Cardiovascular Actions of Estrogens in Men
Krishnankutty Sudhir1 and
Paul A. Komesaroff2
Hormones and Vasculature Laboratory, Baker Medical Research
Institute, Commercial Road, Prahran, Melbourne, Victoria 3181,
Australia
Address all correspondence and requests for reprints to: Dr. K. Sudhir, Alfred Heart Centre, 3rd Floor, Alfred Hospital, Commercial Road, Prahran, Melbourne, Victoria 3181, Australia; E-mail:
Krishna.sudhir{at}baker,edu.au
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Introduction
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Cardiovascular disease is the major
cause of death among both men and women in developed countries.
Coronary artery disease, the single most important component of
cardiovascular disease, is responsible for about one quarter of all
deaths. It is well recognized that, at all ages, women are relatively
protected against cardiovascular disease in comparison with men, and
many observational studies have suggested that estrogen treatment of
postmenopausal women significantly reduces cardiovascular risk (1).
Further, the Postmenopausal Estrogen/Progestin Intervention (PEPI)
Study (2), which assessed the effect of hormonal therapy on
cardiovascular risk factors over a 3-yr period, showed beneficial
effects on lipoproteins in all treatment groups and concluded that the
best regimen for women with an intact uterus was estrogen plus
micronized progesterone, and the best regimen for women without a
uterus was unopposed estrogen. However, the recently concluded Heart
Estrogen/progestin Replacement Study (HERS) found no significant
evidence of a clinical benefit of hormonal therapy in women with
established coronary artery disease (3). The question of whether such
therapy is useful in women as primary prevention against cardiovascular
disease is being addressed by the Womens Health Initiative, the
results of which will not be known for several more years (4).
Although in men estrogens are produced in significant quantities by
local tissue aromatization of androgenic precursors from the testes and
adrenal glands (5), there has been relatively limited study of the
biological role of these hormones or their clinical implications. An
investigation conducted 25 years ago into the cardiovascular effects of
estrogen administration in men after myocardial infarction, the
"Coronary Drug Project" showed an excess of deaths and recurrent
infarction in the treatment group. This trial, which employed high
doses of conjugated equine estrogens, was subsequently abandoned, and
the subject has not been studied in detail since (6). Data gathered
over the last quarter century on the epidemiology of cardiovascular
disease, the mechanisms of actions of estrogens in women and men, and
the biological role of endogenously produced estrogens in men, suggest
that it might be time to re-open the Coronary Drug Project file, and
re-assess the potential for estrogen therapy in men. Newer approaches
to treatment and an ability to identify more precisely individuals at
risk of coronary heart disease (CHD) may lead to new clinical
applications for this group of hormones.
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Evidence of a role for endogenous estrogens in men
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Endogenous estrogens, lipoproteins, and glucose metabolism.
There is now compelling evidence that endogenous production of
estrogens in men plays an important role in cardiovascular health and
disease. Physiological levels of estrogen have been reported to play a
role in influencing plasma lipoprotein concentrations in men. When
selective estrogen deficiency was induced in young men by
administration of combined drug therapy with a GnRH antagonist (to
suppress endogenous steroid hormones), testosterone (to restore
testosterone levels to baseline), and testolactone (an aromatase
inhibitor that prevents conversion of testosterone to estrogens),
plasma high density lipoprotein (HDL) and apolipoprotein A-1 decreased,
while plasma low density lipoprotein (LDL) and triglyceride levels did
not change (7). Shono et al. (8) investigated the
relationships of plasma sex hormones to lipid and glucose metabolism in
a cross-sectional study on 212 apparently healthy men ranging in age
from 18 to 59 yr. They showed that the estradiol level was
negatively related to both LDL cholesterol and fasting blood glucose,
suggesting that the levels of estradiol within the physiological range
for healthy men may help maintain a desirable profile of lipid and
glucose metabolism.
Lessons from "experiments of nature". Recent evidence from
a 28-yr-old man with estrogen insensitivity caused by a disruptive
mutation in the estrogen receptor (ER) gene suggests that estrogen may
play an important role not only in bone metabolism but also in
cardiovascular function. This individual presented with tall stature,
normal masculinization, incomplete epiphyseal closure, and decreased
bone mineral density. His serum estradiol and estrone, FSH, and LH
concentrations were elevated, while testosterone was normal. Direct
sequencing of exon 2 of his ER gene revealed a cytosine-to-thymine
transition at codon 157 of both allelles, resulting in a premature stop
codon and expression of a truncated nonfunctional ER protein (9).
Peripheral vascular studies in this individual revealed an intact rapid
nongenomic vasodilator response to sublingual estradiol; however, he
demonstrated marked endothelial dysfunction evidenced by absence of
flow-mediated vasodilation in the brachial artery (10), an observation
consistent with the impaired basal nitric oxide release in the aorta of
the male estrogen-
receptor knockout mouse (11). Electron beam
computed tomography scanning of the heart in this individual showed
calcium deposition in his left anterior descending coronary artery,
indicating early atherosclerosis (12). Lipoprotein analysis showed
relatively low levels of HDL, but total and LDL cholesterol
concentrations were also low, as were apolipoprotein A-1 and
lipoprotein(a), while triglyceride concentrations were normal (12).
Overall, these observations suggest that some actions of estrogen
likely to be protective against the development of premature vascular
disease in men.
Further evidence for a role for endogenously produced estrogen in
normal male cardiovascular health comes from a condition in which a
deficiency occurs in the enzyme responsible for the conversion
(aromatization) of C19 androgenic steroids to the corresponding
estrogens, involving the conversion of the delta 43-1 A-ring of the
androgens to the corresponding phenolic A-ring characteristic of
estrogens. Recently, a number of mutations of the aromatase gene have
been described that give rise to complete estrogen deficiency. In
females this estrogen deficiency results in virilization
in utero and primary amenorrhea with hypergonadotropic
hypogonadism at the time of puberty. In men the most striking feature
is continued linear bone growth beyond the time of puberty, delayed
bone age, and failure of epiphyseal closure, thus indicating an
important role of estrogens in bone metabolism in men (13). Such
patients also have low HDL and increased total and LDL cholesterol
concentrations and triglycerides, and hyperinsulinemia (14).
Thus, as has been suggested in menstruating women, it is possible that
part of a putative protective role for endogenous estrogens in men is
by maintenance of normal HDL concentrations and possibly by reducing
LDL cholesterol.
Aromatase inhibition in men: vascular effects. In a recent
preliminary study (15), we have demonstrated a potential role for
endogenous sex hormones in vascular reactivity in elderly men taking
the aromatase inhibitor testolactone for benign conditions for
prolonged periods. Cessation of testolactone therapy was associated
with a fall in serum testosterone, a trend to an increase in estrogens,
and significant improvement in forearm endothelium-dependent
vasorelaxation. However, norepinephrine-induced vasoconstriction was
enhanced, and arterial compliance decreased, suggesting a complex
interaction between sex hormones and vascular function. In addition,
because the presence of aromatase has been demonstrated in the
vasculature (16), local changes in steroid concentrations resulting in
vascular effects cannot be excluded.
Of note, variations in endogenous estrogen levels are observed in men
in conditions such as obesity (17). The degree of obesity appears to
have a direct effect on estradiol levels, probably through
transformation of androgens in adipose tissue to estrogens (17).
Moderate to high ethanol intake is also reported to influence sex
hormone levels in men; in particular, plasma testosterone levels
decrease, probably via alcohol-induced inhibition of testosterone (18).
In addition, ethanol induces an increase in cytosolic ER in the human
male liver, a possible explanation for feminization in chronic liver
disease due to alcohol (19). However, the influence of such variations
in endogenous sex hormone levels and ER on cardiovascular physiology in
men with obesity or chronic liver disease is unknown.
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Estrogens and vascular function in women
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In women, estrogens directly influence vascular function.
Estrogens act as vasodilators in the peripheral and coronary
circulations through effects both on the endothelium and on smooth
muscle cells. Several studies have recently shown that estrogen
preserves endothelial function. Physiological levels of estrogen
enhance acetylcholine-induced vasorelaxation in the forearm (20) and
coronary (21) vascular beds in postmenopausal women. The beneficial
effect of estrogens on endothelium dependent dilation are probably
mediated by an increase in nitric oxide production. Postmenopausal
women supplemented with transdermal estradiol have increased serum
concentration of nitrites and nitrates, metabolites of nitric oxide,
compared with women not on hormonal therapy (22). A recent study in
perimenopausal women showed greater basal nitric oxide release in the
forearm vasculature after 8 weeks of estrogen supplementation (23).
Consistent with these observations, studies in human umbilical vein
endothelial cells have shown up-regulation of endothelial nitric oxide
synthase after exposure to estrogen (24).
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Biological effects of estrogens in male tissues
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As already argued, the biological effects of estrogens are less
well defined in men than they are in women. Data from in
vitro studies, however, suggest that estrogens may act directly on
vascular cells in males in a physiologically important manner. Karas
et al. (25) have reported the presence of ER protein by
immunoblotting in human vascular smooth muscle cells from both male and
female sources (25). Dai-do et al. (26) have reported that
estradiol inhibits growth factor-induced proliferation and migration in
smooth muscle cells, independent of gender. Further, in human
endothelial cells, which reportedly have a high density of ER
2080(2080,000/cell), the intensity of immunostaining for ER is similar in
male and female donor cells, and neither electrophoretic mobility shift
assays nor ligand-binding studies show reproducible gender differences
in ER expression (27).
Recently, Kuiper et al. described another ER, termed the
beta receptor (ERß), which probably mediates some of the biological
effects of estrogens (28). There is evidence from studies of human
vascular smooth muscle cells (29), as well as from the ER-
knock-out
mouse that ER-ß exists on the vasculature (30). In the ER-
knock-out mouse, ER-ß in male vascular tissues appears to be induced
after vascular injury (31), supporting a role for ER-ß in the direct
vascular effects of estrogen in males. Preliminary studies in human
vascular smooth muscle cells suggest that, in cells from females,
ER-
is more prevalent than ER-ß, while approximately equal amounts
of both receptors are present in males (32). The significance of this
gender-associated difference in vascular ER subtypes remains to be
determined. Cardiac myocytes from both male and female rats also
express ER-
and ER-ß, and both receptors appear to be up-regulated
in the presence of estrogen (33); however, at present, the significance
of cardiac ER in cardiovascular physiology is unclear.
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Acute vascular effects of estrogen administration in men
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There are conflicting data on the effect of estrogens on coronary
vascular reactivity in men. Collins et al. (34) reported
that short-term administration of 17-ß estradiol did not attenuate
acetylcholine-induced coronary vasoconstriction in men. However, more
recent studies have shown that acute intravenous administration of
conjugated estrogens improved coronary blood flow responses to
acetylcholine (35) and abolished abnormal coronary vasoconstriction in
response to an exogenous cold stimulus, both in men referred for
routine coronary angiography (36) and in male cardiac allografts (37).
In these latter studies, the improvement in response was seen after 15
min of estrogen administration, a likely nongenomic effect of estrogen.
Like other steroid hormones, estrogens have classically been considered
to act through binding to intracellular receptors, which act as
ligand-dependent transcription factors to regulate protein
synthesis. However, as with other steroid hormones (38), in recent
years evidence has accumulated that estrogens may also act rapidly
through nongenomic mechanisms (39). In the dog coronary circulation,
Sudhir et al. (40) have shown that intracoronary
administration of 17-ß estradiol induces rapid coronary vasodilation
of similar magnitude in both males and females, a response that is not
blocked by pretreatment with the ER antagonist ICI 182,780. Komesaroff
et al. (41) investigated the effects of estrogen on the
cutaneous vasculature in young men, and found that at plasma estradiol
concentrations within the physiological range for premenopausal women
estrogens induced rapid onset, rapid offset, nongenomic effects
specific to the endothelium. Following sublingual estradiol or
intravenous conjugated equine estrogens, the vasodilator response
to acetylcholine, but not sodium nitroprusside, was accentuated in
these young male subjects.
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Chronic vascular effects of estrogen administration in men
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Estrogen supplementation in older men reportedly does not augment
flow-mediated dilation in the brachial artery or influence serum levels
of metabolites of nitric oxide (42). However, studies in male-to-female
transsexuals have shown that both flow-mediated and
nitroglycerin-induced vasodilation in the brachial artery are enhanced,
compared to control men, suggesting that high dose estrogen treatment
enhances vascular reactivity in genetic males (43, 44). In a recent
study in hypogonadal men, we showed that 6 weeks of low dose estrogen
supplementation had no effect on acetylcholine- or
nitroprusside-induced vasodilation in forearm resistance arteries, but
attenuated vasoconstrictor responses to norepinephrine and angiotensin
II (45). We also demonstrated an accentuated forearm vasoconstrictor
response to L-NMMA after estrogen supplementation, suggesting an
estrogen-induced increase in basal nitric oxide release. With the dose
administered (1 mg estradiol valerate daily for 8 weeks) minimal
adverse effects were observed (45). In that study, we also observed a
drop in baseline and stress-induced increases in blood pressure
after estrogen supplementation, consistent with previous reports from
our group in perimenopausal women (46, 47). Of note, estrogens increase
sex hormone-binding globulin (SHBG), which may bind testosterone to a
greater degree than estradiol, and thus potentially decrease
bioavailability of testosterone in relation to that of estrogen.
However, such an alteration in the hormonal milieu does not appear to
result from short-term increases in circulating estradiol (48).
Nevertheless, some of the consequences of long-term estrogen
administration in men might be related to androgen withdrawal.
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Effect of estrogens on homocysteine, clotting factors, and
platelets in men
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It has been recognized that an elevated plasma homocysteine level
is an independent risk factor for coronary heart disease. There is
evidence that endogenous estrogens play a role in controlling
circulating levels of homocysteine. Plasma total homocysteine levels
decrease after estrogen and antiandrogen administration to
male-to-female transsexual subjects, and increase after androgen
administration to female-to-male transsexual subjects (49). A recent
short-term (9 week) study in healthy elderly men showed that estradiol
therapy reduced homocysteine, fibrinogen, and PAI-1 concentrations, and
favorably influenced lipoprotein levels, without increasing markers of
thrombotic risk (50). These observations are consistent with animal
experiments showing that administration of both estrogens and
glucocorticoids decrease plasma homocysteine levels, presumably by
enhancing metabolism (51).
Estradiol may also play a role in the control of the membrane protein
P-selectin, which tethers leukocytes to endothelial cells and activated
platelets and may thus play a role in atherosclerosis. Lower plasma
levels of a soluble form of P-selectin have been observed in
premenopausal women compared to men, and it has been shown that a
single dose of estradiol valerate (10 mg, intramuscular injection) in
healthy male volunteers significantly decreases P-selectin levels (52),
suggesting that an additional antiatherogenic mechanism for estradiol
may be important in normal men. Estrogen may also control activity of
the plasma platelet-activating factor (PAF)-acetylhydrolase activity,
as administration of the synthetic estrogen mestranol in healthy men
appears to lead to significant decreases in plasma PAF-acetylhydrolase
activity (53).
Against these potentially beneficial roles for estrogen, a potentially
harmful effect of estrogen in promoting thrombosis needs to be
considered. Estrogens may increase the risk of thromboembolic events,
as the HERS study in postmenopausal women (3) and studies of the
effects of oral contraceptives in premenopausal women (54) have
suggested. Further, female smokers over the age of 35 yr who use oral
contraceptives have an unacceptably high incidence rate of myocardial
infarction and stroke (55), and it is unclear whether such a
smoking-hormone interaction would be observed with administration of
estrogenic compounds in men.
There is limited evidence for a deleterious effect of endogenous
estrogens in men. Phillips et al. (56) have shown, in a case
control study, that the mean serum estradiol level in men who had
suffered myocardial infarction was significantly higher than that in
men with no history of infarction but with comparable established
coronary artery disease, suggesting that higher estrogen levels may
predispose to coronary thrombosis in susceptible individuals. Venous
thromboembolism is a major complication in male-to-female transsexuals
treated with oral estrogens and anti-androgens, but the use of
transdermal estradiol in transsexual subjects over 40 yr of age appears
to attenuate this risk (57). Clearly such data are important when
re-assessing a potential role for estrogens in cardiovascular disease
in men.
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"Designer estrogen" therapy in men
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The recognition that high doses of estrogen may produce effects
distinct from those obtaining at physiological levels, and the
developing appreciation of the complexity of the relationship between
sex steroids and the cardiovascular system in women, suggest a need for
further studies to clarify the roles of these hormones in men. The
effects of newer agents with estrogenic activity, such as the so-called
"selective ER modulators" or "designer estrogens" (58), and
recently identified equine estrogens such as delta 8-estrone (59) and
17
-dihydroequilenin (60), which may have fewer trophic effects on
reproductive organs or mammary glands in males and females, are yet to
be studied in men. Raloxifene, a designer estrogen that has been
examined in postmenopausal women, appears to favorably alter markers of
cardiovascular risk by lowering total and LDL cholesterol (61),
fibrinogen, and lipoprotein(a), and by increasing HDL2 cholesterol,
without raising triglycerides (62); its effects in men are unknown.
Differences between the ER subtypes in relative ligand binding affinity
and tissue distribution could be exploited to achieve selective action
of ER agonists and antagonists in different tissues (63). Thus, the
potential exists to develop an agent that has minimal adverse effects,
but beneficial actions on the cardiovascular and other systems. Such
agents might then bridge the current "gender gap" that exists in
the context of estrogen therapy.
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Potential role of phytoestrogens and other dietary factors
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A significant number of structurally diverse plant and fungal
secondary metabolites exist in nature that may contribute to the total
estrogen exposure of the human population (64). It is now recognized
that these phytoestrogens may act in beneficial ways on the
cardiovascular system (65), and recent research has emphasized the
widespread potential health benefits of dietary phytoestrogens (66). It
is likely that the cardiovascular benefits of these substances would
apply to men as much as to women, but to date little study of their
effects in men has been undertaken. It is also known that other dietary
factors may affect sex hormone metabolism. For example, it has been
shown that in healthy men a high fat, low fiber diet is known to reduce
urinary excretion of estradiol and estrone and their metabolites while
increasing mean plasma concentrations of testosterone (67). It is
therefore possible that dietary modification could also be used to
control endogenous sex hormone levels in men in a manner potentially
beneficial to the cardiovascular system.
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Conclusions
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We conclude that recent evidence shows that: 1) it is likely that
estrogens act on the male cardiovascular system in a manner similar to
that in women; 2) endogenous production of estrogens in men plays a
significant role in cardiovascular health; 3) at least some of the
gender differences in cardiovascular risk are likely to be related to
differing levels of circulating estrogen levels between men and women;
and 4) low dose estrogen supplementation in men may induce beneficial
cardiovascular effects. Against this is the relative lack of clinical
data from randomized placebo controlled trials in women showing
improved clinical outcomes with estrogen-containing postmenopausal
hormonal therapies and the possibility of adverse outcomes as a result
of a possible increased tendency to thromboembolic events. These
caveats notwithstanding, we believe that it is appropriate to
reconsider the adverse outcomes of the Coronary Drug Project in the
light of more recent knowledge, and to consider rigorous clinical
testing of therapeutic estrogen administration in selected groups of
men.
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Footnotes
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1 Dr. Sudhir is a Senior Research Fellow of the National Health and
Medical Research Council of Australia. 
2 Dr. Komesaroffs research is funded in part by a grant from the
Victorian Health Promotion Foundation. 
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