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Editorial

Editorial

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Published by clarajimena25
Previous studies have described an association between
epilepsy and features of the polycystic ovarian syndrome
(PCOS) among women receiving treatment with antiepileptic
drugs (AEDs), including valproic acid (VPA) (1–5).
Previous studies have described an association between
epilepsy and features of the polycystic ovarian syndrome
(PCOS) among women receiving treatment with antiepileptic
drugs (AEDs), including valproic acid (VPA) (1–5).

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Published by: clarajimena25 on Jun 13, 2010
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05/22/2012

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J. Clin. Endocrinol. Metab. 2001 86: 2946-2949, doi: 10.1210/jc.86.7.2946Hadine Joffe, Ann E. Taylor and Janet E. Hall
 
Antiepileptic Drug TherapyEDITORIAL: Polycystic Ovarian Syndrome—Relationship to Epilepsy and
Society please go to: http://jcem.endojournals.org//subscriptions/ or any of the other journals published by The Endocrine
 Journal of Clinical Endocrinology & Metabolism
To subscribe to
Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online
 
Editorial: Polycystic Ovarian Syndrome—Relationship toEpilepsy and Antiepileptic Drug Therapy
Previous studies have described an association betweenepilepsy and features of the polycystic ovarian syndrome(PCOS) among women receiving treatment with antiepilep-tic drugs (AEDs), including valproic acid (VPA) (1–5). Theassociation with PCOS has been attributed to epilepsy itself bysomeinvestigators(2),andtotheuseofVPAbyothers(1).VPA is an anticonvulsant used to treat epilepsy, migraineheadaches, and bipolar disorder (6–9). Data regarding thepotential association of epilepsy and VPA with PCOS aresparse and suffer from substantial methodological and an-alytical problems. Despite the limitations of these data andthe lack of causative evidence supporting an association be-tween VPA use and PCOS, treatment of women with VPA-responsive disorders has been influenced by these reports.The study by Bilo
et al.
(10), in this issue of the journal,provides critical insight into the relationship between epi-lepsy, VPA use, and PCOS, and enriches our understandingof the role of the central nervous system (CNS) in PCOS.The prevalence of PCOS in epilepsy is reported to be between 3.1% and 26% (Table 1) (1–4, 10). This informationis derived from a total of five clinical case series involving20–238 premenopausal-aged women receiving outpatientcare in epilepsy centers in the United States (2), Italy (3, 10),Germany (4), and Finland (1). One study (1) did not reportthe prevalence of the clinical syndrome of PCOS, as defined by the 1990 NIH consensus criteria (11); however, we usedthe frequency of certain PCOS features reported to estimatethat the prevalence of PCOS in this series was between 3.1%and 7.1%. In population-based studies, PCOS has been es-timated to occur in 4.0–6.8% of premenopausal women (12–14). The prevalence of PCOS in epileptic populations waselevated in three of five studies (Table 1) (2, 3, 10) and sig-nificantly so in two studies, including the study by Bilo
et al.
(10).The current study by Bilo
et al.
(10) documented PCOS in13of50(26%)epilepticwomen.TheprevalenceofPCOSwas,thus, 3.8 times greater than that of the general population(Fisher’s exact test,
P
0.001). Using the same methods asearlier clinical series, the current report describes a preva-lence estimate that is somewhat higher than has been re-ported previously (3.1–20%) (1–4). The stronger associationfound in this article may reflect the more rigorous and thor-ough assessment of PCOS, including the definition of men-strual cycle irregularity and hirsutism, and the inclusion ofacne (10). A strength of this report is the superior charac-terization of PCOS and the prospective evaluation of men-strual disturbance. All subjects had an early follicular andluteal-phase hormonal evaluation in the basal cycle to doc-ument the presence and timing of ovulation and those with basal-cycle menstrual, androgen, and/or ovarian abnormal-ities had LH and progesterone drawn frequently during a1-monthfollow-uptodocumentovulation.Thus,althoughitis a relatively small study, the report by Bilo
et al.
(10) addssubstantially to the weight of evidence supporting an asso-ciation between epilepsy and PCOS.An examination of the report of Bilo
et al.
(10) and otherclinical series reveals significant disagreement among themin their conclusions about the association between epilepsyand PCOS (1–4, 10). Several factors may explain the discrep-ancy in the findings. The studies are all relatively small,permitting chance observations and selection bias to exertsubstantial effects. The referral pattern for each of the epi-lepsy clinics in which studies were conducted may differsuch that some may over-represent women with reproduc-tive-endocrine disorders. In addition, the type of epilepsy(generalized, focal), location of seizure focus (temporal lobe,extra-temporal),andresponsivenesstotherapyofstudysub- jects varies among the clinical reports. Associations betweenPCOS and generalized epilepsy (3), temporal-lobe epilepsy(2), and no specific epilepsy type or seizure focus location (1,10) have been reported. Moreover, the frequency of use ofspecific AEDs and the proportion of women receiving notreatment for their epilepsy varies substantially among theclinical reports (1, 3–5, 15, 16). If an association of epilepsywith PCOS is mediated or caused by one or more AEDs, thenumber of subjects receiving that medication must be largeenough to permit accurate analysis. Finally, personal char-acteristics of study subjects that may modulate the relation-ship between epilepsy and PCOS—such as ethnicity and body weight—vary markedly among the clinical reports.There are two primary hypotheses to explain an associa-tion between epilepsy and PCOS (17). The first explanationis that the seizure disorder itself increases the risk of PCOS.Twostudies,includingthereportbyBilo
et al.
(10),foundthatwomen with seizure disorders who were unmedicated hadan elevated prevalence of PCOS, and that PCOS occurred asfrequentlyinunmedicatedepilepticwomenasitdidinmed-icated women, regardless of the specific AED used (2, 10).The greater occurrence of PCOS in untreated epilepticwomen suggests that epilepsy itself is responsible for theassociation.HowcouldepilepsyincreasetheriskforPCOS?Thepatho-genesis of PCOS is probably multifactorial, and abnormali-ties in hypothalamic function, ovarian morphology, and in-sulin resistance have been described (18). Neuroendocrineabnormalities including increased LH amplitude pulsations,fastfrequencyLHsecretion,andlowtonormallevelsofFSHare present in most women with PCOS (19). AcceleratedGnRH pulsatility may be an intrinsic abnormality in PCOS
Received May 11, 2001. Accepted May 13, 2001.Address correspondence and requests for reprints to: Hadine Joffe,M.D., McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478.E-mail: hjoffe@partners.org.
0021-972X/01/$03.00/0 Vol. 86, No. 7The Journal of Clinical Endocrinology & Metabolism
Printed in U.S.A.
Copyright © 2001 by The Endocrine Society
2946
 
(20). In epileptics, ictal and interictal paroxysmal dischargesmay disrupt GnRH pulsatility, modulating CNS regulationof GnRH neurons by excitatory neurotransmitters (21). Re-ceptors for the excitatory neurotransmitters glutamate andnitric oxide, including
-methyl-
d
-aspartate receptors, arelocated in hypothalamic nuclei known to be important forGnRH release (22, 23). The changes in excitatory neurotrans-mitter systems associated with epilepsy may potentially in-crease the risk of PCOS via modulation of GnRH pulsatility(24). The finding of increased LH pulse frequency in un-medicated epileptic women with regular menstrual cyclessupports this hypothesis (16, 25).An alternate explanation for the association between ep-ilepsy and PCOS is that PCOS is induced by use of VPA (17).An association between VPA use and features of PCOS inepileptic women has been reported in one study (1). In thisstudy, ultrasonographic evidence of polycystic ovarian mor-phologyoccurredin14of31(45.2%)epilepticwomentreatedwith VPA, a significant increase over that seen in epilepticwomen treated with other AEDs (1). The prevalence of clin-ical PCOS among VPA users was not specifically reported.However, we can use the information reported about thefrequency of specific PCOS features to estimate that 3–6 of31 (9.7–19.4%) VPA-treated epileptic women met criteria forPCOS(Table2)(1).ArangeofPCOSprevalenceiscalculated becauseitisunclearwhetherthewomenwithhirsutism(n
3) were the same as those with menstrual irregularity andhyperandrogenemia (n
3) in this series. Other clinical re-ports have not found an association between VPA use andPCOS in epileptic women, including that of Bilo
et al.
(4, 10).Inthelatterreport,PCOSoccurredin23.1%ofVPAusersand23.8% of those receiving other AEDs (10).Theinconsistentfindingsregardingthepotentialcausativerole of VPA in the increased risk of PCOS among epilepticsmay have several explanations. Again, these studies are allrelatively small and cross-sectional in nature, allowing for alarge role of chance association. Second, subjects were notrandomizedtotreatmentwithspecificAEDs.Womentreatedwith VPA may have characteristics that differ among thestudies and confound the association between VPA andPCOS. For example, the proportion of VPA-treated womenwithobesity(bodymassindex,
25kg/m
2
)ishigherinsomestudies (1, 26) than in others (4, 10). Obesity might confoundthe association between VPA use and PCOS or it may be amediating factor (1, 2, 26). In addition, other characteristicsthatinfluencetheselectionofVPAtotreataseizuredisorder(suchasseizuretypeandtreatmentresistanceorintolerance)might explain the discrepancy between studies in the rela-tionship of VPA to PCOS.The potential pathophysiology underlying a VPA-medi-
TABLE 1.
Association between epilepsy and PCOS
Study No. No. (%) with PCOS Odds ratio 95% CI
P
Herzog
et al.
, 1986 50 10 (20%) 3.4 1.29.1 0.01Bilo
et al.
, 1988 20 3 (15%) 2.4 0.410.1 0.18Isojarvi
et al.
, 1993 238
a
3 (3.1%) 0.4 0.11.6 0.28to to to7 (7.1%)
b
1.1 0.33.0 1.0Bauer
et al.
, 2000 93 6 (6.5%) 0.9 0.32.8 1.0Bilo
et al.
, 2001 50 13 (26%) 4.8 1.912.2
0.001Odds ratios, 95% confidence intervals (95% CI), and two-sided Fisher’s exact test are used to compare prevalence of PCOS in each study withthe maximum community prevalence of 6.8% (13 of 192 women) (13).
a
Ninety-eightwomenof238totalsubjectshadcompleteevaluationforPCOS(31VPA,49carbamazepine,and18clonazepam,phenobarbital,clonazepam, and/or carbamazepine).
b
The proportion with PCOS calculated from data available on 98 women for whom menstrual cycle irregularity (n
47), hirsutism (n
4), and menstrual irregularity with hyperandrogenemia (n
3) was reported. The range is reported because it is unclear whether women withhirsutism were the same as those with menstrual irregularity and hyperandrogenemia.
TABLE 2.
Association between use of VPA and PCOS in women with epilepsy
StudyNumber of  VPA usersNo. (%) of  VPA userswith PCOSNo. usingnon-VPA AEDsNo. (%) of non-VPA AEDusers with PCOSOdds ratio 95% CI
P
Herzog
et al.
, 1986 Not reported Not reported Not reported Not reported No association
a
Isojarvi
et al.
, 1993 31 3 (9.7%) 67 1 (1.5%)
c
7.0 0.5376.6 0.09to to to6 (19.4%)
b
15.8 1.7739.1 0.004Bauer
et al.
, 2000 34 2 (5.9%) 40 2 (5.0%) 1.2 0.117.2 1.0Bilo
et al.
, 2001 13 3 (23.1%) 21 5 (23.8%) 1.0 0.16.3 1.0Odds ratios, 95% confidence intervals (95% CI), and two-sided Fisher’s exact test are used to compare the prevalence of PCOS in VPA userswith the prevalence of PCOS in epileptics treated with AED that did not include VPA.
a
Odds ratio (and 95% CI) cannot be calculated because the number of women taking each medication and the proportion of each group withPCOS was not reported. However, the paper reports that there was no association between specific medication used and PCOS.
b
The proportion with PCOS calculated from data available on 31 VPA users for whom complete data on menstrual cycle irregularity (n
13), hirsutism (n
3), and menstrual irregularity with hyperandrogenemia (n
3) was available. A range is reported because it is unclearwhether women with hirsutism were the same as those with menstrual irregularity and hyperandrogenemia.
c
The proportion with PCOS calculated from data available on 67 epileptic women taking medications exclusive of VPA (49 carbamazepine;18 clonazepam, phenobarbital, clonazepam, and/or carbamazepine) for whom complete data on menstrual cycle irregularity (n
28), hirsutism(n
1), and menstrual irregularity with hyperandrogenemia (n
0) was available.
EDITORIAL 2947

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