Elsevier

Heart & Lung

Volume 30, Issue 6, November–December 2001, Pages 401-428
Heart & Lung

Issues In Cardiovascular Nursing
Sex differences and the effects of sex hormones on hemostasis and vascular reactivity*,**

https://doi.org/10.1067/mhl.2001.118764Get rights and content

Abstract

Thrombus formation and vasospasm are involved in the initiation of acute ischemic events in the heart. Gender differences in persons with coronary artery disease and the incidence of myocardial ischemia have been clearly documented. In addition, it is well established that sex hormones influence the risk of developing coronary artery disease. Epidemiologic studies suggest that estrogen may exert a protective effect, yet the results of recently completed and ongoing prospective trials of estrogen and hormone (estrogen + progesterone) replacement suggest that these hormones can increase thrombotic events in postmenopausal women. This review focuses on sex (gender) differences in hemostasis and vascular reactivity and on the influence that sex hormones have on these physiologic systems. This review takes the novel approach of focusing on sex differences in hemostasis and vascular reactivity in healthy premenopausal women and men of a similar age. By comparing men and women in this age group, the confounding issues of age, pathology, or decline in sex hormone levels are avoided. Animal and in vitro investigations pertinent to examining potential cellular mechanism(s) of sex hormones in mediating these sex differences are discussed. We assume there is a relationship between the normal physiologic and pathologic effects of sex hormones; elucidating sex differences in normal cardiovascular function will help clarify the basis for sex differences in the incidence and manifestations of coronary heart disease and will aid in the future development of gender-specific therapies for cardiovascular disease. (Heart Lung® 2001;30:401-26.)

Section snippets

Limitations associated with studies examining the influence of sex hormones on gender differences in hemostasis and vascular reactivity

Because physiological systems that regulate hemostasis and vascular reactivity are extremely complex and have multiple components, and because this is a relatively new area of investigation, the results of mechanistic studies can be variable or even contradictory. Therefore, researchers have taken a reductionistic approach by examining underlying mechanisms of sex differences and the role of sex hormones in vascular function in in vitro systems. Such models include isolated heart or vascular

Sex steroid hormone signal transduction

Signal transduction refers to the cascade of biochemical and biophysical events by which a chemical signal, such as a hormone, transfers information into a cell to elicit a response. Sex hormones can acutely alter cell function, promote cellular differentiation, and in some cases, stimulate cell proliferation. Sex hormones elicit a cellular response by way of 2 general signaling pathways. The better known traditional, or genomic, pathway involves binding of a sex hormone to an intra cellular

The function of the endothelium in regulation of hemostasis and vascular reactivity

Vascular endothelial cells play an extremely important role in regulating hemostasis and vascular reactivity (Fig 2).

. Role of the endothelium in hemostasis and vascular reactivity. Vascular endothelial cells produce vasoconstricting signals (endothelin-1, superoxide anions, and angiotensin II), vasodilating signals (nitric oxide and prostacyclin), and signals that affect platelet activation. The production and release of these factors are modulated by platelet-derived factors, neurohormones, and

Hemostasis

Hemostasis, the cessation of blood flow, occurs by several processes including vasoconstriction, platelet activation, and stimulation of the coagulation cascade. Activation of these processes results in thrombus formation. As thrombogenesis occurs, the fibrinolytic system is simultaneously activated to localize the clot and prevent its extension throughout the vessel. Under physiologic conditions, the endothelial cell surface is positively charged and nonthrombogenic and hemostatic and

Sex differences in platelet activity

Studies in humans have revealed differences between men and women in numbers of platelets, extent of platelet adherence to the vessel wall, and platelet activation and aggregation. Bain50 found that women of several ethnic backgrounds have higher platelet counts than their male counterparts. In contrast, Lawrence et al51 found that premenopausal women tended to have lower platelet counts than age-matched men. The difference however, was not significant. Faraday et al52 found that the number of

Sex differences in coagulation and fibrinolysis

Overall hemostasis is dependent on the balance between platelet activation, coagulation, and fibrinolysis. Differences in platelet activation, as well as sex differences between premenopausal women and men of similar age, have been found in coagulation and fibrinolysis. It has also been demonstrated that estrogen and testosterone exert modulating effects on these systems. For example, premenopausal women have been found to have higher fibrinogen levels than men,51, 75 women aged 25 to 44 years

Effects of sex hormone treatment on hemostatic parameters in transsexuals

Studies of sex hormone supplementation in male-to-female or female-to-male transsexuals provide insight into the effects of estrogens and androgens on hemostasis. In one study,91 13 male-to-female transsexuals received cyproterone acetate (an androgen antagonist) and oral ethinyl estradiol. Ten female-to-male transsexuals received testosterone ester injections every 2 weeks. After 4 months of treatment, hemostatic factors and other parameters were compared with baseline values. Before hormonal

Molecular mechanisms

A rational approach to seeking molecular mechanisms for sex differences in hemostasis would be to determine whether genes coding for proteins involved in hemostasis are regulated by sex hormones. Several genes for proteins involved in coagulation, fibrinolysis, and platelet activity have been shown to be regulated by sex hormones or are candidates for regulation by sex hormones. Protein products of estrogen-regulated genes that are associated with platelet activity include: prostacyclin

Endothelium-dependent and independent vascular reactivity

Vascular reactivity refers to the responsiveness of blood vessels to vasodilator and vasoconstrictor signals. Vascular tone is determined by the sum influence of these signals. Basal blood pressure is primarily regulated by vascular tone and thereby vascular reactivity.109 Vessel wall cells that contribute to regulation of vascular tone are VSMCs and endothelial cells. As alluded to previously, signal molecules can mediate vascular tone by direct effects on VSMCs (endothelium-independent) or by

Summary

The risk of coronary artery disease is significantly lower in premenopausal women compared with men of similar age.189, 190 The pathophysiologic basis of coronary artery disease involves the accumulation of cholesterol-rich low-density lipoproteins in the vascular wall, immune responses, and eventual formation of atherosclerotic plaque. The effect of sex hormones (especially the beneficial effect of estrogen) on lipoprotein metabolism and subsequent effect on development of coronary

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    *

    Supported by a grant from the Ralph and Marian Falk Medical Research Trust.

    **

    Reprint requests: Dorie W. Schwertz, PhD, RN, FAAN, Associate Professor, Medical Surgical Nursing and Pharmacology, University of Illinois m/c 802, College of Nursing and College of Medicine, 845 S Damen Ave, Chicago, IL 60612.

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