hormonal therapy for epilepsy

8/13/2019 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



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



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/.



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



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



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/.



-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



@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,



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



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



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.



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.



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.



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



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!



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



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



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



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



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



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.



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



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.



<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.

hormonal therapy for epilepsy

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