Hormonal Therapy for Epilepsy

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Hormonal Therapy for Epilepsy

Abstract In 2011, there are greater than 20 antiepileptic medications available. These medications 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 Therefore, !sing based !pon the ser!m its metabolite estradiol&progesterone 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 ratio. progesterone,

allopregnanolone, or other hormonal therapies have been e"plored in the treatment of

patient with epilepsy. 0atamenial Epilepsy and the 1enstr!al 0ycle 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 .+22/. The average menstr!al cycle is 23 days, with some fl!ct!ation being normal, and begins on 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 lin ed 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 li ely 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 li ely 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$!re occ!r6 rence from days 10 to + of the menstr!al cycle .9/. Hormones and >e!ronal E"citability There has been m!ch research on the role of hormones on ne!ronal e"citability in molec!lar, animal, and clinical levels. Hormones can mod!late ne!ronal e"citability thro!gh nongenomic direct membrane6mediated effects or receptor6mediated effects thro!gh the indirect genomic pathway that reg!lates protein synthesis. Estrogen wor s thro!gh both nongenomic and genomic pathways, by binding to estrogen receptors that are widely spread thro!gho!t the brain .112/. The nongenomic direct pathway has on onset of effect within seconds with a short d!ration of action, whereas the genomic pathway has a more prolonged onset with a long d!ration of action .112/. In animal e"periments on rats, estrogens have been shown to have e"citatory ne!ronal effects by facilitating indling and red!cing the threshold to electroconv!lsive shoc .12/, as well as increasing the severity of chemically ind!ced sei$!res .1+/. This is tho!ght to be secondary to decreasing chloride cond!ction thro!gh the ?6aminob!tyric acid (@AAA*A6receptor comple" and the inhibition of @AAA 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 .182/. 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. ,nli e estrogen, which may decrease the cond!ction of chloride at the @AAAA6receptor comple", progesterone has been fo!nd to increased chloride cond!ctance. This ca!ses a direct ne!ronal inhibitory effect .1922/. 1ost of this is a res!lt of the action of allopregnanolone, a ne!roactive metabolite of progesterone .1922/. Allopregnanolone has a strong effect !pon @AAA A 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 .1922/. However, it has been fo!nd to bind to sites on @AAA A receptors, which are different than those for @AAA, 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$!re threshold .132/. In animals, progesterone has been fo!nd to increase the electroconv!lsive shoc threshold and increase the threshold for chemically ind!ced sei$!res .182/. 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 Aeca!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$ed that progesterone, progesterone metabolites, or estrogen antagonists may be !sed in conB!nction with c!rrent antiepileptic medications to treat patients with refractory epilepsy. <rogestogen Therapy <rogestogen therapy incl!des both nat!rally occ!rring progesterone and synthetic progestational agents. It can be !sed in two waysC 1* cyclically, in which it s!pplements endogeno!s progesterone d!ring the l!teal phase and is withdrawn grad!ally prior to menses, and 2* s!ppressive therapy, in which it is !sed to s!ppress the menstr!al cycle .1922/. Her$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$!re e"acerbation and 14 women had inade5!ate l!teal6 phase or anov!latory cycles. 'ver a +6month period, 92D of the women reported a decrease in sei$!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$!res, it is clear that nat!ral progesterone co!ld play an important role in women with catamenial epilepsy. It has been !sed as on off6label treatment option for patients with catamenial epilepsy, partic!larly in women with impaired l!teal phase cycles. It is !s!ally given d!ring the l!teal phase at 1006 to 200 mg twice a day or three times a day, depending on both the clinical response and&or the achievement of a midl!teal ser!m progesterone level of 20E40 ng&m;. It is grad!ally tapered off near the end of the reprod!ctive cycle. An ongoing ,- >ational Instit!tes of HealthEsponsored m!lticenter, prospective, do!ble6 blinded, randomi$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, wea ness, and depression have been fo!nd to be the most common side effects of progesterone therapy when st!died for !se in epileptic patients .21E2+/. 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 .21E2+/. '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, stro e, retinal thrombosis, hyperlipidemia, and p!lmonary embolism. 1edro"yprogesterone acetate (1<A* is a synthetic contraceptive agent, containing only progestin with an !n nown mechanism of action toward the red!ction of sei$!re fre5!ency. It is inBected intram!sc!larly every 12 wee s at a dose of 170 mg and inhibits normal menstr!ation. Fhen given in doses large eno!gh to ca!se amenorrhea, st!dies have shown that 1<A can red!ce sei$!re fre5!ency by +=D at a 16year follow6!p .24/.

-t!died epileptic patients given intram!sc!lar 1<A were fo!nd to have side effects similar to those enco!ntered with progesterone therapy, with the addition of increased brea thro!gh vaginal bleeding, delayed ret!rn to normal menses ranging from months to years, and hot flashes .24/. to be performed prior to ma ing a B!dgment as to the benefits and ris s of !sing a @n#H analog!e in the treatment of patients with refractory epilepsy. 0lomiphene and 'ral 0ontraceptive <ills 0lomiphene 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 ta en 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$ing hormone (;H*, by binding to the respective receptors in the pit!itary gland after being released in a p!lsatile fashion. Fhen @n#H is released contin!o!sly, in a nonp!lsatile manner, its effects in ca!sing the release of ;H and :-H by the anterior pit!itary are lost and ov!lation does not occ!r. Ay decreasing :-H and ;H prod!ction, the contin!o!s release of @n#H creates a menopa!sal6type state, and can ca!se vaginal dryness, dyspare!nia, and fl!shing .1922/, which may be lessened with concomitant estradiol and progesterone s!pplementation. ;ong6term side effects incl!de osteoporosis and cardiovasc!lar disease. Triptorelin, a @n#H analog!e, was st!died in 10 women with refractory perimenstr!al sei$!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 li ely 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 wee s. Altho!gh the two aforementioned st!dies reported no increased sei$!re fre5!ency with the !se of @n#H analog!es, Her$og .1922/ fo!nd that women may e"perience a mar ed e"acerbation of their sei$!res d!ring the first + wee s of therapy, with a slight increase in ovarian estradiol prod!ction prior to inhibition. :!rther st!dies need @AAA A 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 1en 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$!re fre5!ency. Androgens are converted in the body into estrogens and 7H6red!ced androgens. As previo!sly mentioned, estrogen has proconv!lsant potential. A recent report eval!ating chemically ind!ced sei$!res in rats showed that bloc ing the conversion of testosterone to estrogen by !sing an aromatase inhibitor increased sei$!re threshold .+2/. In contrast, the 7H6red!ced androgens have been fo!nd to have anticonv!lsant properties at the same receptor site of the @AAA receptor as allopregnanolone .++, +4/. It has been shown that lower levels of testosterone and& or higher levels of estradiol may have a direct correlation with se"!al dysf!nction and increased sei$!re fre5!ency in men with epilepsy .+7/. 0hronically 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 ma ing 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$!re fre5!ency d!ring perimenopa!se is li ely secondary to the elevation of the estrogen&progesterone ratio d!ring this period. The menopa!sal gro!p incl!ded 42 women who were nat!rally postmenopa!sal (1 year witho!t menses* .+3/. There was no overall directional change in sei$!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$!re fre5!ency. -i"teen of these womenIboth those with and those witho!t a history of catamenial epilepsyItoo synthetic H#T, which was fo!nd to have a positive correlation with sei$!re fre5!ency. 'f note, almost all s!bBects were ta ing hepatic en$ymeE ind!cing AE)s. :ive women started H#T in menopa!se and noted an immediate increase in sei$!re fre5!ency. 1ost of the women ta ing 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$ed, placebo6controlled trial was performed with three st!dy gro!psC women ta ing single6 dose combination H#T (0.827 mg of conB!gated e5!ine estrogens .0EE/ pl!s 2.7 mg of 1<A, or 0EE&1<A* daily, do!ble6dose 0EE&1<A, or placebo .+=/. :ive of seven s!bBects ta ing do!ble6dose 0EE&1<A had a worsening sei$!re fre5!ency, compared with fo!r of eight ta ing single6 dose 0EE&1<A and one of si" ta ing placebo (<J 0.07*. Increased sei$!re fre5!ency was associated with increasing the 0EE&1<A dose. These res!lts s!ggest that 0EE&1<A may increase the fre5!ency of sei$!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 0EE&1<A might not be the optim!m H#T in women with epilepsy. Aeca!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 1<A.

0oncl!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$ed6controlled trial eval!ating the !se of nat!ral progesterone in women with epilepsy. However, li e other available c!rrent therapies for epilepsy, hormonal therapies are not benign. They may bring abo!t !nwanted side effects and ris s, some of which may be associated with serio!s morbidity. :or e"ample, a recent st!dy by 0helbows i et al. .402/ fo!nd that H#T may have led to an increased ris of breast cancer and a more aggressive form of breast cancer than in women who did not receive H#T. Aeca!se this st!dy investigated the !se of combination agents (0EE&1<A*, it cannot be inferred that all types of hormonal therapy (eg, progesterone6only therapy* are dangero!s to !se in women with epilepsy. :!rther long6term prospective st!dies m!st be performed on these agents before ma ing a concl!sive statement abo!t their safety in epileptic patients. At the c!rrent time, the initial treatment for patients with epilepsy remains the conventional antiepileptic medications. Hormonal therapies have been fo!nd to have a modest red!ction in sei$!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 ta en into acco!nt prior to ma ing 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 be erBa dengan mod!lasi rangsangan saraf. Hormon reprod! si telah ditem! an memili i peran dalam patogenesis dan pengobatan eBang dengan B!ga meng!bah rangsangan saraf, ter!tama pada wanita dengan epilepsi catamenial.Hormon6hormon reprod! si wanita memili i efe yang berlawanan !m!m pada rangsangan saraf, estrogen !m!mnya memberi an nada ne!rofisiologis proconv!lsant, sedang an progestogen memili i efe anti onv!lsan. 1a a em!dian bahwa fl! t!asi ting at progesteron dan estrogen ser!m sel!r!h si l!s reprod! si yang normal membawa pening atan ata! pen!r!nan risi o terBadinya eBang berdasar an rasio ser!m estradiol & progesteron. 'leh arena it!, dengan mengg!na an progesteron, allopregnanolone metabolit, ata! terapi hormonal lainnya telah die splorasi dalam pengobatan pasien dengan epilepsi. <engantar -elama d!a de ade tera hir, banya obat antiepilepsi (AE)* telah dirilis !nt! pengobatan pasien dengan epilepsi. 1es ip!n obat6obat ini tida mamp! obat !nt! pasien dengan epilepsi ata! mencegah epileptogenesis, mere a tetap cara yang paling penting !nt! mencegah eBang pada ehid!pan dari hampir + B!ta orang dengan epilepsi di Ameri a -eri at .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! memili i h!b!ngan yang tepat ne!roactive. Hal ini ter!tama berla ! pada epilepsi catamenial, ditandai dengan eBang yang mengelompo pada wa t! yang berbeda selama si l!s menstr!asi. 'leh arena it!, Bi a hormon endogen dapat meng!bah terBadinya eBang, hormon e sogen m!ng in B!ga memili i emamp!an !nt! meng!bah rangsangan saraf dan memili i peran dalam pengobatan epilepsi. 1es ip!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 -i l!s 1enstr!asi Hal ini B!ga di etah!i bahwa fl! t!asi !tama peremp!an hormon reprod! si, estrogen dan progesteron, selama per!bahan si l!s menstr!asi eBang erentanan normal dalam model e sperimental epilepsi .2/. Ini pengelompo an eBang seBalan dengan si l!s reprod! si wanita yang di enal sebagai epilepsi catamenial. :enomena ini diya ini terBadi se !nder terhadap sifat ne!roactive hormon steroid endogen dalam ombinasi dengan variasi si li alami dalam ser!m mere a sepanBang si l!s menstr!asi .+ 2 2/. -i l!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 dilepas an, fase l!teal dim!lai yang memili i d!rasi yang c! !p invarian dari 14 hari, di mana foli el dominan membent! orp!s l!te!m yang melepas an progesteron. )engan demi ian, ser!m progesteron, dalam si l!s menstr!asi normal, lebih tinggi selama fase l!teal dibanding an 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!ng an dengan fre !ensi eBang, dengan rasio yang lebih tinggi yang mengarah e pengelompo an eBang .4/.<ada si l!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/. Genai an pramenstr!asi fre !ensi eBang telah dianggap se !nder !nt! penari an cepat progesteron, analog dengan penari an ben$odia$epine .4, 9/. <ening atan eBang selama hari6hari menBelang ov!lasi dianggap se !nder !nt! pening atan pesat dan c!ram onsentrasi estradiol ser!m, sebel!m pening atan onsentrasi ser!m progesteron yang terBadi pada ov!lasi .4, 9/. GeBang yang paling m!ng in terBadi selama fase mid6l!teal, di mana ting at progesteron ser!m yang lebih tinggi dibanding an dengan ser!m estradiol.<engec!alian !nt! ini adalah si l!s anov!lasi, di mana masih ada pening atan ser!m estrogen tanpa pening atan progesteron ser!m .9/. H!b!ngan ini dit!nB! an pada @ambar. 1. <ada wanita dengan normal follicle6stim!lating hormone (:-H* se resi, ada per embangan yang b!r! dari foli el dengan !rang ber embang dan berf!ngsi orp!s l!te!m, yang mengarah e pen!r!nan prod! si progesteron. :enomena ini di enal sebagai memadai fase l!teal (I;<*. 1es ip!n si l!s I;< dapat terBadi adang6 adang pada wanita normal, mere a m!ng in disebab an se !nder terhadap masalah dengan

a sis hipotalam!s pit!itary, ovari!m cacat, ata! cacat pada steroidogenesis sel l!teal .3/. Telah terb! ti bahwa si l!s I;< terBadi lebih banya pada wanita dengan epilepsi dibanding an pada wanita ontrol sehat .=, 10/, yang m!ng in berh!b!ngan dengan disf!ngsi inp!t e hipotalam!s dari ictal dan pemb!angan interi tal. <rod! si estrogen dalam tida terpengar!h, yang menyebab an pening atan rasio estradiol & progesteron, dan arena it! mening at an eBang terBadi6rence dari hari 106+ dari si l!s menstr!asi .9/. Hormon dan ne!ronal e sitabilitas Telah ada banya penelitian tentang peran hormon pada rangsangan saraf dalam mole !l, hewan, dan linis ting at. 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 be erBa melal!i ed!a Bal!r nongenomic dan genomi , dengan mengi at reseptor estrogen yang banya tersebar di sel!r!h ota .11 2/. Kal!r langs!ng nongenomic memili i onset pada efe dalam hit!ngan deti dengan d!rasi sing at tinda an, sedang an Bal!r genom memili i onset yang lebih lama dengan d!rasi panBang tinda an .11 2/. <ada hewan percobaan pada ti !s, estrogen telah terb! ti memili i efe saraf rangsang dengan memfasilitasi ay! ba ar dan meng!rangi th e ambang shoc electroconv!lsive .12/, serta mening at an eparahan eBang secara imiawi .1+/. Hal ini did!ga menBadi se !nder !nt! pen!r!nan lorida ond! si melal!i asam ?6aminob!tyric A6reseptor (@AAA* omple s dan inhibiti pada sintesis @AAA, s!at! ne!rotransmitter inhibisi sentral .14/. Estradiol B!ga mening at an respon saraf !nt! gl!tamat, s!at! ne!rotransmitter p!sat rangsang .17/. 1es ip!n estrogen telah ditem! an memili i sifat proconv!lsant, B!ga telah ditem! an memili i efe anti onv!lsan B!ga. )osis, r!te administrasi, ronis dibanding an administrasi a !t, dan Benis estrogen dapat menent! an apa ah estrogen proconv!lsant ata! anti onv!lsan .18 2/. )ata ini m!ng in berg!na dalam menent! an apa ah estrogen dapat dig!na an 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!n an A6, ond! si lorida di omple s reseptor @AAA progesteron telah ditem! an !nt!

mening at an ond! tansi lorida. Hal ini menyebab an saraf langs!ng efe penghambatan .19 2 2/. -ebagian besar ini adalah hasil dari tinda an allopregnanolone, metabolit ne!roactive progesteron .19 2 2/. Allopregnanolone memili i efe yang !at A pada reseptor @AAA dalam sistem saraf p!sat, mirip dengan ben$odia$epin amp!h dan serib! ali lebih !at dibanding an dengan fenobarbital .19 2 2/.>am!n, telah ditem! an A, !nt! mengi at e sit!s pada reseptor @AAA yang berbeda dari yang !nt! @AAA, ben$odia$epine, dan barbit!rat. 'leh arena it! diya ini bahwa progesteron, ter!tama melal!i metabolitnya, memili i sifat anti onv!lsan. Aerbeda dengan estrogen, progesteron mene an ay! ba ar dan mening at an ambang eBang .13 2/. <ada hewan, progesteron telah ditem! an !nt! mening at an shoc ambang electroconv!lsive dan mening at an ambang batas !nt! eBang secara imiawi .18 2/. Hal ini B!ga telah men!nB! an bahwa wanita dengan epilepsi catamenial memili i ting at ser!m rendah progesteron dibanding an pasien ontrol sehat selama fase sama wa t!nya si l!s menstr!asi .1=/. Aah an, penghambatan metabolisme progesteron bah an 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!n an tinda an penghambatan metabolit ini dan mening at an em!ng inan mengalami eBang ata! se elompo 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 memili i efe anti onv!lsan, dan estrogen !nt! sebagian besar memili i tinda an proconv!lsive, dapat dihipotesis an bahwa progesteron, metabolit progesteron, ata! estrogen antagonis dapat dig!na an bersama dengan obat antiepilepsi saat ini !nt! mengobati pasien dengan epilepsi refra ter. <rogestogen Therapy Terapi progestogen menca !p alami progesteron dan agen progestasional sinteti . Hal ini dapat dig!na an dalam d!a caraC 1* si lis, 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!na an !nt! mene an si l!s menstr!asi .19 2 2 /.Her$og .21/ adalah yang pertama !nt! menggambar an pengg!naan progesteron alami sebagai terapi si li

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!ai an !nt! memperoleh ting at 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 memili i lebih sedi it eBang. )emi ian p!la, tah!n 1==7 st!di oleh Her$og.22/ mengeval!asi 27 wanita dengan epilepsi lob!s temporalis dan diagnosis epilepsi catamenial diobati dengan lo$enges progesteron. -ebelas wanita menderita eBang perimenstr!al e saserbasi dan 14 wanita memili i memadai l!teal6fase ata! si l!s anov!latoir. -elama periode + b!lan, 92D dari wanita melapor an pen!r!nan fre !ensi eBang, fre !ensi rata6rata harian mengalami pen!r!nan sebesar 77D. ;ima peremp!an melapor an tida ada per!bahan dalam fre !ensi eBang mere a, dan wanita dengan I;< yang terb! ti memili i pen!r!nan sedi it lebih tinggi fre !ensi eBang dibanding an dengan perimenstr!al epilepsi catamenial. A +6tah!n tinda lanB!t men!nB! an pen!r!nan eBang fo al rata6 rata 74D, dengan tiga dari sisa eBang wanita bebas .2+/. Hal ini men!nB! an bahwa progesteron lebih efe tif bila dig!na an dari hari 17623 dari si l!s menstr!asi dengan lancip secara bertahap pada a hir si l!s, b! an hanya mengg!na annya premenstr!ally .22/. )ari catatan, penelitian ini tida ter ontrol plasebo ata! dib!ta an dan memili i ! !ran sampel yang ecil, meninggal an r!ang !nt! penyelidi an lebih lanB!t. <rogesteron alami, mere 6nama <rometri!m (Abbott ;aboratories, Abbott <ar , I;*, tersedia dengan resep di 100 6 dan tablet 200 mg !nt! gine ologi dan obstetri pengg!naan. 1es ip!n progesteron bel!m diset!B!i !nt! dig!na an dalam pengobatan eBang, Belas bahwa progesteron alami dapat memain an peran penting pada wanita dengan epilepsi catamenial. Telah dig!na an sebagai pilihan pengobatan pada off6label !nt! pasien dengan epilepsi catamenial, ter!tama pada wanita dengan gangg!an si l!s fase l!teal. Hal ini biasanya diberi an 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 ting at ser!m progesteron midl!teal 20640 ng & m;. Hal ini secara bertahap mer!ncing di de at a hir dari si l!s reprod! si. -eb!ah A- yang sedang berlangs!ng >ational Instit!tes of Health yang disponsori m!lticenter, prospe tif, b!ta ganda, aca , plasebo6ter ontrol penyelidi an pengg!naan pengobatan progesteron !nt! eBang medis terselesai an sedang berlangs!ng. )alam

percobaan ini, pasien diberi + b!lan terapi progesteron setelah awal, dengan e stensi open6label ditawar an epada sem!a pasien. Aeberapa 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 eti a diteliti !nt! dig!na an pada pasien epilepsi .21 6 2+/. >am!n, nyeri pay!dara, perdarahan vagina, berat badan, dan e saserbasi asma B!ga telah dilapor an. 1en!r!n an dosis ata! penghentian terapi telah ditem! an !nt! mengatasi masalah ini .21 6 2+/. )i etah!i efe samping !m!m lainnya progesteron secara !m!m termas! diare, m!l!t ering, edema, sa it epala, penya it gastroesophageal refl!", le as marah, nyeri otot, m!al, ram, Berawat, hirs!tisme, dan pen!r!nan libido. -eri!s, efe samping yang Barang progesteron rapy termas! !rti aria, anafila ti la"is, stro e, retina throm bosis, hiperlipidemia, dan p!l emboli monary. 1edro"yprogesterone acetate (1<A* adalah agen ontrasepsi sinteti , mengand!ng hanya progestin dengan me anisme yang tida di etah!i tinda an terhadap peng!rangan fre !ensi eBang. Hal ini dis!nti an e dalam otot setiap 12 mingg! dengan dosis 170 mg dan menghambat menstr!asi normal. Geti a diberi an dalam dosis yang c! !p besar !nt! menyebab an amenore, penelitian telah men!nB! an bahwa 1<A dapat meng!rangi fre !ensi eBang sebesar +=D pada 1 tah!n follow6!p .24/. <asien epilepsi yang diteliti diberi an intram!s !lar 1<A ditem! an memili i efe samping yang ser!pa dengan yang ditem! an dengan terapi progesteron, dengan penambahan pening atan 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 risi o mengg!na an analog @n#H dalam pengobatan pasien dengan epilepsi refra ter. 0lomiphene dan <il Gontrasepsi 'ral 0lomiphene mer!pa an stim!lan ov!lasi yang dig!na an !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 si l!s reprod! si. -eb!ah st!di 1=33 oleh Her$og .29/ menem! an bahwa 10 dari 12 wanita dengan epilepsi parsial refra ter omple s dan gangg!an menstr!asi, pengg!naan clomiphene pen!r!nan eBang sebesar 70D. Ged!a wanita yang tida men!nB! an

perbai an ter!s memili i si l!s yang tida terat!r ber epanBangan. Efe samping telah membatasi pengg!naan clomiphene !nt! pengobatan wanita dengan epilepsi. Hal ini ter ait dengan sindrom hiperstim!lasi ovari!m, yang dapat hadir dengan geBala m!al, penambahan berat badan, emb!ng, dan sa it 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, mere a dapat dig!na an pada wanita dengan epilepsi !nt! mencegah yang tida diingin an ehamilan berisi o tinggi. Geti a dig!na an, har!s dicatat bahwa mere a adalah ind!ser dari sistem <470 dan dapat men!r!n an efe tivitas obat antiepilepsi, yang hepatically metabo li$ed. -eb!ah AE) nonind!cing B!ga har!s dig!na an dalam ombinasi dengan pil ontrasepsi oral bila m!ng in, !nt! mencegah terhadap pening atan metabolisme dan pen!r!nan emanB!ran ontrasepsi. Terapi hormonal terseb!t diteliti dan potensi efe tercant!m pada Tabel 2. @ana"olone @ana"olone, analog sinteti dari allopregnanolone, saat ini sedang diselidi i !nt! pengobatan epilepsi. -eperti diseb!t an sebel!mnya, mod!lasi positif dari samping yang mer!gi an mere a

@onadotropin6#eleasing Hormone Therapy Analog @onadotropin6releasing hormone (@n#H* ter!tama diprod! si di daerah preoptic dari hipotalam!s dan bertinda !nt! merangsang se resi gonadotropin, :-H, dan l!teini$ing hormone (;H*, dengan mengi at reseptor masing6masing di elenBar hipofisis setelah dirilis pada mode berdeny!t. Geti a @n#H dilepas an ter!s mener!s, dengan cara nonp!lsatile, efe nya dalam menyebab an 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 mencipta an eadaan menopa!se6Benis, dan dapat menyebab an e eringan vagina, dispare!nia, dan disiram .19 2 2/, yang dapat di !rangi dengan estradiol bersamaan dan s!plemen progesteron. Efe samping Bang a panBang melip!ti osteoporosis dan penya it ardiovas !lar. Triptorelin, analog @n#H, dipelaBari dalam 10 wanita dengan refra tori eBang p

erimenstr!al dan amin orrhea .27/. It! diberi an intram!s !ler dalam di endali an6 release persiapan depot. Hasil penelitian men!nB! an bahwa tiga wanita dilapor an ebebasan eBang, dengan empat tambahan yang memili i fre !ensi eBang ber !rang. Ini adalah a ibat se !nder terhadap pen!r!nan ;H dan estrogen prod! si yang dihasil an dari rilis @n#H ter!s mener!s. -em!a peremp!an mengalami amenore, delapan wanita mengalami efe samping (sa it 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!. 1es ip!n d!a st!di terseb!t melapor an tida ada pening atan fre !ensi eBang dengan pengg!naan @n#H analog, Her$og .19 2 2/ menem! an bahwa wanita m!ng in ence pengalaman e saserbasi ditandai eBang mere a selama + mingg! pertama terapi, dengan sedi it pening atan estradiol ovari!m prod! si sebel!m penghambatan. <enelitian lebih A lanB!t perl! reseptor @AAA dengan allopregnanolone memili i efe anti onv!lsan. ;onggar et al. .23/ menyelesai an m!lticenter, do!ble6blind, !Bi linis aca , plasebo6ter ontrol monoterapi yang mengeval!asi eamanan, ditahan, dan a tivitas antiepilepsi dari gana"olone. <op!lasi penelitian terdiri dari 72 pasien rawat inap dengan eBang parsial omple s medis refra tori yang telah menBalani penari an leng ap dari sem!a AE) selama ata! setelah eval!asi video ele troensefalografi !nt! menilai eses!aian mere a !nt! intervensi bedah. -etiap pasien dipelaBari hingga 3 hari, dengan pasien yang menerima plasebo ata! gana"olone. , !ran !tama a tivitas antiepilepsi adalah d!rasi pengobatan sebel!m penari an 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 toni 6 loni !m!m, ata! stat!s epilepti !s. ;ima p!l!h persen dari pasien yang diobati gana"olone menyelesai an st!di 36hari sel!r!h, dibanding an 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 a tivitas anti onv!lsan dari gana"olone pada ana 6ana dengan riwayat eBang infantil. <enelitian ini mendaftar an total 20 ana 6ana , dengan 18 ana 6ana menyelesai an sel!r!h st!di. 1engg!na an b! ! harian eBang, fre !ensi eBang

dipanta! dan ++D dari ana 6ana menyelesai an 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, sidang dosis es alasi non6aca dari gana"olone pada pasien ana yang ber!sia antara 7 dan 17 tah!n menderita epilepsi refra ter. 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 rea si samping yang paling !m!m dilapor an. Tahap 1 dan Tahap 2 st!di gana"olone pada pasien dengan eBang infantil, wanita dengan epilepsi catamenial, dan orang dewasa dengan refra tori eBang parsial onset memili i hasil yang menBanBi an .+1/. Testosteron Terapi di <ria dengan Epilepsi 1es ip!n banya penelitian dalam terapi hormonal telah difo !s an pada wanita dengan epilepsi catamenial, diya ini bahwa mengobati epilepsi pria hipogonadisme dengan terapi testosteron bisa men!r!n an fre !ensi eBang. Androgen di onversi dalam t!b!h menBadi estrogen dan androgen 7H6red!ced. -eperti diseb!t an sebel!mnya, estrogen memili i 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!na an aromatase inhibitor pening atan ambang eBang .+2/. -ebali nya, androgen 7H6red!ced telah ditem! an memili i sifat anti conv!lsant di sit!s reseptor yang sama dari reseptor @AAA sebagai allopregnanolone .++, +4/. Telah men!nB! an bahwa ting at yang lebih rendah testosteron dan & ata! ting at yang lebih tinggi estradiol m!ng in memili i orelasi langs!ng dengan disf!ngsi se s!al dan mening at an fre !ensi eBang pada pria dengan epilepsi .+7/. Testosteron rendah ronis dapat menyebab an 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 pening atan hasrat se s!al dan f!ngsi. 'leh arena it!, testoster sat! ting at har!s mon itored pada pria dengan epilepsi mengel!h disf!ngsi se s!al yang pada gilirannya manfaat dari s!plemen testosteron dengan f!ngsi se s!al yang lebih bai , mening at an mood, dan pen!r!nan fre !ensi eBang.

Gombinasi testosteron dan aromatase inhibitor itor m!ng in hipotetis bermanfaat dalam mengobati pria dengan epilepsi dan hipogonadisme, dengan mening at an adar ser!m testosteron bebas dan men!r!n an ting at ser!m estradiol. <engg!naan inhibitor aromatase pada pria dengan epilepsi telah terb! ti !nt! mening at an ting at testosteron dan m!ng in meng!rangi fre !ensi eBang, mening at an mood, dan mening at an f!ngsi se s!al, tapi ombinasi ini perl! di aBi lebih lanB!t sebel!m memb!at ep!t!san definitif tentang peran mere a dalam pra te 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 melapor an tida ada per!bahan dalam serangan di perimenopa!se, lima melapor an pen!r!nan fre !ensi eBang, dan 27 peremp!an melapor an pening atan fre !ensi eBang. )!a p!l!h delapan wanita dilapor an memili i pola eBang catamenial sebel!m menopa!se, dan delapan mata pelaBaran mengambil hormon sintetis terapi pengganti (H#T*. #iwayat pola eBang catamenial secara berma na di ait an dengan fre !ensi eBang mening at pada perimenopa!se, tapi H#T tida berpengar!h signifi an terhadap eBang. <ening atan fre !ensi eBang selama perimenopa!se m!ng in se !nder dari pening atan 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 melapor an tida ada per!bahan dalam fre !ensi eBang, 19 melapor an pen!r!nan fre !ensi eBang, dan 1+ mengalami pening atan fre !ensi eBang. Enam belas dari wanita6bai yang dengan dan mere a yang tida memili i riwayat catamenial H#T sintetis epilepsi6mengambil, yang ditem! an memili i 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 pening atan langs!ng dalam fre !ensi eBang. -ebagian besar peremp!an yang mengg!na an H#T mengambil estrogen dalam ombinasi dengan progestin sintetis. Hasil terseb!t mendorong penyelidi an lebih lanB!t dalam pengg!naan H#T !nt! wanita epilepsi menopa!se. A, aca , plasebo6ter ontrol do!ble6blind dila ! an dengan tiga elompo st!diC wanita mengambil dosis t!nggal ombinasi H#T (0,827 mg estrogen !da ter onB!gasi .0EE/ ditambah 2,7 mg 1<A, ata! 0EE & 1<A* harian, do!ble6 dosis

0EE & 1<A, ata! plasebo .+=/. ;ima dari t!B!h s!bye mengambil dosis ganda 0EE & 1<A memili i fre !ensi eBang memb!r! , dibanding an dengan empat dari delapan mengambil dosis t!nggal 0EE & 1<A dan salah sat! dari enam mengambil plasebo (< J 0,07*. <ening atan fre !ensi eBang di ait an dengan pening atan dosis 0EE & 1<A. Hasil ini men!nB! an bahwa 0EE & 1<A dapat mening at an fre !ensi eBang pada wanita dengan epilepsi, tapi ini tida men!nB! an bahwa ada ontraindi asi langs!ng e H#T pada wanita6wanita. >am!n, it! men!nB! an bahwa 0EE & 1<A m!ng in b! an H#T optim!m pada wanita dengan epilepsi. Garena progesteron alami yang di enal memili i sifat anti onv!lsan a tif, m!ng in reBimen H#T lebih m!Barab m!ng in termas! progesteron alami di samping estrogen, daripada pengg!naan senyawa yang mengand!ng 1<A.

Gesimp!lan Epilepsi adalah gangg!an ne!rologis !m!m yang dapat di endali an, tetapi tida semb!h dengan obat6obatan. Telah terb! ti bahwa hormon reprod! si m!ng in memain an peran dalam patofisiologi epilepsi, dan arena it! m!ng in memain an peran dalam pengobatan gangg!an ini. Ada pemi iran !nt! mengg!na an terapi hormonal berdasar an informasi di atas, dan terapi progesteron m!nc!l !nt! menawar an BanBi terbesar. Gami masih men!ngg! hasil bar!6bar! ini, percobaan aca ter ontrol mengeval!asi pengg!naan progesteron alami pada wanita dengan epilepsi. >am!n, seperti terapi saat ini tersedia lainnya !nt! epilepsi, terapi hormonal tida Bina . 1ere a m!ng in membawa efe samping yang tida diingin an dan risi o, beberapa di antaranya m!ng in berh!b!ngan dengan morbiditas yang seri!s. -ebagai contoh, seb!ah penelitian terbar! oleh 0helbows i et al. .40 2/ menem! an bahwa H#T m!ng in telah menyebab an pening atan risi o an er pay!dara dan bent! yang lebih agresif dari an er pay!dara dibanding an pada wanita yang tida menerima H#T.Garena st!di ini menyelidi i pengg!naan agen ombinasi (0EE & 1<A*, tida dapat disimp!l an bahwa sem!a Benis terapi hormonal (misalnya, progesteron6sat!nya terapi* berbahaya !nt! dig!na an pada wanita dengan epilepsi. Kang a panBang prospe tif <enelitian lebih lanB!t har!s dila ! an pada agen ini sebel!m memb!at pernyataan on l!sif tentang eselamatan mere a pada pasien epilepsi.

<ada wa t! saat ini, pengobatan awal !nt! pasien dengan epilepsi tetap obat antiepilepsi onvensional. Terapi hormonal telah ditem! an memili i peng!rangan sederhana di fre !ensi eBang, nam!n tida boleh dig!na an sebagai terapi lini pertama eti a agen dengan hasiat di enal dan profil efe samping yang lebih aman tersedia. Geti a dig!na an sebagai agen aB!van, terapi hormonal m!ng in memili i tempat dalam pengobatan epilepsi, dan pilihan dan dosis hormon penting. -eperti dengan sem!a perawatan, seBarah dan eb!t!han setiap pasien a an selal! perl! dipertimbang an sebel!m memb!at ep!t!san apa ah ata! tida !nt! mengg!na an terapi hormonal !nt! pengobatan & gangg!an eBang nya.

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