Received: 12 July 2023

| Revised: 27 November 2023

| Accepted: 28 November 2023

DOI: 10.1111/epi.17842

CRITICAL REVIEW

Female sex steroids and epilepsy: Part 1. A review of

reciprocal changes in reproductive systems, cycles, and
seizures

Malak Alshakhouri1 | Cynthia Sharpe2 | Peter Bergin3 | Rachael L. Sumner1

1
School of Pharmacy, University of
Auckland, Auckland, New Zealand
2
Department of Paediatric Neurology,
Starship Children's Health, Auckland,
New Zealand
3
Neurology Auckland Hospital, Te
Whatu Ora, Auckland, New Zealand
Correspondence
Rachael L. Sumner, School of
Pharmacy, University of Auckland,
Private Bag 92019, Auckland 1142, New
Zealand.
Email: rsum009@aucklanduni.ac.nz
Funding information
Maurice and Phyllis Paykel Trust;
Neurological Foundation of New
Zealand
Abstract
Seizures, antiseizure medications, and the reproductive systems are reciprocally
entwined. In Section 2 of this review, we outline how seizures may affect the
hypothalamic–pituitary–gonadal axis, thereby altering sex steroids, and changes
in sex steroids across the menstrual cycle and changes in pharmacokinetics dur-
ing pregnancy may alter seizure susceptibility. The literature indicates that fe-
males with epilepsy experience increased rates of menstrual disturbances and
reproductive endocrine disorders. The latter include polycystic ovary syndrome,
especially for females on valproate. Studies of fertility have yielded mixed results.
We aim to summarize and attempt to detangle the existing knowledge on these
reciprocal interactions. The menstrual cycle causes changes in seizure intensity
and frequency for many females. When this occurs perimenstrually, during ovu-
lation, or in association with an inadequate luteal phase, it is termed catamenial
epilepsy. There is a clear biophysiological rationale for how the key female repro-
ductive neurosteroids interact with the brain to alter the seizure threshold, and
Section 3 outlines this important relationship. Critically, what remains unknown
is the specific pathophysiology of catamenial epilepsy that describes why not all
females are affected. There is a need for mechanism-­focused investigations in
humans to uncover the complexity of the relationship between reproductive hor-
mones, menstrual cycles, and the brain.

KEYWORDS
catamenial epilepsy, endocrine health, fertility, menstrual cycle, pregnancy

1 | I N T RO DU CT ION transmission, and receptor plasticity.1,2 Although they

Female sex steroids, progesterone and estradiol, have
neuroactive properties and are involved in modulat-
ing numerous brain processes, such as neuronal excita-
tion and inhibition balance, neuroprotection, synaptic
are mainly produced peripherally by the ovaries,3 they
are both highly lipophilic, which means they can eas-
ily cross the blood–brain barrier and rapidly diffuse
throughout the brain.4 They are also synthesized de novo
within the brain.5 Therefore, the cyclic fluctuations of

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

556 | wileyonlinelibrary.com/journal/epi
 Epilepsia. 2024;65:556–568.

ALSHAKHOURI et al.
the neuroactive sex steroids across the healthy menstrual
cycle, or changes over pregnancy, have an impact on the
female brain, with multiple cognitive and emotional rami-
fications.6 A growing body of research demonstrates cyclic
exacerbation of psychiatric and neurological symptoms in
disorders such as, but not limited to, depression, migraine,
and epilepsy.7–10
The aim of this review is to provide an up-­to-­date ac-
count of the reciprocal relationship between epilepsy and
sex steroid-­based endocrinological disorders in females.
Section 2 describes the gonadal manifestations of disor-
ders, including menstrual disturbance, polycystic ovarian
syndrome, fertility, and pregnancy. Sections 3 and 4 focus
on the brain-­based manifestations, primarily via seizure
severity and frequency changes. Specifically, Section 3
briefly outlines seizure changes in pregnancy and catame-
nial epilepsy (i.e., menstrual cycle-­linked seizure exacer-
bation), and Section 4 describes the current understanding
of the pathophysiology and the potential molecular mech-
anism underlying catamenial epilepsy.
2 | F E M A L E SE X ST E ROIDS,
E P I L E P S Y, AN D R E PRODU CT IV E
S YST E M S
2.1 | Epilepsy interactions with
reproductive endocrine system
Epilepsy, antiseizure medications (ASMs), and the endo-
crine system have complex interactions. Epileptic activity
has been associated with functional changes in the hy-
pothalamic–pituitary–gonadal (HPG) axis, which regu-
lates sex steroid production and secretion, presumably
through the limbic system.11 These complex interactions
put women with epilepsy at increased risk of various chal-
lenges, including sexual, reproductive, and endocrine
health disturbances.12 These disturbances include men-
strual cycle abnormalities, anovulatory cycles, polycystic
ovary syndrome, and reduced fertility.13
Initially, reproductive health disturbances among
women with epilepsy were thought to be only associ-
ated with epilepsy per se rather than the use of ASMs.14
However, this view had changed since the late 1970s and
early 1980s, when serum levels of sex hormone-­binding
globulin (SHBG) were found to be elevated in women with
epilepsy treated with enzyme-­inducing ASMs but not in
untreated women.15 Prolonged elevated serum SHBG lev-
els led to a decreased bioactivity of testosterone and es-
tradiol, which in turn led to menstrual disturbances that
contributed to a higher risk of infertility among women
with epilepsy.16 Together, these findings indicate that the
cause of reproductive and endocrine health disturbances
|
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   557
Key points
• The reciprocal interactions between epilepsy
and the reproductive systems put women
with epilepsy at heightened risk of endocrine
disturbances
• Seizure activity and antiseizure medications
can disturb the function of the hypothalamic–
pituitary–gonadal axis
• This is experienced as increased menstrual
cycle irregularities and anovulatory cycles
• The interaction of epilepsy and/or antiseizure
medicines with the reproductive systems also
alters seizure severity and frequency
• The complexity of these relationships and a
lack of objective biomarkers hinders progress
in treating issues that arise such as catamenial
epilepsy
in women with epilepsy is multifactorial, wherein epi-
leptiform discharges could cause neuroendocrine alter-
ations,17 and ASMs could lead to metabolic alterations in
hormones.
2.2 | Impact of epilepsy on female
reproductive endocrine health
2.2.1 | Hormone regulation
Both generalized and focal epileptic seizures alter the
input to the HPG axis from the cortex, the amygdala,
and the hippocampus.17 As described above, in females,
the HPG axis is primarily responsible for regulating the
menstrual and ovarian cycles.8 Thus, any alteration to this
cascade of endocrine events will result in menstrual and
ovarian disturbances.
Animal studies have shown that the laterality of the
epileptiform discharge within the limbic system differ-
entially alters the hypothalamic release of gonadotropin-­
releasing hormone (GnRH).18 Herzog et al.11 presented a
comprehensive, controlled clinical study of women with
epilepsy versus healthy controls, showing that luteinizing
hormone (LH) and follicle-­stimulating hormone (FSH)
levels are more variable among women with temporal lobe
epilepsy compared to healthy controls, and estradiol levels
are significantly greater in healthy controls when tested
during the early to mid-­follicular phase (days 3–7). They
also found lateralized asymmetries between unilateral left
and right temporolimbic epilepsy in the pulsatile secre-
tion of LH, prolactin, and gonadal steroids.11 In addition,
 |
558   
women with a variety of epilepsies not treated with ASMs
were found to have increased LH pulsatility, causing estra-
diol level dysregulation.19
Overall, animal and clinical studies evaluating the ef-
fects of seizure laterality and focality on HPG regulation
and hormone levels in women with epilepsy have been
scarce. However, it could be inferred from the above ob-
servations that the nature of the hormone dysregulation
may depend on the focality and laterality of the epileptic
activity, as well as the frequency of seizure occurrence.12
An example is amygdala involvement in temporal lobe ep-
ilepsy. The corticomedial nuclear group of the amygdala
stimulates the release of GnRH, whereas the basolateral
nuclear group inhibits the release of GnRH.20 Depending
on the affected nuclear group, excitation of the amygdala
will either stimulate or inhibit the hypothalamic release of
GnRH and the release of pituitary gonadotropins.12 This
orchestrated impact of the epileptic activity will eventu-
ally disrupt the release of the corresponding sex steroids,
contributing to the greater rate of menstrual disturbances
among women with epilepsy compared to the general
population.
2.2.2 | Menstrual disturbances
Almost one-­ third of women with epilepsy experience
menstrual disturbances, compared to 12%–14% of women
without epilepsy.21 These disturbances include hypotha-
lamic amenorrhea (no menses for 6 months associated
with low gonadotropin and estradiol levels and dimin-
ished LH response to GnRH), oligomenorrhea (cycle
interval > 32 days), polymenorrhagia (cycle interval
< 26 days), abnormal variation in cycle interval (>4 days),
and menometrorrhagia (heavy menses and bleeding be-
tween menses).21 Herzog et al.22 reported amenorrhea in
12%–20% of women with epilepsy, compared to 1.5% of
healthy controls. Hamed et al.23 reported a greater risk of
menstrual irregularities in 71.6% of women with epilepsy
compared to 21.7% of healthy controls, with oligomenor-
rhea being the most common among women with epilepsy
(90.4%), followed by amenorrhea (19.2%) and menorrha-
gia (11.5%).
Elevated prolactin levels without identifiable pituitary
lesions and premature menopause are also more com-
mon among women with epilepsy than the general pop-
ulation.24,25 Klein et al.26 reported that the prevalence of
premature menopause in women with epilepsy is 14%,
compared to 4% in the general population. Catamenial
seizure exacerbation was significantly associated with
premature menopause, which the authors attributed to a
potentially increased sensitivity of temporolimbic epilep-
tiform tissue to gonadal hormonal effects.
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ALSHAKHOURI et al.
Anovulatory cycles are prevalent in women with epi-
lepsy, with more than one-­third of cycles in women with
focal epilepsy being anovulatory, compared to approxi-
mately 8%–10% in women without epilepsy.27 Women with
primary generalized epilepsy are at greater risk of having
anovulatory cycles than women with focal epilepsy.12
2.2.3 | Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is characterized by
heterogeneous clinical symptoms of hyperandrogen-
ism and ovarian dysfunction, provided that other endo-
crinopathies have been excluded.28,29 These symptoms
include cycle irregularities, hirsutism, infertility, and the
presence of polycystic ovarian morphology.30 Women
with epilepsy are said to be at an increased risk of develop-
ing PCOS, especially when their seizures start at an early
age.31 However, the reported prevalence of PCOS varies
according to the diagnostic criteria implemented and the
epilepsy type. PCOS prevalence in the general population
is estimated to be approximately 15% according to the UK
and European criteria, compared to 5%–10% using the
more stringent US criteria32 and 5.5%–6.1% using the strict
National Institutes of Health (NIH) criteria.33 In compari-
son, PCOS prevalence among females with epilepsy was
reported to be anywhere between 11% and 26%.34–38
This wide range of PCOS prevalence among women
with epilepsy is derived from a total of five clinical case
studies.34–38 Four studies found no significant difference
in the prevalence of PCOS between women on ASMs and
women who are not,34–37 three of which controlled for
the use of valproate, carbamazepine, or a combination of
both, or the use of other medications and reported no sig-
nificant differences.34–36 The one study that found an asso-
ciation between PCOS and the use of ASMs reported that
valproate in particular was associated with an increased
risk of PCOS.38
It is possible that women with focal epilepsy are specif-
ically at an increased risk of developing PCOS compared
to those with generalized epilepsy. Yet, the studies that
evaluated the association between PCOS and epilepsy type
found conflicting results. Bauer et al.36 found no differ-
ence in the incidence of PCOS between women with focal
epilepsy and women without epilepsy, whereas Herzog
et al.22 found that PCOS was significantly more preva-
lent in women with temporal lobe epilepsy compared to
women without epilepsy. Interestingly, Herzog et al.11
reported that PCOS was particularly associated with left-­
sided temporal lobe epilepsy compared to right-­sided tem-
poral lobe epilepsy. This could be related to the asymmetry
in the limbic and other brain structures involved in regu-
lating ovarian function.39 In particular, the seminal study

ALSHAKHOURI et al.
by Herzog et al.11 found that women with unilateral left
temporal lobe epilepsy have higher LH pulse frequency,
higher LH:FSH ratio, and higher testosterone levels, all of
which are characteristic of PCOS and are compatible with
the finding that they have a higher occurrence of PCOS.
On the other hand, Betts et al.40 and Zhou et al.31 reported
no association between PCOS and epilepsy type, seizure
frequency, or epilepsy duration.
It has been questioned whether the difference in PCOS
incidence between women with focal epilepsy and the
general population is associated with the use of ASMs, in
particular valproate, or with epilepsy itself.30,41 The rela-
tionship between PCOS and the use of ASMs will be dis-
cussed in more detail in Section 2.3. Future studies would
benefit from unifying the diagnostic criteria of PCOS. They
should ideally be prospective to allow menstrual patterns
to be studied in women with epilepsy before and after the
inception of epilepsy treatment. Although this might be
challenging, as newly diagnosed women may warrant im-
mediate epilepsy treatment, cycle tracking apps are now
widely used, and so pre-­existing records of menstrual
cycle patterns could be utilized to overcome this challenge
without delaying epilepsy treatment.
2.2.4 | Fertility and pregnancy outcomes
Epidemiologic studies have found that both women and
men with epilepsy are less likely to have children, which
may indicate a higher rate of infertility but may also en-
compass social contributing factors, such as lower rates of
being in a relationship, financial security, or lower rates
of seeking pregnancy due to epilepsy-­related risks and
doubts.42,43 According to a survey-­based study by Crawford
and Hudson,44 approximately one-­third of women with
epilepsy of childbearing age were not considering having
children because of their epilepsy. Additionally, survey-­
based studies suggest that decisions to avoid pregnancy
mostly stem from a lack of certainty about pregnancy
trajectories and fetal risks, and in some cases, from false
information suggesting that women with epilepsy are not
fit parents and that the risk of passing on epilepsy or of
congenital disabilities is higher than it actually is.12
Studies assessing fertility in women with epilepsy
have reported conflicted findings. Some studies reported
reduced fertility,45–47 whereas others reported no differ-
ence.48 The only prospective study, to our knowledge,
comparing females with epilepsy to controls attempting to
conceive without prior known infertility or related disor-
ders found no significant differences in the rate of preg-
nancy, time to pregnancy, or live birth rates.42 However,
the study excluded women who had an established diag-
nosis of infertility or related disorders but did not report
|
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   559
the number or proportion excluded from each group,
which would have been insightful.
The proportion of women with epilepsy who achieved
pregnancy was 60.7% of 89 compared to 60.2% of 108 con-
trols, which, although similar, makes the pregnancy rate
in this study lower than expected, at least for the control
group; the expected pregnancy rate over 12 months is ap-
proximately 82%.42 The authors attributed this to enrolling
women up to 6 months after birth control cessation (tracking
them for up to 12 months thereafter). The probability of con-
ception has been found to drop with each menstrual cycle
after cessation.49 Although this may explain the reduced rate
of pregnancy for controls, it may or may not generalize to
women with epilepsy. To control for this, the authors would
have had to have enrolled participants prior to discontinua-
tion of contraception, which may not have been possible. In
summary, further research to fully resolve the relationship
between epilepsy and fertility is still needed.
The Epilepsy Birth Control Registry found that in a sur-
vey of 1000 women with epilepsy, there was a 9.2% infertil-
ity risk and 20.7% impaired fecundity risk among women
with epilepsy in the United States compared to 6.4% and
12.7%, respectively, in the general population.46 The au-
thors of the study noted that both values are higher among
women with epilepsy but that differences in the ascertain-
ment and definition of infertility might complicate a direct
comparison.46 They also found that impaired fecundity
rate trended higher on ASM polytherapy than on no ASM
(24.8% vs. 13.9%), and live birth to pregnancy ratio was sig-
nificantly higher with the use of lamotrigine than valproate
(89.1% vs. 63.3%).46 Yet, they compellingly argue that the
identification of ASM use or polytherapy as a risk factor
does not imply a direct causal role because ASM polyther-
apy may reflect less well-­controlled seizures, which could
also contribute to the higher rates of infertility or adverse
pregnancy outcomes among women with epilepsy. The im-
pact of ASMs on females' reproductive health will be dis-
cussed in more details in the following section.
2.3 | Impact of ASMs on female
reproductive health
ASMs can be divided broadly into enzyme-­inducing and
non-­enzyme-­inducing.50 Phenytoin, carbamazepine, ox-
carbazepine, topiramate, and phenobarbital are potent in-
ducers of liver cytochrome P450 isoforms.50 Hepatic P450
isoforms are involved in metabolizing a variety of drugs
to a more water-­soluble form, making them more readily
excreted.51 The induction of hepatic P450 by phenytoin,
carbamazepine, and phenobarbital has been reported to
be implicated in catalyzing the metabolism of endogenous
progesterone and its neuroactive derivatives,52,53 as well
 |
560   
as synthetic progestogen and estrogen components of oral
contraceptives.51,54 The former may contribute to loss
of seizure control, thereby increasing the risk of break-
through seizures in women with epilepsy treated with
enzyme-­inducing ASMs.50 The latter could reduce the ef-
ficacy of oral contraceptives in preventing pregnancy.51
Moreover, hepatic enzyme-­inducing ASMs have been
found to increase serum SHBG concentrations in women
with epilepsy, which over time lead to diminished concen-
trations of the free, circulating, biologically active forms of
endogenous sex steroids.12 Morrell et al.55 found that women
receiving hepatic enzyme-­inducing ASMs have significantly
reduced serum concentrations of estrone, testosterone, and
dehydroepiandrostenedione compared to healthy controls.
On the other hand, women with epilepsy treated with non-­
enzyme-­inducing ASMs, such as gabapentin or lamotrig-
ine, had sex steroid hormone levels that did not differ from
healthy controls.55 The exact clinical implications of these
hormone changes are yet to be elucidated.
Valproate, one of the most used ASMs, is a liver enzyme
inhibitor rather than an inducer. It inhibits liver CYP19,
causing inhibition of the aromatase complex that converts
androgens to estrogens, leading to hyperandrogenemia and
hyperinsulinemia hormone imbalance.56 Women receiving
valproate have significantly elevated adrenal and gonadal
androgens.16 These valproate-­induced hormone shifts may
cause infertility directly or indirectly through weight gain.56
Valproate, but not carbamazepine, gabapentin, lamotrigine,
phenobarbital, or phenytoin, was significantly associated
with anovulatory cycles.12 Among women with general-
ized genetic epilepsy who are on valproate, 55% of cycles
were anovulatory.57 Furthermore, women currently or re-
cently receiving valproate were more likely to have PCOS,
and women starting valproate monotherapy or adjunctive
therapy can develop PCOS features within several months
of treatment initiation.58 Valproate-­associated hyperandro-
genism and insulin resistance are reversible when valproate
is substituted with lamotrigine.59 It is still unknown whether
valproate is directly associated with increased PCOS rate, or
if it is the induced hormone shifts, the weight gain, or a com-
bination of these factors.56
3 | F E M A L E SE X ST E ROIDS A ND
S E I Z U RE S
3.1 | Epilepsy interactions with
pregnancy
Wide variations in seizure frequency changes during
pregnancy have been reported in the literature, with
seizure exacerbations occurring in 15%–32%, improve-
ments in 3%–25%, and no significant change in 50%–83%
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ALSHAKHOURI et al.
of pregnant women with epilepsy.60 Women with partial
seizures, on ASM polytherapy or who had at least one sei-
zure during the prepregnancy month, had higher risk of
seizures during pregnancy.60,61 Pennell et al.62 recently
reported that when an equivalent nonpregnant compara-
tor group is used, there is no significant change in seizure
frequency during pregnancy or the peripartum period that
can be attributed to pregnancy itself.
Women with catamenial epilepsy, however, might have
different pregnancy trajectories because they show sex
steroid-­dependent changes in seizure occurrence. A study
comparing pregnancy-­related hormone changes and sei-
zure course between women with catamenial epilepsy and
non-­catamenial epilepsy found that women with catame-
nial epilepsy tend to have better seizure control.63 Women
with perimenstrual catamenial epilepsy in particular were
more than twice as likely to remain seizure-­free or to have
a notable decrease (≥50%) in seizure frequency through-
out the pregnancy.63
There is a significant difference in the rates of medication
change. Understandably, pregnant women with epilepsy are
more likely to change medications over the same time pe-
riod. Although one reason for change may be the teratogenic
effects of some medications relative to others, more often a
change in medications to less teratogenic options is com-
pleted at the time of conception planning or when a female
becomes of child-­bearing potential.64 Changes to medica-
tion dose occur due to pregnancy-­induced pharmacokinetic
change (including decreased protein binding, altered he-
patic metabolism, and increased kidney blood flow).65 To
maintain the same therapeutic blood concentration of an
ASM, doses often need to be increased.66
A large prospective study of approximately 3800 preg-
nancies of women with epilepsy on valproate, carbamaz-
epine, phenobarbital, or lamotrigine monotherapy found
that 66% of women with epilepsy remained seizure-­free
during the entire pregnancy.67 Of note, they found that
drug dose was increased or a second drug was added in
almost one-­third of the pregnancies. Although most of
these changes occurred after a seizure and may have been
prompted by poor seizure control, drug doses were also in-
creased in approximately 19% of the pregnancies that re-
mained seizure-­free.67 This suggests that, in some cases,
physicians are adjusting ASM doses as a preventative mea-
sure to account for the pregnancy-­induced pharmacoki-
netic changes and reduce the risk of breakthrough seizures.
3.2 | Epilepsy interactions with
menstrual cycle
The exacerbation of seizure frequency or intensity at spe-
cific phases of the menstrual cycle is termed catamenial

ALSHAKHOURI et al.
epilepsy.68 Generally, catamenial diagnosis is given if sei-
zure frequency increases by at least twofold during a cer-
tain phase of the cycle in two of three cycles.69 Catamenial
exacerbation appears to occur with all seizure types and
epilepsy syndromes, including idiopathic, structural/meta-
bolic, and unknown etiologies.13 The literature suggests that
catamenial seizure exacerbations may be more resistant to
treatment with the standard ASMs.25 Catamenial epilepsy
can therefore be a cause of drug-­resistant epilepsy.70 Current
potential treatment options include the use of hormonal
(progesterone), nonhormonal (e.g., clobazam) medications,
or a complete cessation of menstruation using synthetic
hormones (e.g., medroxyprogesterone acetate).71 However,
although these treatment options hold some merit, accord-
ing to the Maguire and Nevitt71 Cochrane review, there is
currently no class I evidence of an effective treatment for
catamenial seizures. This indicates that a massive gap ex-
ists in our understanding of what changes occur in the brain
in relation to hormonal fluctuations and how these changes
alter seizure susceptibility and drug sensitivity.
4 | PAT H O PH Y SIOLOGY OF
C ATA M E NI AL E PILE PSY
Catamenial epilepsy is a multifaceted neuroendocrine dis-
order, the exact cause of which remains unclear.72 This
is a major barrier to developing objective biomarkers of
catamenial epilepsy. The neuroendocrine properties of
steroid hormones and the cyclic variations in their serum
levels are now widely accepted to play a significant role
in catamenial seizure exacerbation.25 Progesterone and
estradiol can easily cross the blood–brain barrier and rap-
idly diffuse throughout the brain.4 The peripheral levels of
these hormones were found to be highly correlated with
their levels within the brain.4 Progesterone and estradiol
are also synthesized within the brain and are involved in
modulating numerous brain processes, such as neuronal
excitability, neuroprotection, synaptic transmission, and
receptor plasticity.1,2 Progesterone has been shown to
have anticonvulsant effects, whereas estradiol has pro-
convulsant effects.72 However, there are some excep-
tions to this common conception. Furthermore, it is most
often allopregnanolone (ALLO), the major metabolite of
progesterone, that lies at the center of discussion on the
pathophysiology of catamenial epilepsy.
4.1 | Estrogen influence on neuronal
excitability
There are three biologically active forms of estrogens:
(1) 17b-­
estradiol, prevalent in premenopausal women;
|
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   561
(2) estriol, dominant in pregnant women; and (3) es-
trone, which becomes the major form after menopause.50
Estradiol has been extensively investigated in epilepsy
models, as it acts on neurons within the limbic system,
cerebral cortex, and other regions important for seizure
susceptibility.73 Estradiol appears to have primarily pro-
convulsant effects and thus may contribute to the worsen-
ing of seizures in catamenial epilepsy.74
The excitatory effects of estradiol are mediated by
augmenting N-­methyl-­D -­aspartate-­mediated glutamate
receptor activity and regulating neural plasticity.25 Most
of the data suggest that estradiol enhances neuronal ex-
citability by enhancing glutamatergic transmission and
depressing γ-­aminobutyric acid (GABA) inhibition.75–77 It
does so by increasing the number of spine synapses and
spine density, and altering the spine shape on the apical
hippocampal dendrites in CA1 pyramidal neurons.78 A
positive correlation was observed between the dendritic
spine density and levels of circulating estradiol in rodent
models.78 On the other hand, estradiol reduces GABA
synthesis in the corticomedial amygdala by attenuating
glutamic acid decarboxylase (GAD) activity, which is the
main enzyme involved in the synthesis of GABA. Reduced
GABA synthesis and GABAergic inhibition result in en-
hanced neuronal excitability.25
Accordingly, seizure exacerbation during the preovula-
tory phase might be underpinned by the midcycle surge of
estradiol, which is not counterbalanced by progesterone
until the early luteal phase.13,25,73 Likewise, the increase in
the estradiol:progesterone ratio during the perimenstrual
phase might contribute to the pathophysiology of the C1
pattern.25 In a clinical study of women with epilepsy, sei-
zure susceptibility was correlated positively with the estra-
diol:progesterone ratio, which peaks in the perimenstrual
and preovulatory phases and declines in the mid-­luteal
phase.79
However, the effects of estradiol are not linear.
Some studies suggest that estradiol may have inhibi-
tory effects on cortical excitability and thus have neu-
roprotective properties.80,81 For example, GAD mRNA
expression in the cortex and striatum did not appear
to be estradiol-­ dependent in ovariectomized rats.82
Also, no changes were observed in GAD expression in
the cingulate cortex between proestrus or metestrus
rats (equivalent to the preovulatory and premenstrual
phases in humans, respectively).83 The apparent incon-
sistency between these findings and the finding that es-
tradiol suppresses GAD expression in the corticomedial
structures may indicate that estradiol effects on GAD
expression are brain region-­specific. The exact relation-
ship between plasma estradiol levels, GAD expression,
and the frequency of catamenial epilepsy, therefore, is
yet to be elucidated.50
 |
562   
4.2 | Progesterone influence on neuronal
excitability
The expression of progesterone receptors (PRs) is stimu-
lated by estradiol.72 Thus, the regulation of progesterone
sensitivity is determined by prior estradiol exposure. Given
the complex pharmacology of progesterone and its rela-
tionship with estradiol, it is unlikely that it will exert linear
uniform effects.84 In addition to its actions as a PR agonist,
its metabolite ALLO acts as a potent positive modulator of
GABAA.85 Progesterone is most often noted to have anti-
convulsant effects via ALLO-­mediated GABAergic inhibi-
tion.85–87 However, there is also evidence that progesterone
can exert proconvulsant effects through the classic PRs.88,89
In preclinical studies, progesterone administration
was found to have antiseizure effects in different animal
seizure models, including the pentylenetetrazol model72
and the hippocampal kindling model.90 In both studies,
animals were pretreated with finasteride to prevent the
conversion of progesterone to ALLO. In females with par-
tial epilepsy, progesterone infusion during the first week
of the menstrual cycle that reached the plasma concen-
tration of the luteal phase resulted in a significant de-
crease in spike frequency during the infusion period.91
The effects of progesterone in this clinical study cannot
be separated from those of ALLO, unless a control group
of women on progesterone and a 5-­α reductase inhibitor
were used. Hormonal medications, including progestin-­
only, appear to increase seizures92; speculatively, modula-
tion of PRs may be a mechanism. Taken together, these
findings warrant further research to detangle the effects of
progesterone from the effects of ALLO.
In terms of catamenial epilepsy, seizure probability
was found to be the highest on day 1 following the abrupt
withdrawal of progesterone, and the lowest during the mid-­
luteal phase (day −8) when serum progesterone is the high-
est.93 The clustering of seizures around the start of menses
correlates with a significant drop in progesterone and an
increase in the estradiol to progesterone ratio.50 Hence,
progesterone, and thereby ALLO, withdrawal is believed to
have a key role in the pathophysiology of the C1 pattern.
Although the effects of progesterone and ALLO remain to
be elucidated, there is strong evidence that the antiseizure
effect of progesterone is mediated by ALLO instead of the
classical PRs, because progesterone's effect on seizure ac-
tivity is unchanged in PR-­knockout mice,73 nor is it blocked
following progesterone antagonist administration.94
4.3 | Progesterone-­derived neurosteroids
Progesterone is a main intermediate precursor for the syn-
thesis of several neurosteroids in the brain.95 The conver-
sion of progesterone into ALLO occurs both centrally and
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ALSHAKHOURI et al.
peripherally, and because ALLO is highly lipophilic, it can
rapidly cross the blood–brain barrier and modify neuronal
excitability.87 According to Agís-­Balboa et al.,96 recent evi-
dence suggests that neurosteroids are present mainly in
what they termed principal output neurons (referring to
glutamatergic pyramidal, GABAergic reticulothalamic,
striatal, and Purkinje neurons). In contrast, neurosteroids
are absent in GABAergic interneurons in many brain re-
gions relevant to focal epilepsies, including the hippocam-
pus and neocortex. The highly restricted distribution of
neurosteroids to the excitatory principal neurons suggests
that they are mainly derived from local synthesis.74 This is
further supported by the ability of the brain to produce neu-
rosteroids after gonadectomy and adrenalectomy,5 and the
presence of the required enzymes for neurosteroid synthe-
sis in the principal neurons of the amygdala,97 hippocam-
pus, and other brain regions.98–100 The factors that regulate
their local synthesis are still unclear.74
ALLO is a powerful anticonvulsant and potent positive
modulator of GABAA receptors.95 It can rapidly modulate
neuronal excitability through reversible interactions with
synaptic and extra-­ synaptic GABAA receptors.74 ALLO
binds to the neurosteroid site on GABAA receptor, which
is a different site from that of benzodiazepines. The bind-
ing of ALLO to GABAA receptor causes a massive influx
of chloride ions into the cell, leading to hyperpolarization
and a consequent potentiation of inhibitory neurotrans-
mission.74 ALLO's mechanism of action is concentration-­
dependent.73 At low concentrations, it potentiates the
current of GABAA receptor, whereas at higher concen-
trations, it directly activates the receptor.74 Activation of
GABAA receptors mediates two types of GABAergic inhi-
bition, synaptic and extra-­synaptic inhibition.95
Synaptic GABAA receptors mediate transient (pha-
sic) inhibitory postsynaptic current.101 They contain the
γ subunit, have reduced GABA sensitivity, and are likely
insensitive to the low ambient concentration of GABA
throughout the extracellular space.101 Extra-­synaptic
GABAA receptors contain the δ subunit and have high
GABA sensitivity coupled with a low level of desensiti-
zation in the constant presence of ambient GABA con-
centrations, which makes them ideal for providing tonic
inhibition.101 Tonic current is not time-­locked to presyn-
aptic action potentials, leading to steady neuronal inhibi-
tion and attenuated excitability.101
4.4 | Potential mechanisms of
catamenial epilepsy
4.4.1 | ALLO-­linked molecular changes
There is emerging evidence that fluctuations in endoge-
nous neurosteroids with anticonvulsant or proconvulsant

ALSHAKHOURI et al.
effects could lead to a loss of seizure control and con-
tribute to the pathophysiology of catamenial epilepsy.74
As progesterone fluctuates across the menstrual cycle,
so does the progesterone-­derived neurosteroid ALLO.50
ALLO is normally present in the intracellular space at
the nanomolar concentration range, which is enough
to directly activate extra-­synaptic δ-­containing GABAA
receptors, but not synaptic γ-­containing receptors.101
Therefore, ALLO could play a role in seizure control
through the potentiation of tonic inhibition.43 This sug-
gests that the abrupt withdrawal of ALLO at the onset
of menstruation could decrease the inhibitory effects of
δ-­containing GABAA receptors and possibly exacerbate
seizures.50
Animal studies found that ALLO withdrawal was asso-
ciated with upregulation of α4 subunit in the hippocam-
pus, marked decrease in GABA synaptic current, increased
neuronal excitability, and increase in seizure activity.102
Interestingly, it was also found that ALLO withdrawal is
followed by a rapid upregulation of δ-­containing GABAA
receptors and enhanced ALLO sensitivity in the dentate
gyrus granule cells but not in CA1 or CA3 pyramidal cells
in a mouse model of premenstrual like conditions.103 These
changes may confer a neuronal homeostatic response to
the transient reduction in ALLO-­mediated tonic inhibition.
However, the upregulation of δ-­containing GABAA recep-
tors was found to be insufficient to counterbalance the
heightened seizure susceptibility state of the brain triggered
by neurosteroid withdrawal in the absence of ALLO.103
Additionally, animal studies have shown that continu-
ous 2–3-­day exposure to ALLO causes an upregulation of
the normally underexpressed α4 subunit in the hippocam-
pus, an effect that reached significant levels after 48–72 h.104
This increase in α4 mRNA and protein was found to be a
temporary response, as extended exposure to ALLO that
exceeded 72 h resulted in a decrease in α4 expression,
which reached baseline levels after 5–6-­day exposure and
remained at baseline even after 3-­week exposure.104 The
increase in α4 subunit was well correlated with decreased
sensitivity to the benzodiazepine lorazepam, as measured
by a reduction in the anxiolytic effects of lorazepam and its
ability to potentiate GABA-­gated current.104
The α4 subunit is known to preferentially coassemble
with δ, rather than γ2, to form extra-­synaptic GABAA
receptors.95 The δ-­containing GABAA receptors are
highly sensitive to GABA and neurosteroids but not
benzodiazepines.105 These features were used to verify
the functional expression of δ-­containing GABAA recep-
tors in isolated CA1 hippocampal cells, which showed
increased responsiveness to the GABA agonist gaboxa-
dol,106 but were unresponsive to the benzodiazepine
lorazepam.104 Taken together, these findings suggest that
the upregulation of α4 subunit induced by short-­term
|
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   563
exposure to ALLO is associated with an altered benzodi-
azepine sensitivity.104
4.4.2 | Preclinical evidence for molecular
changes across the estrous cycle
Preclinical studies suggest that the structure of the extra-­
synaptic GABAA receptors undergoes drastic alterations
according to the cyclic changes in progesterone levels
across the estrous cycle.95 Maguire et al.107 found that el-
evated progesterone levels during the late diestrous phase
in mice, comparable to the mid-­luteal phase in humans,
correlated with enhanced expression of neurosteroid-­
sensitive δ-­containing GABAA receptors and reduced
expression of benzodiazepine-­ sensitive γ2-­containing
GABAA receptors. These dynamic changes in GABAA
receptor subunit composition were not accompanied by
any changes in α4 subunit density. Maguire et al.107 high-
lighted that this aligns with the suggested rules of GABAA
partnership wherein δ and γ subunits are complementa-
rily regulated and that the loss of one γ subunit would re-
sult in α4 coassembling with δ subunit, and vice versa.108
Because these changes occurred during the late di-
estrous phase, which is marked by increased progesterone
levels, it seems unlikely that progesterone withdrawal is
responsible for these changes. Instead, the prolonged
exposure to progesterone or ALLO might be responsi-
ble.107 In mice, these structural changes correlated with
enhanced tonic inhibition in hippocampal neurons and
reduced seizure susceptibility.107 Therefore, the selective
upregulation of δ subunits might represent the molecular
mechanism underlying the observed reduction in seizure
frequency during the mid-­luteal phase in women with
catamenial epilepsy reported by Herzog.7 This is further
supported by the finding that the prevention of the up-
regulation of δ-­containing GABAA receptors during the
late diestrous phase in mice prevented the enhancement
of tonic GABAergic inhibition.107
4.4.3 | Preclinical evidence for molecular
changes during pregnancy
Pregnancy represents a critical period of chronic exposure
to ALLO, followed by a rapid decline back to baseline im-
mediately before delivery.109 A review on the plasticity
of GABAA receptors during pregnancy and postpartum
period in rodents reported that the marked increase in
ALLO during late pregnancy was associated with down-
regulation of γ2 subunit expression in the cerebral cortex
and hippocampus,110 and upregulation of δ subunit ex-
pression.111 The decrease in γ2 subunit was not associated
 |

15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
564    ALSHAKHOURI et al.

with changes in phasic synaptic currents. The increase in
the δ subunit, however, was accompanied by an increase
in tonic extra-­synaptic currents in granule cells of the
dentate gyrus evaluated by whole-­cell patch-­clamp re-
cordings.111 These findings suggest that plasma changes
in progesterone and ALLO levels during late pregnancy in
rodents are associated with changes in GABAA receptors.
4.4.4 | Clinical evidence
Consistent with preclinical evidence, Voinescu et al.112
found that pregnant women with epilepsy who experi-
enced increased seizure frequency during the third tri-
mester had significantly lower serum ALLO levels. They
also found a similar, but not significant, association be-
tween ALLO serum levels and seizure frequency during
the first trimester.112 This study provides evidence (albeit
in a small study) that fluctuations in ALLO serum levels
during critical periods such as pregnancy, and potentially
the menstrual cycle, are implicated in functional changes
in neuronal excitability threshold.
The exact relationship between the plasticity of GABA
receptors and neuronal excitability in humans remains to
be elucidated. Nevertheless, findings from the preclinical
studies above provide a potential mechanism for perimen-
strual seizure exacerbation and a rationale for treatment
trials with cyclic progesterone supplements that lead to
gradual, rather than abrupt, neurosteroid withdrawal
premenstrually.
The seminal NIH progesterone phase III randomized
controlled trial found that cyclic progesterone treatment
was not effective in treating women with intractable sei-
zures that did not show catamenial exacerbation nor
women who showed C2 or C3 catamenial patterns.113
The prespecified post hoc analysis, however, identified
C1 catamenial level (i.e., level of perimenstrual seizure
exacerbation) as a statistically significant and clinically
meaningful predictor of responder rates. As C1 level in-
creased from 1 to 10, the responder rates to cyclic proges-
terone treatment increased from 21.3% to 57.1%.113 These
findings suggest that cyclic progesterone treatment end-
ing in gradual rather than abrupt ALLO withdrawal could
be effective in treating women who show prominent C1

F I G U R E 1 Schematic summary of this review. This figure demonstrates the direction of influence of major features of epilepsy and
reproductive health that are frequently reciprocal and overlapping and may be experienced as both reproductive system disorders and
exacerbation of epilepsy itself. Catamenial epilepsy exemplifies this relationship, where complex receptor, hormone, and hypothalamic–
pituitary–gonadal axis interactions lead to seizure exacerbations in many females with epilepsy. PCOS, polycystic ovary syndrome.

ALSHAKHOURI et al.
pattern with a three-­fold increase in seizures or higher.113
Therefore, future clinical trials into the effectiveness of cy-
clic progesterone treatment could benefit from specifically
targeting women with a C1 pattern.
5 | G E NE R AL CON CLU SION S
The aim of this review was to summarize the reciprocal re-
lationships among epilepsy, sex steroids, and reproductive
endocrine disorders in females, as depicted in Figure 1. In
summarizing the existing knowledge, it is clear that a large
number of preclinical and clinical studies present compel-
ling evidence for reciprocal interactions between epilepsy
and the major female sex steroids. Although researchers
are uncovering the mechanisms that underlie the experi-
ence of females with epilepsy postmenarche and over the
lifespan, a lack of conclusive outcomes limits both the in-
formation that is provided to clinicians and patients, and
ultimately tailored treatments for females with epilepsy.
There is a need for more clinical and mechanism-­focused
studies.
AUTHOR CONTRIBUTIONS
Malak Alshakhouri: Conceptualization (supporting);
writing–original draft (lead); writing–review & editing
(equal). Cynthia Sharpe: Writing–review and editing
(supporting). Peter Bergin: Writing–review and editing
(supporting). Rachael L. Sumner: Conceptualization
(lead); writing–original draft (supporting); writing–review
& editing (equal); funding acquisition.
ACKNOWLEDGMENTS
We would like to thank Dr. Khalid Hamandi for his help-
ful feedback on the manuscript. Open access publishing
facilitated by The University of Auckland, as part of the
Wiley - The University of Auckland agreement via the
Council of Australian University Librarians.
FUNDING INFORMATION
This work was supported by a Neurological Foundation
First Fellowship awarded to R.L.S. and a Maurice Phyllis
Paykel Trust project grant awarded to R.L.S.
CONFLICT OF INTEREST STATEMENT
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Journal's position on
issues involved in ethical publication and affirm that this
report is consistent with those guidelines.
ORCID
Malak Alshakhouri https://orcid.
org/0000-0002-2633-3159
|
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   565
Cynthia Sharpe https://orcid.org/0000-0002-6194-3307
Peter Bergin https://orcid.org/0000-0003-0181-1959
Rachael L. Sumner https://orcid.
org/0000-0002-2652-4617
REFERENCES
1. Dieni CV, Contemori S, Biscarini A, Panichi R. De novo synthe-
sized estradiol: a role in modulating the cerebellar function. Int
J Mol Sci. 2020;21(9):3316.
2. Guennoun R. Progesterone in the brain: hormone, neuroste-
roid and neuroprotectant. Int J Mol Sci. 2020;21(15):5271.
3. Jackson LM, Parker RM, Mattison DR. Reproductive steroid
hormones: synthesis, structure, and biochemistry, in the clin-
ical utility of compounded bioidentical hormone therapy: a
review of safety, effectiveness, and use. Washington (DC):
National Academies Press (US); 2020.
4. Sacher J, Okon-­Singer H, Villringer A. Evidence from neuro-
imaging for the role of the menstrual cycle in the interplay of
emotion and cognition. Front Hum Neurosci. 2013;7:374.
5. Baulieu E. Neurosteroids: a novel function of the brain.
Psychoneuroendocrinology. 1998;23(8):963–87.
6. Farage MA, Osborn TW, MacLean AB. Cognitive, sensory, and
emotional changes associated with the menstrual cycle: a re-
view. Arch Gynecol Obstet. 2008;278(4):299–307.
7. Herzog AG. Catamenial epilepsy: update on prevalence,
pathophysiology and treatment from the findings of the NIH
Progesterone Treatment Trial. Seizure. 2015;28:18–25.
8. Le J, Thomas N, Gurvich C. Cognition, the menstrual cycle, and
premenstrual disorders: a review. Brain Sci. 2020;10(4):198.
9. Schwartz DH, Romans SE, Meiyappan S, de Souza MJ, Einstein
G. The role of ovarian steroid hormones in mood. Horm Behav.
2012;62(4):448–54.
10. Sundström Poromaa I, Gingnell M. Menstrual cycle influence
on cognitive function and emotion processing—from a repro-
ductive perspective. Front Neurosci. 2014;8:380.
11. Herzog AG, Coleman AE, Jacobs AR, Klein P, Friedman MN,
Drislane FW, et al. Interictal EEG discharges, reproductive
hormones, and menstrual disorders in epilepsy. Ann Neurol.
2003;54(5):625–37.
12. Morrell MJ, Montouris GD. Reproductive disturbances in pa-
tients with epilepsy. Cleve Clin J Med. 2004;71(Suppl 2):S19–24.
13. El-­Khayat HA, Soliman NA, Tomoum HY, Omran MA, El-­
Wakad AS, Shatla RH. Reproductive hormonal changes
and catamenial pattern in adolescent females with epilepsy.
Epilepsia. 2008;49(9):1619–26.
14. Herzog AG. Menstrual disorders in women with epilepsy.
Neurology. 2006;66(6 Suppl 3):S23–8.
15. Gerhard L. Impact of epilepsy and AEDs on reproductive
health. In: Harden CL, Thomas SV, Tomson T, editors. Epilepsy
in women. United Kingdom: John Wiley & Sons; 2013. p. 53–63.
16. Isojarvi JI, Tauboll E, Herzog AG. Effect of antiepileptic drugs
on reproductive endocrine function in individuals with epi-
lepsy. CNS Drugs. 2005;19(3):207–23.
17. Verrotti A, D'Egidio C, Mohn A, Coppola G, Parisi P, Chiarelli
F. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia.
2011;52(2):199–211.
18. Silveira DC, Klein P, Ransil BJ, Liu Z, Hori A, Holmes GL, et al.
Lateral asymmetry in activation of hypothalamic neurons with
unilateral amygdaloid seizures. Epilepsia. 2000;41(1):34–41.
 |
566   
19. Drislane FW, Coleman AE, Schomer DL, Ives J, Levesque LA,
Seibel MM, et al. Altered pulsatile secretion of luteinizing hor-
mone in women with epilepsy. Neurology. 1994;44(2):306–10.
20. Herzog AG. A hypothesis to integrate partial seizures of tempo-
ral lobe origin and reproductive endocrine disorders. Epilepsy
Res. 1989;3(2):151–9.
21. Herzog AG, Friedman MN. Menstrual cycle interval and ovu-
lation in women with localization-­related epilepsy. Neurology.
2001;57(11):2133–5.
22. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind
N. Reproductive endocrine disorders in women with partial sei-
zures of temporal lobe origin. Arch Neurol. 1986;43(4):341–6.
23. Hamed S, Hamed EA, Shokry M, Omar H, Abdellah MM. The
reproductive conditions and lipid profile in females with epi-
lepsy. Acta Neurol Scand. 2007;115(1):12–22.
24. Harden C, Koppel BS, Herzog AG, Nikolov BG, Hauser WA.
Seizure frequency is associated with age at menopause in
women with epilepsy. Neurology. 2003;61(4):451–5.
25. Herzog AG. Catamenial epilepsy: definition, prevalence patho-
physiology and treatment. Seizure. 2008;17(2):151–9.
26. Klein P, Serje A, Pezzullo JC. Premature ovarian failure in
women with epilepsy. Epilepsia. 2001;42(12):1584–9.
27. Cummings LN, Giudice L, Morrell MJ. Ovulatory function in
epilepsy. Epilepsia. 1995;36(4):355–9.
28. Azziz R, Carmina E, Dewailly D, Diamanti-­Kandarakis E,
Escobar-­ Morreale HF, Futterweit W, et al. The Androgen
Excess and PCOS Society criteria for the polycystic ovary
syndrome: the complete task force report. Fertil Steril.
2009;91(2):456–88.
29. Escobar-­ Morreale HF. Polycystic ovary syndrome: defini-
tion, aetiology, diagnosis and treatment. Nat Rev Endocrinol.
2018;14(5):270–84.
30. Duncan S. Polycystic ovarian syndrome in women with epi-
lepsy: a review. Epilepsia. 2001;42(s3):60–5.
31. Zhou J-­Q, Zhou LM, Chen LJ, Han JD, Wang Q, Fang ZY, et al.
Polycystic ovary syndrome in patients with epilepsy: a study in
102 Chinese women. Seizure. 2012;21(9):729–33.
32. Franks S. Polycystic ovary syndrome. N Engl J Med.
1995;333(13):853–61.
33. Ding T, Hardiman PJ, Petersen I, Wang FF, Qu F, Baio G. The
prevalence of polycystic ovary syndrome in reproductive-­aged
women of different ethnicity: a systematic review and meta-­
analysis. Oncotarget. 2017;8(56):96351–58.
34. Bilo L, Meo R, Valentino R, di Carlo C, Striano S, Nappi C.
Characterization of reproductive endocrine disorders in women
with epilepsy. J Clin Endocrinol Metab. 2001;86(7):2950–6.
35. Bilo L, Meo R, Nappi C, Annunziato L, Striano S, Colao AM,
et al. Reproductive endocrine disorders in women with primary
generalized epilepsy. Epilepsia. 1988;29(5):612–9.
36. Bauer J, Jarre A, Klingmüller D, Elger CE. Polycystic ovary
syndrome in patients with focal epilepsy: a study in 93 women.
Epilepsy Res. 2000;41(2):163–7.
37. Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind
N. Reproductive endocrine disorders in men with partial sei-
zures of temporal lobe origin. Arch Neurol. 1986;43(4):347–50.
38. Isojarvi J, Laatikainen TJ, Pakarinen AJ, Juntunen K, Myllyla
VV. Polycystic ovaries and hyperandrogenism in women taking
valproate for epilepsy. N Engl J Med. 1993;329(19):1383–8.
39. Gerendai I, Halász B. Neuroendocrine asymmetry. Front
Neuroendocrinol. 1997;18(3):354–81.
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ALSHAKHOURI et al.
40. Betts T, Yarrow H, Dutton N, Greenhill L, Rolfe T. A study of
anticonvulsant medication on ovarian function in a group of
women with epilepsy who have only ever taken one anticon-
vulsant compared with a group of women without epilepsy.
Seizure. 2003;12(6):323–9.
41. Genton P, Bauer J, Duncan S, Taylor AE, Balen AH, Eberle
A, et al. On the association between valproate and polycystic
ovary syndrome. Epilepsia. 2001;42(3):295–304.
42. Pennell PB, French JA, Harden CL, Davis A, Bagiella E,
Andreopoulos E, et al. Fertility and birth outcomes in
women with epilepsy seeking pregnancy. JAMA Neurol.
2018;75(8):962–9.
43. Harden C, Thomas SV, Tomson T. Epilepsy in women. United
Kingdom: John Wiley & Sons; 2013.
44. Crawford P, Hudson S. Understanding the information needs of
women with epilepsy at different lifestages: results of the ‘Ideal
World’ survey. Seizure. 2003;12(7):502–7.
45. Webber MP, Hauser WA, Ottman R, Annegesr JF. Fertility in
persons with epilepsy: 1935–1974. Epilepsia. 1986;27(6):746–52.
46. MacEachern DB, Mandle HB, Herzog AG. Infertility, impaired
fecundity, and live birth/pregnancy ratio in women with ep-
ilepsy in the USA: findings of the Epilepsy Birth Control
Registry. Epilepsia. 2019;60(9):1993–8.
47. Schupf N, Ottman R. Likelihood of pregnancy in individuals
with idiopathic/cryptogenic epilepsy: social and biologic influ-
ences. Epilepsia. 1994;35(4):750–6.
48. Olafsson E, Hauser AW, Gudmundsson G. Fertility in pa-
tients with epilepsy: a population-­ based study. Neurology.
1998;51(1):71–3.
49. Zinaman MJ, Clegg ED, Brown CC, O'Connor J, Selevan SG.
Estimates of human fertility and pregnancy loss. Fertil Steril.
1996;65(3):503–9.
50. Reddy DS. Perimenstrual catamenial epilepsy. Womens Health
(Lond). 2007;3:195–206.
51. Reddy DS. Clinical pharmacokinetic interactions between an-
tiepileptic drugs and hormonal contraceptives. Expert Rev Clin
Pharmacol. 2010;3(2):183–92.
52. Hiroi T, Kishimoto W, Chow T, Imaoka S, Igarashi T, Funae Y.
Progesterone oxidation by cytochrome P450 2D isoforms in the
brain. Endocrinology. 2001;142(9):3901–8.
53. Wang H, Napoli KL, Strobel HW. Cytochrome P450 3A9 cat-
alyzes the metabolism of progesterone and other steroid hor-
mones. Mol Cell Biochem. 2000;213(1–2):127–35.
54. Lynch T, Price A. The effect of cytochrome P450 metabolism
on drug response, interactions, and adverse effects. Am Fam
Physician. 2007;76(3):391–6.
55. Morrell MJ, Flynn KL, Seale CG, Doñe S, Paulson AJ, Flaster
ER, et al. Reproductive dysfunction in women with epilepsy:
antiepileptic drug effects on sex-­steroid hormones. CNS Spectr.
2001;6(9):771–86.
56. Markoula S, Siarava E, Keramida A, Chatzistefanidis D,
Zikopoulos A, Kyritsis AP, et al. Reproductive health in patients
with epilepsy. Epilepsy Behav. 2020;113:107563.
57. Morrell MJ, Giudice L, Flynn KL, Seale CG, Paulson AJ, Doñe
S, et al. Predictors of ovulatory failure in women with epilepsy.
Ann Neurol. 2002;52(6):704–11.
58. Morrell MJ, Hayes FJ, Sluss PM, Adams JM, Bhatt M, Ozkara
C, et al. Hyperandrogenism, ovulatory dysfunction, and poly-
cystic ovary syndrome with valproate versus lamotrigine. Ann
Neurol. 2008;64(2):200–11.

ALSHAKHOURI et al.
59. Isojärvi JIT, Rättyä J, Myllylä VV, Knip M, Koivunen R, Pakarinen
AJ, et al. Valproate, lamotrigine, and insulin-­mediated risks in
women with epilepsy. Ann Neurol. 1998;43(4):446–51.
60. EURAP Study Group. Seizure control and treatment in preg-
nancy: observations from the EURAP epilepsy pregnancy regis-
try. Neurology. 2006;66(3):354–60.
61. Thomas SV, Syam U, Devi JS. Predictors of seizures during preg-
nancy in women with epilepsy. Epilepsia. 2012;53(5):e85–8.
62. Pennell PB, French JA, May RC, Gerard E, Kalayjian L, Penovich
P, et al. Changes in seizure frequency and antiepileptic therapy
during pregnancy. N Engl J Med. 2020;383(26):2547–56.
63. Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini
M. Seizure course during pregnancy in catamenial epilepsy.
Neurology. 2014;83(4):339–44.
64. Houben E, Benson RJ, Steegers EAP, Herings RMC. Twenty-­year
trends in the use of anti-­seizure medication among pregnant
women in The Netherlands. Epilepsy Behav. 2022;127:108549.
65. Anderson GD. Pregnancy-­induced changes in pharmacokinet-
ics. Clin Pharmacokinet. 2005;44(10):989–1008.
66. Pennell PB, Karanam A, Meador KJ, Gerard E, Kalayjian
L, Penovich P, et al. Antiseizure medication concentrations
during pregnancy: results from the maternal outcomes and
neurodevelopmental effects of antiepileptic drugs (MONEAD)
study. JAMA Neurol. 2022;79(4):370–9.
67. Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers
A, et al. Seizure control and treatment changes in pregnancy:
observations from the EURAP epilepsy pregnancy registry.
Epilepsia. 2013;54(9):1621–7.
68. Herzog AG, Klein P, Rand BJ. Three patterns of catamenial epi-
lepsy. Epilepsia. 1997;38(10):1082–8.
69. Herzog AG, Harden CL, Liporace J, Pennell P, Schomer DL,
Sperling M, et al. Frequency of catamenial seizure exacerba-
tion in women with localization-­related epilepsy. Ann Neurol.
2004;56(3):431–4.
70. Reddy DS. Pharmacotherapy of catamenial epilepsy. Indian J
Pharm. 2005;37:288–93.
71. Maguire MJ, Nevitt SJ. Treatments for seizures in catamenial
(menstrual-­ related) epilepsy. Cochrane Database Syst Rev.
2019;10:CD013225.
72. Reddy DS. The role of neurosteroids in the pathophysiology and
treatment of catamenial epilepsy. Epilepsy Res. 2009;85(1):1–30.
73. Reddy DS. Role of neurosteroids in catamenial epilepsy.
Epilepsy Res. 2004;62(2–3):99–118.
74. Reddy DS. Neuroendocrine aspects of catamenial epilepsy.
Horm Behav. 2013;63(2):254–66.
75. Murphy DD, Cole NB, Greenberger V, Segal M. Estradiol in-
creases dendritic spine density by reducing GABA neurotrans-
mission in hippocampal neurons. J Neurosci. 1998;18(7):2550–9.
76. Wong M, Moss RL. Patch-­clamp analysis of direct steroidal mod-
ulation of glutamate receptor-­ channels. J Neuroendocrinol.
1994;6(3):347–55.
77. Smith SS, Waterhouse BD, Woodward DJ. Locally applied es-
trogens potentiate glutamate-­evoked excitation of cerebellar
Purkinje cells. Brain Res. 1988;475(2):272–82.
78. Woolley CS, McEwen BS. Roles of estradiol and progesterone in
regulation of hippocampal dendritic spine density during the
estrous cycle in the rat. J Comp Neurol. 1993;336(2):293–306.
79. Bäckström T. Epileptic seizures in women related to plasma
estrogen and progesterone during the menstrual cycle. Acta
Neurol Scand. 1976;54(4):321–47.
|
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   567
80. Weiland NG. Glutamic acid decarboxylase messenger ribonu-
cleic acid is regulated by estradiol and progesterone in the hip-
pocampus. Endocrinology. 1992;131(6):2697–702.
81. Nakamura NH, Rosell DR, Akama KT, McEwen BS. Estrogen
and ovariectomy regulate mRNA and protein of glutamic
acid decarboxylases and cation-­ chloride cotransporters in
the adult rat hippocampus. Neuroendocrinology. 2004;80(5):​
308–23.
82. Joh H-­D, Searles RV, Selmanoff M, Alkayed NJ, Koehler RC,
Hurn PD, et al. Estradiol alters only GAD67 mRNA levels in
ischemic rat brain with no consequent effects on GABA. J
Cereb Blood Flow Metab. 2006;26(4):518–26.
83. Grattan DR, Rocca MS, Strauss KI, Sagrillo CA, Selmanoff M,
McCarthy MM. GABAergic neuronal activity and mRNA lev-
els for both forms of glutamic acid decarboxylase (GAD65 and
GAD67) are reduced in the diagonal band of Broca during the
afternoon of proestrus. Brain Res. 1996;733(1):46–55.
84. Scharfman HE, Maclusky NJ. The influence of gonadal hor-
mones on neuronal excitability, seizures, and epilepsy in the
female. Epilepsia. 2006;47(9):1423–40.
85. Taubøll E, Sveberg L, Svalheim S. Interactions between hor-
mones and epilepsy. Seizure. 2015;28:3–11.
86. Belelli D, Bolger MB, Gee KW. Anticonvulsant profile of the
progesterone metabolite 5α-­pregnan-­3α-­ol-­20-­one. Eur J
Pharmacol. 1989;166(2):325–9.
87. Reddy DS. Pharmacology of endogenous neuroactive steroids.
Crit Rev Neurobiol. 2003;15(3-­4):197–234.
88. Kapur J, Joshi S. Progesterone modulates neuronal excitability
bidirectionally. Neurosci Lett. 2021;744:135619.
89. Shiono S, Williamson J, Kapur J, Joshi S. Progesterone recep-
tor activation regulates seizure susceptibility. Ann Clin Transl
Neurol. 2019;6(7):1302–10.
90. Jeffrey M, Lang M, Gane J, Chow E, Wu C, Zhang L. Novel
­anticonvulsive effects of progesterone in a mouse model of
­hippocampal electrical kindling. Neuroscience. 2014;257:65–75.
91. Bäckström T, Zetterlund B, Blom S, Romano M. Effects of in-
travenous progesterone infusions on the epileptic discharge
frequency in women with partial epilepsy. Acta Neurol Scand.
1984;69(4):240–8.
92. Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA.
Differential impact of contraceptive methods on seizures var-
ies by antiepileptic drug category: findings of the epilepsy birth
control registry. Epilepsy Behav. 2016;60:112–7.
93. Herzog AG, Fowler KM, Sperling MR, Massaro JM, Progesterone
Trial Study Group. Distribution of seizures across the menstrual
cycle in women with epilepsy. Epilepsia. 2015;56(5):e58–62.
94. Mohammad S, Abolhassan A, Pourgholami MH. Evaluation of
the anticonvulsant profile of progesterone in male amygdala-­
kindled rats. Epilepsy Res. 1998;30(3):195–202.
95. Reddy DS. Catamenial epilepsy: discovery of an extra-­synaptic
molecular mechanism for targeted therapy. Front Cell Neurosci.
2016;10:101.
96. Agís-­Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa
E, et al. Characterization of brain neurons that express en-
zymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci
U S A. 2006;103(39):14602–7.
97. Wartenberg P, Farkas I, Csillag V, Colledge WH, Hrabovszky
E, Boehm U. Sexually dimorphic neurosteroid synthesis reg-
ulates neuronal activity in the murine brain. J Neurosci.
2021;41(44):9177–91.
 |
568   
98. Stoffel-­ Wagner B. Neurosteroid metabolism in the human
brain. Eur J Endocrinol. 2001;145(6):669–79.
99. Beyenburg S, Stoffel-­Wagner B, Bauer J, Watzka M, Blümcke I,
Bidlingmaier F, et al. Neuroactive steroids and seizure suscepti-
bility. Epilepsy Res. 2001;44(2–3):141–53.
100. Majewska MD. Steroids and brain activity: essential di-
alogue between body and mind. Biochem Pharmacol.
1987;36(22):3781–8.
101. Zheleznova NN, Sedelnikova A, Weiss DS. Function
and modulation of δ-­ containing GABAA receptors.
Psychoneuroendocrinology. 2009;34:S67–73.
102. Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-­Mullen
JM, Li X. GABAA receptor α4 subunit suppression prevents
withdrawal properties of an endogenous steroid. Nature.
1998;392:926–30.
103. Carver CM, Wu X, Gangisetty O, Reddy DS. Perimenstrual-­like
hormonal regulation of extrasynaptic δ-­containing GABAA re-
ceptors mediating tonic inhibition and neurosteroid sensitivity.
J Neurosci. 2014;34(43):14181–97.
104. Gulinello M, Gong QH, Li X, Smith SS. Short-­term exposure
to a neuroactive steroid increases α4 GABAA receptor subunit
levels in association with increased anxiety in the female rat.
Brain Res. 2001;910(1–2):55–66.
105. Smith SS, Shen H, Gong QH, Zhou X. Neurosteroid regulation
of GABAA receptors: focus on the α4 and δ subunits. Pharmacol
Ther. 2007;116(1):58–76.
106. Shen H, Gong QH, Yuan M, Smith SS. Short-­term steroid treat-
ment increases δ GABAA receptor subunit expression in rat
CA1 hippocampus: pharmacological and behavioral effects.
Neuropharmacology. 2005;49(5):573–86.
107. Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle–
linked changes in GABAA receptors mediating tonic inhi-
bition alter seizure susceptibility and anxiety. Nat Neurosci.
2005;8(6):797–804.
15281167, 2024, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.17842 by Cochrane Chile, Wiley Online Library on [27/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ALSHAKHOURI et al.
108. Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Mäkelä R,
et al. Ligand-­gated ion channel subunit partnerships: GABAA
receptor alpha6 subunit gene inactivation inhibits delta subunit
expression. J Neurosci. 1997;17(4):1350–62.
109. Turkmen S, Backstrom T, Wahlstrom G, Andreen L, Johansson
IM. Tolerance to allopregnanolone with focus on the GABA-­A
receptor. Br J Pharmacol. 2011;162(2):311–27.
110. Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML,
Trabucchi M, et al. Role of brain allopregnanolone in the
plasticity of γ-­aminobutyric acid type A receptor in rat brain
during pregnancy and after delivery. Proc Natl Acad Sci U S A.
1998;95(22):13284–89.
111. Sanna E, Mostallino MC, Murru L, Carta M, Talani G, Zucca
S, et al. Changes in expression and function of extrasynaptic
GABAA receptors in the rat hippocampus during pregnancy
and after delivery. J Neurosci. 2009;29(6):1755–65.
112. Voinescu PE, Pennell KD, Bay CP, Stowe ZN, Peng L, Frye CA,
et al. Pregnant women with more seizures have lower allopreg-
nanolone concentrations. Epilepsy Res. 2021;177:106778.
113. Herzog AG, Fowler KM, Smithson SD, Kalayjian LA, Heck
CN, Sperling MR, et al. Progesterone vs placebo therapy for
women with epilepsy: a randomized clinical trial. Neurology.
2012;78(24):1959–66.
How to cite this article: Alshakhouri M, Sharpe C,
Bergin P, Sumner RL. Female sex steroids and
epilepsy: Part 1. A review of reciprocal changes in
reproductive systems, cycles, and seizures. Epilepsia.
2024;65:556–568. https://doi.org/10.1111/epi.17842