363 ISSN 1473-7175 2012 Expert Reviews Ltd 10.1586/ERN.12.20 www.expert-reviews.

com
Editorial
Could estrogen protect younger
menopausal women from stroke?
The ndings from seven recent observational studies, from a
2011 Womens Health Initiative report and from a UK study
challenge the consensus that estrogen is invariably a risk factor
for ischemic stroke.
The hypothesis that estrogen might be
protective for younger women but might
become neutral, or even harmful, for older
women has been proposed for both cardio-
vascular disease and dementia [1,2]. When
referring specically to the benets or risks
of estrogen therapy (ET), this hypothesis
has been called the window of opportu-
nity, window of vulnerability, or timing
hypothesis. For simplicity, we will call it
the timing hypothesis. It remains unclear
whether the timing hypothesis applies to
stroke in general or to ischemic stroke (IS)
in particular.
The general consensus has been that
estrogen is invariably a risk factor for IS,
probably because of its short-term pro-
thrombotic and proinammatory effects.
For example, the experimental data from
the Womens Health Initiative (WHI) clini-
cal trials and the observational data from
the Nurses Health Study (NHS) indicate,
with remarkable consistency, that estrogen
is a risk factor for IS when administered
orally to women older than 50 years of age,
alone or in combination with a progestin
(primarily conjugated equine estrogens at
a dose of 0.625 mg/day) [35]. The same
conclusion was reached by three meta-
analyses of clinical trials of ET and risk of
stroke [68].
However, in the past 5 years, newer
observational studies have challenged this
simple conclusion. In a review of obser-
vational studies of the association of pre-
mature or early menopause with stroke
or IS, published in English from 2006
through to 2010, we found seven studies
providing evidence for a protective role of
estrogen in younger women [9].
More recent evidence on the
effects of estrogen before the age
of 50 years
A direct way of testing the effects of estro-
gen in young women is to study women
who underwent bilateral oophorectomy
before reaching natural menopause.
These women experience an abrupt drop
in circulating estrogen and other ovarian
hormones unless they receive ET after the
surgery. To mimic the natural time course
of hormonal changes, estrogen should be
administered for replacement until the age
of natural menopause, which occurs at an
average age of 51.4 years in the USA [10].
It remains unclear whether the
timing hypothesis applies to
stroke in general or to ischemic
stroke in particular.
Three cohort studies showed an
increased risk of all stroke in women who
underwent bilateral oophorectomy before
50 years of age compared with women who
conserved their ovaries: the Mayo Clinic
Cohort Study of Oophorectomy and
Aging [11]; the NHS [12]; and a Swedish
nationwide cohort study [13]. In the NHS,
ET taken after the surgery eliminated the
increased risk of stroke, suggesting that
Expert Rev. Neurother. 12(4), 363365 (2012)
KEYWORDS: early menopause estrogen ischemic stroke oophorectomy premature menopause
risk factors
Walter A Rocca
Author for correspondence:
Mayo Clinic College of
Medicine, Division of
Epidemiology, Department of
Health Sciences Research,
Mayo Clinic, 200 First Street
SW, Rochester, MN 55905,
USA
Tel.: +1 507 284 3568
Fax: +1 507 284 1516
rocca@mayo.edu
Lynne T Shuster
Mayo Clinic College of
Medicine, Womens Health
Clinic, Department of Internal
Medicine, Mayo Clinic,
200 First Street SW,
Rochester, MN 55905, USA
Robert D
Brown Jr
Mayo Clinic College of
Medicine, Department of
Neurology, Mayo Clinic,
200 First Street SW,
Rochester, MN 55905, USA
For reprint orders, please contact reprints@expert-reviews.com
Expert Rev. Neurother. 12(4), (2012) 364
Editorial
estrogen deprivation is involved in the association. The NHS
also showed that the association of bilateral oophorectomy with
increased risk of stroke is not due to confounding by the usual
cardiovascular risk factors or by genetic predisposition [12].
The Swedish study showed that the association is not due to
confounding by socioeconomic factors [13].
Four additional observational studies showed an association
of all stroke or IS with the early onset of menopause or with
a shorter lifespan of ovarian function: the Japan Collaborative
Cohort Study [14]; a Spanish study [15]; the Framingham Heart
Study [16]; and a second Japanese study [17]. Three of the studies
were cohort studies, and the Spanish study was a casecontrol
study [15]. The Japanese cohort study by Baba et al. showed that
the increased risk of stroke was not explained by confounding due
to the usual cardiovascular risk factors [17].
Stroke is generally classied as ischemic, the most common type
including embolic and thrombotic mechanisms, or hemorrhagic,
including subarachnoid or intracerebral locations [9]. Not all of
the studies described above distinguished IS from hemorrhagic
stroke. In three of the seven studies, estrogen deciency was asso-
ciated specically with increased risk of IS, suggesting that the
protective effects of estrogen on stroke overall are mediated by
mechanisms underlying ischemic lesions.
women who experienced an early estrogen
deciency, approximately before 45 years of
age should consider taking hormone therapy
unless there is a clear contraindication.
In the studies published so far, younger age at menopause was
more important than the type of menopause (natural vs induced)
in increasing the risk of stroke, suggesting that age at onset of
hormonal deprivation may be a key factor. However, we remain
concerned that the abrupt drop in circulating estrogen and other
hormones caused by bilateral oophorectomy may further increase
the risk compared with a premature or early menopause occurring
less abruptly via natural mechanisms [9]. In summary, new data
suggest that estrogen, naturally produced by the ovaries or given
as a replacement therapy before the age of 50 years, may protect
younger women from stroke.
More recent evidence on the effects of estrogen after
age 50 years
In 2011, LaCroix et al. reported new analyses from the WHI,
which included a post-intervention phase of follow-up [18]. In
contrast to the initial WHI clinical trial reports, the authors
showed that unopposed estrogen taken orally at a dose of
0.625 mg/day for a median of 5.9 years in women who had
undergone hysterectomy was not associated with an increased
risk of stroke or any other adverse outcomes after 10.7 years of
follow-up [18]. The risk of stroke was particularly low among
women who initiated treatment in the age group of 5059 years.
Approximately 40% of the women in this arm of the WHI trial
had undergone bi lateral oophor ectomy along with hysterectomy.
These new ndings suggest that estrogen is not a risk factor for
IS in women aged 5059 years who are treated with estrogen
alone.
A recent casecontrol study based on a large sample of UK gen-
eral practices (UK General Practice Research Database) showed
that estrogen alone or estrogen plus progestogen given to women
aged 5079 years is not a risk factor for stroke if the estrogen is
administered transdermally and at low doses. By contrast, the risk
of stroke was increased when the hormonal treatment included
estrogen administered transdermally at higher doses or orally at
any dose [19]. This observational study suggests that both the dose
and the route of administration of hormone therapy may modify
the risk of stroke. In summary, new analyses from the WHI
study combined with the ndings from a UK study suggest that
estrogen, given pharmacologically as part of hormone therapy
after 50 years of age, may not actually increase the risk of stroke.
Interpretation
The ndings from seven recent observational studies, from a
2011 WHI report and from a UK study challenge the consensus
that estrogen is invariably a risk factor for IS. The contra diction
between protective effects in younger women and deleterious
effects in older women can be reconciled by a unifying tim-
ing hypothesis. We hypothesize that estrogen is protective for IS
before the age of 50 years and may become a risk factor for IS
after the age of 50 years or, more likely, after the age of 60 years,
particularly if given orally at high doses [9]. The bene cial effects
of estrogen on blood vessels probably occur throughout the life-
span of women, so that an adequate amount of endogenous or
exogenous estrogen early in life may change the trajectory of
athero sclerosis and vascular aging, and may reduce the risk of IS
30 or 40 years later (long-term protective effects). By contrast,
the deleterious effects of estrogen therapy after the age of 50 years
appear to be related to prothrombotic and pro inammatory
effects, which tend to be more proximate or contemporary to the
ischemic event (short-term deleterious effects) [1,9]. These delet-
erious effects may be avoided using lower doses and transdermal
preparations.
Clinical implications
These ndings have two major clinical implications. First,
women who are considering bilateral oophorectomy before
the age of natural menopause should be counseled about the
increased risk of IS as part of the discussion of the risks and
benets of the surgery [11,12,20]. Second, women who experi-
enced an early estrogen deciency, approximately before 45 years
of age, either naturally or because of a medical condition or
surgical intervention, should consider taking hormone therapy
unless there is a clear contraindication [10]. Unfortunately, the
results from the WHI clinical trials have been inappropriately
extrapolated from women who were older than 50 years of age
to younger women. Thus, many women have now discontinued
hormone therapy or avoid starting hormone therapy at any age,
potentially putting those who experience an early or prema-
ture menopause, who are at increased risk of long-term health
consequences [9,10]. The short- and long-term risk of stroke in
Rocca, Shuster & Brown
www.expert-reviews.com
365
Editorial
women who receive hormone therapy between the ages of 50
and 59 years remains unclear, and may depend on the type
of treatment (estrogen alone vs estrogen plus progestogen), on
the route of administration (oral vs transdermal), on the dose
(lower vs higher), and on the presence or absence of known risk
factors for stroke.
Acknowledgements
The authors thank Lori Klein for typing the manuscript.
Financial & competing interests disclosure
The Mayo Clinic Cohort Study of Oophorectomy and Aging was funded by
the NIH (grant NS 033978) and was made possible by the Rochester
Epidemiology Project (grant AG 034676). The authors have no other rel-
evant afliations or nancial involvement with any organization or entity
with a nancial interest in or nancial conict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
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