EDITORIAL: Polycystic Ovarian Syndrome—Relationship to Epilepsy and Antiepileptic Drug Therapy

Hadine Joffe, Ann E. Taylor and Janet E. Hall J. Clin. Endocrinol. Metab. 2001 86: 2946-2949, doi: 10.1210/jc.86.7.2946

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Editorial: Polycystic Ovarian Syndrome—Relationship to Epilepsy and Antiepileptic Drug Therapy
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). The association with PCOS has been attributed to epilepsy itself by some investigators (2), and to the use of VPA by others (1). VPA is an anticonvulsant used to treat epilepsy, migraine headaches, and bipolar disorder (6 –9). Data regarding the potential association of epilepsy and VPA with PCOS are sparse and suffer from substantial methodological and analytical problems. Despite the limitations of these data and the lack of causative evidence supporting an association between VPA use and PCOS, treatment of women with VPAresponsive 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 epilepsy, VPA use, and PCOS, and enriches our understanding of 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 information is derived from a total of five clinical case series involving 20 –238 premenopausal-aged women receiving outpatient care in epilepsy centers in the United States (2), Italy (3, 10), Germany (4), and Finland (1). One study (1) did not report the prevalence of the clinical syndrome of PCOS, as defined by the 1990 NIH consensus criteria (11); however, we used the frequency of certain PCOS features reported to estimate that the prevalence of PCOS in this series was between 3.1% and 7.1%. In population-based studies, PCOS has been estimated to occur in 4.0 – 6.8% of premenopausal women (12– 14). The prevalence of PCOS in epileptic populations was elevated in three of five studies (Table 1) (2, 3, 10) and significantly so in two studies, including the study by Bilo et al. (10). The current study by Bilo et al. (10) documented PCOS in 13 of 50 (26%) epileptic women. The prevalence of PCOS was, thus, 3.8 times greater than that of the general population (Fisher’s exact test, P 0.001). Using the same methods as earlier clinical series, the current report describes a prevalence estimate that is somewhat higher than has been reported previously (3.1–20%) (1– 4). The stronger association found in this article may reflect the more rigorous and thorough assessment of PCOS, including the definition of menstrual cycle irregularity and hirsutism, and the inclusion of acne (10). A strength of this report is the superior characterization of PCOS and the prospective evaluation of menstrual disturbance. All subjects had an early follicular and
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.

luteal-phase hormonal evaluation in the basal cycle to document the presence and timing of ovulation and those with basal-cycle menstrual, androgen, and/or ovarian abnormalities had LH and progesterone drawn frequently during a 1-month follow-up to document ovulation. Thus, although it is a relatively small study, the report by Bilo et al. (10) adds substantially to the weight of evidence supporting an association between epilepsy and PCOS. An examination of the report of Bilo et al. (10) and other clinical series reveals significant disagreement among them in their conclusions about the association between epilepsy and PCOS (1– 4, 10). Several factors may explain the discrepancy in the findings. The studies are all relatively small, permitting chance observations and selection bias to exert substantial effects. The referral pattern for each of the epilepsy clinics in which studies were conducted may differ such that some may over-represent women with reproductive-endocrine disorders. In addition, the type of epilepsy (generalized, focal), location of seizure focus (temporal lobe, extra-temporal), and responsiveness to therapy of study subjects varies among the clinical reports. Associations between PCOS 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 of specific AEDs and the proportion of women receiving no treatment for their epilepsy varies substantially among the clinical reports (1, 3–5, 15, 16). If an association of epilepsy with PCOS is mediated or caused by one or more AEDs, the number of subjects receiving that medication must be large enough to permit accurate analysis. Finally, personal characteristics of study subjects that may modulate the relationship between epilepsy and PCOS—such as ethnicity and body weight—vary markedly among the clinical reports. There are two primary hypotheses to explain an association between epilepsy and PCOS (17). The first explanation is that the seizure disorder itself increases the risk of PCOS. Two studies, including the report by Bilo et al. (10), found that women with seizure disorders who were unmedicated had an elevated prevalence of PCOS, and that PCOS occurred as frequently in unmedicated epileptic women as it did in medicated women, regardless of the specific AED used (2, 10). The greater occurrence of PCOS in untreated epileptic women suggests that epilepsy itself is responsible for the association. How could epilepsy increase the risk for PCOS? The pathogenesis of PCOS is probably multifactorial, and abnormalities in hypothalamic function, ovarian morphology, and insulin resistance have been described (18). Neuroendocrine abnormalities including increased LH amplitude pulsations, fast frequency LH secretion, and low to normal levels of FSH are present in most women with PCOS (19). Accelerated GnRH pulsatility may be an intrinsic abnormality in PCOS

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EDITORIAL
TABLE 1. Association between epilepsy and PCOS
Study No. No. (%) with PCOS Odds ratio 95% CI P

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Herzog et al., 1986 Bilo et al., 1988 Isojarvi et al., 1993 Bauer et al., 2000 Bilo et al., 2001

50 20 238a 93 50

10 (20%) 3 (15%) 3 (3.1%) to 7 (7.1%)b 6 (6.5%) 13 (26%)

3.4 2.4 0.4 to 1.1 0.9 4.8

1.2–9.1 0.4–10.1 0.1–1.6 to 0.3–3.0 0.3–2.8 1.9–12.2

0.01 0.18 0.28 1.0 1.0 0.001

Odds ratios, 95% confidence intervals (95% CI), and two-sided Fisher’s exact test are used to compare prevalence of PCOS in each study with the maximum community prevalence of 6.8% (13 of 192 women) (13). a Ninety-eight women of 238 total subjects had complete evaluation for PCOS (31 VPA, 49 carbamazepine, and 18 clonazepam, 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 with hirsutism were the same as those with menstrual irregularity and hyperandrogenemia. TABLE 2. Association between use of VPA and PCOS in women with epilepsy
Study Number of VPA users No. (%) of VPA users with PCOS No. using non-VPA AEDs No. (%) of non-VPA AED users with PCOS Odds ratio 95% CI P

Herzog et al., 1986 Isojarvi et al., 1993 Bauer et al., 2000 Bilo et al., 2001

Not reported 31 34 13

Not reported 3 (9.7%) to 6 (19.4%)b 2 (5.9%) 3 (23.1%)

Not reported 67 40 21

Not reported 1 (1.5%)c 2 (5.0%) 5 (23.8%)

7.0 to 15.8 1.2 1.0

0.5–376.6 to 1.7–739.1 0.1–17.2 0.1– 6.3

No associationa 0.09 0.004 1.0 1.0

Odds ratios, 95% confidence intervals (95% CI), and two-sided Fisher’s exact test are used to compare the prevalence of PCOS in VPA users with 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 with PCOS 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 unclear whether 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.

(20). In epileptics, ictal and interictal paroxysmal discharges may disrupt GnRH pulsatility, modulating CNS regulation of GnRH neurons by excitatory neurotransmitters (21). Receptors for the excitatory neurotransmitters glutamate and nitric oxide, including N-methyl-d-aspartate receptors, are located in hypothalamic nuclei known to be important for GnRH release (22, 23). The changes in excitatory neurotransmitter systems associated with epilepsy may potentially increase the risk of PCOS via modulation of GnRH pulsatility (24). The finding of increased LH pulse frequency in unmedicated epileptic women with regular menstrual cycles supports this hypothesis (16, 25). An alternate explanation for the association between epilepsy and PCOS is that PCOS is induced by use of VPA (17). An association between VPA use and features of PCOS in epileptic women has been reported in one study (1). In this study, ultrasonographic evidence of polycystic ovarian morphology occurred in 14 of 31 (45.2%) epileptic women treated with VPA, a significant increase over that seen in epileptic women treated with other AEDs (1). The prevalence of clinical PCOS among VPA users was not specifically reported. However, we can use the information reported about the frequency of specific PCOS features to estimate that 3– 6 of 31 (9.7–19.4%) VPA-treated epileptic women met criteria for PCOS (Table 2) (1). A range of PCOS prevalence is calculated

because it is unclear whether the women with hirsutism (n 3) were the same as those with menstrual irregularity and hyperandrogenemia (n 3) in this series. Other clinical reports have not found an association between VPA use and PCOS in epileptic women, including that of Bilo et al. (4, 10). In the latter report, PCOS occurred in 23.1% of VPA users and 23.8% of those receiving other AEDs (10). The inconsistent findings regarding the potential causative role of VPA in the increased risk of PCOS among epileptics may have several explanations. Again, these studies are all relatively small and cross-sectional in nature, allowing for a large role of chance association. Second, subjects were not randomized to treatment with specific AEDs. Women treated with VPA may have characteristics that differ among the studies and confound the association between VPA and PCOS. For example, the proportion of VPA-treated women with obesity (body mass index, 25 kg/m2) is higher in some studies (1, 26) than in others (4, 10). Obesity might confound the association between VPA use and PCOS or it may be a mediating factor (1, 2, 26). In addition, other characteristics that influence the selection of VPA to treat a seizure disorder (such as seizure type and treatment resistance or intolerance) might explain the discrepancy between studies in the relationship of VPA to PCOS. The potential pathophysiology underlying a VPA-medi-

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ated increase in PCOS prevalence is unknown. VPA may influence the risk of PCOS by its CNS activity, but a mechanism that explains a specific effect of VPA on PCOS has not been found (17). VPA increases -aminobutyric acid synthesis and release and may block N-methyl-d-aspartate-type glutamate receptors, but other AEDs share these CNS properties (27, 28). VPA administration also alters the density of -aminobutyric acid-ergic inputs to GnRH neurons in the medial preoptic area of the hypothalamus in pubertal mice, but this effect does not occur in postpubertal mice (29 –31). An alternative explanation for why VPA increases the risk of PCOS is related to the association between VPA use and weight gain, which increases insulin resistance and, potentially, the risk for PCOS (26, 32). VPA use causes more weight gain than carbamazepine (6, 33). However, obesity alone is unlikely to fully explain the association of VPA use with PCOS as some VPA-treated epileptic women are lean (10), and other medications that cause significant weight gain (e.g. clozapine) have not been associated with PCOS. A pharmacodynamic property of VPA that might contribute to an association with PCOS is that VPA lacks the effects on induction of hepatic cytochrome P450 (CYP) enzymes associated with other AEDs (17). Induction of CYP isozymes facilitates clearance of gonadal steroids and reduces circulating testosterone levels (34). Because VPA does not induce CYP enzymes, it lacks these mitigating actions against hyperandrogenemia, which may contribute selectively to the increased risk of PCOS. If VPA increases the risk of PCOS, it is likely that the pathophysiology is multifactorial and that several factors act simultaneously to cause this reproductive-endocrine disorder. Epilepsy may be required as a component factor in the association between VPA and PCOS. To date, the prevalence of PCOS is not known to be increased in women taking VPA for other indications, such as bipolar or migraine disorders. One small pilot study of PCOS in 22 women with bipolar disorder found no association of VPA with PCOS (35). It is plausible that the effect of VPA on PCOS may be specific to epileptic women if ictal and interictal discharges and altered GnRH pulsatility are required to increase risk for PCOS in the setting of VPA exposure. Neuroendocrine abnormalities that occur in epilepsy may make women with seizure disorders particularly susceptible to the effects of VPA on the hypothalamic-pituitary-ovarian axis (36). More data in nonepileptic VPA users are needed to determine whether VPA alone increases the risk of PCOS, or whether the association is found only in women with seizure disorders. Despite the strength of the observations in the paper by Bilo et al. (10), there is no conclusive evidence that epilepsy or the use of VPA causes PCOS. All studies describing a relationship between epilepsy, VPA use, and PCOS suffer from several major methodological limitations. All studies are cross-sectional in nature, and none reports whether epilepsy preceded the onset of PCOS or whether PCOS began before or after the initiation of VPA for treatment of epilepsy. Epilepsy and VPA use must be established to precede the onset of PCOS symptoms to infer that epilepsy or VPA are risk factors for PCOS. Given the typically perimenarchal onset of PCOS in the general population (37), and the absence of data about the temporal sequence of epilepsy, VPA use,

and PCOS, PCOS may precede the onset of epilepsy and its treatment. Clinicians prescribing VPA for seizure, bipolar, or migraine disorders should be aware of the contradictory data describing the relationship between epilepsy, VPA use, and PCOS. There are currently two multicenter studies with longitudinal components underway— one in epileptic women and the other in bipolar women—that will address whether VPA use increases the risk of PCOS. These large studies will provide information about the temporal relationship of the initiation of VPA and the onset of PCOS symptoms so that clinical decisions about the use of VPA can be informed by reliable data. Hadine Joffe, Ann E. Taylor, and Janet E. Hall Women’s Center for Behavioral Endocrinology, McLean Hospital (H.J.), Belmont, Massachusetts 02478; and Perinatal and Reproductive Psychiatry Clinical Research Program, Department of Psychiatry (H.J.), and Reproductive Endocrine Unit, Department of Medicine (A.E.T., J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
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