Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
EDITORIAL COMMENT
Estrogens, Lipids and
Cardiovascular Disease:
No Easy Answers*
Vera Bittner, MD, MSPH, FACC
Birmingham, Alabama
Postmenopausal hormone therapy as a means of cardiovascular risk reduction remains highly controversial. Advocates
point to the numerous experimental studies that show
beneficial vascular effects and favorable effects on lipoprotein
profiles and to the myriad of observational epidemiologic
studies showing improved cardiovascular disease morbidity
and mortality among hormone users (1–3). Opponents of
such therapy point out that reductions in cardiovascular
morbidity and mortality have yet to be proven in randomized clinical trials and that the only trials published to date
have not shown any benefit of hormone replacement therapy on clinical end points or angiographic coronary disease
progression (4,5) and may have even resulted in an increase
See page 425
in cardiovascular events early after initiation of therapy (4).
The Adult Treatment Panel II of the National Cholesterol
Education Program suggested in 1993 that oral estrogens be
considered as an alternative to standard lipid-lowering
therapy among postmenopausal women (6). More recent
American Heart Association/American College of Cardiology guidelines instead recommend standard pharmacologic
lipid-lowering therapy for coronary heart disease risk reduction
in hyperlipidemic postmenopausal women and endorse the
recommendation by the Heart and Estrogen/progestin Replacement Study (HERS) investigators not to initiate hormone
replacement therapy among postmenopausal women with
established coronary artery disease (7). Clearly more research is
needed to disentangle potential beneficial and potential detrimental effects of hormone therapy after menopause.
Menopause and therapy with oral estrogens: Effects on
lipoprotein profiles in postmenopausal women. After
menopause (natural or surgical), total cholesterol rises, low
density lipoprotein (LDL) cholesterol rises, and high density lipoprotein (HDL) cholesterol does not change or
decreases slightly (8,9). There is a decrease in the HDL-2
subfraction and a shift in LDL particle size toward smaller
and denser LDL particles (9,10). Does postmenopausal
hormone therapy reverse these potentially atherogenic
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the author and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the University of Alabama at Birmingham, Birmingham, Alabama.
Vol. 37, No. 2, 2001
ISSN 0735-1097/01/$20.00
PII S0735-1097(00)01149-9
changes? In cross-sectional studies, postmenopausal women
taking estrogens tend to have more favorable coronary heart
disease risk factor profiles than those who are not, including
higher HDL cholesterol levels and lower LDL cholesterol
levels (11). These seemingly beneficial lipid effects of oral
estrogens have been confirmed in prospective, randomized
controlled trials. In the Postmenopausal Estrogen/Progestin
Interventions (PEPI) trial (12), for example, women randomized to oral conjugated equine estrogen increased their
HDL-cholesterol by 5.6 mg/dl (9%) and reduced their total
cholesterol and LDL cholesterol by 7.6 mg/dl (3.4%) and
14.5 mg/dl (10.3%), respectively. The beneficial effect of
estrogen on HDL cholesterol was attenuated when medroxyprogesterone acetate, a commonly used progestin, was
added, while the degree of LDL lowering was similar with
all regimens tested. Oral estrogens also reduce plasma levels
of lipoprotein (a) (Lp[a]) (13). Conversely, oral estrogens
tend to increase plasma triglyceride levels: in the PEPI trial,
triglycerides increased 13.7 mg/dl (13.9%) among women
treated with conjugated equine estrogen (12). Women who
are hypertriglyceridemic at baseline may experience much
larger increases in plasma triglycerides.
Why do these changes in lipoprotein profiles occur? The
available kinetic data have been summarized by Sacks et al.
(14). Exogenously administered oral estrogen increases apo
B gene transcription and increases production of very low
density lipoprotein (VLDL) particles in the liver. Clearance
of these VLDL particles is accelerated, reducing residence
time and thus reducing the potential for cholesteryl ester
enrichment and oxidative modification, changes believed to
be atherogenic. Hypertriglyceridemia in the setting of estrogen therapy may thus not have the same atherogenic
consequences as hypertriglyceridemia due to obesity or
diabetes where particle clearance is diminished. Estrogen
therapy also enhances LDL catabolism, presumably due to
increased expression of LDL receptors. The rise in HDL
and apo A-I is primarily attributable to increased synthesis
with decreased clearance of HDL particles through diminished hepatic lipase activity playing a lesser role. Prior
studies have documented a shift toward smaller LDL
particles after oral estrogen therapy, but this shift appeared
to be due to a decrease in the LDL subfraction with the
largest particles rather than to an increase in the number of
small, dense LDL particles, and none of the women
changed from pattern A to pattern B (14).
Estrogen as an antioxidant. Oxidative modification of
LDL particles is believed to be a significant contributor to
atherogenesis (15). Susceptibility to oxidation varies from
LDL particle to LDL particle and is determined by, among
other factors, particle size (small, dense LDL particles are
more easily oxidized than are larger particles), particle
composition (e.g., high content of polyunsaturated fatty
acids increases susceptibility to oxidation), and level of
antioxidants such as vitamin E within the particle (16).
432
Bittner
Editorial Comment
High density lipoprotein protects LDL from oxidation, but is
itself susceptible to oxidation. Such oxidation has been shown
to increase HDL clearance and could be pro-atherogenic.
Estrogens share structural similarities with vitamin E and
other lipophilic antioxidants and are thus able to function as
scavengers for lipid peroxyl radicals and interrupt the chain
reaction of lipid peroxidation. Estrogens vary in their
antioxidant potency: equine estrogens appear to have greater
antioxidant effects than do estradiol and estrone, at least in
vitro (17). Several studies in postmenopausal women have
shown decreased susceptibility of LDL particles to oxidation in
women who have been treated with oral and transdermal
estrogens, an effect that is independent of the lipid-lowering
effects (18 –20). Estrogens also protect HDL from oxidation,
an effect that should preserve the beneficial functions of HDL,
including the protection of LDL from oxidation (21). To date,
however, there are no controlled studies to show that such
antioxidant effects translate into a slowing of atherosclerosis
progression or a decrease in clinical cardiovascular events.
Clinical trials addressing this question are in progress.
The current study. In this issue of the Journal, Wakatsuki
et al. (22) add to the complexity of the existing data. They
treated 24 lean, healthy, naturally postmenopausal Japanese
women, mean age 53 years and without coronary heart
disease risk factors, with 0.625 mg of oral conjugated equine
estrogen daily for three months and determined plasma
lipoprotein concentrations, LDL particle size, and susceptibility of LDL particles to oxidation before and after
hormone therapy. Treatment with estrogen decreased LDL
cholesterol (⫺17.7%) and apo B concentrations (⫺8.4%),
increased HDL cholesterol (3.96%) and apo A1 concentrations (6.3%), and increased triglyceride concentration
(16.5%). The LDL particle size decreased during treatment,
and 6 of 16 subjects (38%) converted from LDL pattern A
to pattern B. The investigators observed a negative correlation between LDL particle size and plasma triglyceride
concentration pre- and posttherapy, and a decrease in LDL
particle size during therapy was significantly correlated with
an increase in triglyceride concentration. Regression analysis
suggested a threshold of 15 mg/dl increase in triglyceride
levels beyond which LDL particle size decreased and beyond
which LDL particles became more susceptible to oxidation.
Among women who did not experience an increase in triglycerides, estrogen therapy reduced the susceptibility of LDL
particles to oxidation. The investigators concluded that the
estrogen-induced increase in plasma triglycerides could be
atherogenic via a decrease in LDL particle size and could
partially offset the otherwise beneficial changes in LDL and
HDL cholesterol and the antioxidant effects of estrogen.
The current study in perspective. Wakatsuki et al. (22)
equate small, dense LDL particles with increased atherogenicity. Although there is certainly substantial evidence to
support this contention, there is also data to the contrary
(23,24). In primate models of atherosclerosis, the group at
Wake Forest has shown that larger LDL particles were
more atherogenic than were the smaller particles, and some
JACC Vol. 37, No. 2, 2001
February 2001:431–3
human studies have had similar findings (24). Rudel and
Kesäniemi (25) thus concluded that no one particle is
inherently more atherogenic than another, but that any
LDL particle can contribute to atherogenesis depending on
the surrounding milieu in the body and that lowering of
LDL concentration overall thus remains the most appropriate therapeutic target. Without outcome data we cannot
conclude that the estrogen-induced LDL particle changes
observed in the current study were necessarily detrimental,
but further studies relating LDL subfractions and modification of LDL subfractions by hormone therapy to cardiovascular outcomes in women are clearly needed.
Can the changes in LDL subfractions and LDL oxidation
observed in this study be generalized to other populations of
postmenopausal women? The current study was performed in
Japanese women. Wakatsuki et al. (22) do not provide information on their subjects’ diets. Because the Japanese diet differs
significantly from Western diets, it is likely that fatty acid
composition of LDL particles also differs between Japanese
and Western women and could modify the impact of estrogen
therapy on oxidative susceptibility and atherogenic potential.
Whether phytoestrogen intake (which is also greater among
Japanese women than women in Western societies) may have
further modified the results is also unknown, but it should at
least be considered (26).
All subjects in the current study had undergone natural
menopause. Postmenopausally, ovaries secrete androgens,
some of which are converted to estrogen in the periphery. The
impact of exogenous estrogen is likely to vary depending on the
baseline hormonal milieu—women who have undergone surgical menopause may well show different responses from those
who have undergone natural menopause, and those with
relatively high estrogen levels due to peripheral conversion may
show different responses from those with low baseline levels.
Although Wakatsuki et al. (22) measured estrone and estradiol
plasma levels before and after treatment, they did not report on
the relationship between circulating estrogen levels and lipoprotein profiles including LDL subclass patterns at baseline
and during therapy.
Women in the current study were also carefully selected not
to have any coronary disease risk factors. Obesity and diabetes,
for example, have been associated with secondary dyslipidemias
and potentially more atherogenic LDL subclass patterns.
Whether introduction of exogenous estrogens into a dyslipidemic environment would have similar effects as those described in the current study is unknown, but, given that many
such dyslipidemic individuals appear to be more prone to the
triglyceride raising effects of oral estrogens, caution in the use
of such therapy may be warranted among high-risk individuals
until more definitive results are available.
Can we predict which women will have a potentially
adverse impact of estrogen therapy and which women are
likely to benefit? Baseline lipid profiles were similar among
the 11 women who did and the 13 women who did not
experience a triglyceride increase in this study, but there was
a suggestion that women who increased their triglycerides
Bittner
Editorial Comment
JACC Vol. 37, No. 2, 2001
February 2001:431–3
during therapy had lower HDL cholesterol levels at baseline
(22) (Table 3). Low HDL cholesterol is believed to be a
marker for abnormal metabolism of triglyceride-rich lipoproteins. It is thus possible that the increase in VLDL
production induced by oral estrogen therapy unmasked a
latent defect in the catabolism and clearance of apo
B-containing lipoproteins among these women with lower
baseline HDL cholesterol levels. Whether women with
lower HDL cholesterol levels are more susceptible to
adverse effects of estrogen therapy should be determined in
larger samples of postmenopausal women.
Although the small sample size and highly selected
population in the current study limit its generalizability,
Watsuki et al. (22) have made a significant contribution to
the current knowledge base by pointing out that lipoprotein
responses to estrogen therapy are heterogeneous and that an
increase in triglycerides after initiation of oral estrogen
therapy may not be a benign phenomenon.
Current recommendations and future directions. The
relationship between menopause, estrogens, lipids and cardiovascular risk is complex and there are no easy answers.
Rather than recommending oral estrogen therapy across the
board for most if not all postmenopausal women as has been
advocated in the past, therapy must be individualized, and
potential risks and benefits should be assessed on an
individual basis. Such individual counseling, if it is to be
successful, requires a much more comprehensive research
database than is currently available. In addition to mechanistic studies at the bench, larger and more detailed clinical
studies of the impact of estrogen therapy on coronary
disease risk factors and cardiovascular disease outcomes in
different subsets of postmenopausal women are clearly
needed. When discussing options for modification of cardiovascular risk with postmenopausal women, evidencebased interventions such as lifestyle modifications (e.g.,
smoking cessation, consumption of a low-fat diet and
maintenance of normal weight, increase in physical activity)
and, when indicated, pharmacologic treatment of hypertension and hyperlipidemia should be emphasized. Until further data are available, a cautious approach to the use of
postmenopausal hormone therapy appears to be advisable.
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Reprint requests and correspondence: Dr. Vera Bittner, University of Alabama at Birmingham, LHRB 310-UAB Station, Birmingham, Alabama 35294. E-mail: [email protected].
22.
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