1. Hormonal profile and fertility in women with epilepsy
Carmen Gabriela Barbu
Carol Davila University,
Endocrinology Department, Elias Hospital,
Bucharest, Romania

2. The hormonal profile related to menstrual cycle in healthy women is notoriously dynamic

3. Hormones influence on epilepsy
Cortical excitability is known to be affected by pituitary and gonadal hormones. Estrogens can activate seizures and interictal discharges when directly applied to the cerebral cortex or infused intravenously. Progesterone decreases cortical excitability, by enhancing GABA effects, and increases electroshock seizure threshold in experimental models.

4. Fig 2. The effects of hormonal changes in cortical excitability.
A) ICI changes during three Ax sessions in men and women. B) ICF changes during three Ax sessions in men and women. 1st, 2nd and 3rd Ax for men is equivalent to follicular, ovulation and mid-luteal phases respectively for female participants. *: p < MEP: Motor evoked potential; ICI: intracortical inhibition; ICF: intracortical facilitation; Ax: assessment.
Zoghi M, Vaseghi B, Bastani A, Jaberzadeh S, Galea MP (2015) The Effects of Sex Hormonal Fluctuations during Menstrual Cycle on Cortical Excitability and Manual Dexterity (a Pilot Study). PLOS ONE 10(8): e doi: /journal.pone

5. Proposed mechanisms
the plasticity and function of synaptic and extrasynaptic GABA-A receptors in the hippocampus.
δ-subunit-containing GABA-A receptors are elevated at diestrous (high P) than estrous (low P) stage. promoting greater tonic inhibition in the hippocampus and resistance against seizure susceptibility
A proposed model of ovarian-cycle related changes in the plasticity and function of synaptic and extrasynaptic GABA-A receptors in the hippocampus.
Postsynaptic GABA-A
receptors, which are pentameric chloride channels composed of 2 α 2 βγ
subunits, mediate the phasic portion of GABAergic inhibition, while extrasynaptic GABA-A receptors,
pentamers composed of 2 42 βδ
subunits, primarily contribute to tonic inhibition in the hippocampus. The abundance of δ
-subunit-containing GABA-A receptors is elevated at
diestrous (high P) than estrous (low P) stage. Such plasticity promotes greater tonic inhibition in the hippocampus and thereby provides resistance
against seizure susceptibility (
Reddy et al., 2011 ).
D.S. Reddy / Hormones and Behavior 63 (2013) 254–266

6. Steroid hormones and seizures susceptibility

7. Catamenial epilepsy
one third to one half of women report increased cyclic seizures related primarily to hormonal factors
true catamenial epilepsy requires reproducible and consistent increase or change in character of seizures at the same point in a regular menstrual cycle. Difficult to assess in anovulatory cycles.
Plurifactorial through other causes influenced by menstrual cycle
Conclusions
ict of interest statement fl
Con
References
Acknowledgments
characterized by the unpredictable occurrence of seizures that differ in
Epilepsy is one of the most common chronic neurological disorders
Introduction
type,cause,andseverity.However,seizuresdonotoccurrandomlyin
epilepsy, seizure periodicity may conform to the menstrual cycle
periodicity following circadian or lunar periodicity. In women with
many women with epilepsy. Seizure clusters occur with a temporal
according to a ”
menstrual clock “
provided by a common phase marker
). Catamenial epilepsy, derived
Gowers, 1881
of the onset of menses (
from the Greek word
, meaning
katomenios
monthly
by seizures that cluster around speci
, is characterized (
c points in the menstrual cycle fi
Fig. 1
in which seizures are most often clustered around perimenstrual or
eted neuroendocrine condition
). Catamenial epilepsy is a multifac
periovulatory period. Epilepsy affects an estimated 1.3 million women
). Catamenial
Kaplan et al., 2007; Pennell, 2008
in the United States (
epilepsy affects from 10 to 70% of women with epilepsy (
). The large
2005; Gilad et al., 2008; Herzog et al., 2004; Reddy, 2009
Bazan et al.,
methodological differences such as the criteria used for de
variation in the prevalence of catamenial epilepsy is partly because of
ycle, patients' self-report, diaries,
exacerbation in relation to menstrual c
ning seizure
and other records of seizures relating to menses. Overall, these studies
a form of intractable epilepsy beca
epilepsy shows catamenial seizure exacerbation. Catamenial epilepsy is
support the prevailing notion that at least 1 in every 3 women with
use catamenial seizures are often
gap in our understanding of what changes occur in the brain in relation
effective prevention or cure for catamenial epilepsy. There is a large
quite resistant to available drug treatments. Presently, there is no
to the hormonal
detailed understanding of the patterns and pathophysiology is essential
how these changes alter sensitivity to anticonvulsant drugs. Thus, a
uctuations associated with catamenial epilepsy and
treatment of catamenial epilepsy.
for the development of rational approaches for the prevention or
phase (C3), have been identi
(C2), and inadequate luteal-
Three types of catamenial seizures, perimenstrual (C1), periovulatory
ed ( )(
et al., 1997
Herzog ;
clinical type. Perimenstrual and periovulatory types are illustrated in
). The perimenstrual type is the most common
Table 1
.Thespeci
c pattern of catamenial epilepsy can be identi
by charting menses and seizures and obtaining a mid-luteal phase serum
ed simply
progesterone (P) level to distinguish between normal and inadequate
). The diagnosis
Herzog et al., 2008; Quigg et al., 2009
luteal phase cycles (
of catamenial epilepsy is mainly based on the assessment of
2003; Herzog, 2006
Foldvary-Schaefer and Falcone,
menstruation and seizure records (
). The simple approach of evaluation of catamenial
trong relationship
Temporal relationship between ovarian hormones and occurrence of catamenial seizures during the menstrual cycle. The upper panel illustrates the s
Fig. 1.
between seizure frequency and estradiol/P levels. The lower panel illustrates the three types of catamenial epilepsy. The vertical gray bars (left a
rk gray bar (bottom) represents
for the perimenstrual (C1) type, while the vertical gray bar (middle) represents the likely period for the periovulatory (C2) type. The horizontal da
nd right) represent the likely period
ed to last 29 days. Day 1 is the onset
the inadequate luteal (C3) type that likely occur starting early ovulatory to menstrual phases. In general, the female reproductive cycle is estimat ) i
of menstruation, and ovulation occurs 14 days before the onset of menstruation. The menstrual cycle is divided into four phases: (
menstrual phase −
days ,
3to ;( 3 + ii
phase
follicular
4to 9
iii
ovulatory phase
10 to 16
and iv
luteal phase
17 to 4
. As ovulation approaches,
synthesis and secretion of estrogens and P from the ovaries are controlled primarily by the hypothalamic GnRH and pituitary gonadotropins, FSH and LH
. The early follicular phase is associated with low levels of estrogens and P. The
the level of estrogen rises and triggers the release of a large surge of LH leading to ovulation. Following ovulation, the ruptured follicle luteinize
the luteal phase and declines
secretes P and estrogen. Estradiol is secreted in the second half of the follicular phase and increases to a peak at midcycle, while P is elevated during
s and forms a corpus luteum that
Reddy, 2009
before menstruation begins. The neurosteroid AP is increased in parallel to its precursor, P ( ).
Reddy, 2009).

8. Hormonal changes induced by epilepsy
Fluctuations of luteinizing hormone (LH) and pulsatile release of prolactin and sex steroids have been observed in temporal relation to some seizures but American Academy of Neurology guideline for the use of serum prolactin level documents that this is not a consistent enough relationship for diagnostic purposes.

9. Hormonal changes induced by epilepsy
The reciprocal feedback of the temporal and limbic structures with the hypothalamus can alter secretion of hypothalamic, pituitary, and gonadal hormones.
A structural neurologic abnormality of the amygdala or mesial temporal lobe may cause both epilepsy and altered hypothalamic hormonal function.

10. Hormonal changes induce by AEDs

11. Clinical consequences
Seizure frequence can be modified by menarche and menopause OR an associated ovarian disfunction
Catamenial epilepsy
Menstrual disorders
Contraception particularity
Sexual dysfunction
Infertility
PCOS
Early menopause

12. Menstrual disorders in women with epilepsy
in 1 of 3 women with epilepsy vs 1 in 7 in the general population.
Oligomenorrhea and abnormal cycle length (< 23 d or >35 d) occur in up to 30% of women with epilepsy.
More common in women with high seizure frequency (>5sz/year)
More common in women on multiple AEDs
More common in women on Valproate than Carbamazepine.

13. Fertility
Overall, women with epilepsy have lowered fertility compared with women in the general population but social inhibitions, older age when pregnancy is desired could be a confusing factor

14. However, anovulatory cycles are more frequent in…
Women with Idiopathic Generalized Epilepsy (27.1%)
Women with Focal Epilepsy (14.3%)
Controls (10%)
Recent (within last 3 years)users of Valproate (38%) vs non recent users (10.7%)

15. PCOS
PCOS has been reported in 41% of women with idiopathic generalized epilepsy and in 26% of women with localization-related epilepsy
Valproate treatment is asoc to PCOS (60%) vs carbamazepine 33% or lesss than 15% with other AEDs
Treatment of PCOS includes clomiphene, which is also used as a fertility-enhancing agent which has been anecdotally reported to be associated with a reduction in seizures; explanation resonable due to normalization on menstrual cycle

16. Contraception
Women taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.
Carbamazapine
Oxcarbazepine
Phenytoin
Phenobarbitol/Primidone
Topiramate (doses above 200mg/day)
Rufinamide
Perampanel
Lamotrigine level is lowered by OCP

17. Sexual dysfunction
up to one third of women with epilepsy self-report sexual dysfunction
difficulty with sexual arousal and increased occurrence of vaginal dryness and vaginismus.
In an observational study, an improvement in sexual dysfunction was observed in association with lamotrigine. (the result of improvement of the epilepsy, changes in quality of life, elimination of side effects from other AEDs, or a mood-stabilizing effect of lamotrigine).
Total score in the CSFQ in sexual function. Solid
line, patients beginning their treatment with lamotrigine
(group A); dotted line, patients whose AED was substi-
tuted by lamotrigine. * p
<
0.05 final visit vs. baseline
(group B)

18. Practical conclusions 1

19. Practical conclusions 2
Valproate should not be used if possible in adolescent or women desiring pregnancy in the close future
Treatment for infertility may improve seizure control through restoration of a normal menstrual cycle/ planning of pregnancy
Oral contraception with increased dose of ethinyl estradiol AND if found to improve seizure control, long acting progestins might be prefered
Active interview regarding sexual disfunction should be mandatory and psychological counseling should be offered to the patient ; Lamotrigine could be used
Monotherapy, simplification of AEDs

20. Thank you!

21. S.M.S.Tamijani et al./Seizure 31 (2015)155–164
that
the of
function
proper in
THs
prevent
might
brain
slow or
down
development
5.3.
seizures.
epileptic
and
hormones
Thyroid
neurons
GABAergic
lines
Several
show
evidence
modulate .
[8,9] An
vitro
fatal on
study
rat
reports
increase
developmental
activity
decarboxylase
acid
glutamic as
(GAD)
enzyme
main
conversion to be
could
GABA by
increased T3
[84]
administration
Experimental
has
hypothyroidism
neonatal
been
also
shown
decrease
this
[85–87]
Beside
activities
enzyme,
enzymes
other
participate
such
metabolism
GABA-transaminase
(GABA-T)
dehydrogenase
semialdehyde
succinate
are
(SSDH)
affected
THs,
consequently
disturbance
affects
cycle.
life
While
induction
developing
decreases
generating
destroying
replacement
enzymes, is TH
restore It
changes.
these
proposed
impairment
inter-
contribute
may
locomotor
dysfunction
induced
anxiety
deficits
[88–91]
Effects
deficiency
complexity
adult
injection I
131
[92]
but ,
contrast,
rats
induce
onset
adult-
impairs
exchange
mine
gluta-
glutamate,
neuronal
between
compartments
glial
[93]
concentration
similar
Results
reported
those
were
adult-onset
when
observed
was
[94]
carbimazole
intraperitoneal
This
following
with
consistent
showing
GAD
increases
cortex
visual
[95]
Induction
hyperthyroidism T4
glutamate
levels
thalamus
hypothalamus an
addition, In
revealed
synaptosomes
nanomolar
low
concentrations
depolarization-induced a
through
release
mechanism
non-genomic
direct,
[96]
thought
via
achieved
direct
effect
which 2+ Ca
uptake
[97]
Based
evidences,
presented
can it
summarized
differentially
regulate
system.
brain,
oppose
brain.
matured
presents
linkage
field
new
research if
elucidate
effects
systems
pathogenesis
researches
Interestingly,
epilepsy.
proved
have
thyroid
modulates
system
[91]
Generally,
inhibits at
three
all
pituitary,
hypothalamus,
axes ( ) 2
Fig.
interplay
bidirectional
plays
role
important
seizure
suppression
neurotransmitter.
inhibitory
Thus,
contrast
presumed
seizures
increasing
during
development.
Schematic 2.
representation
interactions
possible
The
vertebrates. +
symbols
stimulation
indicate
respectively.
inhibition,
-aminobutyric g
GABA,
TRH,
acid;
hormone;
releasing
thyrotropin
TSH,
stimulating
triiodothyronine;
T3,
T4,
thyroxine. et
Tamijani
S.M.S.
al. 31
Seizure /
155–164
(2015)
159
S.M.S.Tamijani et al./Seizure 31 (2015)155–164
American Academy of Neurology 62nd Annual Meeting: Poster PD Presented April 13, 2010.