The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 3913-3918
Copyright © 1997 by The Endocrine Society
Female Sex Hormones and Cardiovascular Disease in Women1
Debra F. Skafar,
Rui Xu,
Juan Morales,
Jeffrey Ram and
James R. Sowers
Departments of Physiology and Medicine (J.R.S.), Wayne State
University, Detroit, Michigan 48201
Address all correspondence and requests for reprints to: James R. Sowers, M.D., Division of Endocrinology, Metabolism, and Hypertension, Wayne State University School of Medicine, 4201 St. Antoine, UHC-4H, Detroit, Michigan 48201. E-mail: sowers{at}oncgate.roc.wayne.edu
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Abstract
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Cardiovascular disease is the leading cause of mortality in women, a
fact that is underappreciated by women and physicians. Clinical and
experimental data underscore the cardioprotective effects of female sex
hormones, particularly estrogen. Indeed, the loss of female sex
hormones after menopause contributes to the striking increase in the
incidence of cardiovascular morbidity and mortality after menopause.
Estrogen replacement therapy improved lipoprotein profiles in the
postmenopausal women, but this accounts for less than half of the
cardioprotective effects of estrogen replacement therapy. Addition of
progestins to estrogen therapy in women appears not to significantly
attenuate the cardioprotective effects of estrogen replacement therapy
despite experimental data suggesting otherwise. This review addresses
potential mechanisms, other than influences on lipoproteins, by which
estrogen and progesterone exert their cardiovascular protective
effects. Particular emphasis is directed to genomic and nongenomic
effects of estrogen and progesterone that are exerted directly on
cardiovascular tissue.
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Introduction
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CORONARY artery disease (CAD) is the
leading cause of death among women in the United States, accounting for
nearly 30% of deaths (1, 2). The incidence of CAD and associated
morbidity/mortality rises with age (3). Below age 55 yr, the incidence
of CAD in women is one third that in men; however, at age 75 yr, the
incidence is essentially the same in both genders. Indeed, over a
quarter million women aged 50–75 yr die of CAD in the United States
each year (3, 4).
The disparity between CAD in premenopausal women and men of the same
age suggests that endogenous sex hormones such as estrogen,
progesterone, and/or androgens have a major impact on atherosclerotic
processes (4). Estrogen is of primary importance in CAD protection both
premenopausally and when replaced postmenopausally (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26). Although
estrogen replacement therapy (ERT) has beneficial effects on the
lipoprotein profile [increases in high density lipoprotein (HDL) and
decreases in low density lipoprotein (LDL) cholesterol, LDL oxidation,
and lipoprotein(a)] (27, 28, 29, 30, 31, 32, 33, 34, 35, 36), only 25–50% of the antiatherogenic
effects of ERT are attributable to effects on lipoprotein metabolism
(5, 7, 14, 15, 16). Further, despite the fact that progestins raise LDL and
reduce HDL cholesterol levels (37, 38, 39, 40, 41) and attenuate vascular
estrogen-induced nitric oxide (NO) production (42) and vasorelaxation
(43), there is accumulating evidence that the protective effects of ERT
against CAD are preserved when progestins are added (26). Thus, effects
of female sex hormones on the cardiovascular system, independent of the
impact on lipids, are the focus of this review.
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Estrogen receptors in cardiovascular tissue
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The mechanism by which estradiol mediates its biological effects
has been intensively studied. The estrogen receptor (ER), a member of
the nuclear receptor superfamily (44), is associated with heat shock
proteins in the absence of hormone (45). Hormone binding causes
conformational changes in the ER, which promote dissociation of the
heat shock protein complex (46, 47) and homodimerization of the
receptor (44, 45, 46, 47). The hormone-bound, dimeric receptor exhibits a
higher affinity for DNA in general (48) as well as for the specific DNA
sequence to which the receptor binds, the estrogen response element
(49). The hormone-bound ER also interacts with transcriptional
coactivators (50, 51). The result is a change in the level of
transcription of specific genes, leading to altered messenger
ribonucleic acid (mRNA) levels and, ultimately, changes in the types
and levels of cellular proteins.
Until recently, only a single major form of the ER had been detected
(52, 53). However, a protein (ER-ß) has been identified that is 96%
identical to the classical ER in the DNA-binding domain and 60%
identical in the hormone-binding domain (54, 55). There is almost no
homology in the N-terminal domain of the two proteins. Because the
N-terminal domain contains a transcription activation function in the
classical ER (ER-
), it has been speculated that the two proteins may
regulate different genes. ER- and ER-ß bind estradiol with similar
affinity, (Kd = 0.2–0.5 nmol/L) (56). The
binding specificity for other ligands and the response to tamoxifen are
reported to be different (56). ER-ß has recently been demonstrated in
the mouse aorta (57). In this review, ER refers in most cases to
ER-, but the reader should be aware that in functional studies, some
responses could be mediated by ER-ß.
Estrogen receptors are found in myocardial, vascular smooth muscle
cells (VSMC), and endothelial cells in both humans and animals
(58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74). In VSMC, immunoreactive ER has been observed in both
cytoplasm and nuclei (65), especially in the perinuclear region (65, 67). Heterogeneity of ER distribution has been noted among various
vascular beds, between female and male animals, and between normal and
atherosclerotic vascular beds (68, 69, 70, 71, 72). Changes in plasma estradiol
concentrations also appear to regulate ER in vascular tissue, as
binding of estradiol is higher in coronary arteries of sexually mature
female pigs than in comparable arteries from castrated males (73).
Further, ER levels in the cytosol of uterine artery are highest in the
late follicular phase of the menstrual cycle and higher in uterine
arteries in pregnant vs. nonpregnant females (74). In
premenopausal women, atherosclerotic coronary arteries express
considerably less ER than do normal arteries (68). These observations
suggest that the antiatherogenic effects of estradiol are in part
mediated through cardiovascular ER, and that atherosclerosis is
associated with diminished ER expression (68, 72).
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Biological effects of estradiol on VSMC
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Estradiol affects a number of VSMC functions, including
contractility and growth (72). Some of the vasodilatory effects are
mediated through indirect actions exerted through the endothelium
(discussed later) and directly through effects on VSMC (72). Estradiol
hyperpolarizes the resting membrane potential of VSMCs in culture (72, 75). Estradiol acutely attenuates voltage-dependent T- and L-type
calcium channel currents in VSMC (75), perhaps contributing to the
hyperpolarization (60) and attenuation of myocardial and vascular
contractility (76, 77, 78, 79, 80). However, estradiol also attenuates the
contractile responses to angiotensin II and norepinephrine (76, 81),
agents that primarily increase the release of Ca2+ from
intracellular storage sites. Thus, estradiol has multiple effects on
VSMC divalent cation metabolism.
The inhibitory effects of estrogens on VSMC contraction may also be
partly due to activation of potassium (K) channels. The synthetic
estrogen diethylstilbestrol causes hyperpolarization of canine coronary
VSMC (82); the VSMC input resistance is decreased, and the dependence
of the membrane potential on external potassium is enhanced, consistent
with an increased K conductance. Patch-clamp experiments demonstrated
that physiological levels of estradiol can activate large
Ca2+-dependent K channels (BKCa) in porcine
coronary artery VSMC (83). In rats, iberiotoxin, a blocker of
BKCa channels, causes greater constriction of coronary
arteries from intact females than from ovariectomized females,
consistent with the activation of these channels in the presence of
estradiol (84).
Estradiol increases the vascular production of NO, leading to increased
production of cGMP via guanylate cyclase and subsequent activation of
protein kinase G, which phosphorylates and stimulates BKCa
channels (85, 86, 87). Activation of cGMP in response to NO (88) and
activation of BKCa channels in VSMC by cGMP (89, 90) are
well established phenomena; however, the source of NO that mediates the
response of BKCa to estradiol remains uncertain. In rat
coronary artery, endothelial NO appears to be required; however, in
porcine coronary artery, activation of NO synthesis in the VSMC appears
to be capable of mediating the activation of BKCa (85).
Additionally, NO can directly activate BKCa channels in
rabbit aorta VSMC (91). Thus, there is activation of VSMC
Ca2+-dependent K, but the mechanisms involved need further
clarification.
Antiatherogenic effects of estradiol are partially due to inhibition of
VSMC growth and proliferation (72, 73, 92, 93, 94). Estradiol inhibits
neointimal formation (VSMC proliferation and extracellular matrix
formation) after balloon injury of iliac arteries of rabbits (95).
Myointimal proliferation after balloon injury of the carotid artery in
rats (96) and the abdominal aorta of rabbits (93) is attenuated by
estradiol. Estradiol may also alter VSMC production of matrix elements,
attenuate inflammatory responses (97), and regulate VSMC proliferation
through alterations in early response gene expression and synthesis of
proteins involved in the regulation of the VSMC cell cycle.
Interestingly, estradiol inhibits increases in vascular medial area and
VSMC proliferation after vascular injury in transgenic mice lacking
ER- as well as in wild-type mice, which suggests that a novel
mechanism, such as ER-ß, is involved (57).
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Effects of estradiol on vascular endothelial cells
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There are considerable data indicating that estradiol stimulates
vascular endothelial cell secretion of NO. Long term estradiol
replacement improves endothelium-dependent relaxation in ovariectomized
rabbits (98, 99) and endothelium-dependent vasodilation in coronary
arteries of ovariectomized monkeys (100). Physiological levels of
estradiol enhance acetylcholine-vasorelaxation in the forearm (101, 102) and coronary vasculatures (103) in peri- and postmenopausal women.
Estrogen-induced vasodilation of uterine vasculature is mediated in
part through a NO-dependent mechanism (104). Estrogen supplementation
also enhances endothelium-dependent, flow-mediated vasodilation in the
brachial artery in hypercholesterolemic postmenopausal women (105).
Several observations suggest that estradiol modulates
endothelium-dependent relaxation by increasing vascular NO
production/release. Basal vascular release of NO is generally higher in
vessels derived from females than in those from males, and this
difference is due to female sex hormones (106). The number of estrogen
receptors has been correlated with basal release of NO in the mouse
aorta (107). Both pregnancy and estradiol treatment increase
Ca2+-dependent endothelial NO synthase (eNOS) activity and
mRNA in skeletal muscle (108). Estradiol also increases eNOS activity
and NO production in cultured endothelial cells in some studies (109, 110). Preliminary studies by our group indicate that the mRNA for eNOS
is expressed in cultured human VSMC as well as in endothelial cells
(Fig. 1
). There is accumulating evidence
that NO may attenuate atherogenic processes, including VSMC
proliferation (111), monocyte adhesion (112), and platelet aggregation
(113). Thus, estradiol-induced NO release is probably an important
mechanism underlying the cardioprotective effects of this hormone. The
effects of estradiol on cardiovascular NO production and release could
be mediated by both nongenomic effects (i.e.
posttranslational activation of the NOS enzyme) or through changes in
the level of NOS in various cells of the cardiovascular system (Fig. 2).
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Figure 1. Reverse transcription-PCR analysis of
constitutive NOS (cNOS) and inducible NOS (iNOS) mRNA expression in
human vascular smooth muscle cells (HVSMC) and umbilical vein
endothelial cells (HUVEC). PCR products were obtained using primers
specific for cNOS and iNOS and the product of a reverse transcriptase
reaction using RNA derived from cultured HVSMC and HUVEC. Primer pairs
were selected to produce PCR products of 213 bp (cNOS 249–462) or 402
bp (iNOS 2852–3254). DNA size markers (M; in base pairs) are shown on
the left. The PCR products were cloned and sequenced,
then compared with human cNOS and iNOS sequences in GenBank to confirm
their identity.
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Estradiol may also affect endothelial cell regeneration and
angiogenesis. It promotes neovascularization as well as migration,
proliferation, and differentiation of endothelial cells in
vitro and in vivo (114). Estradiol enhances
ER-dependent adhesion of human umbilical vein endothelial cells to
matrix proteins, stimulates proliferation, and increases formation of
capillary-like networks. The ability of estradiol to augment basic
fibroblast growth factor-induced angiogenesis is lost in transgenic
mice lacking functional ER- receptors, providing additional strong
evidence for receptor dependence (115). Estradiol enhances
transcription of the genes for endothelial cell leukocyte adhesion
molecules and integrins (116). Estradiol may also stimulate expression
of endothelial growth factors such as fibroblast growth factor,
vascular endothelial growth factor, and tumor necrosis factor-
(117). Furthermore, vascular endothelial growth factor is found in
tissues that have high estradiol content and may represent a target for
the vascular actions of estradiol, i.e. in modulating the
response to vascular injury (118).
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Progesterone effects on the vasculature
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Like estradiol, progesterone acts by binding to a specific, high
affinity receptor protein (44) (Kd = 2–3 nmol/L)
(119, 120). The progesterone receptor (PR), like the ER, is a member of
the nuclear receptor superfamily of ligand-activated transcription
factors (44). The PR exists in two forms that differ only in that the A
form is an N-terminal truncation of the B form; it lacks 164 amino
acids present at the N-terminus of the B form. These two forms
differentially modulate gene expression depending on the ligand, cell
type, and promoter used (121, 122, 123, 124). Indeed, the A form can repress the
ability of the B form to activate transcription from some promoters.
This implies that a change in the ratio of A and B isoforms may alter
the biological response to progesterone. In the human endometrium, the
ratio of A and B forms fluctuates during the menstrual cycle (125). The
ratio of isoforms in endothelial cells and whether that ratio changes
during the menstrual cycle or after menopause are unknown. In
cardiovascular tissues, as in others, PR expression can be induced by
estrogen (63), possibly mediated by putative estrogen response elements
in the 5'-flanking untranslated region and the first exon of the PR
gene (126). Because of this interrelation between estrogen and PR
levels, the action of progesterone is generally studied in combination
with estrogen.
Progesterone is frequently described as opposing the actions of
estradiol; however, this may be an oversimplification. For example, in
the uterus, progesterone does inhibit estrogen-induced growth, whereas
in the breast, both estrogen and progesterone promote growth
(127, 128, 129). The cardiovascular effects of progesterone remain
unclear. Progestins inhibit estradiol-induced endothelium-mediated
vascular relaxation (130). High doses of progesterone also negate the
ability of estradiol to reduce intimal plaque size and cellular
proliferation in a rabbit model of experimental atherosclerosis (131, 132). Progestins increase LDL and decrease HDL cholesterol levels
(27, 28, 29, 30, 31). Progesterone stimulates thrombospondin-1 expression by both
endothelial cells and VSMC, which potentially inhibits endothelial cell
adhesion, migration, proliferation, and angiogenesis (133). Micromolar
concentrations of progesterone have been reported to induce
endothelium-dependent relaxation of rabbit coronary artery (134)
and inhibit the induction of platelet calcium responses (135). There
may also be an intriguing difference in the effects of different
progestins; medroxyprogesterone, but not progesterone itself, has been
reported to interfere with the ability of estradiol to protect against
coronary artery vasospasm in rhesus monkeys (43).
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Effects of combination hormonal replacement on CAD risk
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Experimental studies suggested that addition of a progestin,
although necessary to prevent potential neoplastic effects of unopposed
estrogen on the endometrium, would negate some of the cardiovascular
protective effects of estrogen (72). For example, it had been predicted
that norethisterone acetate, a progestin used in hormone replacement
therapy (HRT), would prevent estradiol-induced increases in circulating
NO during HRT (42). However, there was no difference in flow-mediated
vasodilation between postmenopausal women receiving estrogen alone or
those receiving HRT including progesterone (136). The Nurses’ Health
Study showed a substantial reduction in the risk of major CAD among
women who used combined HRT compared with women who took estrogen alone
or did not use HRT (26). Furthermore, in the PEPI trial, the
combination of a progestin with estrogen did not negate the
LDL-lowering effects of estrogen, but did prevent the increased
occurrence of endometrial hyperplasia seen with estrogen therapy alone
(19). The beneficial increase in HDL cholesterol was less pronounced,
however, in patients taking combination therapy (19).
Combination therapy is also associated with a lowering of fibrinogen,
and there are no increases in either blood pressure or glucose
intolerance (19). Plasma levels of plasminogen activator inhibitor type
I were reduced to similar levels when either conjugated estrogen or
combined estrogen and medroxyprogesterone acetate were administered
(137). Both therapies also led to significant increases in cross-liked
fibrin (D-dimers), an index of fibrinolysis, correlated with the degree
of reduction in plasminogen activator inhibitor type I levels. These
effects on fibrinogen may well contribute to the protective effects of
HRT. Overall, these results suggest that cardiovascular protection can
be maintained with appropriate combination therapy.
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Summary
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Estrogen appears to reduce the risk of CVD through a combination
of effects, including changes in lipid profile, endothelial NO
generation, cell proliferation and angiogenesis, and regulation of VSMC
Ca2+ and K channels. These effects may be mediated through
genomic and/or nongenomic mechanisms. Progesterone, which was predicted
to negate some of the beneficial effects of estrogen, does not appear
to do so in postmenopausal women. The vascular effects, the
interactions between the two steroid hormones, and the mechanisms
underlying the biological effects are complex and in need of further
investigation.
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Acknowledgments
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We thank Paddy McGowan and Linda McCraw for their fine work in
preparing this manuscript.
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Footnotes
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1 This work was supported by NIH Grant RO1-HD24497, a V.A. research
grant, the American Heart Association, and Wayne State University
Interdisciplinary Seed Fund. 
Received June 13, 1997.
Revised September 5, 1997.
Accepted September 9, 1997.
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Top
Abstract
Introduction
