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Epilepsy, sex hormones and
antiepileptic drugs in
female patients
Expert Rev. Neurother. 9(12), 1803–1814 (2009)
Alberto Verrotti†,
Claudia D’Egidio,
Giangennaro Coppola,
Pasquale Parisi and
Francesco Chiarelli
Author for correspondence
Department of Pediatrics,
University of Chieti, Via dei
Vestini 5, 66100 Chieti, Italy
Tel.: +39 087 135 8015
Fax: +39 087 157 4831
[email protected]
†
Women with epilepsy have a higher incidence of reproductive endocrine disorders than the
general female population. These alterations include polycystic ovary syndrome,
hyperandrogenemia, infertility, hypothalamic amenorrhea and hyperprolactinemia. Reproductive
dysfunction is attributed both to epilepsy itself and to antiepileptic drugs (AEDs). Focal epileptic
discharges from the temporal lobe may have a direct influence on the function of the
hypothalamic–pituitary axis, thus altering the release of sex steroid hormones, including the
production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing
hormone and prolactin. AEDs may modulate hormone release from the hypothalamic–pituitary–
gonadal axis and they may alter the metabolism of sex hormones and their binding proteins.
Hepatic enzyme-inducing AEDs, such as carbamazepine and phenytoin, may be most clearly
linked to altered metabolism of sex steroid hormones, but valproic acid, an enzyme inhibitor,
has also been associated with a frequent occurrence of polycystic ovary syndrome and
hyperandrogenism in women with epilepsy. Therefore, treatment of epilepsy and selection of
AEDs are important for reproductive health in female patients. The aim of the present review
is to critically evaluate the recently published data concerning the interactions between sex
hormones, epilepsy and AEDs.
Keywords : amenorrhea • antiepileptic drug • epilepsy • hyperandrogenemia • hyperprolactinemia
• polycystic ovary syndrome • sex hormone dysfunction
Epilepsy is a common neurologic disorder affecting women during their reproductive years, and
is associated with hormonal disturbances resulting in altered endocrine reproduction and sexual
function [1,2] . A possible role for seizure disorder
or, alternatively, of the use of antiepileptic drugs
(AEDs), have been suggested as the patho­genetic
mechanisms. The brain regulates hormonal
secretion and is sensitive to hormonal feedback;
the neuroendocrine feedback system includes the
hypothalamus, pituitary, gonads and amygdala.
The amygdala is linked to the hypothalamic–
pituitary axis (HPA) [3] , which is involved in the
regulation, production and secretion of ovarian
steroids. Reproductive endocrine disorders associated with epilepsy can be expected in view of
the complex interconnections between the HPA
and the limbic system; the involvement of medial
temporal lobe regions in epilepsy may cause
changes in sex hormone secretion and, consequently, reproductive function [4] . Moreover,
AEDs may also alter hormone levels and interfere
with reproductive function [5,6] .
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10.1586/ERN.09.112
This review evaluates whether and to what
degree epilepsy and its treatment can affect
reproductive function. For this purpose, this
review is subdivided into two main sections: the
effects of epilepsy on reproductive function and
the effects of AEDs on sex hormones.
Effects of epilepsy on
reproductive function
Reproductive endocrine disorders, such as menstrual cycle disturbances and ovulatory dysfunctions, have frequently been reported in epileptic
women [1–3,5–13] . These abnormalities usually
result from abnormal reproductive endocrine
function and are associated with lower rates
of ovulation and higher rates of infertility [12] .
Menstrual disorders are currently estimated to
occur in a third of women with epilepsy compared with 12–14% of women in the general
population [13] . Anovulation, hypothalamic
amenorrhea (HA), hyperandrogenemia, poly­
cystic ovary syndrome (PCOS), functional
hyperprolactinemia, premature menopause and
© 2009 Expert Reviews Ltd
ISSN 1473-7175
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Verrotti, D’Egidio, Coppola, Parisi & Chiarelli
risk of infertility are over-represented in women with epilepsy
(Box 1) [1,9,14–20] . Epilepsy itself may have effects on sex hormone
levels and reproductive endocrine function [1,5,21–22,23] .
Animal studies have demonstrated that reproductive endocrine and sexual dysfunction is more common in partial compared with generalized epilepsy, especially in temporal lobe epilepsy [24–26] ; animal investigations demonstrated that induction
of temporo–limbic seizures can cause changes in reproductive
hormone levels and reproductive function [24,25,27] . In particular,
amygdala seizures in female rodents can cause anovulation, elevated serum testosterone levels and the accumulation of follicular
cystis in the ovaries [24] .
These findings have also been confirmed in human studies
[14,28] . More than a third of cycles in women with localizationrelated epilepsy are anovulatory, compared with 8–10% in controls [11,13,29–33] . Partial epilepsy, mainly when originating in
the temporal lobe, is the form most frequently associated with
reproductive dysfunction [1,13,19,34] . However, other studies
demonstrated that more than 50% of patients with generalized
convulsions may develop reproductive and sexual abnormalities [21,29,35] ; in particular, hyperandrogenemia and PCOS are
more frequent in women with idiopathic generalized epilepsy
than in localization-related epilepsy [14,29,36] . Interestingly,
Herzog et al., examined 50 women with tempolimbic epilepsy
and found that 28 patients had amenorrhea, oligoamenorrhea,
or abnormally long or short menstrual cycle intervals; 19 out of
the 28 women with epilepsy and menstrual disorders had readily
identifiable reproductive endocrine disorders: PCOS in ten, HA
in six, premature menopause in two and hyperprolactinemia in
one [1] . Since no significant relationship between the occurrence
of menstrual disorders and the use of AEDs has been found, it
is suggested that epilepsy may have an independent effect on
reproductive function. This is in agreement with a previous
study describing a significantly higher frequency of ovulatory
dysfunction in female patients, not correlated with the use of
any specific AED [35] .
Moreover, high levels of luteinizing hormone (LH) and an
altered LH-to-follicle-stimulating hormone (FSH) ratio have been
reported in women with epilepsy [17–19] . The presence of elevated
LH pulse frequency in untreated or epileptic women with regular menstrual cycles supports the notion that epilepsy itself may
contribute to reproductive abnormalities [21,35] .
Box 1. Frequent reproductive dysfunctions in
women with epilepsy.
• Hyperandrogenism [29,36,46,94]
• High levels of luteinizing hormone and luteinizing hormone-tofollicle-stimulating hormone ratio [16,17,36,55]
• Polycystic ovary syndrome [1,13,14,30,31,46,47,92–93]
• Menstrual irregularities [1,17,32,35,92]
• Premature menopause [1,15,16]
• Infertility [7,9,110,149]
• Hyperprolactinemia [42,53,150,151]
• Sexual dysfunction [14,50,52,152,153]
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Interestingly, a recent cross-sectional observational study of
Murialdo et al. evaluated the relationships between sex steroids
and seizure frequency in women with partial epilepsy on AED
treatments [37] . The authors found that estrodiol, free estrodiol and
progesterone levels were lower in both ovarian phases in patients,
whereas those of sex hormone-binding globulin (SHBG) were
higher than in controls. When changes in hormone levels were compared with those in healthy controls, luteal-free estrodiol and progesterone levels were chiefly impaired in women with more frequent
seizures, mostly undergoing AED polytherapies, but not in those
with absent or rarer seizures. Furthermore, an inverse relationship
was found between free estrodiol levels and seizure frequency scores
during the follicular phase, and with disease duration in the luteal
phase. However, the authors suggested that these findings may be
attributed to the longer duration of AED treatments and the more
frequent use of enzyme-inducing AEDs (EIAEDs) in subjects with
more severe seizures. Accordingly, a previous retrospective study
reported that menstrual disorders were more frequent in patients
with high seizure frequency (less than five seizures per year) [38] .
The mechanisms underlying the association between epilepsy
and reproductive endocrine disorders are still not clear. HPA dysfunction is suggested by observations that pituitary release of
LH in women with epilepsy is altered both spontaneously and
in response to gonadotropin-releasing hormone (GnRH) [1,30,31] .
The brain controls reproductive function primarily through
hypothalamic regulation of pituitary secretion [39] . The hypo­
thalamus receives direct connections from the cerebral hemispheres, especially from temporolimbic structures that are
commonly involved in epilepsy and, most notably, from the
amygdala [1,40,41] . In the majority of cases, the epileptic activity
in the frontal lobe exhibits a propagation towards the temporal
lobe and, thereby, influences the hormonal pathway of prolactin
(PRL). [42] . Clinically, there is evidence to suggest that epileptiform discharges may disrupt the temporolimbic modulation of
hypothalamic–pituitary function [14,26] and, ultimately, lead to
changes in ovarian steroidogenesis and morphology [43] . There are
also important clinical findings that indicate that the laterality
and focality of epilepsy may be important determinants of certain
reproductive endocrine disorders [1,14,28,44–46] . In fact, unilateral
temporolimbic discharges are associated with laterally differing
changes in hormonal secretion at all levels of the neuroendocrine
reproductive axis. Consequently, different reproductive disorders
may develop in relation to left- and right-sided temporolimbic epilepsy; in particular, left unilateral temporolimbic epilepsy is associated with a higher occurrence of PCOS [14,47] . Indeed, seizures in
the left side of the limbic system increase the pulse frequencies of
GnRH secretion that, in turn, increases the LH/FSH ratios and
testosterone levels. By contrast, right unilateral temporolimbic
epilepsy is associated with lower GnRH pulse frequency, which
causes a decrease in LH and estrogen levels [1,14] . These hormonal
changes are characteristic of HA [9,28,48] .
Nevertheless, a recent experiment using the amygdala kindling
model in rats demonstrated that, in female rats, seizures that
originate in the left or right amygdala do not result in lateralized
effects on the reproductive system [27] .
Expert Rev. Neurother. 9(12), (2009)
Epilepsy, sex hormones & antiepileptic drugs in female patients
Epileptic discharges in limbic structures may also contribuite
to sexual dysfunction in women, such as lack of sexual interest
and high rates of orgasmic dysfunction, including anorgasmia,
dyspareunia, vaginism or insuffcient vaginal lubrication [49,50] .
Herzog et al. found that right temporal epileptic discharges in
women were associated with hypogonadotropic hypogonadism,
including decreased sexual interest [1] . Sexuality in people with
epilepsy may be adversely affected by alterations in the pituitary
gonado­tropins, PRL and sex steroid hormones [1,12] . Limbic efferents seem to exhibit an impact on the HPA even in the interictal phase of the disorder, and post-ictally elevated PRL serum
concentrations can be detected. In correlation with the type of
seizures, evidence of elevated PRL is found in 88% of seizures
following generalized tonic–clonic seizures, in 78% of seizures
following complex partial seizures and in 22% of seizures following simple partial seizures [51] . The epileptic activity in the frontal
lobe exhibits propagation towards the temporal lobe and thereby
influences the hormonal pathway of PRL, which can also show
tendencies to post-ictal elevation [42] .
In women (and men) with epilepsy, reduced genital blood
flow during erotic stimulation was found via video. The women
with epilepsy who were examined showed a reduced elevation of
genital blood flow during the presentation of erotic video movies
in comparison with healthy controls [52] . Irrespective of gender,
sexual questionnaires revealed reduced libido more commonly in
the right- than in the left-sided temporal lobe seizure origin 44] .
However, compelling explanation remains to be found. It is possible that the right sided temporal lobe disturbance may have a
more pronounced influence on emotions and, therefore, indirectly
on libido [53] .
Baird et al. reported that a third of their 58 lobectomy patients
had an increase in sexual activity after surgery, compared with
a quarter of patients having decreased postsurgical sexual activity [45] . Furthermore, Manna et al. recently���������������������
demonstrated
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a relationship between a serotonin transporter genetic polymorphism
and temporal lobe epilepsy, suggesting that the serotonin transporter gene may play a role in the development of temporal lobe
epilepsy [54] . These findings indicate that some patients with epilepsy may be genetically susceptible to sexual dysfunction through
a serotonin transport mechanism.
In conclusion, an increased frequency of reproductive endocrine disorders, secondary to pituitary hormone changes, has been
reported in women with epilepsy, especially among those with
partial epilepsy of temporal lobe origin. Therefore, regular monitoring of reproductive function, including menstrual disorders,
infertility, hirsutism and galactorrhea, are recommended.
Effects of antiepileptic drugs on sex hormone levels
A large body of literature addresses the presence of alterations in
sex hormone levels in women taking AEDs [2,5,11,17,18,55–62] .
Antiepileptic drugs may have an influence on the metabolism of the central and/or peripheral endocrine hormones and
their binding proteins. Hepatic EIAEDs, such as phenobarbital
(PB), phenytoin (PHT) and carbamazepine (CBZ), are most
clearly linked to altered metabolism of sex steroid hormones.
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In fact, in the late 1970s and 1980s, serum sex hormone levels
were reported to be abnormal in female patients treated with
EIAEDs [55,56] .
Victor et al. were the first to report elevated serum SHBG
concentrations in women treated with PHT [57] , and this finding was later confirmed [55,56] . Low dehydroepiandrosterone sulphate (DHEAS) levels have also been reported in women taking PHT [58] , but its clinical significance is unknown. However,
similarly impaired steroid levels have also been shown in women
with epilepsy treated with other EIAEDs [60,63] . In particular,
Galimberti et al. reported decreased DHEAs levels and increased
cortisol levels in women treated with CBZ, PHT, PB in monoor poly-therapy, but not in those treated with non-EIAEDs
(NEIAEDs) [63] . The most interesting finding in this study concerned the relation between epilepsy severity, increased cortisol,
and decreased DHEAs levels. In fact, cortisol and DHEAS levels
were directly and indirectly correlated with seizure frequency,
respectively, suggesting that changes in adrenal steroid levels must
be ascribed mainly to the frequency of seizures, which are known
to activate the hypothalamus–pituitary–adrenal axis [64] .
The most recent cross-sectional study showed that women with
epilepsy taking EIAED polytherapies had lower levels of estradiol
and a lower free estrogen index (FEI) than patients treated with
a single EIAED [59] . EIAEDs induce hepatic cytocrome P450dependent steroid hormone breakdown and production of SHBG,
thereby reducing biologically active sex hormone serum concentrations, such as estrodiol and testosterone [5,18,60–62] . Galimberti
et al. reported that the older patients and those with longer disease duration showed higher levels of SHBG [59] . This can be
attributed to the physiologic increase in binding protein levels
with aging and to the use of EIAEDs. These changes in serum
SHBG levels, and the lowered total estrodiol levels, implied a
global decrease in biologically active free estrodiol. Conversely,
significant differences in estrodiol levels and in FEI were found
between women on different AED regimens. Patients treated with
EIAED polytherapies showed estrodiol and FEI values that were
lower than those recorded both in patients treated with a single
EIAED or NEIAED, or in those on combined (EIAED plus
NEIAED) therapies.
Recently, Jacobsen et al. reported that PB, PHT, valproic acid
(VPA), oxcarbazepine (OXC) and lamotrigine (LTG), but not
CBZ, inhibit the aromatase complex (CYP19) activity that converts testosterone into estrodiol in vitro [65] . Accordingly, a more
recent study demonstrated that VPA and LTG reduced CYP19
aromatase activity in human ovarian follicular cells, but only in
FSH-stimulated cells and at higher concentrations [66] . Additive
enzyme inhibition has been observed in combination experiments with multiple AEDs; therefore, aromatase inhibition might
explain the decreased production of estrodiol observed in vivo,
mainly when combined AED therapies were employed [59] .
Many studies that have evaluated the reproductive endocrine
effects of CBZ in female patients have consistently reported
increased serum SHBG levels and other sex hormone abnormalities [2,62,65,67–71] . Interestingly, Hamed et al. reported elevated
levels of LH and FSH in 28.1 and 34.4% of CBZ-treated patients,
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Verrotti, D’Egidio, Coppola, Parisi & Chiarelli
respectively [17] . Dana-Haeri et al. observed that epileptic patients
on CBZ had elevated baseline LH levels and a exaggerated LH
response to the GnRH and thyrotropin-releasing hormones
stimulation [72] . This exaggerated LH response may be related
to a positive-feedback mechanism. Furthermore, they reported
slightly higher PRL levels 2 h after stimulation with GnRH and
thyrotropin-releasing hormone. These changes have not been
confirmed by other studies [60,72–74] . Recently, a double-blind,
randomized, controlled withdrawal study, reported that CBZ
withdrawal was associated with a significant decrease in SHBG
levels and a increase in serum testosterone concentrations, free
androgen index (FAI) and estrogen/SHBG ratio; these results
demonstrated that potential changes in sex steroid levels, induced
by CBZ treatment, could be reversible [71] .
However, most of the studies have not shown an increased frequency of menstrual disorders or hyperandrogenism and polycystic
ovaries (PCO) in women taking CBZ [2,60,67,75,76] , despite alterations in serum sex hormone concentrations. In fact, single abnormal laboratory findings without symptoms may not constitute a
clinically relevant endocrine disorder.
Among NEIAEDs, VPA appears to be associated with frequent
reproductive endocrine disorders, such as polycystic changes in
the ovaries, high serum testosterone concentrations and amenorrhea [2,38,77] . These abnormalities are especially common among
women who have gained weight during VPA therapy [61] . In 1993,
Isojarvi et al. through a cross-sectional study showed that menstrual disorders were common among women taking VPA monotherapy for epilepsy and that they were frequently associated with
PCOs and/or hyperandrogenism [2] . PCOs and hyperandrogenism
were expecially common if VPA medication was started before
the age of 20 years [70] . An increased number of ovarian cysts
and PCOS in women on VPA monotherapy was subsequently
confirmed [75,78,79] . In another study of women taking VPA currently or within the preceding 3 years, 38.1% had experienced at
least one anovulatory cycle in contrast to 10.7% of women not
using VPA within the preceding 3 years [11] . Interestingly, women
with idiopathic generalized epilepsy receiving VPA were at highest
risk for anovulatory cycles, polycystic ovaries, elevated BMI and
hyperandrogenism.
A more recent prospective study by Morrell et al. reported a
higher incidence of hyperandrogenism or ovulatory dysfunction in
women taking VPA for epilepsy than in women taking LTG [80] .
Moreover, a significant increase in serum testosterone concentration
was especially prominent in women initiating treatment before the
age of 20 years, suggesting that young women with epilepsy seem
to be especially vulnerable to the effects of VPA on ovarian function [70] . By contrast, in two prospective randomized studies by
Kwan et al. [81] and Stephen et al. [82] , comparing women receiving
VPA and LTG monotherapy, no significant difference in change of
testosterone levels from baseline was found between the VPA and
LTG groups. This discrepancy is probably owing two main reasons.
First, the sample size in these two studies [81,82] were comparatively
smaller than in the study by Morrell et al. [80] . Second, the mean
age of female subjects in the study by Kwan et al. [81] was more than
10 years older than that of subjects in the study by Morrell et al. [80] .
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Alterations in serum androgen levels have even been detected
before and during pubertal development in young girls taking
VPA [83] . The mean serum testosterone levels and FAI were high
in all pubertal phases in girls on VPA, even if the frequency
of hyperandrogenism increased with pubertal development.
Therefore, it is likely that VPA may affect steroid metabolism
during the sensitive period, at the onset of puberty. Accordingly,
hyperandrogenism observed in most adult women on VPA therapy can already be induced before the emergence of clinical signs
of puberty. A recent cross-sectional study showed that VPA treatment was only associated with higher testosterone levels in girls
after menarche, suggesting that the sensitivity to VPA-induced
hyperandrogenism is a function of sexual maturation [6] . In postmenarcheal girls, the presence of hyperandrogenemia without
clinical hyperandrogenism may reflect the increase in testosterone that precedes the appearance of clinical signs (i.e., hirsutism, acne, menstrual disorders and PCOs). This emphasizes
the importance of careful endocrine observation of girls treated
with VPA.
However, it is encouraging to note that the reproductive endocrine effects of VPA may be reversible after the medication is
discontinued; a 5 year follow-up study in young women showed
that the 60% of the patients who were administered VPA had
PCOS compared with 5.5% of the girls whose medication had
been discontinued [82] .
The mechanism by which VPA could cause hyperandrogenism
and related reproductive disorders is still unclear. It may be that
VPA can have a direct effect on ovarian androgen production or
that, acting as enzyme inhibitor, VPA may inhibit the metabolism
of sex hormones and thereby lead to increased serum androgen
levels [53,84,85] . Moreover, obesity (induced by VPA treatment) and
associated hyperinsulinemia could be implicated in the development
of PCOS and hyperandrogenism (see later) [2,70] .
Recently, it has been shown that VPA blocks the androgen
and progesterone receptors, but not the estrogen receptor [86] .
The strong progesterone receptor antagonism by VPA suggests
that some biological effects in women may be at least partly due
to impaired progesterone receptor-mediated progesterone action
on reproductive tissue (a previously unrecognized factor contri­
buting to the low fertility of women with epilepsy). In addition,
antiprogestin effects may contribute to the higher frequency of
anovulation among VPA-treated women with epilepsy [57,77] .
The reproductive endocrine effects of the new AEDs have not
been widely studied. However, most of the data suggest that OXC
therapy is not associated with changes in reproductive function
in epileptic patients [83,87] . Only one recent study reported low
serum testosterone concentrations, low FAI, elevated levels of
androstendione and DHEAS and increased prevalence of PCO in
women during OXC treatment [88] . A low prevalence of reproductive disorders has been reported during LTG therapy [5,73] , and
replacement of VPA with LTG resulted in normalization of endocrine function in women with previously identified endocrine
disorders (PCO, hyperandrogenism and increase in bodyweight),
probably related to VPA medication [89] ; serum insulin and testosterone levels returned to normal within 2 months following
Expert Rev. Neurother. 9(12), (2009)
Epilepsy, sex hormones & antiepileptic drugs in female patients
VPA replacement, and the levels remained normal thereafter.
Consistent with these findings, Morrell et al. reported that
women taking LTG had lower serum testosterone levels than
women taking VPA [90] .
In conclusion, careful endocrine observation of girls treated
with EIAED and VPA is important, while it seems that the new
AEDs may offer an alternative if reproductive endocrine problems
emerge during treatment with the older AEDs. Ovarian function
should be monitored closely as part of the comprehensive care of
women with epilepsy to prevent adverse effects of ovarian failure,
mainly in patients with more frequent seizures who need AED
polytherapies and/or in patients treated with old AEDs.
AEDs & PCOS
The most common reproductive endocrine disorder in women
with epilepsy is PCOS [13,21,75] . PCOS occurs in 10–20% of
women with epilepsy compared with 5–6% of women in the
general population [9,13,14,75] .
Polycystic ovary syndrome represents the failure of the ovarian follicle to complete normal maturation during the menstrual
cycle or a series of cycles, a failure that is perhaps related to the
presence of inadequate levels of pituitary FSH, while levels of LH
are normal or elevated [61] . These conditions can produce a failure
of ovulation and the partially developed follicle is retained in the
ovary in the form of a tiny cyst [46,47] . This partially developed
follicle is secretory but it is deficient in aromatase, the enzyme
that converts testosterone to estrogen and, therefore, this follicle
has testosterone as its principal secretory product. Testosterone
may increase the positive feedback of estrogen on pituitary LH
secretion, resulting in increased ovarian steroid secretion, and
can result in hyperandrogenism. Testosterone is aromatized in
peripheral adipose tissue, generally producing high–normal levels of estrogen [61] . Women with this syndrome frequently have
elevated cholesterol with abnormal lipid profiles, elevated insulin
and glucose intolerance [90,91] .
Although women with epilepsy may already have a higher
instance of the PCOS, it has been suggested that treatment with
certain AEDs, particularly VPA, increases this risk further [2,70,89] .
The role of VPA in the pathogenesis of PCOS has been first raised
by Isojärvi et al., who showed that PCOS and hyper­androgenism
may be more common in women with epilepsy who were treated
with VPA than in women treated with other AEDs [2] . Other studies confirmed these findings [69,70,75,92] . Interestingly, Gorkemli
et al. found no statistically significant duration-related rise of risk
for patients who developed PCOS; the lack of a duration-related
reproductive dysfunction may support the hypothesis of early
occurring VPA-associated endocrine changes [93] .
However, recent research did not substantiate the role of
VPA [60,76,94–96] ; the relationship between PCOS and AED
treatment remains controversial [75,95,97] .
The pathogenesis of PCOS appears to be multifactorial, including
genetic predisposition and the intervention of environmental factors.
An important risk factor for PCOS is weight gain [98–101] , which is a
common and undesirable effect of certain AEDs, notably VPA and,
to a lesser extent, CBZ, vigabatrin and gabapentin [102–107] . Weight
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gain may lead to the expression or exacerbation of PCOS in some
genetically predisposed women, reducing insulin sensitivity. Thus,
AED-related weight increases could trigger the manifestation of a
clinically relevant endocrine disorder; in particular, VPA-induced
weight gain and the related endocrine abnormalities (e.g., hyperinsulinemia and hyperandrogemia) may induce the development
of PCOS [18] .
The pathogenic mechanisms underlying weight gain during
VPA treatment are still unclear [70,108–111] . The observation that
VPA-treated epileptic patients who reported weight gain developed increased appetite, thirst and quenching with calorie-rich
beverages supports the hypothesis of a stimulating effect of VPA
on the hypothalamus [89,109,112,113] .
It has been also suggested that VPA-related obesity may be
associated with elevated serum leptin levels in women with epilepsy [70,102] , but it is unclear whether leptin behavior in VPAinduced obesity is similar to that in any other obesity situation, as
supported by some data [114] . VPA can modify leptin levels through
the increase of bodyweight, and this modification is related to BMI.
Moreover, it is likely that obesity is the cause of insulin resistance
and related hyperinsulinemia [103] , which are often associated
with PCOS [115] . By suppressing the synthesis of SHBG, insulin
increases free androgen concentrations, subsequently increasing
the degree of hirsutism. The positive correlation between insulin
resistance and obesity means that in some women with PCO, the
clinical manifestation of menstrual irregularity and hirsutism
will only become apparent if there is an increase in weight and
associated metabolic changes [98] .
It has also been proposed that weight gain is associated with
low serum IGF-binding protein 1 levels, which may lead to
hyperandrogenism and PCO [70] . In addition, a significant
weight gain was recorded in a retrospective ana­lysis of hospital records of the women taking VPA who also had PCO and
hyperandrogenism; these women had higher insulin and lower
IGF-binding protein 1 levels.
The specific mechanism by which VPA induces insulin resistance remains to be determined. It is likely that, because VPA is a
branched-chain fatty acid, it can compete with free fatty acids for
albumin binding, increasing their local availability and thus their
physiological modulation of insulin secretion [94] . Moreover, it has
been demonstrated that VPA can directly stimulate pancreatic
b-cells [116] and inhibit GLUT-1 activity [117] .
Finally, in animal experiments VPA has been shown to alter
steroidogenesis and increase testosterone-to-estrodiol ratios in
porcine ovarian follicles [118] . Continuous treatment with VPA
increased the number of follicular cysts and altered sex steroid
hormone levels in rats [119] and increased the number of ovarian
follicular cysts in rats [120] . It remains to be proven that these
direct gonadal VPA effects are clinically relevant in humans.
Moreover, VPA is associated with another phenomenon potentially associated with the development of PCOS; it is an AED
with an inhibitory effect on the hepatic P450 enzyme system and,
therefore, it may inhibit the metabolism of sex steroids, such as
testosterone, and thereby lead to increased androgen levels [121] .
On the contrary, EIAEDs, such as CBZ, PHT or PB, may exert
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Verrotti, D’Egidio, Coppola, Parisi & Chiarelli
a protective effect against the development of PCOS by reducing
biologically active testosterone in the serum and by increasing the
binding and metabolism of testosterone.
In conclusion, it remains unclear whether VPA is directly
responsible for the development of PCOS from otherwise normal ovaries. Although it is possible that weight gain may alter
the endocrine and biochemical features to produce PCOS, there
is no conclusive evidence to support this hypothesis. For these
reasons, to date, VPA remains a first-line option for treatment of
many epilepsy types, including in young women. However, since
VPA treatment is associated with greater disruption of reproductive endocrine functions than other AEDs, the length of the
menstrual cycles and bodyweight should be monitored in women
with epilepsy after beginning treatment with VPA.
Pregnancy & epilepsy
Good seizure control is paramount during pregnancy, especially
in the light of the observation that maternal mortality rates are
higher in women with epilepsy compared with the general population [122] . Regarding the effects of seizures of the fetus, seizures
other than generalized tonic–clonic seizures are unlikely to cause
harm. Convulsive seizures, on the other hand, induce lactic acidosis, which is transferred to the fetus and may also cause fetal
bradycardia [123,124] . In addition, status epilepticus can result in
intrauterine death [125] . The risk for the latter may have been overestimated, since one large prospective study reported only one case
of intrauterine death and no maternal mortality among 36 cases
with status epilepticus [126] . Furthermore, recent data suggest
that the number of stillbirths is not increased among women
that are adequately treated for their epilepsy during pregnancy
[127,128] . Finally, there is no clear evidence that partial, absence or
myoclonic seizures adversely affect a pregnancy or the developing
fetus, other than by effects of trauma.
In the past, women with epilepsy were considered at greater
risk for obstetric complications, including Cesarean delivery, preeclampsia, pregnancy-related hypertension, premature contractions
or premature labor and delivery. Most recent studies, however, suggest that with appropriate medical management the incidence of
complications in women with epilepsy is similar to that of the general population [128–133] . AED therapy should be optimized at least
6 months before conception. The reduction or withdrawal of AED
therapy during pregnancy is pointless because any congenital malformations occur in very early stages of develop­ment. The reduction
or withdrawal of AED therapy during pregnancy is also hazardous
because, although maternal seizures do not seem to increase the risk
of congenital malformations [134–138] , they may be harmful to both
the mother and the fetus Mothers should be strongly encouraged to
maintain adequate compliance with drug therapy [139] .
On the other hand, the risk of major congenital malformations is
two-to-three-times higher in children of mothers treated for epilepsy
during pregnancy than is expected in the general population [124] .
The reasons for this increased risk are mainly owing to teratogenic
effects of AEDs. In fact, a meta-ana­lysis suggested that the malformation rate among the offspring of women with untreated epilepsy
was similar to that of nonepileptic controls [134] . The incidence of
1808
congenital malformations has been reported to increase with the
number of AEDs used in polytherapy [140,141] . For some AEDs, notably VPA [127,142,143] and possibly LTG [144] , the risk in monotherapy
appears to be dose dependent. Comparative studies suggest that the
risk of malformation, in particular of neural tube defects, seems to
be greater with VPA compared with other AEDs [144–146] .
In conclusion, available information indicates that the risk of
congenital malformations is increased among offspring of women
with epilepsy, and that this increase may be attributed largely to the
effects of AEDs. However, the incidence of congenital malformations varies 20-fold across published studies [147,148] , mainly because
of methodological differences. In fact, there are major differences
in the populations studied, the diagnostic criteria used to identify
abnormalities, exclusion criteria and the denominators used to
calculate the risk of malformations. Therefore, although the use
of AEDs during pregnancy is associated with an increased risk for
birth defects, this risk must be balanced against those associated
with uncontrolled seizures. Furthermore, AED-related risks to the
fetus could probably be reduced by appropriate treatment adjustments (e.g., a switch from polytherapy to mono­therapy, avoidance
of VPA when possible and titration to the lowest effective dosage).
Expert commentary
Sexual dysfunction in women suffering from epilepsy is an important issue and in recent years there has been growing evidence to
support the role of both epilepsy per se and different AEDs in the
development of this comorbidity.
Endocrinologic abnormalities related to epilepsy can reasonably be expected in view of the complex and close interconnections between the HPA and the cortex. Focal epileptic discharges (in particular from the temporal lobe) can affect HPA
function. Consequently, the production of LH, FSH, GnRH
and PRL and the concentrations and metabolism of their end
products (e.g., estrogen, testosterone and DHEAS) appears to
be modified in epileptic women. Most of the older AEDs (PB,
CBZ and PHT) are known to affect levels of steroid hormones
by enhancing their metabolism through activation of the cytochrome P450 oxidative system, thereby also inducing SHBG
synthesis in hepatocytes.
Moreover, VPA is associated with a frequent occurrence of
reproductive endocrine disorders characterized by polycystic
changes in the ovaries, high serum testosterone concentrations
(hyperandrogenism) and menstrual disorders. Young women with
epilepsy seem to be especially vulnerable to the effects of VPA
on serum androgen levels. It is probable that obesity and related
hyperinsulinemia may exacerbate the VPA-related reproductive
endocrine disorders; in the majority of cases these disorders are
reversible. There is a significant lack of data regarding the effects
of new AEDs.
Physicians should be aware of reproductive endocrine dysfunction that may occur in women with epilepsy during treatment. If a reproductive endocrine disorder is found AEDs
should be reviewed in terms of their indication for the particular seizure type and their tolerability vis-à-vis their potential
for contributing to these endocrine problems.
Expert Rev. Neurother. 9(12), (2009)
Epilepsy, sex hormones & antiepileptic drugs in female patients
Five-year view
It is now clear that both seizures and some old AEDs have detrimental effects on reproductive function in epileptic patients.
In the coming years, understanding the underlying mechanisms
of these effects will provide more information about the direct
influence of the epileptogenic lesion and about the central and
peri­pheral effects on endocrine glands, the metabolism of sex
hormones and binding proteins and the secondary endocrine
complications of AED-related weight changes.
One of the challenges of the next few years is to better define the
endocrine and reproductive effects of the new AEDs, especially in
long-term therapy. These findings will change our policy toward
female patients and enable us to better choose the appropriate
AEDs (particularly in subpopulations at risk, e.g., adolescents,
Review
obese patients and/or patients with previous ovarian dysfunctions). Currently, the concept of ‘personalized’ medicine is receiving much attention; as research in this area advances rapidly, it is
probably that the choice of AEDs will be driven by more accurate
and complete considerations to optimize the treatment of epilepsy
for the individual patients.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Reproductive endocrine disorders, including polycystic ovary syndrome (PCOS), have been associated with epilepsy and the incidence of
menstrual irregularities appears to be more common among women with epilepsy than among women without epilepsy.
• Epilepsy itself may directly influence the endocrine control centers in the brain by altering the release of sex steroid hormones including
the production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone and prolactin and the
concentrations and metabolism of its end products such as estrogen and testosterone.
• In localization-related epilepsy, clinical investigations indicate a close relationship between the occurrence of temporolimbic discharges
and pituitary hormone changes, and an association between epilepsy laterality in temporolimbic epilepsy and the occurrence of certain
reproductive endocrine disorders.
• Left unilateral temporolimbic epilepsy is associated with a higher occurrence of PCOS, while right unilateral temporolimbic epilepsy is
associated with hypothalamic amenorrhea.
• A possible role for the use of antiepileptic drugs as an alternative pathogenic mechanism has been suggested.
• The use of enzyme-inducing antieplileptic drugs, such as phenobarbital, phenytoin and carbamazepine, increases serum sex hormonebinding globulin concentrations leading to diminished bioactivity of estrodiol, which may result in menstrual disorders in some women,
and thus to reduced fertility.
• The inhibition of the aromatase complex (CYP19) activity, induced by phenobarbital, phenytoin, valproic acid (VPA), oxcarbazepine and
lamotrigine, may explain the decreased production of estrodiol observed in vivo.
• In women, the use of valproic acid (VPA), a non-enzyme-inducing antiepileptic drug, appears to be associated with a frequent
occurrence of menstrual disorders, hyperandrogenisn and polycystic changes. These disorders are especially common among women
who have gained weight during VPA treatment.
• The mechanism of VPA-associated hyperandrogenism may result from inhibition of the conversion of testosterone to estrogen induced
by VPA.
• The mechanisms of VPA-induced PCOS are still controversial. VPA-induced weight gain or obesity and the resultant insulin resistance
have been suggested to predispose patients to PCOS.
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•
•
Affiliations
•
Alberto Verrotti
Department of Pediatrics, University of
Chieti, Via dei Vestini 5, 66100 Chieti,
Italy
Tel.: +39 087 135 8015
Fax: +39 087 157 4831
[email protected]
1814
Claudia D’Egidio
Department of Pediatrics, University of
Chieti, Via dei Vestini 5, 66100 Chieti,
Italy
Tel.: +39 087 135 8015
Fax: +39 087 157 4831
[email protected]
Giangennaro Coppola
Clinic of Child Neuropsychiatry, Second
University of Naples, Italy
Tel.: +39 081 566 6695
Fax: +39 081 566 6694
[email protected]
•
Pasquale Parisi
Department of Child Neurology and Sleep
Centre, University of Rome, Italy
Tel.: +39 068 213 529
Fax: +39 068 245 556l
•
Francesco Chiarelli
Department of Pediatrics, University of
Chieti, Via dei Vestini 5, 66100 Chieti,
Italy
Tel.: +39 087 135 8015
Fax: +39 087 157 4831
[email protected]
Expert Rev. Neurother. 9(12), (2009)