Review

doi: 10.4183/aeb.2014.102

Implications of sex hormones in the treatment of women

with epilepsy: catamenial epilepsy

D. Craiu*

Alexandru Obregia Hospital - Pediatric Neurology, Bucharest

Romania
Abstract
The impact of sex hormones
on body development is well known
and extensively studied. It is important
for physicians dealing with women
with epilepsy (WWE) to understand the
relationship between hormones brain
excitability antiepileptic medication in
the attempt of finding the most appropriate
care for this population. This article presents
current knowledge concerning 1. Influence
of hormones on neuronal excitability and
epilepsy (with general proconvulsant
effect of estrogens and anticonvulsant of
progesterone); 2. Role of sex hormones on
brain development during puberty; 3. The
influence of epilepsy and antiepileptic drugs
(AEDs) on hormonal constellation, fertility
and reproductive endocrine disorders
including polycystic ovary syndrome; 4.
Catamenial epilepsy (endocrinologists and
neurologists should carefully investigate
menstrual and epilepsy diaries, antiepileptic
treatment and contraceptive method and
choose treatment with either progesterone
for C1 menstrual type, or acetazolamide,
benzodiazepines, antiepileptic medication
for C2 and C3 types); 5. Contraception in
WWE. Theoretical and practical issues are
being discussed and organised into clinical
practice recommendations.
Key words: sex hormones,
epilepsy, catamenial, contraception, brain
development, women, antiepileptic drugs.
Introduction
Hormones are involved in the
normal development and functioning
of the human body. As I already
presented in my previous article (1),
impressive progress have been made
in the understanding of intimate
mechanisms underlying influence of sex
hormones on brain development and on
brain excitability. Hormones produce
changes of neuronal excitability.
Epilepsy (seizure frequency and/or
interictal discharges) may influence the
hypothalamic-pituitary axis and may
be associated with polycystic ovary
syndrome or menstrual irregularities.
Hormonal changes during menstrual
cycle may have important implications
in some women with epilepsy (WWE)
leading to catamenial epilepsy. Although
extensively studied, it is not yet precisely
known the mechanism leading to
catamenial seizures in some WWE,

*Correspondence to: Dana Craiu MD, Alexandru Obregia Hospital, Pediatric Neurology,
Sos. Berceni 10-12, Sector 4, Bucharest, 7000, Romania, E-mail: dcraiu@yahoo.com
Acta Endocrinologica (Buc), vol. X, no. 1, p. 102-117, 2014

102
 Sex hormones and women with epilepsy
why not all WWE have catamenial
seizures, why they have seizures related
to different phases of the menstrual
cycle? The bidirectional interactions
contraceptives-antiepileptic medication
are well known and now it is possible
to choose the most appropriate drugs
starting even from the teenage period, in
accordance with patients particularities.
This article concentrates on the impact
of hormones and hormonal changes on
brain development and excitability, and
the interactions hormones antiepileptic
medication, with the aim of presenting
current data from the literature, which
may guide physicians dealing with
WWE to choose the best approach for
management of WWE.
1. Influence of hormones on
neuronal excitability and epilepsy
Hormonal influence becomes
evident at puberty (1) and continues
through menopause. It is currently not
known why some epilepsies occur at
menarche suggesting a direct relationship,
but without definite evidence. Dramatic
changes in hormonal levels (see Role
of sex hormones on brain development
during puberty) may serve as an
argument. Boys may also experience
onset of epilepsy at puberty, but
different hormonal influences have been
suggested. Hormonal changes during the
menstrual cycle may also affect seizure
control (see also Catamenial epilepsy)
(2). Optimal management of women with
epilepsy (WWE) includes understanding
the effect of endogenous and exogenous
hormones, throughout the reproductive
years, from puberty through pregnancy
and menopause (3).
There is evidence that
sex hormones influence neuronal
excitability, with proconvulsant/
excitatory effect of estradiol and
anticonvulsant of progesterone (4).
Changes in endogenous neurosteroids
(including androgens and derivates of
adrenal hormones) may have a serious
impact on seizure susceptibility (4).
Estrogens (estrone, estradiol,
and estriol) have a general proconvulsant
effect as shown by preclinical and
clinical studies. Estrogens bind in the
nucleus on ER and ER, with ER
being more widely distributed in the
female brain, leading to modulation of
target genes. Estrogens impact synaptic
structure and function by enhancing
glutamate receptor-mediated excitatory
neurotransmission and decreasing
GABAergic inhibition and by delay of
dendritic pruning (important process
in decrease of excitatory circuits) at
adolescence (defective pruning may
lead to maintenance of hyperexcitable
synapses, aberrant circuitry, and brain
hyperexcitability) (5).
Estrogens facilitate kindling in
animals, potentiate seizures induced by
kainic acid or pentetrazole, increases
electrographic activity of the cortical
neurons, especially after chronic
treatment in male rodents (6). There
are controversies on the effect of
estrogens on hippocampus excitability,
some studies showing estrogen seizure
facilitation (7), possibly by increasing the
number and density of dendritic spines
and excitatory synapses on hippocampal
neurons, or by increased glutamatergic
transmission by BDNF (Brain-derived
neurotrophic factor) upregulated by
103
 D. Craiu
estrogens (8), while others support lack
of effect or even protective effect in
status epilepticus models (9). Intravenous
estrogen is followed by increase
interictal EEG activity and seizures in
women with epilepsy (10). There seems
to be a direct relation between seizure
susceptibility and estrogen/progesterone
ratio, leading to supposition that estrogen
might contribute to premenstrual seizure
exacerbation (11), supposition supported
by demonstration of an elevated estrogen-
to-progesterone ratio in women with
catamenial exacerbation of their epilepsy
(12).
Progesterone has proven to have
anticonvulsant and antiepileptic properties
in both animal and human studies. It is not
yet clear how progesterone acts, but, due
to rapid antiseizure effect of progesterone
(minutes), it seems improbable the effect
through progesterone receptors (PR)
which would necessitate activation of
transcription machinery. It is possible
that anticonvulsive activity is due to
conversion to reduced metabolites,
allopregnanolone. Progesterone has
anticonvulsant properties in different
animal models of epilepsy and in
clinical studies in humans (11, 13, 14).
It is possible that the cyclic variation of
progesterone concentration may influence
catamenial seizure exacerbation in
WWE. The reduced progesterone levels
and increased estrogen-to-progesterone
ratio have been correlated with increased
seizure frequency (12) in some WWE.
Catamenial seizures are associated with
a rapid decline in progesterone levels at
immediately before, during, and after
menstruation. These studies led to the
idea of progestin therapy which has
104
proved to be beneficial for catamenial
epilepsy (14).
Neurosteroids are synthesized
in the brain from cholesterol
(allopregnanolone) and from circulating
steroid hormones (15).
Several neurosteroids with
anticonvulsant or proconvulsant
properties have been identified.
Among anticonvulsant neurosteroids,
Allopregnanolone, Pregnanolone,
A n d r o s t a n e d i o l ,
Allotetrahydrodeoxycorticosterone
(THDOC) have a common
mechanism, potentiation of GABA-A
receptor function, Progesterone and
Dihydroprogesterone are precursors
for neurosteroid allopregnanolone
synthesis, and Dihydrotestosterone and
Deoxycorticosterone are precursors
for THDOC synthesis. Among the
proconvulsant neurosteroids, estradiol
acts as shown above, by control of
hippocampal dendritic spine density,
enhanced NMDA receptor function,
induction of neurotrophin BDNF;
Pregnenolone sulfate by potentiation of
NMDA receptor function and inhibition
of GABA-A receptor function, DHEA
sulfate potentiates the NMDA receptor
function and Cortisol influences
corticosteroid receptors and plasticity.
Androgenic neurosteroids (derived
from testosterone), androstenediol
and estradiol, mediate the testosterone
effects on neural excitability (16, 17).
While testosterone may raise seizure
susceptibility and may be part of the
mechanism generating seizures around
ovulation, androstenediol is a powerful
antiseizure and neuroprotective agent as
shown above.
 Sex hormones and women with epilepsy
2. Role of sex hormones on
brain development during puberty
There is growing evidence on
continuous brain changes from fetal life
to adulthood in the process of adapting
the brain functions to the requirements
of each age (1). Dramatic structural brain
changes have been demonstrated during
adolescence.
These changes increase brain
efficiency and functional refinement,
resulting in cognitive and behavioural
changes characteristic for the transition
towards adult life. The remodelling of the
adolescent brain is accomplished through
a variety of mechanisms, including both
progressive events such as increases
in cell number, dendritic elaboration,
axonal sprouting, and myelination, and
regressive events like apoptosis and
synaptic pruning. These processes are
known to be influenced by both androgens
and estrogens (18). We now know that
normal pubertal development implies a
26-fold increase in testosterone plasma
levels in males and 10-fold increase in
estradiol plasma levels in females (19).
Different studies suggested that estradiol
positively influences hippocampal
cell proliferation, number of dendritic
spines, and synaptogenesis and delays
synaptic pruning in other brain regions.
Testosterone may be associated with
myelinogenesis, but this assumption is
disputed by other authors who propose
that testosterone increases axonal caliber
perhaps by influencing the number and/
or properties of microtubules and/or
neurofilaments or glial proliferation (20,
21).
Adolescence is characterised by a
reduction of cortical and subcortical gray
matter structures, in parallel with increase
in white matter volumes (22-25, http://
www.loni.ucla.edu/~thompson/DEVEL/
dynamic.html). Important changes in all
neurotransmitter systems (influenced by
sex hormones) are demonstrated (26-29)
together with profound alterations of
brain connectivity (22, 25, 30). These
changes are non-linear, they evolve
with different speed at different times
for each brain area, with a sex and age-
dependent velocity. There are clear
differences in brain maturation timing
among sexes during adolescence (sexual
dimorphism). It has been speculated
the possible influence of sex hormones
on brain maturation (31) leading to the
known 1-2 years earlier maturation of
the cortex in girls than in boys (32). Not
only the developmental speed, but also
the volumes differ among sexes, with
a greater increase of WM and a greater
decrease of GM in boys than in girls, as
shown by magnetic resonance imaging
studies and specific gender development
of certain brain areas during puberty,
with increases in left amygdala volume
during puberty in males and increases
in left striatal and bilateral hippocampal
GM volume in females (23, 33).
Speculations on possible future
therapies
It has also been speculated
that sex hormones may be implicated
in epileptogenic process. It is currently
not known if estrogens may be involved
in the onset of some forms of epilepsy
during puberty or female predominance
of some types of epilepsy simply by
delay of dendritic pruning. It is a daring
thought that the epileptogenic processes
may be reversed if we could alter
105
 D. Craiu
specific hormonal targets during brain
developmental period (1).
It is now known the importance
of GABAergic system maturation in
maintaining brain functionality and
normal excitability. Influencing the
maturation (development and plasticity)
of the GABAergic system earlier may be
a good antiepileptogenic remedy (1).
3. The impact of epilepsy
and antiepileptic drugs on hormonal
constellation, fertility and reproductive
endocrine disorders
Reproductive endocrine
disorders have been described more often
in WWE than in general population.
These include polycystic ovary syndrome
(PCOS), hyperandrogenaemia,
hypothalamic amenorrhoea, and
functional hyperprolactinaemia (34,
35). The most likely explanations for
endocrine disorders related to epilepsy
or antiepileptic drugs are: a direct
influence of the epileptogenic lesion,
epilepsy, or AEDs (36) on the endocrine
control centres in the brain; the effects
of AEDs on peripheral endocrine glands;
the effects of AEDs on the metabolism
of hormones and binding proteins; and
secondary endocrine complications of
AED-related weight changes or changes
of insulin sensitivity (37) and direct
insulin role in PCOS clinical signs (38).
There is evidence that both epileptic
seizures (high seizure frequency)
(39) and epileptic activity (interictal
discharges) (40) may influence the
hypothalamic-pituitary axis and, disrupt
the activity of the GnRH (gonadotropin-
releasing hormone) pulse generator.
Increased pulse frequency of GnRH
106
secretion and, consequently, of the LH/
FSH (luteinizing hormone/follicle-
stimulating hormone) ratio may be
associated with PCOS. In contrast, a
lower GnRH pulse frequency causes a
decrease of LH and estradiol levels that
is characteristic of hyperandrogenism
and menstrual irregularities (36, 41).
Fertility in WWE. Many factors
may concur leading to a decreased fertility
in women with active epilepsy: low self-
esteem, social stigma, lower marriage
rate comparing to general population,
endocrine dysfunctions, low pregnancy
rates because of hyposexuality or
sexual dysfunction, concern on epilepsy
deterioration or impact of epilepsy or
AEDs on the future child (42).
AEDs such as carbamazepine,
phenobarbital and phenytoin (enzyme-
inducing drugs) may influence
metabolism of sex steroid hormones with
an important effect on sexual function
and fertility (43).
PCOS might be more frequent
in women with epilepsy, although their
prevalence is not actually known. PCOS
might have a genetic basis with possible
prenatal origin (44) and onset of clinical
signs during adolescence/adulthood
after maturation of the hypothalamic-
pituitary-ovarian axis. Different studies
suggest an important role of valproate
for reproductive endocrine disorders
including PCOS (43, 45), but this issue
was controversial (46, 47). A German
study found similar rates of PCOS
among women treated with valproic
acid (VPA) and carbamazepine and in
untreated patients with epilepsy (48).
A recent meta-analysis shows that the
raw incidence of PCOS in VPA treated
 Sex hormones and women with epilepsy

women with epilepsy is approximately able to avoid enzyme-inducing AEDs

1.95 folds greater than in other AEDs
treated women and recommends
monitoring PCOS and its components in
women with VPA mono-/polytherapy.
A proposed mechanism is that VPA
and other AEDs may cause weight
gain that triggers insulin resistance and
hyperandrogenism indirectly leading
to PCOS, but comparative randomised
trials using different AEDs are needed
(46, 47).
Practical approach concerning
management of reproductive endocrine
disorders in WWE
Whenever possible, it is advis-
or valproate when choosing the first
AED in a young girl/WWE. New AEDs
might offer an alternative, although not
enough data is available. Young women
that are prescribed valproate should be
closely monitored and treatment should
be reassessed if adverse effects such as
considerable weight gain or menstrual
disturbances occur. Regular monitoring
of reproductive function at each visit
is recommended in WWE. Single
abnormal laboratory or imaging findings
without symptoms may not constitute a
clinically relevant endocrine disorder.
If WWE present clinical signs of

Table 1. Clinical features of reproductive disorders in women with epilepsy

Symptom/sign Method Abnormal findings Comment
Look for other symptoms of
<23 days: polymenorrhoea
endocrine disorder including
Menstrual Menstrual chart for at >35 days: oligomenorrhoea
thyroid dysfunction;
irregularity least 6 months No bleeding >6 months:
Investigate or refer for
amenorrhoea
investigation
Assess menstrual
regularity. Endocrinologist
and/or gynaecologist
Inability to conceive after more
should be consulted
than 12 months of regular
Infertility Clinical history to exclude endocrine
unprotected intercourse and
disorders such as PCOS,
exclusion of male causes
hypothalamic amenorrhoea,
hyperprolactinaemia, thyroid
dysfunction
Assess menstrual regularity.
BMI (weight (kg)/
In case of cycle disturbance:
height2 (cm)) Obese: BMI > 25
Obesity and investigate or refer
WHR: ratio of supine Significant weight gain > 5kg
weight gain Assess menstrual regularity.
circumference of Truncal obesity: WHR > 0.9
In case of cycle disturbance:
waist/hips
investigate or refer
May be genetic or ethnic.
Inspection or
Assess menstrual regularity.
Hirsutism Ferriman-Gallwey Male escutcheon
In case of cycle disturbance:
score
investigate or refer
Assess menstrual regularity,
Crusting on nipples; expression
look for hirsutism, signs of
Glactorrhoea History of breast milk in non-lactating
hypothyroidism. Investigate
women
or refer
BMI, body mass index; PCOS, polycystic ovary syndrome; WHR, waist/hip ratio
Reproduced from 35 (http://jnnp.bmj.com/content/73/2/121/T1) with permission (Elsevier License).

107

reproductive endocrine disorders (weight
gain, hirsutism, menstrual irregularity,
infertility, galactorrhoea, etc.) (Table 1),
correct history and investigations to
diagnose them should be performed
(Table 2) to allow immediate treatment.
4. Catamenial epilepsy
Catamenial epilepsy seems not
to be a different form of epilepsy, but a
term used to describe a seizure pattern -
the cyclical seizure exacerbations during
specific phases of menstrual cycle in
Table 2. Investigation of women with epilepsy and symptoms or signs of reproductive endocrine disorder
Test Method
Measurement of serum
levels (calculation based
on an average of three
LH, FSH
estimations taken 20
minutes apart between day 3
and 6 of the cycle)
Measurement of morning
Prolactin resting serum levels (not
postictal!)
Measurement of serum level
(blood taken during mid-
Progesterone
luteal phase according to
the menstrual cycle)
Measurement of serum level
Testosterone
day 3-6 of the cycle
Androstendione Measurement of serum level
DHEAS Measurement of serum level
Fasting, morning levels;
Glucose/Insulin
glucose/insulin ratio
Transvaginal or
Pelvic
transabdominal (day 3 to 9
ultrasound
of the cycle)
Exact values and units of measurement may vary from laboratory to laboratory
FSH, follicle stimulating hormone; DHEAS, dehydroepiandrosterone sulphate; HA, hypophyseal adenoma; HPRL,
hyperprolactinaemia; LH, luteinising hormone; PCOS, polycystic ovary syndrome
Reproduced from 35 (http://jnnp.bmj.com/content/73/2/121/T1) with permission (Elsevier License).
108
D. Craiu
WWE. The prevalence of catamenial
epilepsy (10-70%) varies with the
definition, study methodology, accuracy
of patient-reporting seizures (49).
At least three patterns of
catamenial seizure exacerbation have
been described: perimenstrual and
periovulatory in ovulatory cycle and
entire luteal phase in anovulatory
cycle (Fig. 1). These patterns have
been considered reflecting the cyclical
changes in the circulating levels
of estrogen (proconvulsant) and
Abnormal findings Comment
LH/FSH ratio > 2 Suggestive of PCOS
FSH >35 IU/L; LH Suggestive of menopause
>11IU/L Suggestive of hypothalamic
LH <7 IU/mL amenorrhoea
May be mildly raised in patients with
epilepsy; rule out hypothyroidism
>20g/L
or pituitary tumour; drugs may have
impact on PRL levels
Low levels indicate anovulation;
<6nmol/L
common cause: PCOS, HA, HPRL
Common cause: PCOS, valproate;
non classical adrenal hyperplasia
>2.5nmol/L
may cause modest elevation of
>4 nmol/L
testosterone
Rule out adrenal/ovarian tumour
Rule out non classical congenital
>10 nmol/L
adrenal hyperplasia
Age 20-29 > 3800ng/mL Rule out non classical adrenal
Age 30-39 > 2700 ng/mL hyperplasia
Suggestive of diabetes
Fasting glucose > 7.8
Suggestive of reduced insulin
mmol/L
sensitivity; associated with obesity
Glucose/insulin ratio > 4
and PCOS
> 10 peripheral cysts,
2-8 mm diameter in Polycystic ovaries; associated with
one ultrasound plane, PCOS
thickening of ovarian Tumours, atrophy, multifolicular
stroma. Other structural ovaries, etc.
abnormalities of ovaries
 Sex hormones and women with epilepsy

The upper panel illustrates the strong relationship between seizure frequency and estradiol/progesterone levels.
The lower panel illustrates the three types of catamenial epilepsy. The vertical gray bars (left and right) represent
the likely period for the perimenstrual (C1) type, while the vertical gray bar (middle) represent the likely period for
the periovulatory (C2) type. The horizontal dark gray bar (bottom) represent the inadequate luteal (C3) type that
likely occur starting early ovulatory to menstrual phases.
(Reproduced from 50 with permission (Elsevier license).
Figure 1. Temporal relationship between ovarian hormones and occurrence of catamenial seizures
during the menstrual cycle.

progesterone (anticonvulsant) (Table for most of the remedies. Treatment of

3); variations in concentrations of
antiepileptic drugs across the menstrual
cycle may contribute to increased seizure
susceptibility (50, 51).
The diagnosis of catamenial
epilepsy can be made through careful
assessment of menstrual and seizure
diaries and characterization of cycle type
and duration (52).
There is no specific treatment of
catamenial epilepsy which is refractory
seizures with catamenial occurrence is
guided based on a series of cases and
case-reports; there are no randomized
controlled trials in the literature except
one phase III placebo-controlled double-
blind study using progesterone (53).
A variety of therapies have been
proposed, with disappointing results.
Acetazolamide has been
prescribed based on anecdotal reports
demonstrating efficacy in small or

109
 D. Craiu
Table 3. Potential changes in neurosteroid levels and seizure susceptibility in catamenial epilepsy.
(Reproduced from 50 with permission (Elsevier License)
Seizure
Type Changes in neurosteroids Neuronal excitability
susceptibility
Very low neurosteroids
C1 Perimenstrual* (withdrawal) Decreased GABAergic inhibition Increased
Low estradiol
High estradiol Increased excitation
C2 Periovulatory** Increased
Low neurosteroids Decreased GABAergic inhibition
Very low neurosteroids Decrease in GABAergic inhibition
C3 Inadequate luteal*** Increased
Moderate estradiol Persistent excitation
*Perimenstrual type occurs in women with normal menstrual cycle possibly due to a sharp decline (withdrawal) in the serum
level of progesterone and, consequently, of the level of progesterone-derived anticonvulsant neurosteroids in the brain around
perimenstrual period. The estradiol/neurosteroid ratio is highest during menstruation. Because neurosteroid potentiates GABA-A
receptor-mediated inhibition, the rapid loss of neurosteroid-mediated inhibition, such as that occur before, during or after the
onset of menses, could exacerbate seizures in many women with catamenial epilepsy.
**Periovulatory type occurs in women with normal menstrual cycle possibly due to estradiol surge just before ovulation, and low
neurosteroid levels do not offset the estradiol-induced excitation because the rise of anticonvulsant neurosteroid levels would not
occur until after ovulation. Subsequently neurosteroid synthesis is strikingly high during the luteal phase and is long-lasting until
they decline rapidly around perimenstrual period. The relatively low neurosteroid inhibition and marked estradiol excitation could
lead to periovulatory seizures.
***Inadequate luteal type occurs in women with anovulatory cycles possibly due to a loss of neurosteroid-mediated inhibition
during luteal phase for a prolonged time. Progesterone secretion that occurs normally during the luteal phase is markedly decreased
during anovulatory cycle resulting in abnormally low levels of neurosteroid in the brain. The midcycle surge in estradiol still occurs
in anovulatory cycle at moderately reduced levels. Because neurosteroid potentiates GABA-A receptor-mediated inhibition, low
levels or lack of sufficient neurosteroids may possibly result in minimal or no such potentiation which is accompanied by unopposed
estradiols excitability. This imbalance in neurosteroid inhibition and estradiol excitation could ultimately trigger occurrence of C3
type seizures. In addition, the striking reductions in the levels of adrenally-derived neurosteroid THDOC during both follicular and
luteal phases would most likely exacerbate type C1 and C2 seizures.

poorly characterized populations or on effects (sedation), in doses of 20-

retrospective analysis of larger cohorts, 30 mg/day in an intermittent way
showing more than 50% seizure reduction of administration 10 days around
in 40% of the analysed population, with menstruation, with no tolerance effect
a 15% women who developed tolerance (57).
in continuous acetazolamide administra- Conventional antiepileptic
tion (54). Therefore, intermittent use drugs (AEDs) may also be used,
of acetazolamide, which is suitable also in an intermittent or continuous
for catamenial epilepsy, may be of administration, choosing the most
benefit. The mechanism of action is appropriate for the womans type of
not well understood, it was speculated seizures/syndrome. Lamotrigine has
that a reduced neuronal excitability been given special attention in small
results following an accumulation of studies proving a good effect on seizures
CO2 in the brain (55) and by reducing and elevated levels of progesterone in
intracellular bicarbonate. Outflux of treated women (58).
bicarbonate through GABAA receptors Hormonal therapies. Based
has a depolarizing action that balances on the mechanism of action, variate
the hyperpolarization caused by influx types of hormonal treatments with
of chloride (56). anticonvulsant properties have been
Benzodiazepines proved proposed: Medroxyprogesterone acetate,
efficacious and had reduced adverse Progesterone, and other hormonal

110
 Sex hormones and women with epilepsy
therapies (133). The most promising
intervention appeared to be introduction
of natural progesterone on days 14 to 25 of
the menstrual cycle, but all data emerged
from low power studies. A recent
randomized, double-blind, placebo-
controlled, phase III, multicenter,
clinical trial compared the efficacy
and safety of adjunctive cyclic natural
progesterone therapy versus placebo
treatment of intractable seizures in 294
subjects randomized 2:1 to progesterone
or placebo, stratified by catamenial
and noncatamenial status. There was
no significant difference in proportions
of responders between progesterone
and placebo in the catamenial and
noncatamenial groups (53). Post hoc
analysis identified a subset of women
with higher levels of perimenstrual
seizure exacerbation (between days 3
to 3 of the menstrual cycle, the so-called
C1 pattern) that were responsive to
treatment and who may benefit from
intermittent progesterone administration
(59).
As a result of the decrease
in progesterone levels at the time
of menstruation. the progesterone-
derived GABA(A) receptor modulating
neurosteroid allopregnanolone is
reduced, leading to an increased
seizure susceptibility in perimenstrual
catamenial epilepsy. In the catamenial
epilepsy model, there is a reduction
in the potency of AEDs, including
benzodiazepines and valproate, but an
increase in the anticonvulsant potency and
protective index of neurosteroids such as
allopregnanolone and the synthetic form
of allopregnanolone, ganaxolone. From
the group of Neurosteroids, ganaxolone
has been tried with different results (60,
61).
5. Contraception and epilepsy
Contraception in WWE. Even
from the first consultation, girls and
WWE should be offered information
and advice concerning all contraceptive
methods, interactions between AEDs and
oral contraceptives (Table 4, Table 5)
(62, 63). The choice of the antiepileptic
medication (AED) should be always
made thinking at AEDs contraceptives
bidirectional interactions and future
pregnancies.
AEDs-contraceptives interaction
Enzyme-inducing AEDs
(EIAEDs), phenytoin, barbiturates,
carbamazepine, primidone (68), and to
a lesser extent second generation AEDs
felbamate, topiramate (doses above
200 mg/day) (69), and oxcarbazepine
(70) induce the metabolism of estradiol
and progestogen components of the
contraceptives, leading to increased
contraceptive failure. Failure rate is up
to 3.1 per 100 women-years in WWE
treated with EIAEDs comparing with 0.7
per 100 woman-years in untreated WWE
using oral contraceptives (71) , combined
contraceptive patches, progestogen only
pill, progestogen implant (72).
Progestogen only subcutaneous
implants or oral contraceptive is not
recommended in WWE taking EIAEDs
(high failure rate), unless double dose is
used.
A starting dose of 50 g/day of
estradiol should be used in WWE taking
COC and EIAEDs, and increased to 75
to 100 g/day if breakthrough bleeding
occurs. Additional contraceptive
111
 D. Craiu
Table 4. Recommendations for contraception in women with epilepsy (64,65,66)

In WWE contraceptive methods that are unaffected by EIAEDs may be first considered.
Nonhormonal methods of contraception are not contraindicated (including Mirena coil).
Hormonal forms of contraception are affected by enzyme-inducing AEDs; women taking these forms
of contraception should be counseled on their risks and benefits
Hormonal contraception may still be used. A higher dose of oral contraceptives (of at least 50 g
estrogen) is indicated
For WWE on non-EIAEDs (sodium valproate, benzodiazepines, vigabatrin, gabapentin, tiagabine,
levetiracetam, pregabalin), all current contraceptive methods are suitable; a normal dose oral
contraceptive pill should be used
For WWE on EIADs (phenytoin, barbiturates, carbamazepine, felbamate, oxcarbazepine, topiramate
>200 mg/day)
- Start with 50 g/day estrogen dosage
- If breakthrough bleeding occurs, increase the dose of oestrogen to 75 or 100 g/day or
consider giving three packs of the pill without a break (tricycling) or reduce break from 7 to 4 days
Even on a higher-dose COCP with normal cycles, full oral contraceptive efficacy cannot be guaranteed
in WWE taking EIAEDs
Double Lamotrigine doses should be used in WWE taking COCPs; decrease LTG dose during pill-
free period (see Table 6. and text d.3.1.3.)
The progestogen-only pill is likely to be unreliable in women taking enzyme-inducing AEDs.
Progestogen implants (specifically levonorgestrel implants) should be not used as a method of
contraception by WWE taking EIAEDs (limited evidence of ineffectiveness)
Medroxyprogesterone injections appear to be effective; the frequency of injection for depot
progestogen should be increased to every 10 weeks (compared with the usual 12 weeks) in WWE
taking EIAEDs
The emergency contraceptive pill can be used in women with epilepsy after unprotected sexual
intercourse. A higher dose may be needed in WWE taking EIAEDs.
Post-partum contraception
- Should be started three weeks post- partum.
- POPs should be used in breast-feeding mothers.
- If the mother is not breast feeding, a COCPs (which reduce milk secretion).
- WWE taking EIAEDs should follow the protocols outlined above
WWE = women with epilepsy; EIAED = enzyme inducing antiepileptic drug; AED = antiepileptic drug; COCP = combined oral
contraceptive; LTG = lamotrigine

Table 5. Supplementary issues and concerns in adolescent contraceptive councelling

Compliance in AED therapy and oral contraception might be reduced. Use AED medication
twice a day and keep a pill box and establish a daily routine (68).
Use of the intrauterine device is discouraged (risk for pelvic inflammatory disease) (67).
Tubal ligation is inappropriate for adolescents (67).
Use driving regulations motivation to increase compliance.
Medroxyprogesterone injections may be an appropriate alternate short-term contraceptive method
in adolescents; avoid long-term use (risk of reduced bone mineral density)(66).

AED = antiepileptic drug.

methods should be used even with releasing intrauterine systems (68), and
high doses. Shortening the pill free other intrauterine contraceptive devices
interval from 7 to 4 days may give better are apparently unaffected by enzyme
protection (68). inducers (73); experts recommend
Depot injections of more frequent medroxyprogesterone
medroxyprogesterone, hormone injections if used in combination with

112
 Sex hormones and women with epilepsy
EIAEDs (every 10 weeks rather than 12
weeks) (68).
The emergency contraceptive
pill can be used in women with epilepsy
after unprotected sexual intercourse. In
women taking EIAEDs the first dose
should be doubled to two pills with a
second dose at 12 hours of one pill (65,
68).
Nonenzyme-inducing AEDs
(valproate sodium, benzodiazepines,
ethosuximide, zonisamide,
levetiracetam, tiagabine, gabapentin,
pregabalin) have no interactions with
oral contraceptives (68). Vigabatrin
(non-inducer) produced lower levels of
ethinyl estradiol in healthy volunteers
(74).
The effect of oral contraceptives
on AEDs
No evidence suggests that
hormonal contraception increases seizure
frequency WWE receiving AEDs;
the use of hormonal contraceptives is not
contraindicated in WWE (68).
The case of Lamotrigine (Table 6).
Lamotrigine does not
affect estradiol levels but reduces
the progestagen concentrations by
approximately 20% (75). Whether
this leads to higher failure rates is
not known. Estradiol containing oral
Table 6. Effects of contraceptives on LTG
LTG plasma
concentration
Estradiol containing OC 40-60%
Estradiol containing OC
>50%
pill free week
Progestagen only OC Unaffected or
Vaginal ring releasing
15-50%
estradiol and progestagen
LTG = lamotrigine.
contraceptives reduce lamotrigine
plasma concentrations by 40 - 60% (76)
followed by reduced seizure protection.
Double LTG dose might be necessary.
Withdrawing oral contraceptives (pill
free week) can produce toxic (double
or more) lamotrigine levels and
symptoms and might necessitate LTG
dose reduction (77). Changes in LTG
dose should be guided by drug level
monitoring (76).
LTG concentration might be not
affected or increased by progestogen
only pill (78).
In conclusion, WWE are
probably the highest challenge for
neurologists, endocrinologists and
gynecologists who may need to work
together in a multidisciplinary approach
in order to touch all aspects of the care of
a WWE in the attempt of offering them a
normal life.
It is important to understand
the influence of hormones on neuronal
excitability and epilepsy and the
modalities in which hormones or
hormonal products may be used for the
benefit of patients.
In case of WWE with catamenial
seizures, assessment of seizures
journal in parallel with menstrual diary,
cycle type characterization, AEDs
Clinical effect Reference Action
Reduced seizures
76 Give double normal dose
protection
Toxic symptoms 77 Give half normal dose
- 78 -
77 Give higher to double dose
113
 D. Craiu
and possible contraceptives inventory
should be performed. Treatment should
be individualized. Women with C1
pattern of exacerbation of menstrual
seizures may benefit from hormonal
therapy (intermittent progesterone)
comparing with C2 and C3 types which
are usually non-responsive. These last
two groups may show good results
with acetazolamide, benzodiazepines,
conventional AEDs.
It is important to choose the most
appropriate AED even from the first
consultation in a girl / WWE, starting
from the well-known bidirectional
interactions contraceptives-antiepileptic
medication and avoid valproate which
may associate PCOS.
Conflict of interest
We declare that there is no conflict
of interest.
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