6ris pregnancies. Fhen !sed, it m!st be noted that
they are ind!cers of the <470 system and may decrease the effectiveness of antiepileptic
medications, which are hepatically metaboli$ed. A nonind!cing AE) sho!ld also be !sed
in combination with oral contraceptive pills when possible, to prevent against increased
metabolism and decreased contraceptive efficacy.
The aforementioned investigational hormonal therapies and their potential adverse side
effects are listed on Table 2.
@ana"olone
@ana"olone, a synthetic analog!e of allopregnanolone, is c!rrently !nder investigation
for the treatment of epilepsy. As previo!sly mentioned, positive mod!lation of the
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@onadotropin6#eleasing Hormone Analog!e Therapy
@onadotropin6releasing hormone (@n#H* is mainly man!fact!red in the preoptic area of
the hypothalam!s and acts to stim!late the secretion of the gonadotropins, :-H, and
l!teini$ing hormone (;H*, by binding to the respective receptors in the pit!itary gland
after being released in a p!lsatile fashion. Fhen @n#H is released contin!o!sly, in a
nonp!lsatile manner, its effects in ca!sing the release of ;H and :-H by the anterior
pit!itary are lost and ov!lation does not occ!r. y decreasing :-H and ;H prod!ction,
the contin!o!s release of @n#H creates a menopa!sal6type state, and can ca!se vaginal
dryness, dyspare!nia, and fl!shing 19/, which may be lessened with concomitant
estradiol and progesterone s!pplementation. ;ong6term side effects incl!de osteoporosis
and cardiovasc!lar disease.
Triptorelin, a @n#H analog!e, was st!died in 10 women with refractory perimenstr!al
sei$!res and amenorrhea 27/. It was given intram!sc!larly in a controlled6 release depot
preparation. The res!lts showed that three women reported sei$!re freedom, with an
additional fo!r having a red!ced sei$!re fre5!ency. This was liely secondary to the
decreased ;H and estrogen prod!ction res!lting from contin!o!s @n#H release. All of
the women e"perienced amenorrhea% eight of the women e"perienced side effects
(headaches, weight gain, or feeling fl!shed*.
@oserelin, another @n#H synthetic analog!e, was st!died in one woman with rec!rrent
catamenial episodes of stat!s epileptic!s 28/. The researchers fo!nd that her admissions
for stat!s epileptic!s decreased after administration of goserelin s!bc!taneo!sly every 4
wees.
Altho!gh the two aforementioned st!dies reported no increased sei$!re fre5!ency with
the !se of @n#H analog!es, Her$og 19/ fo!nd that women may e"perience a mared
e"acerbation of their sei$!res d!ring the first + wees of therapy, with a slight increase in
ovarian estradiol prod!ction prior to inhibition. :!rther st!dies need @AAA receptors
by allopregnanolone has anticonv!lsant effects. ;a"er et al. 23/ completed a m!lticenter,
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do!ble6 blind, randomi$ed, placebo6controlled monotherapy clinical trial that eval!ated
the safety, tolerability, and antiepileptic activity of gana"olone. The st!dy pop!lation
consisted of 72 inpatients with medically refractory comple" partial sei$!res who had
!ndergone complete withdrawal from all AE)s d!ring or after video6
electroencephalographic eval!ations to assess their s!itability for s!rgical intervention.
Each patient was st!died for !p to 3 days, with patients receiving placebo or gana"olone.
The primary meas!re of antiepileptic activity was the d!ration of treatment prior to
withdrawal from the st!dy. <atients were withdrawn from the st!dy at the occ!rrence of
one of the followingC fo!r sei$!res of any type (with the e"ception of simple partial
sei$!res*, three generali$ed tonic6clonic sei$!res, or stat!s epileptic!s. :ifty percent of
the gana"olone6treated patients completed the entire 36day st!dy, in comparison to 27D
of the placebo6treated individ!als. Tolerability of gana"olone was similar to that of
placebo.
An earlier clinical trial by Gerrigan et al. 2=/ was an open6label, add6on trial of the
anticonv!lsant activity of gana"olone in children with a history of infantile spasms. This
st!dy enrolled a total of 20 children, with 18 children completing the entire st!dy. sing
sei$!re diaries, spasm fre5!ency was monitored and ++D of those children completing
the trial showed a 70D red!ction in sei$!re fre5!ency, another third showing between a
27D and 70D red!ction in sei$!re fre5!ency, and the remaining third were non
responders.
A third st!dy by <ieribone et al. +0/ was a non6 randomi$ed, non6blinded, open6label,
dose6escalation trial of gana"olone in pediatric patients aged between 7 and 17 years of
age s!ffering from refractory epilepsy. It showed a moderate to s!bstantial decrease in
sei$!re fre5!ency in half of the st!died patients. All three of the aforementioned st!dies
showed a low side6effect profile, with somnolence being the most common reported
adverse reaction. <hase 1 and phase 2 st!dies of gana"olone in patients with infantile
spasms, women with catamenial epilepsy, and ad!lts with refractory partial6onset
sei$!res have had promising res!lts +1/.
Testosterone Therapy in en with Epilepsy
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Altho!gh m!ch of the research in hormonal therapy has foc!sed on women with
catamenial epilepsy, it is believed that treating hypogonadal epileptic men with
testosterone therapy co!ld decrease sei$!re fre5!ency. Androgens are converted in the
body into estrogens and 76red!ced androgens. As previo!sly mentioned, estrogen has
proconv!lsant potential. A recent report eval!ating chemically ind!ced sei$!res in rats
showed that blocing the conversion of testosterone to estrogen by !sing an aromatase
inhibitor increased sei$!re threshold +2/. In contrast, the 76red!ced androgens have
been fo!nd to have anticonv!lsant properties at the same receptor site of the @AA
receptor as allopregnanolone ++, +4/.
It has been shown that lower levels of testosterone and& or higher levels of estradiol may
have a direct correlation with se"!al dysf!nction and increased sei$!re fre5!ency in men
with epilepsy +7/. hronically low testosterone can lead to testic!lar fail!re and
hypergonadotropic hyopgonadism, which are both fo!nd in men with epilepsy. Her$og et
al. +7/ showed that testosterone normali$ation in men with hypogonadism statistically
elevated se"!al desire and f!nctioning. Therefore, testosterone levels sho!ld be
monitored in men with epilepsy complaining of se"!al dysf!nction that may in t!rn
benefit from testosterone s!pplementation with improved se"!al f!nction, increased
mood, and decreased sei$!re fre5!ency.
A combination of testosterone and an aromatase inhibitor may hypothetically be
beneficial in treating men with epilepsy and hypogonadism, by increasing free ser!m
testosterone levels and decreasing ser!m estradiol levels. The !se of aromatase inhibitors
in men with epilepsy has been shown to increase testosterone levels and possibly
decrease sei$!re fre5!ency, increase mood, and improve se"!al f!nctioning, b!t this
combination needs to be f!rther st!died prior to maing any definitive B!dgments abo!t
their role in clinical practice +8, +9/.
Hormone #eplacement Therapy in Epilepsy
A 1=== cross6sectional st!dy eval!ated the effect of menopa!se and perimenopa!se on
the co!rse of epilepsy +3/. The perimenopa!sal gro!p consisted of += perimenopa!sal
women with a history of epilepsy. >ine s!bBects reported no change in sei$!res at
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perimenopa!se, five reported a decrease in sei$!re fre5!ency, and 27 women reported an
increase in sei$!re fre5!ency. Twenty6eight women reported having a catamenial sei$!re
pattern before menopa!se, and eight s!bBects too synthetic hormone replacement
therapy (H#T*. A history of catamenial sei$!re pattern was significantly associated with
an increased sei$!re fre5!ency at perimenopa!se, b!t H#T had no significant effect on
sei$!res. The increase in sei$!re fre5!ency d!ring perimenopa!se is liely secondary to
the elevation of the estrogen&progesterone ratio d!ring this period.
The menopa!sal gro!p incl!ded 42 women who were nat!rally postmenopa!sal (1 year
witho!t menses* +3/. There was no overall directional change in sei$!re fre5!ency
within this gro!pC 12 women reported no change in sei$!re fre5!ency, 19 reported
decreased sei$!re fre5!ency, and 1+ had increased sei$!re fre5!ency. -i"teen of these
womenboth those with and those witho!t a history of catamenial epilepsytoo
synthetic H#T, which was fo!nd to have a positive correlation with sei$!re fre5!ency. 'f
note, almost all s!bBects were taing hepatic en$yme ind!cing AE)s. :ive women
started H#T in menopa!se and noted an immediate increase in sei$!re fre5!ency. ost
of the women taing H#T too an estrogen in combination with a synthetic progestin.
The aforementioned res!lts prompted f!rther investigation in the !se of H#T for
menopa!sal epileptic women. A do!ble6blind, randomi$ed, placebo6controlled trial was performed with three st!dy gro!psC women taing single6 dose combination H#T (0.827
mg of conB!gated e5!ine estrogens EE/ pl!s 2.7 mg of <A, or EE&<A* daily,
do!ble6dose EE&<A, or placebo +=/. :ive of seven s!bBects taing do!ble6dose
EE&<A had a worsening sei$!re fre5!ency, compared with fo!r of eight taing single6
dose EE&<A and one of si" taing placebo (<J 0.07*. Increased sei$!re fre5!ency was
associated with increasing the EE&<A dose. These res!lts s!ggest that EE&<A may
increase the fre5!ency of sei$!res in women with epilepsy, b!t this does not indicate that
there is a direct contraindication to H#T in these women. However, it does s!ggest that
EE&<A might not be the optim!m H#T in women with epilepsy. eca!se nat!ral
progesterone is nown to have active anticonv!lsant properties, perhaps a more
efficacio!s H#T regimen may incl!de nat!ral progesterone in addition to estrogen, rather
than the !se of a compo!nd containing <A.
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oncl!sions
Epilepsy is a common ne!rologic disorder that can be controlled, b!t not c!red with
medication. It has been shown that reprod!ctive hormones may play a role in the
pathophysiology of epilepsy, and therefore may play a role in the treatment of this
disorder.
There is rationale for !sing hormonal therapy based on the above information, and
progesterone therapy appears to offer the greatest promise. Fe are still awaiting the
res!lts of the recent, randomi$ed6controlled trial eval!ating the !se of nat!ral
progesterone in women with epilepsy. However, lie other available c!rrent therapies forepilepsy, hormonal therapies are not benign. They may bring abo!t !nwanted side effects
and riss, some of which may be associated with serio!s morbidity. :or e"ample, a recent
st!dy by helbowsi et al. 40/ fo!nd that H#T may have led to an increased ris of
breast cancer and a more aggressive form of breast cancer than in women who did not
receive H#T. eca!se this st!dy investigated the !se of combination agents (EE&<A*,
it cannot be inferred that all types of hormonal therapy (eg, progesterone6only therapy*
are dangero!s to !se in women with epilepsy. :!rther long6term prospective st!dies m!st
be performed on these agents before maing a concl!sive statement abo!t their safety in
epileptic patients.
At the c!rrent time, the initial treatment for patients with epilepsy remains the
conventional antiepileptic medications. Hormonal therapies have been fo!nd to have a
modest red!ction in sei$!re fre5!ency, b!t sho!ld not be !sed as first6line therapies when
agents with nown efficacy and safer side6effect profiles are available. Fhen !sed as
adB!nctive agents, hormonal therapies may have a place in the treatment of epilepsy, and
the choice and dose of the hormone is important. As with all treatments, the history and
needs of each individ!al patient will always need to be taen into acco!nt prior to maing
a decision as to whether or not to !se hormonal therapy for the treatment of his&her
sei$!re disorder.
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Hormonal Terapi !nt! Epilepsi
Abstra <ada tah!n 2011, terdapat lebih dari 20 obat antiepilepsi yang tersedia. 'bat6obat
ini beerBa dengan mod!lasi rangsangan saraf. Hormon reprod!si telah ditem!an
memilii peran dalam patogenesis dan pengobatan eBang dengan B!ga meng!bah
rangsangan saraf, ter!tama pada wanita dengan epilepsi catamenial.Hormon6hormon
reprod!si wanita memilii efe yang berlawanan !m!m pada rangsangan saraf, estrogen
!m!mnya memberian nada ne!rofisiologis proconv!lsant, sedangan progestogen
memilii efe antionv!lsan. aa em!dian bahwa fl!t!asi tingat progesteron dan
estrogen ser!m sel!r!h sil!s reprod!si yang normal membawa peningatan ata!
pen!r!nan risio terBadinya eBang berdasaran rasio ser!m estradiol & progesteron. 'leh
arena it!, dengan mengg!naan progesteron, allopregnanolone metabolit, ata! terapi
hormonal lainnya telah diesplorasi dalam pengobatan pasien dengan epilepsi.
<engantar
-elama d!a deade terahir, banya obat antiepilepsi (AE)* telah dirilis !nt!
pengobatan pasien dengan epilepsi. esip!n obat6obat ini tida mamp! obat !nt! pasien dengan epilepsi ata! mencegah epileptogenesis, merea tetap cara yang paling
penting !nt! mencegah eBang pada ehid!pan dari hampir + B!ta orang dengan epilepsi
di Ameria -eriat 1/. 'bat6obat ini ber!saha !nt! memod!lasi rangsangan saraf !nt!
mencegah ter!langnya eBang pada pasien yang didiagnosis dengan epilepsi.
<enting !nt! dicatat bahwa steroid reprod!si endogen B!ga telah fo !nd !nt! memilii
h!b!ngan yang tepat ne!roactive. Hal ini ter!tama berla! pada epilepsi catamenial,
ditandai dengan eBang yang mengelompo pada wat! yang berbeda selama sil!s
menstr!asi. 'leh arena it!, Bia hormon endogen dapat meng!bah terBadinya eBang,
hormon esogen m!ngin B!ga memilii emamp!an !nt! meng!bah rangsangan saraf
dan memilii peran dalam pengobatan epilepsi. esip!n obat antiepilepsi tetap menBadi
andalan terapi eBang, banya penelitian telah dila!an pada !tilitas terapi hormonal
!nt! mengobati pasien dengan epilepsi.
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Gatamenial Epilepsi dan -il!s enstr!asi
Hal ini B!ga dietah!i bahwa fl!t!asi !tama peremp!an hormon reprod!si, estrogen
dan progesteron, selama per!bahan sil!s menstr!asi eBang erentanan normal dalam
model esperimental epilepsi 2/. Ini pengelompoan eBang seBalan dengan sil!sreprod!si wanita yang dienal sebagai epilepsi catamenial. :enomena ini diyaini
terBadi se!nder terhadap sifat ne!roactive hormon steroid endogen dalam ombinasi
dengan variasi sili alami dalam ser!m merea sepanBang sil!s menstr!asi + /.
-il!s menstr!asi rata6rata adalah 23 hari, dengan beberapa fl!t!asi yang normal, dan
m!lai pada hari pertama menstr!asi. 'v!lasi terBadi pada hari e614, didah!l!i oleh fase
foli!ler selama hari6hari 1 sampai 1+. -etelah oosit dilepasan, fase l!teal dim!lai yang
memilii d!rasi yang c!!p invarian dari 14 hari, di mana foliel dominan membent!
orp!s l!te!m yang melepasan progesteron. )engan demiian, ser!m progesteron,dalam sil!s menstr!asi normal, lebih tinggi selama fase l!teal dibandingan fase
foli!ler, sebel!m cepat men!r!n beberapa hari sebel!m menstr!asi.
#asio ser!m estradiol & progesteron telah terb!ti dih!b!ngan dengan fre!ensi eBang,
dengan rasio yang lebih tinggi yang mengarah e pengelompoan eBang 4/.<ada sil!s
normal, rasio ini adalah yang terbesar selama periode pramenstr!asi dan hari6hari
menBelang ov!lasi, dan terendah selama fase mid6l!teal. )!a penelitian lain telah
menem!an h!b!ngan positif antara eBadian eBang dan lebih tinggi rasio estrogen &
progesteron 7, 8/. Genaian pramenstr!asi fre!ensi eBang telah dianggap se!nder
!nt! penarian cepat progesteron, analog dengan penarian ben$odia$epine 4,
9/. <eningatan eBang selama hari6hari menBelang ov!lasi dianggap se!nder !nt!
peningatan pesat dan c!ram onsentrasi estradiol ser!m, sebel!m peningatan
onsentrasi ser!m progesteron yang terBadi pada ov!lasi 4, 9/. GeBang yang paling
m!ngin terBadi selama fase mid6l!teal, di mana tingat progesteron ser!m yang lebih
tinggi dibandingan dengan ser!m estradiol.<engec!alian !nt! ini adalah sil!s
anov!lasi, di mana masih ada peningatan ser!m estrogen tanpa peningatan progesteron
ser!m 9/. H!b!ngan ini dit!nB!an pada @ambar. 1.
<ada wanita dengan normal follicle6stim!lating hormone (:-H* seresi, ada
perembangan yang b!r! dari foliel dengan !rang berembang dan berf!ngsi orp!s
l!te!m, yang mengarah e pen!r!nan prod!si progesteron. :enomena ini dienal
sebagai memadai fase l!teal (I;<*. esip!n sil!s I;< dapat terBadi adang6adang
pada wanita normal, merea m!ngin disebaban se!nder terhadap masalah dengan
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asis hipotalam!s pit!itary, ovari!m cacat, ata! cacat pada steroidogenesis sel
l!teal 3/. Telah terb!ti bahwa sil!s I;< terBadi lebih banya pada wanita dengan
epilepsi dibandingan pada wanita ontrol sehat =, 10/, yang m!ngin berh!b!ngan
dengan disf!ngsi inp!t e hipotalam!s dari ictal dan pemb!angan interital. <rod!si
estrogen dalam tida terpengar!h, yang menyebaban peningatan rasio estradiol &
progesteron, dan arena it! meningatan eBang terBadi6rence dari hari 106+ dari sil!s
menstr!asi 9/.
Hormon dan ne!ronal esitabilitas
Telah ada banya penelitian tentang peran hormon pada rangsangan saraf dalam mole!l,
hewan, dan linis tingat. Hormon dapat memod!lasi rangsangan saraf melal!i
nongenomic efe membran6dimediasi langs!ng ata! efe reseptor6dimediasi melal!i Bal!r
tida langs!ng genom yang mengat!r sintesis protein.
Estrogen beerBa melal!i ed!a Bal!r nongenomic dan genomi, dengan mengiat
reseptor estrogen yang banya tersebar di sel!r!h ota 11 /. Kal!r langs!ng nongenomic
memilii onset pada efe dalam hit!ngan deti dengan d!rasi singat tindaan,
sedangan Bal!r genom memilii onset yang lebih lama dengan d!rasi panBang
tindaan 11 /. <ada hewan percobaan pada ti!s, estrogen telah terb!ti memilii efe
saraf rangsang dengan memfasilitasi ay! baar dan meng!rangi th e ambang shoc
electroconv!lsive 12/, serta meningatan eparahan eBang secara imiawi 1+/. Hal ini
did!ga menBadi se!nder !nt! pen!r!nan lorida ond!si melal!i asam ?6aminob!tyric
(@AA* omples
A6reseptor
dan inhibiti pada sintesis @AA, s!at! ne!rotransmitter
inhibisi sentral 14/. Estradiol B!ga meningatan respon saraf !nt! gl!tamat, s!at!
ne!rotransmitter p!sat rangsang 17/.
esip!n estrogen telah ditem!an memilii sifat proconv!lsant, B!ga telah ditem!an
memilii efe antionv!lsan B!ga. )osis, r!te administrasi, ronis dibandingan
administrasi a!t, dan Benis estrogen dapat menent!an apaah estrogen proconv!lsant
ata! antionv!lsan 18 /. )ata ini m!ngin berg!na dalam menent!an apaah estrogendapat dig!naan sebagai terapi dalam mengobati pasien dengan epilepsi.
<rogesteron, hormon reprod!si wanita !tama lainnya, B!ga telah dit!nB!an !nt!
mempengar!hi saraf e"citabil6ity. Tida seperti estrogen, yang dapat men!r!nan
ond!si lorida di omples reseptor @AA
A6,
progesteron telah ditem!an !nt!
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meningatan ond!tansi lorida. Hal ini menyebaban saraf langs!ng efe
penghambatan 19 /. -ebagian besar ini adalah hasil dari tindaan allopregnanolone,
metabolit ne!roactive progesteron 19 /. Allopregnanolone memilii efe yang !at
pada reseptor @AA A
dalam sistem saraf p!sat, mirip dengan ben$odia$epin amp!h danserib! ali lebih !at dibandingan dengan fenobarbital 19 /.>am!n, telah ditem!an
!nt! mengiat e sit!s pada reseptor @AA
A,
yang berbeda dari yang !nt! @AA,
ben$odia$epine, dan barbit!rat.
'leh arena it! diyaini bahwa progesteron, ter!tama melal!i metabolitnya, memilii
sifat antionv!lsan. erbeda dengan estrogen, progesteron menean ay! baar dan
meningatan ambang eBang 13 /. <ada hewan, progesteron telah ditem!an !nt!
meningatan shoc ambang electroconv!lsive dan meningatan ambang batas !nt!
eBang secara imiawi 18 /. Hal ini B!ga telah men!nB!an bahwa wanita dengan
epilepsi catamenial memilii tingat ser!m rendah progesteron dibandingan pasien
ontrol sehat selama fase sama wat!nya sil!s menstr!asi 1=/. ahan, penghambatan
metabolisme progesteron bahan telah dit!nB!an dalam laporan as!s !nt!
memperb!r! eBang pada pasien dengan epilepsi catamenial 20/, men!nB!an bahwa
pen!r!nan a!t allopregnanolone dalam fase pramenstr!asi dapat men!r!nan tindaan
penghambatan metabolit ini dan meningatan em!nginan mengalami eBang ata!
seelompo eBang. Efe !tama progesteron dan estrogen dalam sistem saraf p!sat yang
tercant!m pada Tabel 1.
Terapi hormonal !nt! <engobatan Epilepsi
Garena progesteron ter!tama telah terb!ti memilii efe antionv!lsan, dan estrogen
!nt! sebagian besar memilii tindaan proconv!lsive, dapat dihipotesisan bahwa
progesteron, metabolit progesteron, ata! estrogen antagonis dapat dig!naan bersama
dengan obat antiepilepsi saat ini !nt! mengobati pasien dengan epilepsi refrater.
<rogestogen Therapy
Terapi progestogen menca!p alami progesteron dan agen progestasional sinteti. Hal ini
dapat dig!naan dalam d!a caraC 1* silis, di mana s!plemen progesteron endogen
selama fase l!teal dan ditari secara bertahap sebel!m menstr!asi, dan 2* terapi s!presif,
di mana ia dig!naan !nt! menean sil!s menstr!asi 19 /.Her$og 21/ adalah yang
pertama !nt! menggambaran pengg!naan progesteron alami sebagai terapi sili
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dalam pengobatan eBang. -eb!ah st!di pilot dirawat delapan wanita dengan epilepsi
lob!s temporalis dan I;< dengan s!positoria vagina progesteron alami selama fase
fre!ensi eBang tertinggi. )osis dises!aian !nt! memperoleh tingat progesteron
ser!m m!lai dari 7 sampai 27 ng & m; 2 sampai 8 Bam setelah dosis. -t!di ini
men!nB!an bahwa fre!ensi eBang b!lanan mengalami pen!r!nan sebesar 83D
selama perawatan + b!lan, dan 97D dari peremp!an memilii lebih sediit
eBang. )emiian p!la, tah!n 1==7 st!di oleh Her$og22/ mengeval!asi 27 wanita
dengan epilepsi lob!s temporalis dan diagnosis epilepsi catamenial diobati dengan
lo$enges progesteron. -ebelas wanita menderita eBang perimenstr!al esaserbasi dan 14
wanita memilii memadai l!teal6fase ata! sil!s anov!latoir. -elama periode + b!lan,
92D dari wanita melaporan pen!r!nan fre!ensi eBang, fre!ensi rata6rata harian
mengalami pen!r!nan sebesar 77D. ;ima peremp!an melaporan tida ada per!bahan
dalam fre!ensi eBang merea, dan wanita dengan I;< yang terb!ti memilii pen!r!nan sediit lebih tinggi fre!ensi eBang dibandingan dengan perimenstr!al
epilepsi catamenial. A +6tah!n tinda lanB!t men!nB!an pen!r!nan eBang foal rata6
rata 74D, dengan tiga dari sisa eBang wanita bebas 2+/. Hal ini men!nB!an bahwa
progesteron lebih efetif bila dig!naan dari hari 17623 dari sil!s menstr!asi dengan
lancip secara bertahap pada ahir sil!s, b!an hanya mengg!naannya
premenstr!ally 22/. )ari catatan, penelitian ini tida terontrol plasebo ata! dib!taan
dan memilii !!ran sampel yang ecil, meninggalan r!ang !nt! penyelidian lebih
lanB!t.
<rogesteron alami, mere6nama <rometri!m (Abbott ;aboratories, Abbott <ar, I;*,
tersedia dengan resep di 100 6 dan tablet 200 mg !nt! gineologi dan obstetri
pengg!naan. esip!n progesteron bel!m diset!B!i !nt! dig!naan dalam pengobatan
eBang, Belas bahwa progesteron alami dapat memainan peran penting pada wanita
dengan epilepsi catamenial. Telah dig!naan sebagai pilihan pengobatan pada off6label
!nt! pasien dengan epilepsi catamenial, ter!tama pada wanita dengan gangg!an sil!s
fase l!teal. Hal ini biasanya diberian selama fase l!teal pada 100 6 200 mg d!a ali
sehari ata! tiga ali sehari, tergant!ng pada ed!a respon linis dan & ata! pencapaian
tingat ser!m progesteron midl!teal 20640 ng & m;. Hal ini secara bertahap mer!ncing di
deat ahir dari sil!s reprod!si.
-eb!ah A- yang sedang berlangs!ng >ational Instit!tes of Health yang disponsori
m!lticenter, prospetif, b!ta ganda, aca, plasebo6terontrol penyelidian pengg!naan
pengobatan progesteron !nt! eBang medis terselesaian sedang berlangs!ng. )alam
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percobaan ini, pasien diberi + b!lan terapi progesteron setelah awal, dengan estensi
open6label ditawaran epada sem!a pasien. eberapa rat!s pasien yang terdaftar di
p!sat6p!sat di sel!r!h bangsa !nt! mengetah!i pengar!h progesteron pada fre!ensi
eBang. <enelitian ini masih menBalani analisis saat ini, dan hasilnya bel!m tersedia.
-edasi, elemahan, dan depresi telah ditem!an !nt! menBadi efe samping yang paling
!m!m dari terapi progesteron etia diteliti !nt! dig!naan pada pasien
epilepsi 21 6 2+/. >am!n, nyeri pay!dara, perdarahan vagina, berat badan, dan
esaserbasi asma B!ga telah dilaporan. en!r!nan dosis ata! penghentian terapi telah
ditem!an !nt! mengatasi masalah ini 21 6 2+/. )ietah!i efe samping !m!m lainnya
progesteron secara !m!m termas! diare, m!l!t ering, edema, sait epala, penyait
gastroesophageal refl!", leas marah, nyeri otot, m!al, ram, Berawat, hirs!tisme, dan
pen!r!nan libido. -eri!s, efe samping yang Barang progesteron rapy termas! !rtiaria,
anafilati la"is, stroe, retina throm bosis, hiperlipidemia, dan p!l emboli monary.
edro"yprogesterone acetate (<A* adalah agen ontrasepsi sinteti, mengand!ng
hanya progestin dengan meanisme yang tida dietah!i tindaan terhadap peng!rangan
fre!ensi eBang. Hal ini dis!ntian e dalam otot setiap 12 mingg! dengan dosis 170
mg dan menghambat menstr!asi normal. Getia diberian dalam dosis yang c!!p besar
!nt! menyebaban amenore, penelitian telah men!nB!an bahwa <A dapat
meng!rangi fre!ensi eBang sebesar +=D pada 1 tah!n follow6!p 24/.
<asien epilepsi yang diteliti diberian intram!s!lar <A ditem!an memilii efe
samping yang ser!pa dengan yang ditem!an dengan terapi progesteron, dengan
penambahan peningatan perdarahan vagina terobosan, tert!nda embali e menstr!asi
yang normal m!lai dari b!lan sampai tah!n, dan hot flashes 24/. har!s dila!an
sebel!m memb!at ep!t!san mengenai manfaat dan risio mengg!naan analog @n#H
dalam pengobatan pasien dengan epilepsi refrater.
lomiphene dan <il Gontrasepsi 'ral
lomiphene mer!paan stim!lan ov!lasi yang dig!naan !nt! mengobati infertilitas
pada wanita dengan oligoanov!lation ata! anov!lasi. Ini adalah agonis & antagonis pada
reseptor estrogen yang diambil selama 7 hari dim!lai pada hari e67 dari sil!s
reprod!si. -eb!ah st!di 1=33 oleh Her$og 29/ menem!an bahwa 10 dari 12 wanita
dengan epilepsi parsial refrater omples dan gangg!an menstr!asi, pengg!naan
clomiphene pen!r!nan eBang sebesar 70D. Ged!a wanita yang tida men!nB!an
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perbaian ter!s memilii sil!s yang tida terat!r berepanBangan. Efe samping telah
membatasi pengg!naan clomiphene !nt! pengobatan wanita dengan epilepsi. Hal ini
terait dengan sindrom hiperstim!lasi ovari!m, yang dapat hadir dengan geBala m!al,
penambahan berat badan, emb!ng, dan sait per!t.
<il ontrasepsi oral telah ditem!an dalam laporan as!s !nt! meng!rangi fre!ensi
eBang, tetapi bel!m dipelaBari secara sistemi. >am!n, merea dapat dig!naan pada
wanita dengan epilepsi !nt! mencegah yang tida diinginan ehamilan berisio
tinggi. Getia dig!naan, har!s dicatat bahwa merea adalah ind!ser dari sistem <470
dan dapat men!r!nan efetivitas obat antiepilepsi, yang hepatically metabo
li$ed. -eb!ah AE) nonind!cing B!ga har!s dig!naan dalam ombinasi dengan pil
ontrasepsi oral bila m!ngin, !nt! mencegah terhadap peningatan metabolisme dan
pen!r!nan emanB!ran ontrasepsi.
Terapi hormonal terseb!t diteliti dan potensi efe samping yang mer!gian merea
tercant!m pada Tabel 2.
@ana"olone
@ana"olone, analog sinteti dari allopregnanolone, saat ini sedang diselidii !nt!
pengobatan epilepsi. -eperti diseb!tan sebel!mnya, mod!lasi positif dari
@onadotropin6#eleasing Hormone Therapy Analog
@onadotropin6releasing hormone (@n#H* ter!tama diprod!si di daerah preoptic dari
hipotalam!s dan bertinda !nt! merangsang seresi gonadotropin, :-H, dan l!teini$ing
hormone (;H*, dengan mengiat reseptor masing6masing di elenBar hipofisis setelah
dirilis pada mode berdeny!t. Getia @n#H dilepasan ter!s mener!s, dengan cara
nonp!lsatile, efenya dalam menyebaban pelepasan ;H dan :-H oleh hipofisis anterior
hilang dan tida terBadi ov!lasi. )engan meng!rangi :-H dan ;H prod!si, rilis ter!s
mener!s @n#H menciptaan eadaan menopa!se6Benis, dan dapat menyebaban
eeringan vagina, dispare!nia, dan disiram 19 /, yang dapat di!rangi dengan
estradiol bersamaan dan s!plemen progesteron. Efe samping Banga panBang melip!ti
osteoporosis dan penyait ardiovas!lar.
Triptorelin, analog @n#H, dipelaBari dalam 10 wanita dengan refratori eBang p
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erimenstr!al dan amin orrhea 27/. It! diberian intram!s!ler dalam diendalian6
release persiapan depot. Hasil penelitian men!nB!an bahwa tiga wanita dilaporan
ebebasan eBang, dengan empat tambahan yang memilii fre!ensi eBang
ber!rang. Ini adalah aibat se!nder terhadap pen!r!nan ;H dan estrogen prod!si
yang dihasilan dari rilis @n#H ter!s mener!s. -em!a peremp!an mengalami amenore,
delapan wanita mengalami efe samping (sait epala, berat badan, ata! merasa
memerah*.
@oserelin, lain sinteti analog @n#H, dipelaBari dalam sat! wanita dengan episode
ber!lang catamenial stat!s epilepti!s 28/. <ara peneliti menem!an bahwa penerimaan
nya !nt! stat!s epilepti!s men!r!n setelah pemberian goserelin s!b!tan setiap 4
mingg!.
esip!n d!a st!di terseb!t melaporan tida ada peningatan fre!ensi eBang dengan pengg!naan @n#H analog, Her$og 19 / menem!an bahwa wanita m!ngin ence
pengalaman esaserbasi ditandai eBang merea selama + mingg! pertama terapi, dengan
sediit peningatan estradiol ovari!m prod!si sebel!m penghambatan. <enelitian lebih
lanB!t perl! reseptor @AA A dengan allopregnanolone memilii efe
antionv!lsan. ;onggar et al. 23/ menyelesaian m!lticenter, do!ble6blind, !Bi linis
aca, plasebo6terontrol monoterapi yang mengeval!asi eamanan, ditahan, dan ativitas
antiepilepsi dari gana"olone. <op!lasi penelitian terdiri dari 72 pasien rawat inap dengan
eBang parsial omples medis refratori yang telah menBalani penarian lengap dari
sem!a AE) selama ata! setelah eval!asi video eletroensefalografi !nt! menilai
eses!aian merea !nt! intervensi bedah. -etiap pasien dipelaBari hingga 3 hari, dengan
pasien yang menerima plasebo ata! gana"olone. !ran !tama ativitas antiepilepsi
adalah d!rasi pengobatan sebel!m penarian dari penelitian. <asien ditari dari st!di
pada terBadinya salah sat! dari beri!tC empat eBang dari setiap Benis (dengan
pengec!alian eBang parsial sederhana*, tiga eBang toni6loni !m!m, ata! stat!s
epilepti!s. ;ima p!l!h persen dari pasien yang diobati gana"olone menyelesaian st!di
36hari sel!r!h, dibandingan dengan 27D dari individ! yang diobati dengan
plasebo.Tolerabilitas gana"olone mirip dengan plasebo.
-eb!ah !Bi linis sebel!mnya oleh Gerrigan et al. 2=/ adalah seb!ah open6label, add6on
percobaan ativitas antionv!lsan dari gana"olone pada ana6ana dengan riwayat
eBang infantil. <enelitian ini mendaftaran total 20 ana6ana, dengan 18 ana6ana
menyelesaian sel!r!h st!di. engg!naan b!! harian eBang, fre!ensi eBang
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dipanta! dan ++D dari ana6ana menyelesaian persidangan men!nB!an peng!rangan
70D pada fre!ensi eBang, men!nB!an sepertiga lainnya antara 27D dan 70D
peng!rangan fre!ensi eBang, dan sepertiga sisanya adalah non responden.
-eb!ah st!di etiga dengan <ieribone et al. +0/ adalah, non6b!ta, open6label, sidangdosis esalasi non6aca dari gana"olone pada pasien ana yang ber!sia antara 7 dan 17
tah!n menderita epilepsi refrater. Ini men!nB!an moderat !nt! pen!r!nan s!bstansial
dalam fre!ensi eBang pada setengah dari pasien yang diteliti.Getiga st!di terseb!t
men!nB!an profil efe samping rendah, dengan mengant! menBadi reasi samping
yang paling !m!m dilaporan. Tahap 1 dan Tahap 2 st!di gana"olone pada pasien
dengan eBang infantil, wanita dengan epilepsi catamenial, dan orang dewasa dengan
refratori eBang parsial onset memilii hasil yang menBanBian +1/.
Testosteron Terapi di <ria dengan Epilepsi
esip!n banya penelitian dalam terapi hormonal telah difo!san pada wanita dengan
epilepsi catamenial, diyaini bahwa mengobati epilepsi pria hipogonadisme dengan terapi
testosteron bisa men!r!nan fre!ensi eBang. Androgen dionversi dalam t!b!h menBadi
estrogen dan androgen 76red!ced. -eperti diseb!tan sebel!mnya, estrogen memilii
potensi proconv!lsant. -eb!ah laporan ecent r mengeval!asi eBang yang diind!si
secara imia pada ti!s men!nB!an bahwa menghalangi onversi testosteron menBadi
estrogen dengan mengg!naan aromatase inhibitor peningatan ambang
eBang +2/. -ebalinya, androgen 76red!ced telah ditem!an memilii sifat anti
conv!lsant di sit!s reseptor yang sama dari reseptor @AA sebagai
allopregnanolone ++, +4/.
Telah men!nB!an bahwa tingat yang lebih rendah testosteron dan & ata! tingat yang
lebih tinggi estradiol m!ngin memilii orelasi langs!ng dengan disf!ngsi ses!al dan
meningatan fre!ensi eBang pada pria dengan epilepsi +7/. Testosteron rendah ronis
dapat menyebaban egagalan testis dan hypergonadotr opic hyopgonad ism, yang
ed!anya ditem!an pada pria dengan epilepsi. Her$og et al. +7/ men!nB!an bahwa
normalisasi testosteron pada pria dengan hipogonadisme statisti peningatan hasrat
ses!al dan f!ngsi. 'leh arena it!, testoster sat! tingat har!s mon itored pada pria
dengan epilepsi mengel!h disf!ngsi ses!al yang pada gilirannya manfaat dari s!plemen
testosteron dengan f!ngsi ses!al yang lebih bai, meningatan mood, dan pen!r!nan
fre!ensi eBang.
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Gombinasi testosteron dan aromatase inhibitor itor m!ngin hipotetis bermanfaat dalam
mengobati pria dengan epilepsi dan hipogonadisme, dengan meningatan adar ser!m
testosteron bebas dan men!r!nan tingat ser!m estradiol. <engg!naan inhibitor
aromatase pada pria dengan epilepsi telah terb!ti !nt! meningatan tingat
testosteron dan m!ngin meng!rangi fre!ensi eBang, meningatan mood, dan
meningatan f!ngsi ses!al, tapi ombinasi ini perl! diaBi lebih lanB!t sebel!m
memb!at ep!t!san definitif tentang peran merea dalam prate linis +8, +9/.
Hormone #eplacement Therapy di Epilepsi
-eb!ah st!di cross6sectional 1=== mengeval!asi efe menopa!se dan perimenopa!se
terhadap Balannya epilepsi +3/. Gelompo perimenopa!se terdiri dari += wanita
perimeno pa!sal dengan riwayat epilepsi. -embilan s!bye melaporan tida ada
per!bahan dalam serangan di perimenopa!se, lima melaporan pen!r!nan fre!ensieBang, dan 27 peremp!an melaporan peningatan fre!ensi eBang. )!a p!l!h delapan
wanita dilaporan memilii pola eBang catamenial sebel!m menopa!se, dan delapan
mata pelaBaran mengambil hormon sintetis terapi pengganti (H#T*. #iwayat pola eBang
catamenial secara bermana diaitan dengan fre!ensi eBang meningat pada
perimenopa!se, tapi H#T tida berpengar!h signifian terhadap eBang. <eningatan
fre!ensi eBang selama perimenopa!se m!ngin se!nder dari peningatan rasio
estrogen & progesteron selama periode ini.
Gelompo menopa!se termas! 42 peremp!an yang secara alami menopa!se (1 tah!n
tanpa menstr!asi* +3/. Tida ada per!bahan arah esel!r!han fre!ensi eBang dalam
elompo iniC 12 peremp!an melaporan tida ada per!bahan dalam fre!ensi eBang, 19
melaporan pen!r!nan fre!ensi eBang, dan 1+ mengalami peningatan fre!ensi
eBang. Enam belas dari wanita6bai yang dengan dan merea yang tida memilii
riwayat catamenial H#T sintetis epilepsi6mengambil, yang ditem!an memilii orelasi
positif dengan fre!ensi eBang. )ari catatan, hampir sem!a s!bBe mengambil hati AE)
en$im6merangsang. ;ima peremp!an m!lai H#T di menopa!se dan mencatat
peningatan langs!ng dalam fre!ensi eBang. -ebagian besar peremp!an yang
mengg!naan H#T mengambil estrogen dalam ombinasi dengan progestin sintetis.
Hasil terseb!t mendorong penyelidian lebih lanB!t dalam pengg!naan H#T !nt! wanita
epilepsi menopa!se. A, aca, plasebo6terontrol do!ble6blind dila!an dengan tiga
elompo st!diC wanita mengambil dosis t!nggal ombinasi H#T (0,827 mg estrogen
!da teronB!gasi EE/ ditambah 2,7 mg <A, ata! EE & <A* harian, do!ble6 dosis
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EE & <A, ata! plasebo +=/. ;ima dari t!B!h s!bye mengambil dosis ganda EE &
<A memilii fre!ensi eBang memb!r!, dibandingan dengan empat dari delapan
mengambil dosis t!nggal EE & <A dan salah sat! dari enam mengambil plasebo (< J
0,07*. <eningatan fre!ensi eBang diaitan dengan peningatan dosis EE &
<A. Hasil ini men!nB!an bahwa EE & <A dapat meningatan fre!ensi eBang
pada wanita dengan epilepsi, tapi ini tida men!nB!an bahwa ada ontraindiasi
langs!ng e H#T pada wanita6wanita. >am!n, it! men!nB!an bahwa EE & <A
m!ngin b!an H#T optim!m pada wanita dengan epilepsi. Garena progesteron alami
yang dienal memilii sifat antionv!lsan atif, m!ngin reBimen H#T lebih m!Barab
m!ngin termas! progesteron alami di samping estrogen, daripada pengg!naan senyawa
yang mengand!ng <A.
Gesimp!lan
Epilepsi adalah gangg!an ne!rologis !m!m yang dapat diendalian, tetapi tida semb!h
dengan obat6obatan. Telah terb!ti bahwa hormon reprod!si m!ngin memainan peran
dalam patofisiologi epilepsi, dan arena it! m!ngin memainan peran dalam
pengobatan gangg!an ini.
Ada pemiiran !nt! mengg!naan terapi hormonal berdasaran informasi di atas, dan
terapi progesteron m!nc!l !nt! menawaran BanBi terbesar. Gami masih men!ngg! hasil bar!6bar! ini, percobaan aca terontrol mengeval!asi pengg!naan progesteron alami
pada wanita dengan epilepsi. >am!n, seperti terapi saat ini tersedia lainnya !nt!
epilepsi, terapi hormonal tida Bina. erea m!ngin membawa efe samping yang
tida diinginan dan risio, beberapa di antaranya m!ngin berh!b!ngan dengan
morbiditas yang seri!s. -ebagai contoh, seb!ah penelitian terbar! oleh helbowsi et
al. 40 / menem!an bahwa H#T m!ngin telah menyebaban peningatan risio
aner pay!dara dan bent! yang lebih agresif dari aner pay!dara dibandingan pada
wanita yang tida menerima H#T.Garena st!di ini menyelidii pengg!naan agen
ombinasi (EE & <A*, tida dapat disimp!lan bahwa sem!a Benis terapi hormonal
(misalnya, progesteron6sat!nya terapi* berbahaya !nt! dig!naan pada wanita dengan
epilepsi. Kanga panBang prospetif <enelitian lebih lanB!t har!s dila!an pada agen ini
sebel!m memb!at pernyataan onl!sif tentang eselamatan merea pada pasien
epilepsi.
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<ada wat! saat ini, pengobatan awal !nt! pasien dengan epilepsi tetap obat antiepilepsi
onvensional. Terapi hormonal telah ditem!an memilii peng!rangan sederhana di
fre!ensi eBang, nam!n tida boleh dig!naan sebagai terapi lini pertama etia agen
dengan hasiat dienal dan profil efe samping yang lebih aman tersedia. Getia
dig!naan sebagai agen aB!van, terapi hormonal m!ngin memilii tempat dalam
pengobatan epilepsi, dan pilihan dan dosis hormon penting. -eperti dengan sem!a
perawatan, seBarah dan eb!t!han setiap pasien aan selal! perl! dipertimbangan
sebel!m memb!at ep!t!san apaah ata! tida !nt! mengg!naan terapi hormonal
!nt! pengobatan & gangg!an eBang nya.
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