(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
-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
(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,
)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-
Association between epilepsy and PCOS
Study No. No. (%) with PCOS Odds ratio 95% CI
, 1986 50 10 (20%) 3.4 1.2–9.1 0.01Bilo
, 1988 20 3 (15%) 2.4 0.4–10.1 0.18Isojarvi
, 1993 238
3 (3.1%) 0.4 0.1–1.6 0.28to to to7 (7.1%)
1.1 0.3–3.0 1.0Bauer
, 2000 93 6 (6.5%) 0.9 0.3–2.8 1.0Bilo
, 2001 50 13 (26%) 4.8 1.9–12.2
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).
Ninety-eightwomenof238totalsubjectshadcompleteevaluationforPCOS(31VPA,49carbamazepine,and18clonazepam,phenobarbital,clonazepam, and/or carbamazepine).
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.
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
, 1986 Not reported Not reported Not reported Not reported No association
, 1993 31 3 (9.7%) 67 1 (1.5%)
7.0 0.5–376.6 0.09to to to6 (19.4%)
15.8 1.7–739.1 0.004Bauer
, 2000 34 2 (5.9%) 40 2 (5.0%) 1.2 0.1–17.2 1.0Bilo
, 2001 13 3 (23.1%) 21 5 (23.8%) 1.0 0.1–6.3 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.
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.
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.
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
1), and menstrual irregularity with hyperandrogenemia (n
0) was available.