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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 3913-3918
Copyright © 1997 by The Endocrine Society

Special Articles

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


   Abstract
Top
 Abstract
Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
 Summary
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
 Summary
 References
 
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.


   Estrogen receptors in cardiovascular tissue
Top
 Abstract
 Introduction
 Estrogen receptors in...
Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
 Summary
 References
 
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-{alpha}), it has been speculated that the two proteins may regulate different genes. ER-{alpha} 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-{alpha}, 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).


   Biological effects of estradiol on VSMC
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 Abstract
 Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
 Summary
 References
 
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-{alpha} as well as in wild-type mice, which suggests that a novel mechanism, such as ER-ß, is involved (57).


   Effects of estradiol on vascular endothelial cells
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 Abstract
 Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
Progesterone effects on the...
 Effects of combination hormonal...
 Summary
 References
 
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. 1Go). 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. 2Go).



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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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  		Figure 2. Direct and indirect (lipoprotein metabolism) cardiovascular effects of estrogen.

 
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-{alpha} 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-{alpha} (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).


   Progesterone effects on the vasculature
Top
 Abstract
 Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
Effects of combination hormonal...
 Summary
 References
 
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).


   Effects of combination hormonal replacement on CAD risk
Top
 Abstract
 Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
Summary
 References
 
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.


   Summary
Top
 Abstract
 Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
 Summary
References
 
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.


   Acknowledgments
 
We thank Paddy McGowan and Linda McCraw for their fine work in preparing this manuscript.


   Footnotes
 
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. Back

Received June 13, 1997.

Revised September 5, 1997.

Accepted September 9, 1997.


   References
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 Abstract
 Introduction
 Estrogen receptors in...
 Biological effects of estradiol...
 Effects of estradiol on...
 Progesterone effects on the...
 Effects of combination hormonal...
 Summary
 References
 

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