Download interaction between epilepsy and endocrine

REVIEW
INTERACTION BETWEEN EPILEPSY AND ENDOCRINE HORMONES:
EFFECT ON THE LIFELONG HEALTH OF EPILEPTIC WOMEN
—
Cynthia L. Harden, MD*
ABSTRACT
Women with epilepsy face unique challenges,
some of which arise from the interaction between
epilepsy and endocrine hormones. Epilepsy and
endocrine hormones reciprocally influence one
another such that hormonal changes impact epilepsy and epilepsy impacts hormonal functioning. In
this article, the effect of that interaction on the lifelong health of epileptic women is examined.
Fluctuations in sex hormones can increase the vulnerability to seizures in many epileptic women. One
third to one half of women with epilepsy experience
catamenial seizures (changes in seizure frequency
at specific times during the menstrual cycle).
Seizures can result in endocrine abnormalities that
can effect menstrual irregularities, fertility, and sexual dysfunction and have been linked to polycystic
ovary syndrome. The mechanisms of seizure-associated abnormalities have not been determined, but
some theories include seizure-related disruption of
hormones or brain regions mediating reproduction;
antiepileptic drugs; and structural or functional central nervous system dysfunction associated with the
disease of epilepsy (but not with seizure activity per
se). By being aware of how endocrine hormones
and epilepsy interact throughout the patient’s life
span, the healthcare provider is better equipped to
manage endocrine-associated changes in seizure
frequency and epilepsy-associated changes in neuroendocrine function.
(Adv Stud Med. 2003;3(8A):S720-S725)
*Associate Professor of Neurology, Department of
Neurology and Neuroscience, New York-Presbyterian
Hospital, Weill Medical College of Cornell University, New
York, New York.
Address correspondence to: Cynthia L. Harden, MD,
New York-Presbyterian Hospital, 520 East 70th St, Starr
Pavilion, Suite K-615, New York, NY 10021.
S720
omen with epilepsy face unique
challenges, some of which arise
from the interaction between
endocrine hormones and the
mechanism of epilepsy. The reciprocal influence of epilepsy and endocrine hormones
affect one another such that hormonal changes impact
epilepsy and epilepsy impacts hormonal functioning.1-5
These relationships affect the health of women with
epilepsy. The interaction of endocrine hormones and
epilepsy in men is less obvious because men, unlike
women, do not experience marked monthly hormonal fluctuations that occur with menstruation. This article considers the relationships between epilepsy and
endocrine hormones in women and discusses the
implications of these relationships for women’s health
throughout the life span.
W
ENDOCRINE HORMONES AND
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
THE
Endocrine hormones are chemical messengers that
are produced by glands and released into the bloodstream. By interacting with organs throughout the
body, endocrine hormones control a variety of bodily
functions and processes (eg, reproduction, emotions,
responses to stress, carbohydrate and lipid metabolism). Endocrine glands, such as the ovaries, which are
ductless and secrete hormones internally (usually into
the bloodstream) are differentiated from exocrine
glands, such as sweat glands, which secrete hormones
through ducts to the outside surface of tissue.
Of the many hormones in the human body, the sex
hormones estrogen and progesterone are particularly
important in epilepsy.3,6 Estrogen and progesterone are
released by the ovary in response to hormonal signals
from the hypothalamus and the anterior pituitary gland
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in the midbrain (Figure 1).2 The hypothalamus and the
implants in the uterine lining and menstruation
anterior pituitary gland regulate the endocrine system by
does not occur. If the egg is not fertilized with
modulating the secretion of hormones from a variety of
sperm, the egg is discharged, and menstruation (ie,
glands throughout the body. The hypothalamus produces
shedding of the uterine lining) occurs.
releasing hormones that stimulate the anterior pituitary
gland to produce and release stimulating or inhibiting
The events occurring during the follicular and
hormones. The stimulating or inhibiting hormones affect
luteal phases are controlled by hormones released from
target organs throughout the body to influence their
the hypothalamus, the anterior pituitary gland, and
function—usually by causing the target organs themthe ovaries (Figures 1 and 2).2,7 Estrogen and progesterone play key roles in the events of ovulation, prolifselves to release hormones. Via negative feedback loops,
eration of the uterine lining, and menstruation:
the target organs in turn modulate release of releasing
hormones from the hypothalamus and stimulating or
• An estrogen surge late in the follicular phase causinhibiting hormones from the anterior pituitary.
es the anterior pituitary to release a pulse of
The ovary is one of the target organs for hormones
luteinizing hormone, which causes ovulation.
secreted by the hypothalamus and anterior pituitary
• The decidualization of the uterine lining to pregland. Together, the hypothalamus, the anterior pituitary
pare it for implantation of a fertilized ovum is
gland, and the ovary control the menstrual cycle, which
mediated by progesterone.
culminates either in pregnancy (when a fertilized ovum
• A rapid decline in estrogen and progesterone is
attaches to the lining of the uterus and begins to grow)
responsible for menstruation.
or in shedding of the uterine lining (when fertilization
does not occur).
The menstrual cycle, which
begins during female puberty,
repeats approximately every 28
days unless pregnancy occurs
Figure 1.The Hypothalamic-Pituitary-Ovarian Axis
(Figure 2).7 Each cycle is divided into 2 phases:
• During the follicular
phase, which constitutes
the first half of the 28-day
cycle and begins on the
first day of menstruation,
the ovum develops and
matures in the ovarian follicle, in which it is housed
during the follicular phase.
• The luteal phase, which
constitutes the second half
of the 28-day cycle, begins
with ovulation (the release
of the ovum from the ovarian follicle) and lasts until
the first day of menstruation. During the luteal
phase, the ovum travels
through the fallopian tubes
to the uterus. If the egg is
fertilized with sperm, it
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Hormones released from the hypothalamus and anterior pituitary affect the release of estrogen and progesterone from the ovary. Estrogen and progesterone, in turn, modulate release of hypothalamic and pituitary hormones via negative feedback loops. Data from Morrell.2
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Many other endocrine hormones in addition to
those produced by the ovaries are modulated by the
hypothalamus and the anterior pituitary. Although
estrogen and progesterone are the best studied of the
hormones in patients with epilepsy, the effects of other
endocrine hormones may also be important.6,8 Given
the interconnection of the endocrine system and the
range of ways in which the endocrine system and
epilepsy can interact (see below) most neuroendocrine pathways will probably be shown to affect
and be affected by epilepsy.
other times during the menstrual cycle, and blood levels of the drugs decrease. Some studies have confirmed
a decline in blood levels of antiepileptic drugs around
the time of menstruation11 whereas the results of other
studies are inconclusive.
Figure 2. Hormonal Fluctuations During the
Menstrual Cycle
EFFECTS OF HORMONES ON EPILEPSY
Hormonal fluctuations—particularly fluctuations
in estrogen and progesterone—coincide with changes
in seizure patterns. These sex hormones are not
thought to be the primary cause of seizures, but they
alter the vulnerability to seizures.1-4 One third to one
half of women with epilepsy experience catamenial
seizures (changes in seizure frequency at specific times
during the menstrual cycle).3 Some women experience
these changes in seizure frequency just before the start
of their menstrual period. Changes in seizure frequency may also occur around the time of ovulation.
The causes of catamenial seizures are not fully
understood but are hypothesized to involve fluctuations in estrogen or progesterone, or changes in the
estrogen-progesterone ratio.9 Both estrogen and
progesterone can influence brain function by interacting with specific hormone receptors on neurons.
High concentrations of these hormone receptors are
found in brain regions thought to be important in
generating epileptic seizures.1 By interacting with
hormone receptors on brain cells, estrogen can
increase the likelihood of seizures, and progesterone
can decrease the likelihood of seizures.3
In addition to influencing seizure frequency via a
direct effect on brain cells, hormones can affect
seizure frequency by changing the blood level of
antiepileptic drugs, many of which are metabolized
by the same enzymes that metabolize hormones such
as estrogen and progesterone.10,11 It is hypothesized
that the characteristic decline in estrogen and progesterone that immediately precedes menstruation may
make enzymes usually involved in breaking down
estrogen and progesterone available to break down
antiepileptic drugs. As a result, antiepileptic drugs
are degraded to a greater extent than they are at
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E2 = estrogen; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
Adapted with permission from Loose-Mitchell et al. Estrogens and progestins. In:
Hardman et al, eds. Goodman and Gilman’s The Pharmacologic Basis of
Therapeutics. Copyright 2001, The McGraw-Hill Companies.
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EFFECTS OF EPILEPSY ON HORMONES
As hormones can affect epilepsy by altering the
likelihood of seizures, so can epilepsy affect bodily
functions dependent on hormones (Table 1).1-4
Women with epilepsy are more likely than those without
epilepsy to experience menstrual dysfunction, including
abnormalities in cycle length (ie, polymenorrhea characterized by cycle length of fewer than 23 days or
oligomenorrhea characterized by cycle length of more
than 35 days), irregular cycles, amenorrhea (absence of
menstruation), and anovulation (failure to ovulate).
Women with epilepsy are more likely than those
without epilepsy to have ovaries that appear polycystic
as well as polycystic ovary syndrome (PCOS), which is
characterized by enlarged, cystic ovaries and is accompanied by clinical features such as obesity, high blood
insulin levels (hyperinsulinemia), high blood lipid levels
(dyslipidemia), and amenorrhea or oligomenorrhea.12-14
Hyperinsulinemia, obesity, and poor lipid profiles are
independent risk factors for coronary artery disease.15
Ovarian abnormalities in the absence of PCOS have also
been found more often in women with epilepsy compared with nonepileptic women. In a recent study,
ovaries appearing polycystic were described in 16% of
nonepileptic women (controls), 26% of women with
localization-related epilepsy, and 41% of women with
generalized epilepsy.16
Some research suggests that women with epilepsy
have lower fertility rates compared with women without epilepsy, but the evidence of infertility in epilepsy
is not strong.2,3,17 In epidemiologic studies, women
with epilepsy are approximately two thirds less likely
to have children compared with women without
epilepsy.2 However, other research did not find a
decreased rate of live births to women with epilepsy
compared with a population control.17 The reasons for
the possible lower fertility rates in women with epilepsy have not been definitively established. Social factors
probably play an important role, and it is postulated
that epilepsy-associated disruption of the menstrual
cycle may be responsible.3 Other possible reasons for
the lower fertility rates among women with epilepsy
include a reluctance to become pregnant because of
fear of complicating the outcome of pregnancy or fear
of having a child with epilepsy.
Women with epilepsy may also be more likely to
experience sexual dysfunction than women without
epilepsy.18,19 They experience not only reduced desire
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but also impaired sexual function, both of which are
mediated at least in part by endocrine hormones.
The reasons for the reproductive abnormalities
described in this article have not been determined, but
several possible mechanisms have been suggested
(Table 2).3 Some evidence suggests that reproductive
dysfunction in women with epilepsy may be caused by
seizure-induced disruptions of hormonal functioning.
The activation of brain circuits that occurs during
seizures may disrupt the brain’s regulation of hormone
release from the hypothalamus.2 Because the release of
hormones by the anterior pituitary gland and the
ovary is controlled by hormones released from the
hypothalamus, the hypothalamic disruption in turn
disrupts hormone release from the anterior pituitary
and the ovary. Studies in patients with epilepsy confirm that seizures alter circulating levels of endocrine
hormones such as prolactin, luteinizing hormone, and
growth hormone.8,20
Table 1. Endocrine Abnormalities in Women with
Epilepsy
Menstrual dysfunction
Polycystic-appearing ovaries
Low fertility rates
Sexual dysfunction
Table 2. Potential Mechanisms of Reproductive
Dysfunction in Women with Epilepsy
Seizure-related disruption of hormones or brain regions
that mediate reproduction
Antiepileptic drugs
Structural or functional disruption of brain regions
that mediate reproduction
Data from Morell.3
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It is postulated that antiepileptic drugs may alter
hormonal functioning and cause reproductive
endocrine abnormalities in women with epilepsy.
For example, PCOS has been attributed to valproate-associated increases in circulating testosterone although available data has not yet confirmed
this hypothesis.21
Finally, structural or functional central nervous system dysfunction associated with the disease of epilepsy (but not with seizure activity per se) may also
explain reproductive dysfunction in women with
epilepsy.3 Epilepsy is a disease of altered central nervous
system structure and function. Independent of the neuronal activity associated with seizures, the altered structure and function of brain regions may affect
reproductive function when areas of the brain that are
affected by epilepsy are also involved in reproduction.
HORMONES AND EPILEPSY THROUGHOUT THE LIFE SPAN
PUBERTY
Puberty relative to childhood is a time of marked
hormonal fluctuations. 1 Some seizure disorders
become evident for the first time during puberty,
whereas others remit, perhaps due to the hormonal
changes occurring during puberty. For example,
juvenile myoclonic epilepsy typically develops
around the onset of puberty, whereas childhood
absence seizures often remit during puberty. In studies conducted to date, the frequency of seizures in
preexisting seizure disorders is not markedly altered
during puberty, but some types of seizures begin or
remit during puberty.1,3
The potential interaction of antiepileptic drugs
with hormonal contraception during puberty and
continuing into later years is a growing concern.11
Interactions with some antiepileptic drugs can reduce
the effectiveness of hormonal contraception, the
birth-control pill being one such example. The incidence of oral contraceptive failure is higher among
women taking antiepileptic drugs compared with
those who are not.18 This finding is attributed to
increased metabolism of exogenous hormones stimulated by enzyme-inducing medications, including
phenytoin, carbamazepine, and oxcarbazepine.
Changes in reproductive hormones can also
affect the anticonvulsant efficacy of antiepileptic
drugs. For example, preliminary evidence shows that
birth-control pills and pregnancy may lead to low-
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ered levels of lamotrigine, which may hypothetically
affect seizure control.22
MENARCHE
A seizure disorder may first become evident around
the time of menarche (ie, the first menstrual period),
particularly among women who develop catamenial
epilepsy. However, in studies conducted to date, preexisting seizure disorders have not been found to
respond predictably to menarche.1
PREGNANCY
Pregnancy is associated with marked increases in
estrogen and progesterone levels as well as alterations in
the metabolism of hormones and antiepileptic drugs.
Both factors may be expected to influence seizure frequency. Up to one third of women have been reported
to experience increased seizure frequency during pregnancy.23,24 More research is needed to characterize the
relationship between seizures and pregnancy.
MENOPAUSE
Estrogen can increase the likelihood of seizures by
interacting with hormone receptors on neurons. The
estrogen deficiency that characterizes menopause might
be expected to result in a reduction in seizure frequency.1
Seizures and menopause show a variable relationship in
which some women experience decreases in seizure frequency, some experience increases, and some experience
no change.25 Women who suffered from catamenial
epilepsy were more likely to experience remission of
seizures during menopause compared with women who
did not suffer from catamenial epilepsy.
CONCLUSIONS
The interaction between endocrine hormones and
epilepsy poses unique challenges for women with
epilepsy and the physicians who treat them.
Fluctuations in sex hormones can increase vulnerability to seizures in many women. Conversely, seizures can
cause endocrine abnormalities that can result in menstrual irregularities, altered fertility, and sexual dysfunction that have been linked to PCOS. The
healthcare provider is better equipped to manage
endocrine-associated changes in seizure frequency and
epilepsy-associated changes in neuroendocrine function by being aware of how endocrine hormones and
epilepsy interact throughout the patient’s life span.
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