JoAnn Manson talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Clinical
Article Title: Estrogen therapy and coronary-artery
JE, et al.
Journal: N ENGL J MED
Year: JUN 21 2007
* Harvard Univ, Sch Med, Brigham & Womens Hosp, Div
Prevent Med, 900 Commonwealth Ave E,3rd Fl, Boston, MA
(addresses have been truncated)
Why do you think your paper is highly
There's enormous interest in the role of estrogen in the development of
coronary heart disease (CHD) and in understanding the basis for the glaring
discrepancies between observational studies and randomized trials of
estrogen and CHD. An emerging body of evidence supports the theory that age
or time since menopause influence the relationship between menopausal
estrogen therapy and CHD outcomes.
The results suggest that estrogen may have a beneficial effect on the heart
if started in early menopause, when a woman's arteries and endothelium are
still likely to be relatively healthy, but a harmful effect if started in
late menopause, when advanced atherosclerosis and unstable plaques may be
present. The Women's Health Initiative Coronary Artery Calcium Study
(WHI-CACS) was designed to assess subclinical coronary disease among
younger women in the WHI trial, to see if estrogen treatment was associated
with a reduced burden of calcified plaque in the coronary arteries at the
completion of the randomized trial.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The study describes a new discovery that estrogen treatment was associated
with lower levels of subclinical coronary artery disease (coronary artery
calcium by noninvasive CT imaging) in women aged 50-59 in the WHI
estrogen-alone trial. The key findings are summarized in the table below.
Higher levels of coronary artery calcium are a strong marker for future
risk of cardiovascular events and younger women treated with estrogen were
less likely to have severe calcification. To our knowledge, the study is
the first to assess the association between estrogen and coronary artery
calcification in a clinical trial setting.
Table: Extent of Coronary Artery Calcium in Women
Randomized to Conjugated Equine Estrogens (CEE) vs Placebo in the WHI CEE
Coronary Artery Calcium Score
Analyses Restricted to Adherent Participants*
Participants adherent to >80% of study
pills for at least 5 years.*
Data from Manson JE, et al.NEJM, 2007
Would you summarize the significance of your paper
in layman's terms?
The results suggest that estrogen may slow plaque build-up in the coronary
arteries and have a beneficial effect on the heart if started in early
menopause, when a woman's arteries are likely to be relatively healthy.
However, we know from the WHI and other studies that hormone therapy can
have a harmful effect on the heart (including plaque rupture) if started in
late menopause, when advanced stages of atherosclerosis may be present.
The implication of the "timing hypothesis" is not that recently menopausal
women should be given estrogen for CHD prevention but rather that younger
women can be reassured about cardiac risks when considering short-term use
of estrogen therapy for relief of hot flashes, night sweats, and other
menopausal symptoms. The reduction in menopausal symptoms must be weighed
against other risks and benefits of treatment, but heart disease is
typically not a major factor in the equation for women who are recently
How did you become involved in this research, and
were there any problems along the way?
"An emerging body of evidence
supports the theory that age or time since
menopause influence the relationship between
menopausal estrogen therapy and CHD
I'm one of the Principal Investigators of the Women's Health Initiative and
have been involved in this large-scale randomized trial since 1993. I'm
also one of the lead investigators on the
Nurses' Health Study, a large observational study
that has been assessing the benefits and risk of hormone therapy for
more than 20 years.
The Nurses' Health Study and several other observational studies had
suggested a 40-50% lower risk of CHD among women who were current users of
hormone therapy compared with nonusers, with nearly 80% of hormone therapy
users initiating treatment within 2-3 years of menopause onset (as compared
with an average of >12 years past menopause in the clinical trials).
After the initial reports from the WHI estrogen + progestin trial, as well
as the estrogen-alone trial (age range of participants 50-79 yrs, mean age
63), we took a closer look at the data, focusing on the timing of
initiation of hormone therapy. Not only were absolute rates of adverse
outcomes attributable to estrogen considerably lower in younger than in
older women, but the hazard ratios also appeared more favorable in recently
menopausal women than in those distant from menopause onset. (Related
Where do you see your research leading in the
We're interested in assessing the role of other clinical characteristics,
as well as the role of genetic factors and other biomarkers, in predicting
which women will have favorable outcomes on hormone therapy and which women
should avoid treatment. Such findings will help women and their clinicians
make more informed decisions about the use of hormone therapy.
For example, another factor that appeared to influence coronary outcomes on
hormone therapy in the WHI was the participant’s lipid profile at
baseline. In a recently published analysis, women with an LDL/HDL
cholesterol ratio <2.5 had more favorable CHD outcomes on hormone
therapy than women with a ratio >2.5 (odds ratio 0.60 [95% CI,
0.34-1.06] vs. 1.73 [1.18-2.53], respectively, p for interaction = 0.02).
We're also interested in evaluating the role of different formulations of
hormones, dosages, and routes of administration (such as transdermal vs
oral) in relation to health outcomes and quality of life.
Do you foresee any social or political implications
for your research?
We hope that our findings will help to inform decision-making about the use
of hormone therapy and help women and their clinicians make more informed
choices. However, it's important to emphasize that the implication of the
"timing hypothesis" is not that recently menopausal women should be given
estrogen for CHD prevention (or other chronic disease prevention) but
rather that it may be possible to reassure younger women about cardiac
risks when considering short-term use of estrogen therapy for relief of
menopausal symptoms (such as moderate-to-severe hot flashes and night
sweats that can interrupt sleep and impair quality of life).
The reduction in menopausal symptoms must be weighed against other risks
and benefits of treatment, but younger women tend to have lower absolute
rates of adverse events on hormone therapy than older women more distant
from menopause onset.
JoAnn E. Manson, M.D., Dr. PH.
Chief, Division of Preventive Medicine
Brigham and Women's Hospital
Professor of Medicine and the Elizabeth F. Brigham Professor of Women's
Harvard Medical School
Boston, MA, USA
•>See also a Fast Breaking Paper comment by
JoAnn Manson from June 2004.
Keywords: estrogen, coronary heart disease, menopause,
menopausal estrogen therapy, early menopause, arteries and endothelium,
late menopause, advanced atherosclerosis, unstable plaques, women's
health initiative coronary artery calcium study, calcified plaque,
coronary arteries, coronary artery calcium, relief of hot flashes, night
sweats, menopausal symptoms, nurses' health study.