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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The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
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 antiepilep-
tic 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 an-
alytical problems. Despite the limitations of these data and
the 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 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 es-
timated 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 sig-
nificantly 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 preva-
lence estimate that is somewhat higher than has been re-
ported previously (3.1–20%) (1– 4). The stronger association
found 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 of
acne (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 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.
2946
Vol. 86, No. 7
Printed in U.S.A.
luteal-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 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 asso-
ciation 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 discrep-
ancy 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 epi-
lepsy clinics in which studies were conducted may differ
such 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), and responsiveness to therapy of study sub-
jects 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 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 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 med-
icated 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 patho-
genesis of PCOS is probably multifactorial, and abnormali-
ties in hypothalamic function, ovarian morphology, and in-
sulin 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
 EDITORIAL 2947

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 1.2–9.1 0.01
Bilo et al., 1988 20 3 (15%) 2.4 0.4–10.1 0.18
Isojarvi et al., 1993 238a 3 (3.1%) 0.4 0.1–1.6 0.28
to to to
7 (7.1%)b 1.1 0.3–3.0 1.0
Bauer et al., 2000 93 6 (6.5%) 0.9 0.3–2.8 1.0
Bilo et al., 2001 50 13 (26%) 4.8 1.9–12.2 ⬍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

No. (%) of No. (%) of

Number of No. using
Study VPA users non-VPA AED Odds ratio 95% CI P
VPA users non-VPA AEDs
with PCOS users with PCOS
Herzog et al., 1986 Not reported Not reported Not reported Not reported No associationa
Isojarvi et al., 1993 31 3 (9.7%) 67 1 (1.5%)c 7.0 0.5–376.6 0.09
to to to
6 (19.4%)b 15.8 1.7–739.1 0.004
Bauer et al., 2000 34 2 (5.9%) 40 2 (5.0%) 1.2 0.1–17.2 1.0
Bilo et al., 2001 13 3 (23.1%) 21 5 (23.8%) 1.0 0.1– 6.3 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). Re-
ceptors 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 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 cycles
supports 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 in
epileptic women has been reported in one study (1). In this
study, ultrasonographic evidence of polycystic ovarian mor-
phology 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 clin-
ical 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 re-
ports 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 rela-
tionship of VPA to PCOS.
The potential pathophysiology underlying a VPA-medi-
2948 JOFFE ET AL.
ated increase in PCOS prevalence is unknown. VPA may
influence the risk of PCOS by its CNS activity, but a mech-
anism that explains a specific effect of VPA on PCOS has not
been found (17). VPA increases ␥-aminobutyric acid synthe-
sis and release and may block N-methyl-d-aspartate-type
glutamate receptors, but other AEDs share these CNS prop-
erties (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, poten-
tially, 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 pharma-
codynamic property of VPA that might contribute to an
association with PCOS is that VPA lacks the effects on in-
duction of hepatic cytochrome P450 (CYP) enzymes associ-
ated with other AEDs (17). Induction of CYP isozymes fa-
cilitates clearance of gonadal steroids and reduces circulating
testosterone levels (34). Because VPA does not induce CYP
enzymes, it lacks these mitigating actions against hyperan-
drogenemia, which may contribute selectively to the in-
creased 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 disor-
der. 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 hypo-
thalamic-pituitary-ovarian axis (36). More data in nonepi-
leptic 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 ep-
ilepsy 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,
JCE & M • 2001
Vol. 86 • No. 7
and PCOS, PCOS may precede the onset of epilepsy and its
treatment.
Clinicians prescribing VPA for seizure, bipolar, or mi-
graine disorders should be aware of the contradictory data
describing the relationship between epilepsy, VPA use, and
PCOS. There are currently two multicenter studies with lon-
gitudinal 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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