Estradiol: a hormone with diverse and contradictory neuroprotective actions.

2009·1.2 MB·English

by  Wise, Phyllis M.

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Estradiol: a hormone with diverse and
contradictory neuroprotective actions
Phyllis M. Wise, PhD, Shotaro Suzuki, PhD, Candice M. Brown, PhD
I
n 2002 we contributed an article to Dialogues
in Clinical Neurosciencewhich discussed the neuropro-
tective actions of estrogens.1In this review we build on
the understanding we had at that point, and will discuss
the importance of the accumulating data that point to
the complexities of estrogen action. Clearly, many fac-
tors, including the type of estrogen used, the dose and
route of administration, and the age and previous hor-
monal and health status of the women being treated,
must be taken into consideration when designing clini-
cal studies and when interpreting results.
Women usually undergo the menopausal transition when
they are about 51 years of age. This dramatic physiological
change, which may be abrupt or may occur over a period
The concept that estrogens exert important neuroprotective actions has gained considerable attention during the past
decade. Numerous studies have provided a deep understanding of the seemingly contradictory actions of estrogens.
We realize more than ever that the effects of estrogens (with and without simultaneous or sequential progestins) are
diverse and sometimes opposite, depending on the use of different estrogenic and progestinic compounds, on dif-
ferent delivery routes, on different concentrations, on treatment sequence, and on the age and health status of the
women who receive hormone therapy. During the past few years, we have gained an increasing appreciation of the
impact of estrogens on the immune system and on inflammation. In addition, we have learned that estrogens cannot
only protect against cell death, but can also stimulate the birth of new neurons. Here we posit the concept that estro-
gen’s modulation of the immune status may be the basic mechanism that underlies its ability to protect against neu-
rodegeneration and its powerful neuroregenerative actions. We hope that this update will encourage even richer dia-
logues between basic and clinical scientists to ensure that future clinical studies fully consider the information that can
be derived from basic science studies. Only then will we have a better understanding of the impact of hormones on
the menopausal and postmenopausal period in a woman’s life.
© 2009, LLS SAS Dialogues Clin Neurosci.2009;11:297-303.
Keywords: estradiol; stroke; estrogen therapy; menopause; brain injury; cell Address for correspondence: Dr Phyllis M. Wise, University of Washington, 301
death; neuroprotection; neurogenesis; inflammation; immune system; animal Gerberding Hall, Box 351237, Seattle, WA 98195-1237, USA
model (E-mail: [email protected])
Author affiliations:Departments of Physiology and Biophysics (Phyllis M. Wise,
Shotaro Suzuki, Candice M. Brown), Biology (Phyllis M. Wise), and Obstetrics and
Gynecology (Phyllis M. Wise),University of Washington, Seattle, Washington,
USA
Copyright © 2009 LLS SAS. All rights reserved 297 www.dialogues-cns.org
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of a few years, is marked by a decline in ovarian hormone affects 500 000 Americans each year.3 Every year
secretion and cessation of reproductive fertility. The post- approximately 40 000 more women than men are
menopausal period is often associated with vaginal dry- affected by stroke.4Initially, this gender difference was
ness, urinary symptoms, osteoporosis, and a panel of neu- thought to be explained by a combination of both the
rological manifestations such as hot flushes, and greater longer life expectancy of women and the protective roles
instances of sleep disturbance, emotional instability, cere- of estrogen, since the incidence of stroke increases after
brovascular stroke, and Alzheimer's disease. Over the past menopause and the risk continues to rise with age.5
century the average life expectancy in the United States However, this interpretation has been questioned since
has increased to over 80 years, while the age of menopause recent clinical trials including the Women's Health ini-
has remained fixed at age 51. Thus, today, more than ever tiative (WHI) reported negative impact of estrogen ther-
before, a greater number of women and a larger propor- apy (ET)4,6-8and some studies in animal models also sug-
tion of women are destined to spend over three decades gest that estrogens are not universally protective and can
of their lives in a hypoestrogenic state. This makes it imper- be deleterious under some circumstances.9In an attempt
ative that we understand the intricacies of estrogen action, to reconcile these seemingly contradictory data, our lab
when it is protective, and when it increases risk. has used animal models to explore the mechanisms of
estrogen’s neuroprotective and neuroregenerative
Estrogens and progestins actions.
Estradiol and progesterone belong to a family of steroid Estrogens and stroke: use of animal models
hormones with complex actions. Estradiol-17β(E ), the to decipher mechanisms of action
2
predominant and most biologically active estrogen, is an
18 carbon (C-18) steroid with an aromatic A-ring. It is Even the best, well-designed clinical studies cannot ben-
synthesized mainly by the ovary; however, other organs efit from the experimental advantages of many basic sci-
and tissues, including adipose tissue, the brain (neurons, ence studies, since studies performed with experimental
astrocytes, and microglia), cells of the immune system, and animal models allow replication with adequate numbers
bone, are thought to produce it as well. Progesterone is of animals, controls with equivalent genetic backgrounds
a C-21 steroid hormone, which is not only an active hor- and previous exposure to similar environments, well-
mone in and of itself, but is also a precursor to estrogens. controlled environments during the entire study, and
In addition to the estrogens and progestins produced in lack of selection or recall bias. Thus, investigators have
human tissues, a wide variety of estrogenic and progesto- developed several animal models to investigate the
genic compounds are synthesized in other species or are pathophysiology and potential treatments for stroke.
pharmacologically manufactured through pathways that Since most cerebrovascular strokes (>70%) in aging
have been developed by researchers and have been used human populations are ischemic, and not hemorrhagic,
widely by the pharmaceutical industry. When used in hor- we adopted an animal model that reproduces ischemic
mone therapy for postmenopausal women, the actions of infarcts. We have utilized permanent middle cerebral
these different compounds are diverse, complex, and artery occlusion (MCAO) as a model of permanent
sometimes contradictory. Their effects depend upon the occlusion of the middle cerebral artery, which vascular-
concentration, whether they are given simultaneously or izes the cerebral cortex, the striatum, and the hip-
sequentially, the route of delivery, and on the age and pocampus, to examine the effects of estrogen in neu-
health status of the women who receive hormone therapy. rodegeneration. Blockade of this artery at its base
Turgeon et al2have provided a detailed review of our cur- results in about a 50% decrease in blood flow and causes
rent understanding of estrogens, progestogens, their severe metabolic impairment in a core region, called the
related compounds, agonists, and antagonists. “ischemic core” and many neurons in these regions die
by necrosis within hours following injury. In contrast,
Estrogens and stroke regions that surround the ischemic core, the ischemic
penumbra, undergo more moderate metabolic impair-
Stroke is the third leading cause of death for middle- ment and are potentially salvageable by effective thera-
aged and older women and a major health problem that peutic agents. We have previously demonstrated that E
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Estrogen and stroke injury - Wise et al Dialogues in Clinical Neuroscience - Vol 11 .No. 3 .2009
exerts powerful neuroprotective action in ischemic the ability of E to exert protective action against
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penumbra where E protects neurons from delayed pro- ischemic injury.18Taken together, the injured brain seems
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grammed cell death or apoptosis.10-12 to provide signals conveying the need for the reappear-
Studies in the early 1990s suggested that estradiol is a neu- ance of ERα, which may mediate the ability of E to
2
roprotective factor that profoundly attenuates the degree protect against neuronal apoptosis and possibly reiniti-
of ischemic brain injury: i) female gerbils demonstrate less ate differentiation of the injured brain.
neuronal pathology than males after ischemia induced by
unilateral carotid artery occlusion; ii) female rats sustain Anti-inflammatory actions of estrogens
over 50% less infarction than males and ovariectomized
female rats following ischemia induced by transient occlu- More recently we have begun to appreciate the impor-
sion of the middle cerebral artery (MCA); iii) both tance of inflammation in neurodegeneration and the
ovariectomized females and castrated males that are role of E acting as an anti-inflammatory factor. Many
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treated with estradiol suffer less MCAO-induced injury neurological disorders such as Alzheimer’s disease,
than vehicle-treated gonadecetomized controls.1 Our Parkinson’s disease, multiple sclerosis, and cerebrovas-
work has contributed significantly to the understanding cular stroke include inflammation processes in the
of the neuroprotective actions of physiological levels of underlying mechanisms of the disorder.19In vivo and in
E . We have shown that low, physiological levels of E , vitro models of brain injury and neurodegenerative dis-
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exert profound neuroprotective actions after MCAO.10-13 eases have provided substantial evidence that physio-
We have also demonstrated that E effectively reduces logical levels of E suppress inflammation through ERα
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the infarct volume in middle-aged animals, suggesting that and ERβ(reviewed in refs 19-22). These studies demon-
a constellation of factors responsible for mediating E ’s strate that estrogens act not only on neurons and astro-
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protective actions is preserved during the initial stages of cytes, but also on microglia, the resident macrophages of
aging.14Further, we have found that E must be adminis- the brain (Figure 1). These studies also highlight the
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tered prior to the onset of injury, since acute administra- tremendous importance of understanding the crosstalk
tion of E at the time of injury does not reduce the extent between the nervous, endocrine, and immune systems to
2
of infarction.15Collectively, the results of these studies sug- fully appreciate the protective role of E during neuro-
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gest that postmenopausal women who are estrogen- logical diseases and injury.19,23
replaced may suffer a decreased degree of brain injury The inflammatory response associated with stroke is
following a stroke, compared with their hypoestrogenic complex, but an accumulating body of evidence clearly
counterparts. However, we must be careful in extrapolat- shows that estrogens may directly or indirectly regulate
ing from rodents to humans until the appropriate clinical three components of the inflammatory response: i)
studies are performed. microglial activation; ii) activation of the enzyme;
inducible nitric oxide synthase (iNOS); and iii) the acti-
Estrogen receptor α mediates vation of cytokines/chemokines. These components of
estrogen’s neuroprotective actions inflammation may interact with each other and are not
mutually exclusive. Microglia become activated in
To date, two forms of nuclear estrogen receptor (ER) response to injury, proliferate, migrate to the site of
have been cloned. Since the discovery of the second injury, and change in both morphology and cell surface
form of ER (ERβ) in 1996, researchers have investigated markers. E suppresses microglial activation, and this
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the similarities and differences in the distribution and response is regulated by both estrogen receptors.
actions of these two forms of ER. Recently, we found Microglia, peripheral infiltrating macrophages, and astro-
that ischemic injury upregulates ERα expression in the cytes are the primary source of the iNOS enzyme during
cortex of ovariectomized animals without influencing stroke. Activation of iNOS during stroke produces high,
ERβ expression.16Consequently, we hypothesized that concentrated levels of nitric oxide that promote neuronal
the dramatic re-expression of ERαafter stroke injury cell death. Many studies have shown that E suppresses
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mediates E ’s profound neuroprotection against iNOS in animal models of neuroinflammation, stroke,
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ischemia.17,18Using ERαknockout mice, we found that and Alzheimer’s disease, and this response is also regu-
the presence of this receptor subtype is a prerequisite for lated by both estrogen receptors.19,24,25
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Cytokines are secreted proteins that appear to play a Estradiol and neurogenesis
critical role in the pathophysiology of human cerebral
ischemia. There is a positive correlation between high One of the most remarkable discoveries in modern neu-
levels of proinflammatory cytokines in serum or cere- roscience is that the adult brain continues to generate
brospinal fluid greater stroke severity. These cytokines new neurons under both normal and neurodegenerative
include: interleukin 6 (IL-6), IL-1β, tumor necrosis fac- conditions. We have explored whether E stimulates gen-
2
tor alpha (TNF-α), and macrophage chemoattractant eration of newborn neurons after stroke. We have found
protein–1 (MCP-1). Conversely, increased levels of anti- that low, physiological levels of E increase the number
2
inflammatory cytokines (eg, IL-10) correlate with dimin- of newborn neurons (Figure 2). Interestingly, both ERα
ished stroke severity and an improved outcome. and ERβplay essential functional roles, and the pres-
Cytokines in the brain perform pleiotropic functions in ence of both receptor forms is the prerequisite for E to
2
inflammation and are synthesized primarily by microglia enhance neurogenesis. Although precise roles for each
and astrocytes, but also can be produced by neurons.26,27 ER form are yet to be determined, our study clearly
In several different brain injury paradigms, subcutaneous demonstrates that the presence of both receptors is
E generally suppresses proinflammatory cytokines, and important in expansion of neuronal populations in the
2
enhances the production anti-inflammatory cytokines.16,27 subventricular zone after ischemic injury.28
Studies from our laboratory have shown that immediate So far, we have not been able to determine whether
treatment with E following MCAO suppresses brain these newborn neurons actually differentiate into
2
levels of the proinflammatory cytokines IL-6 and MCP- mature neurons at this time point, whether they migrate
1.16 to the site of injury, and whether they undergo synapse
formation with neighboring neurons. These future stud-
ies will allow us to determine whether this elevated level
of neurogenesis is critical to the recovery of function.
Importance of timing of estrogen therapy
Recent studies describing the seemingly contradictory
actions of estrogens in stroke injury have led us to
believe that the timing of estrogen therapy relative to the
time of the menopause may be an important factor to
consider. It is important to remember that in the WHI,
the mean age of the subjects was 63 years, and thus, the
majority of subjects were 12 years past the peri-
menopausal transition prior to the initiation of any hor-
A B 250 #
ns 200
o
ur
ne 150
n
or 100
b
w
ne 50
#
Figure 1. Overview of the brain cell types and neuromodulators influenced 0
by estrogens. The ability of estrogens to exert trophic and pro- Oil E2
tective actions depends upon their ability to alter the birth and
death of neurons, synaptogenesis, and neuritogenesis. Estradiol Figure 2. Estradiol influences the number of newborn neurons. Panel A
influences neurons, astrocytes, and microglia through altering shows confocal micrographs of newborn neurons dual-labeled
the expression of a broad profile of neurotransmitters and neu- with bromodeoxyuridine and doublecortin in vehicle and estra-
ropeptides and their receptors, pro- and anti-inflammatory diol-treated mice following stroke injury. Panel B shows the
agents, and factors which influence, birth, survival, growth, and mean of groups of 4 to 6 animals in each experimental group
maturation of neurons. and shows that the differences are statistically significant.
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Estrogen and stroke injury - Wise et al Dialogues in Clinical Neuroscience - Vol 11 .No. 3 .2009
mone treatment.5,29 We tested the hypothesis that an production of proinflammatory cytokines after ischemic
extended period of hypoestrogenicity both prevents E stroke. In contrast, E did not suppress production of
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from protecting the brain against ischemia, and simulta- proinflammatory molecules when it was administered 10
neously suppresses its anti-inflammatory actions. We weeks postovariectomy.16These results demonstrate that
found that E exerts profound neuroprotective action a prolonged period of hypoestrogenicity disrupts both
2
when administered immediately upon ovariectomy, but neuroprotective and anti-inflammatory actions of E .
2
not when administered after 10 weeks of hypoestro- Our findings may help to explain the results of the WHI
genicity. This dichotomous action is due to differential that reported no beneficial effect of ET against stroke
actions that estradiol has when administered immediately because the majority of the subjects initiated ET after an
versus when treatment is initiated after a delay (Figure extended period of hypoestrogenicity.
3). Consistently, E treatment given immediately at the
2
time of ovariectomy attenuated central and peripheral Summary
We have summarized recent studies that have increased
Estrogen therapy
our understanding of the complex actions of estrogens
on the brain. These basic science and clinical studies give
Early Delayed
us a new appreciation of the breadth of estrogen actions
Brain infarction in the adult brain to maintain function after injury or
during disease. Much more work is necessary before we
ER expression
fully understand the many ways through which estrogens
exert beneficial actions, but it is clear that estradiol pro-
Inflammation
tects the brain from injury and enhances neurogenesis
Overall effect Beneficial Detrimental by acting to both enhance survival of neurons and stim-
ulate the birth of new neurons, respectively. Estradiol’s
anti-inflammatory actions may underpin both the pro-
Figure 3. Estradiol protects the brain only if treatment is initiated imme-
tective and reparative effects. We hope that our growing
diately after hypoestrogenicity is induced. Estradiol decreases
the size of the infarct, induces estrogen receptor (ER) and sup- knowledge of the pleiotropic actions of this hormone
presses inflammation only if it is administered immediately after will lead to preventative and restorative therapies for
ovariectomy. We have used ovariectomy to mimic the neurodegenerative conditions, which will, in turn
menopause. These findings strongly suggest that, if estrogen improve the lives of our aging population. ❏
therapy (ET) is initiated after several years of postmenopause, as
was the case in the Womens' Health Initiative, that ET will not
Acknowledgements: This work was supported by the NIH: AG02224 (PMW)
be effective in protecting the brain against neurodegeneration. and NRSA AG27614 (CMB).
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Estradiol: una hormona con diversas y Œstradiol : une hormone aux actions
contradictorias acciones neuroprotectoras neuroprotectrices diverses et contradictoires
Durante la última década el concepto de que los Ces 10 dernières années, l’idée d’une action neuro-
estrógenos ejercen importantes acciones neuro- protectrice importante des œstrogènes a retenu par-
protectoras ha ganado considerable atención. Hay ticulièrement l’attention. Les actions apparemment
numerosos estudios que han proporcionado una contradictoires de ces hormones sont nettement
comprensión profunda de las acciones aparente- mieux comprises grâce aux nombreuses études cli-
mente contradictorias de los estrógenos. niques. Nous réalisons plus que jamais que leurs
Actualmente se comprende más que nunca que los effets (avec ou sans progestatif associé de façon
efectos de los estrógenos (con y sin progestinas simultanée ou séquentielle) sont variés et parfois
simultáneas o en secuencia) son diversos y algunas opposés, dépendant de l’utilisation des différents
veces opuestos. Estos efectos dependen del uso de composés œstrogéniques ou progestatifs, des diffé-
diferentes compuestos estrogénicos y progestínicos, rents modes d’administration et concentrations, de
de las variadas vías de administración, de las diver- la chronologie des traitements, et enfin de l’âge et
sas concentraciones, de la secuencia de tratamiento de l’état de santé des femmes qui reçoivent le trai-
y de la edad y estado de salud de la mujer que tement hormonal. Ces dernières années, l’apprécia-
recibe la terapia hormonal. Durante los últimos tion de l’impact des œstrogènes sur le système
años, se ha alcanzado una mayor comprensión immunitaire et l’inflammation s’est considérable-
acerca del impacto de los estrógenos en el sistema ment étendue. Nous avons appris non seulement
inmune y en la inflamación. Además, se sabe que qu’ils protégeaient les cellules de l’apoptose, mais
los estrógenos no sólo pueden proteger contra la qu’ils stimulaient également la production de nou-
muerte celular, sino que también pueden estimular veaux neurones. Nous postulons dans cet article que
el nacimiento de nuevas neuronas. Se propone que la modulation œstrogénique de l’état immunitaire
el concepto de la modulación que tienen los estró- pourrait être le mécanisme de base qui sous-tend sa
genos sobre el sistema inmune puede ser el meca- capacité protectrice contre la neurodégénération et
nismo básico que subyace a su capacidad de pro- sa puissante activité neurorégénératrice. Nous espé-
tección contra la neurodegeneración y sus rons que cette mise à jour encouragera un dialogue
poderosas acciones neurorregenerativas. Se espera plus riche entre des scientifiques cliniciens et fon-
que esta actualización fomente los enriquecedores damentalistes pour s’assurer que les études cliniques
diálogos entre los cientistas básicos y los clínicos futures prendront complètement en compte l’in-
para asegurar que los futuros estudios clínicos con- formation provenant de la recherche fondamentale.
sideren muy bien la información que pueda deri- C’est seulement alors que nous comprendrons l’im-
varse de estudios de ciencia básica. Sólo entonces pact des hormones sur la période de ménopause et
se tendrá una mejor comprensión del impacto de de post-ménopause dans la vie d’une femme.
las hormonas en el período menopáusico y post-
menopáusico en la vida de la mujer.
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