Cardiovascular Research

Cardiovascular Research 2000 46(1):28-49; doi:10.1016/S0008-6363(00)00005-5
© 2000 by European Society of Cardiology

This Article Extract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Hayward, C. S. Articles by Collins, P. Search for Related Content PubMed PubMed Citation Articles by Hayward, C. S. Articles by Collins, P. Social Bookmarking          What's this?

Copyright © 2000, European Society of Cardiology

The roles of gender, the menopause and hormone replacement on cardiovascular function

Christopher S. Hayward^a,b, Raymond P. Kelly^b and Peter Collins^a,*

^aDepartment Cardiac Medicine National Heart and Lung Institute, Imperial College School of Medicine, London, UK
^bCardiology Department, St Vincent's Hospital, Sydney, Australia

^* Corresponding author. Tel.: +44-171-351-8112; fax: +44-171-823-3392 peter.collins{at}ic.ac.uk

Received 12 July 1999; accepted 12 November 1999

KEYWORDS Gender; Hormones; Epidemiology

	1 Introduction

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
While it is recognised that gender differences exist in cardiovascular disease, it has only recently been appreciated that significant gender differences also exist in cardiovascular function. Ageing is associated with a different spectrum of cardiac and vascular maladaptations in women compared to men. These differences may contribute to poorer outcome in women affected by ischaemic disease compared to men as well as the higher prevalence of symptomatic cardiac failure seen in women. The most obvious gender-related difference in physiological ageing is the menopause in women. The relation of this ‘event’ to cardiovascular disease has generated much controversy, especially with respect to hormone replacement therapy in the management of cardiac patients. Controversy also exists in the role of declining androgen levels in men with age and the advisability of testosterone supplementation in men. This review will examine gender differences which become apparent due to ageing, as well as the specific effect of the menopause and hormone replacement on cardiac and vascular structure and function. It will also summarise the impact of these physiological and epidemiological differences on the expression of cardiovascular disease in men and women. Studies examining the role of gender and hormone withdrawal and administration in animal studies will also be summarised. Limitations in current research and recommendations for future areas of research are put forward.

	2 Gender and cardiovascular disease

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
Because of the higher cardiac mortality in men compared to women until late in life [1], most early studies focused exclusively on that gender. Women have been excluded from research protocols during childbearing years and in old age because of co-morbidities [2]. Recently research emphasis has shifted in line with the recognition that cardiovascular disease remains the most prevalent illness affecting women and remains the most frequent cause of female death in most Western nations [3]. Furthermore, it has repeatedly been shown that women, once affected by ischaemic heart disease, actually do worse than their male counterparts. This is true following myocardial infarction [4–9], as well as following coronary intervention [10–12] and coronary artery bypass surgery [13,14]. Some of the procedural difficulties have been attributed to smaller vascular calibre in women related to their smaller stature [11,15]. Gender disparity in the manifestation of cardiovascular disease has been attributed to the excess co-morbidity seen in women because they are older [16], have less aggressive investigation [17], or present later in the course of their coronary disease [9,14,18]. The occurrence of adverse outcomes in women is extremely consistent however, and extends even to women who present early, before the age of 65 years [19]. Apart from ischaemic complications, gender disparities are evident in the manifestation of cardiac failure [20], cardiac rupture [6,21,22] and ventricular remodeling, both under the influence of ageing [23] as well as due to elevated afterload [24,25].

	3 Gender and cardiac physiology

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
Over the last 20 years, accurate non-invasive information concerning cardiac structure and function has become routinely available through echocardiography. The definition of left ventricular (LV) hypertrophy has been refined and is now recognised as a powerful predictor of cardiovascular events [26]. In this period, terms such as remodeling have been defined and developed [27], with the recognition that different geometric patterns have different prognosis [28]. Recent developments have also provided accurate information on ventricular and other cardiac chamber function [29]. Despite the fundamental anatomic similarity of the heart in men and women, gender differences in cardiac function and response to age and disease are increasingly recognised.

3.1 Gender and cardiac size
It is well recognised that cardiac dimensions vary predictably with body size and gender [30,31]. These may be adequately accounted for by indexing to body surface area, however, the variability in LV mass with gender remains [32]. Because of the prognostic significance of LV hypertrophy [26,28,33], gender-specific indexing techniques have been suggested to account for physiological variance due to body size [30]. A significant implication of these results is that gender-related differences in LV structure exist.

3.2 Ageing and left ventricular mass
While LV mass is greater in men [34] most of the differences are eliminated by indexing to lean body mass [32,35]. Notwithstanding these baseline differences, a number of studies have found an increase in LV mass with age in women, while LV mass remains fairly constant in men [23,36,37]. The differing effect of age on echocardiographic LV mass (indexed to body surface area) in men and women from a healthy population is shown in Fig. 1. In that study, there was no effect of age on LV mass in males (P=0.73), whereas there was a relationship with age in females (P=0.03). The effect of age was significantly different for men and women, even after incorporating systolic BP into a multiple regression equation (P<0.0001). A similar positive relationship between age and LV mass was found in women from a highly selected healthy cohort of the Framingham population, but again not in men [36].

View larger version (26K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 The effect of age and gender on LV mass (from Shub [23]). Even after correcting for body size differences, women tend to increase LV mass with age to a greater extent than men. The slope of the two regression lines are significantly different (see Section 3.2 for details).

 
In an autopsy series which excluded primary cardiac pathology accurately, measured (rather than calculated by echocardiography), LV mass decreased with age in men, but remained constant in women [38], suggesting a similar gender disparity to that found in population echocardiographic studies. In women cardiomyocyte number and volume remained stable, whereas in men there was a prominent decrease in myocyte number associated with an increase in volume. These findings suggest that the cellular hypertrophy in male cardiomyocytes may be a response to cellular depletion with ageing. It is of particular note that right ventricular and LV morphometry changed in a parallel fashion, supporting the hypothesis that the gender differences seen were indeed involutional rather than secondary to (silent) ischaemia (in men) or hypertension. Gender differences in LV hypertrophy are not addressed by this study as hypertrophic hearts were excluded.

Determinants of LV mass (other than ageing) are also consistently different in men and women. Suggestive of a hormone-related gender effect on LV mass is the fact that gender differences in indexed LV mass are not apparent prior to puberty [39]. Whereas men may be more responsive to blood pressure [40,41], women are more responsive to the effects of obesity [37,41]. This finding has not been found in a separate East Asian population [42]. In the Strong Heart Study of an American Indian population, the complexity of determinants of LV mass is confirmed, as almost 50% of the variability in LV mass remains unexplained even after accounting for volume, contractility, body mass, height, blood pressure as well as gender [43].

3.3 Left ventricular hypertrophy
Gender differences in the effect of age on LV mass are paralleled by differences seen in the prevalence of LV hypertrophy. In the Framingham study, after the age of 60, the prevalence of LVH in women increased by 69% per decade of life compared to only 15% in men [44]. While the rate of LVH is dependent on the definition used [45], gender differences remain apparent in the effect of age. This disparity in LV remodeling is particularly marked in pressure overload states such as hypertension [46] and aortic stenosis [24,47]. Women are more likely to develop concentric hypertrophy in response to hypertension, whereas men tend to develop eccentric hypertrophy [25]. This results in greater relative wall thickness for female hypertensives. It has been suggested that hypertensive women have a greater volume load (stroke volume indexed to body surface area) compared to hypertensive men, which may further contribute to their greater hypertrophy [48]. Because these studies are echocardiographic, cellular or molecular differences remain to be defined.

Excessive cardiac hypertrophy in hypertensive subjects is most commonly seen in women [49–51]. This syndrome, entitled ‘hypertrophic hypertensive cardiomyopathy’ [49] is characterised by pulmonary oedema despite supranormal systolic function and associated with severe LVH and marked impairment of diastolic function. Even the pathological hypertrophy of hypertrophic obstructive cardiomyopathy is associated with a gender disparity, with male dominance in youth [52]. While the reversal of this gender disparity may suggest a gender-linked inheritance for the classic hypertrophic obstructive cardiomyopathy, it seems more likely to be a gender-specific remodeling effect, related to hypertensive hypertrophy predominating in elderly women. In the Systolic Hypertension in the Elderly Program (SHEP), women were found to be more likely to have elevated pulse pressure compared to men, suggesting greater pulsatile vascular load [53]. This may further contribute to a greater hypertrophic response in women seen in other studies.

Similar to extremes of hypertrophy with hypertension, clinical studies have confirmed excessive LV hypertrophy in women with aortic stenosis. Despite similar valve areas or pressure gradients, women have been found to not only have greater relative wall thickness, but also more maintained LV ejection fractions [24,47]. Better chamber function has also been shown in women with higher load-independent indices of chamber performance in the presence of chronic pressure overload [54]. These findings of maintained systolic function are translated into lower rates of cardiac failure in the presence of aortic stenosis in women [47].

3.4 Left ventricular function
Gender differences apparent in ventricular structure also extend to function. A number of studies have shown that women have higher ejection phase indices compared to men in the absence of cardiac failure. One study, in subjects with normal coronary arteries undergoing routine cardiac catheterisation, found that women had higher ejection fractions at rest [55]. It has also been shown using echocardiography, that normotensive women tend to have greater fractional shortening and that afterload-corrected fractional shortening is greater in women after the age of 55 years [48]. This finding has been confirmed in the Cardiovascular Health Study of over 5000 subjects older than 65 years, where women were found to have greater fractional shortening than men [56]. This gender difference remained after exclusion of (predominantly male) subjects with abnormal echocardiograms. In a study using nuclear magnetic resonance myocardial tagging to measure wall thickening with age, women were not only shown to increase (diastolic) wall thickness with age more than men, but also to have higher ejection fractions and systolic wall thickening [57]. Midwall fractional shortening has also been shown to be higher in normal women compared to men [29]. In a small invasive study using pressure–volume loops, postmenopausal women undergoing routine cardiac catheterisation were found to have enhanced LV chamber function compared to similar aged men measured either by end-systolic pressure volume relations or preload recruitable stroke work relations, consistent with the above findings [58]. These physiological differences of higher chamber performance and greater myocardial stiffness may be important in understanding the higher rate of cardiac rupture seen in postmenopausal women [6,21,22]. Gender differences in rupture rates are not easily explained by the relative size of infarctions, as transmural Q wave infarctions are less common in women [59].

3.5 Left ventricular failure
In population studies of congestive cardiac failure, despite women having a lower incidence of failure compared to men, the prevalence is similar [60,61]. This is due to a lower mortality for women with cardiac failure, and may partially be explained by a lower incidence of ischaemic heart disease in women [62]. In non-ischaemic cardiomyopathy, women have been shown to have lower mortality than men [63,64]. Surprisingly, in the presence of ischaemic heart disease, while women typically have higher ejection fractions than men [65,66], they continue to experience higher rates of cardiac failure [20,67,68]. This ‘gender paradox’ [66] has also been found in thrombolytic trials following myocardial infarction [69]. The higher rate of cardiac failure with better-maintained ejection fractions suggests that diastolic dysfunction is an important cause of the symptoms of congestive cardiac failure in women [60,62]. Indeed, from the Framingham study, two-thirds of those with normal systolic function and congestive cardiac failure were women [70]. The increase in LV mass with age and greater hypertrophy in the presence of hypertension and elevated afterload, discussed in Sections 3.2 and 3.3 above, is consistent with diastolic dysfunction and may provide a structural substrate for gender differences in clinical symptoms.

Despite the discussion of diastolic dysfunction being proposed as a significant cause of congestive cardiac failure in women, studies examining gender differences in diastolic function are rare. Large echocardiographic studies that have examined ageing effects on transmitral flow ratios have generally found similar results for men and women [71,72]. One study did find women to have lower peak velocity ratios during middle age [73], which may be consistent with diastolic dysfunction. We found that women had significantly greater diastolic stiffness as measured by end-diastolic pressure volume studies, though in that cohort, women were slightly more likely to be hypertensive than men [58].

3.6 Animal models of gender and cardiac function
Experimental animal models have supported the gender differences found in clinical studies. Papillary muscles from female rats have greater rates of shortening than from male rats [74]. This has been further confirmed in in vitro experiments, where female rat atrial and papillary muscle preparations developed greater tension per unit tissue mass compared to males, see Fig. 2 [75]. This difference was most marked in atrial muscle, though Ca²⁺dose–response curves were uniformly higher in female papillary muscle preparations. Differences in both studies may be attributable to differences in excitation–contraction coupling, as maximum developed tension did not differ in the presence of high calcium concentrations. One working heart model with contrary findings showed male rat hearts have greater stroke work per unit weight [76]. The apparent anomaly presented by that study might be partially explained by different aged rats being studied for each gender, in an attempt to account for the disparity in ventricular mass [76].

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 The effect of gender on tension development from rat atrial and papillary muscle (from Wang [75]). The gender differences are more marked for atrial tissue. At all concentrations of perfusing calcium, it can be seen that female myocardium generates a higher tension than male myocardium. While this was not significant for peak tension development in the papillary muscle preparation, the gender difference for all concentrations was significantly different by ANOVA.

 
Gender differences in clinical studies of LV hypertrophy and heart failure are also supported by findings from animal models. In response to similar pressure increases (by aortic banding), male rats develop ventricular dysfunction at an earlier stage than female rats [77]. Even at similar pressure loads, female rats have greater LV hypertrophy and maintained chamber function [78]. In the spontaneously hypertensive heart failure rat, female rats not only develop greater hypertrophy but the transition to failure is delayed compared to male rats [79]. The nature of pressure loading may be important, as one study found that noradrenaline infusion increased LV mass in male rats more than female rats [80]. Consistent with these phenotypic changes, gene expression was also found to be gender distinctive, with lower b-myosin and higher sarcoplasmic reticulum Ca²⁺ATPase expression in one study [81], and increased ACE expression in female pressure overloaded rats in another [82]. These gender differences in gene expression were not seen in control rats with no pressure overload. It has been hypothesised that the development of concentric hypertrophy in females may be protective, by reducing systolic wall stress [78], thereby limiting the development of cardiac dilatation and systolic dysfunction. Such a response, however, may contribute to diastolic dysfunction, as discussed above.

One hypothesis suggested to account for the delay in the failure of female rat hearts is that they have greater ‘hypertrophic reserve’ than male rats before the limit of cardiomyocyte enlargement is reached and failure ensues [79]. A greater degree of upregulation of beta-myosin in male rats with LV hypertrophy, may also contribute to poorer ventricular function [81].

3.7 Gender and cardiac physiology — summary
Apart from gross baseline differences in cardiac size between the genders, significant differences in the structural and functional adaptation of the male and female heart are apparent. Tables 1 and 2 show a summary of clinical and animal studies examining gender and cardiac physiology discussed above. The change in LV mass with age in women is significant, although minor compared to the changes seen in response to pressure overload states. The greater cardiomyocyte loss with ageing in males [38] is consistent with the clinical data and may suggest gender differences in cellular programming, though at present there are no studies showing differing gene expression in male and female myocardium at rest. It may be that the findings of heart failure in animal models of hypertrophy are an extension of human pathological findings [38]. Concordance of animal and clinical findings suggest that baseline LV function may be higher in females, though most reports are in the presence of disease or a selected population. At present there are no gender differences in cellular physiology which would account for such differences in animals as well as humans. While findings are at present descriptive, mechanistic gender differences in gene expression are starting to be recognised in response to overload states [81,82]. The role of hormonal modulation on these differences in gene expression has been suggested, though not yet proven. Gender differences in both cellular morphology and gene expression in response to ageing or pressure overload have not been demonstrated in humans.

View this table: [in this window] [in a new window]   Table 1 Clinical studies examining gender and cardiac functiona

 

View this table: [in this window] [in a new window]   Table 2 Animal studies examining gender and cardiac functiona

 

	4 Gender and vascular physiology

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
The vascular tree has traditionally been viewed merely as a conduit. A paradigmatic shift occurred with the recognition that it has an important role in the maintenance of constant flow in the face of intermittent cardiac ejection due to its distensibility or compliance [83]. More recently, it has been recognised that the arterial lining (endothelium) is active not only in paracrine function, in terms of vascular dilatation [84], but also in the limitation of atheroma development [85]. At each level, the vascular tree of women has been shown to behave differently to that of men.

4.1 Endothelial function
Significant gender-related differences in endothelial function with ageing have been shown in subjects with [86] and without cardiovascular risk factors [87] assessed by brachial artery flow-mediated dilatation. This technique relies on the measurement of brachial artery diameter change due to endothelial nitric oxide (NO) release in response to reactive hyperaemic flow following forearm circulatory arrest. In one study of healthy subjects [87], women had marginally higher rates of adjusted flow-mediated dilatation than men until the age of the menopause, after which the age-related decline accelerated from that time (Fig. 3). In men, the age-related decline in endothelial function occurred earlier (early 40s) and was more gradual. This study was mainly descriptive in the analysis of gender differences, and whether women had significantly higher flow mediated dilatation is not stated. A smaller study using intra-arterial methacholine infusions and venous occlusion plethysmography to characterise endothelial function found that healthy premenopausal women had greater endothelium dependent vasodilatation compared to similar aged men, whereas post menopause the results were similar [88]. In a larger study including subjects with atherosclerotic risk factors, men were shown to have lower endothelium-dependent dilatation after accounting for other factors by multivariate analysis [86]. Another indirect measure of endothelial NO production, urinary nitrate increase in response to L-arginine, also shows gender differences [89]. That study found that urinary nitrate increased significantly more in premenopausal women compared to similar aged healthy men. A number of studies have shown that endothelial function may be modulated by the menstrual cycle in women [90,91] and that vascular production of NO is significant enough to increase nitrate excretion in women in a cyclical fashion [92]. This gender difference may contribute to the finding that women have higher nitrate excretion than age-matched men in response to oestrogen supplementation [93]. Vascular smooth muscle function (independent of endothelial cell function) has been assessed using brachial artery diameter response to nitroglycerin in a large cohort [94]. In that study, while men had lower percent dilatation than women in univariate analysis, this did not remain significant in multivariate analysis, suggesting that the apparent gender difference may be related to other variables such as baseline vessel size, age and vascular risk factors.

View larger version (22K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 The effect of age and gender on flow mediated dilatation (FMD), a marker of endothelial function. (from Celermajer [87]). In this study, women had marginally higher rates of adjusted FMD until the age of the menopause than men, after which the rate of age-related decline in FMD was significantly greater than men in whom the more gradual decline occurred earlier.

 
4.2 Large arterial function
A convincing demonstration of gender-related differences in large arterial compliance has been shown in a cohort study of 600 subjects ranging in age from 2 to 85 years [95]. Women had higher arterial compliance (corresponding to less stiff vessels) than men throughout all age groups until age 50 (Fig. 4). A distinct acceleration of the age-related decrease in aortic compliance can be seen in women after the age of 45 years consistent with an increase in arterial stiffness at the time of the menopause. Similar conclusions have been made using pulse wave velocity (PWV) to measure arterial stiffness [96,97]. In London's study [97], postmenopausal women had similar brachial and femoral arterial pulse wave velocity (PWV) to age-matched men, whereas premenopausal women had lower PWV than similarly aged men. A similar change was seen in aortic PWV, though the differences were not significant. The effect of ageing on increasing arterial stiffness appears to be less in women than men [96,98]. In Sonesson’s study, whereas female aortic stiffness tended to increase linearly with age, male aortic stiffness increased exponentially [98]. As calculation of arterial stiffness incorporates a measure of vessel wall thickness, differences in vascular size are unlikely to account for the variation in stiffness found.

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 The effect of age and gender on aortic compliance. Women have higher arterial distensibility than men until the age of the menopause (from Laogun [95]).

 
As with gender differences in cardiac structure and function, gender-related differences in body height or body size have a significant impact on vascular function. Separation of a gender from stature effect is difficult however, and often is achieved statistically through multiple linear regression analysis or analysis of covariance in large population studies. Body size is an important determinant of vascular function as it defines the capacity of the arterial tree (hence capacitance) [99] as well as the distances to reflecting sites for arterial wave reflection [100]. Studies have suggested that women not only have smaller calibre and lesser arterial (carotid) wall thickness [101], but also a greater degree of arterial tapering further contributing to greater pulse wave reflection [97]. Gender-related differences seen in the central arterial pressure waveform, as quantified by the augmentation index, which suggest greater pulsatile vascular loading in women are consistent with this, Fig. 5 [102]. In the recent analysis of the Systolic Hypertension in the Elderly Program, a higher proportion of women had elevated pulse pressure compared to men [53]. While it is likely that the arterial stiffness of men and women was similar in that study because of the subjects’ advanced age, the elevated pulse pressure in women may be a manifestation of lower arterial capacity in the presence of an age-stiffened arterial tree [53]. The higher pulsatile load in women suggested by both the augmentation index and the pulse pressure may contribute to the increase in LV mass with age seen in women described earlier.

View larger version (18K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 5 Augmentation index, a non-invasive measure of pulsatile vascular load based on analysis of central arterial pressure waveforms (from Hayward [102]). The augmentation index quantifies the late systolic increase in the central arterial pressure waveform due to the effects of wave reflection (termed the augmented pressure) and is calculated by the ratio of the augmented pressure to the pulse pressure. It has been shown to be a valid non-invasive index of aortic impedance, which is an accepted measure of the pulsatile vascular load due to a composite of arterial stiffness and wave reflection. It can be seen that from an early age, women have higher pulsatile vascular load than men. In a separate analysis this difference remained significant after accounting for differences in blood pressure, height, and heart rate.

 
In light of the apparently adverse effects of ageing on arterial pulsatile load in women, the higher arterial distensibility seen in women before the menopause [95] may be particularly important. The greater distensibility in women offsets the increased pulsatile load related to a smaller arterial tree and maintains appropriate ventriculo-vascular coupling, at least until after the menopause. During pregnancy, arterial compliance is further enhanced to minimise the effects of the associated increase in cardiac output [103]. This has the effect of normalising pulsatile vascular load and maintaining ventricular efficiency [103].

4.3 Animal studies of gender and vascular function
Pathological sequelae to lower NO production in males have been shown in a rabbit model of atherosclerosis [104]. In that study, vascular relaxation was diminished in male rabbits compared to female. Animal models have also found that in the presence of similar serum cholesterol concentration, male rabbits accumulate more cholesterol into the aortic wall compared to females [105]. This difference was dependent on an intact endothelium in the female rabbits, suggesting a role of the endothelium in minimising cholesterol uptake by mononuclear cells. There have not been any animal studies examining the effect of gender on arterial compliance or large arterial function. Matsuzaki and co-workers, however, found that proximal aortic banding in rats (which produced a central arterial pressure waveform similar to the typical waveform found in women) was associated with greater increase in LV mass compared to the waveform produced by more distal banding [106], consistent with clinical studies of LV hypertrophy.

4.4 Gender and vascular physiology — summary
As can be seen in Table 3, differences in vascular physiology may to be more dependent on the hormonal milieu, as gender differences in compliance are only apparent during reproductive years [95,97] and are prominent during pregnancy [103]. Gender differences in endothelial function also appear to be age dependent with men having lower baseline endothelial function before age 50 [87,88]. These findings, in combination with vascular responsiveness to exogenous sex steroids (discussed later), suggest that the vascular tree is more sensitive than the heart to endogenous hormonal levels. While both arterial stiffness and endothelial function appear to behave in a similar fashion with respect to age in men and women, a direct relationship between the two has not been defined. Apparent gender differences in vascular capacitance [99] and smooth muscle function [94] appear to be related to differences in body or vessel size and suggest that while vascular responsiveness may vary, arterial wall structure is likely to be the same in men and women. There are no animal data examining gender differences in vascular function independent of disease.

View this table: [in this window] [in a new window]   Table 3 Clinical studies examining gender and vascular functiona

 

	5 Menopause

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
As it is acknowledged that women have less heart disease than men until the age of the menopause, it is assumed that menopause constitutes a significant cardiovascular milestone in terms of physiology, as well as pathology. While the menopause remains a convenient chronological cutoff in epidemiological studies of cardiovascular disease, the emphasis placed on it cannot be misconstrued to suggest a causal relation between physiology and disease. Studies of menopause are complicated by interactive effects of smoking, both on vascular disease, as well as induction of earlier menopause [107]. The natural variation in the onset and abruptness of the menopause further cloud chronological criteria used in epidemiological studies. When physiological variables are examined under the context of the menopause, few parameters, (apart from serum cholesterol as a significant exception), alter significantly. A frequent problem with studies of the menopause is the lack of acknowledgment of the importance of ageing on the parameters under study. Many reports compare young premenopausal women with older postmenopausal women attributing differences to menopause alone. Longitudinal studies exist, but are few.

Menopause is frequently studied in light of the effect it apparently has on known cardiovascular risk factors. Many studies have found an increase in total or low-density lipoprotein cholesterol, as well as a decrease in high density lipoprotein [108–113]. Most studies have not found a significant effect of menopause on body weight [109–112] or blood pressure [109–113]. As systolic blood pressure increases with age, it is perhaps not surprising that cross-sectional studies might find a relationship between BP and menopause [114]. It has been suggested that exaggerated stress responses may have contributed to the higher blood pressure found in postmenopausal women (compared to premenopausal women) in one study [115]. That study however was confounded by small numbers and significant differences in ages between the study groups.

5.1 Menopause and ventricular function
There have been few studies of the effect of menopause specifically on ventricular function. Interpretation of commonly cited papers is hampered by small numbers and significant differences in age between the pre- and post-menopausal women studied [116–118]. In one study, Pines and co-workers found that while blood pressure did not change, there were significant changes in aortic flow and ventricular ejection using echocardiography. Eight premenopausal women (mean age 52 years) had higher ‘pressure–volume’ ratio, ejection fraction and ejection rate when compared to six postmenopausal women (mean age 58 years) [117]. Menopause, it was concluded, was associated with a state of decreased contractility. In a similar study, Prelevic found decreased ejection fraction and peak flow velocity in postmenopausal women compared to premenopausal controls, but again marked demographic differences existed between the two groups [119]. A further study, examining 55 postmenopausal women in three groups, according to time since menopause, suggested that peak aortic flow velocity, and aortic flow acceleration decreased the longer after menopause that the subjects were studied [116]. A final study of 39 women suggested that the menopausal state was associated with increased LV wall thickness, though again postmenopausal women were significantly older than the comparison premenopausal group [118]. In a three year longitudinal study of 18 subjects going through the menopause Karpanou found that LV dimensions increased and relative wall thickness decreased [120]. In the control groups of similar aged premenopausal women and of men, however, ventricular dimensions and wall thickness changes occurred in the same direction, underlining the need for large, well controlled studies before physiological changes can be attributed solely to the menopause. Despite these structural changes, there were no inter-group differences in that study for a menopausal effect on LV function.

The sole effect of hormone withdrawal was studied in 15 young menstruating women who underwent induction of a hypo-oestrogenic state by long acting gonadotropin-releasing hormone (GnRH) agonist treatment (for endometriosis or prior to in vitro fertilisation) [121]. Compared to their pretreatment values, there was a significant fall in aortic peak flow velocity, mean aortic acceleration and cardiac index. These results were attributed to either a decrease in contractility, or an increase in afterload, due to the hypo-oestrogenic state. There was no effect on blood pressure.

5.2 Animal studies of hormone withdrawal — effect on LV function
The only available animal model of the menopause involves gonadectomy. Whether this is a valid surrogate of the menopause is questionable, though the studies do shed light on the role of hormones in maintaining normal function. The effect of gonadectomy on cardiac function is to impair systolic function as well as limit ventricular filling [122]. In a study of both male and female sham and gonadectomised rats, Schaible demonstrated, using a working heart apparatus, that gonadectomy induced a decrease in ventricular size per gram body weight, a decrease in ejection fraction and a downward shift in the mean force–velocity relationship. Gonadectomy caused a decrease in Ca²⁺-myosin ATPase activity in both sexes and was associated with a reduction in the content of V₁ isoenzyme and an increase in V₃ isoenzyme. While the findings of this study were consistent across a range of loading conditions, a number of points need to be made. Firstly, the changes in ventricular function were uniformly more extensive in male gonadectomised rats, and only occurred in a number of studies at high loading conditions for female rats, suggesting that gonadectomy may have less relevance to female ventricular function. In this study while gonadectomy was performed prior to sexual maturation, similar decreases in ventricular size, function and isoenzyme switching were confirmed in a parallel study of gonadectomy in postpubertal rats [123] suggesting that the changes reported were due to an active effect of sex hormones on maintenance of cardiac function.

5.3 Menopause and vascular function
Studies of vascular function in relation to the menopause have not been any more convincing than those reported for ventricular function. As discussed previously, most studies have found little change in blood pressure in response to the menopause [109–113]. Healthy cohort studies do suggest a change in endothelial function at approximately the appropriate age for the menopause to have an effect [87,88]. This is supported by a further study which have suggested that menopause is associated with an impairment in endothelial function, even in hypertensive women [124]. Whether these changes are due to menopause or merely ageing is not definite as there have been no longitudinal studies to examine this question.

A longitudinal study of large artery function in hypertensive subjects has suggested that menopause may be associated with ‘abrupt and devastating’ changes in aortic root stiffness [120]. Comparing similarly aged groups of 18 hypertensive women who went through menopause in the study period, with women who remained premenopausal and also men, Karpanou found over a relatively short follow-up period (3 years) that only the group of women who changed their menopausal status underwent a change in aortic root distensibility. This was independent of significant changes in vascular dimension or blood pressure. In a rigorously age-matched case-control study of 186 women, a decrease in carotid distensibility was also found [125]. This study used a population database of 12 675 women to accurately age and risk-match pre- and postmenopausal women. While these findings suggest menopause related changes in arterial wall function, the Atherosclerosis Risk in Communities (ARIC) Study of 5436 women found no effect of the menopause on carotid intima-media wall thickness after age and risk adjustment [126]. In a group of 429 middle aged women, Taquet found no effect of the menopause on aortic PWV after controlling for other contributors to arterial stiffness using regression analysis [127]. Support for a menopausal role in aortic stiffness can be seen in Fig. 4 where women have higher compliance than men until the approximate age of the menopause [95].

In a small study of postmenopausal women, it has been found that the carotid pulsatility index (a measure of impedance to cerebral blood flow) increased with time from the menopause [128]. This measure, derived from the internal carotid artery flow waveform, suggested that menopause was associated with changes in arterial flow in non-urogenital arterial beds. These changes could be reversed by oestrogen. Such changes may help to explain the decreases in peak aortic flow-rates found by Pines and co-workers and attributed to alteration of ventricular function [116]. Perhaps surprisingly, in light of Gangar's study [128], a dichotomous analysis of recent versus distant menopause did not find any significant difference in systemic vascular resistance [117]. The discrepancy between the two studies is most likely due to the small number of subjects in both.

5.4 Menopause and cardiovascular function — summary
Studies examining the effect of the menopause on cardiovascular physiology are less convincing than those concerning gender. Sample sizes are significantly smaller than gender studies and there is a lack of longitudinal studies of either cardiac or vascular function examining changes across the time of the menopause in healthy individuals. The two most convincing studies involving rigorous case-control [125] and large cross-sectional analysis [126] suggest that arterial function may alter independently of changes in wall structure and are consistent with the hypothesis that the vasculature is hormone-sensitive. Most studies define menopause historically rather than by serum hormone levels. While cardiac studies examining the menopause are generally concordant, the majority are in small numbers and all are cross-sectional. The results of the only prospective hormone withdrawal study following GnRH induction of hypo-oestrogenaemia [121], were consistent with the other case-control studies in the effect on aortic flow velocities. It should be recognised in light of the vascular sensitivity to hormones, however, that changes in aortic flow velocity or even ejection indices are not reliable indicators of ventricular function. Gonadectomy studies in animals cannot be held as valid surrogates of the menopause which occurs gradually in association with ageing.

	6 Hormone replacement therapy in women

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
As mentioned previously, one consistent finding in cardiovascular risk factor studies of the menopause is predictable changes in lipid profile [109,110,112]. A possible role for hormone replacement therapy (HRT) as an adjunctive therapy in postmenopausal women was first suggested by a beneficial oestrogenic effect on lipoprotein levels in the 1950s [129]. However as significant cardiovascular mortality benefit attributable to HRT remains after accounting for lipid effects [130], alternate cardiac or vascular effects of HRT have been sought. Demonstration of oestrogen, progesterone and androgen receptors in cardiac [81,131] and vascular tissue [132,133] further supports, in principle, a significant role for sex hormones in the modulation of cardiovascular function.

6.1 Hormone replacement therapy and ventricular function
The main focus of research into HRT has been its role in atherosclerotic disease. Direct cardiac effects have been relatively ignored. This is despite the finding that oestrogen and progesterone receptors have been demonstrated in myocardial tissue [81,134–136]. It has been recognised for many years that oestrogen, at least, may be involved in the regulation of β-adrenergic receptors in animal studies [137,138]. While these responses are generally considered to be via genomic receptors, sex steroids have also been shown to have rapid effects through non-genomic mechanisms [139–142]. It has been suggested that most of the rapid smooth muscle relaxant effects of oestrogen are likely to by non-genomic mechanisms, while the anti-proliferative effects are most likely receptor and gene mediated [143].

Studies of the effect of HRT on LV mass have been inconclusive. One short-term study suggested no effect, though, was limited in follow-up [144]. A beneficial effect for combined HRT on LV hypertrophy is suggested by a preliminary report in 574 postmenopausal women, which found a lower rate of LV hypertrophy in women taking combined HRT compared to either controls or to those taking unopposed oestrogen [145]. Significant demographic differences between the groups complicated the analysis, limiting interpretation of the results. In a small case-control study of 39 normotensive postmenopausal women, long-term HRT use (>10 years) was associated with lower LV mass in women receiving long-term HRT compared to those who had not used HRT even after controlling for age, blood pressure, body mass index and alcohol consumption [146].

Human studies have concentrated on echocardiographic data for evidence of an oestrogenic effect. In a group of postmenopausal women, Pines showed that 10 weeks of sequential combined HRT was associated with a significant increase in peak aortic flow velocity and stroke volume [147]. A similar unrandomised study of 34 postmenopausal women receiving combined HRT also found significant increases in ejection indices [119], attributed to enhanced inotropism and systemic vasodilatation. A subsequent randomised trial examining cardiac effects of unopposed oestrogen over a 12-week period, however, found only marginal effects on end-diastolic volume, with no effects on ejection indices or flow velocities [144]. The serum oestradiol level in this latter study was relatively low for HRT at 32 pmol/l. Serum oestradiol levels were not reported for the earlier studies. A short-term (3 week) study of a synthetic oestrogen using radionuclide angiography found a significant decrease in cardiac output associated with a fall in blood pressure [148]. There was a marked negative chronotropic response to oestrogen in that study, with average heart rates falling by nine beats per minute. In a non-invasive study of high-dose oestrogen in transsexuals, cardiac output increased related to significant vasodilation [149]. Whether there was a direct ventricular effect of oestrogen could not be determined by that study and no effect on LV mass was reported.

6.2 Animal studies of hormone replacement — effect on LV function
Because of the gender differences in LV remodeling under load, discussed earlier, there has been interest whether this may also be modified by HRT. Sino-aortic denervation in rats, which increases arterial pressure, is known to be associated with significant increases in LV mass. Pretreatment with oestrogen has been shown to abolish this increase in ventricular remodeling [150]. Studies of vascular smooth muscle have also shown an inhibitory influence of oestrogen on cellular hypertrophy [151]. It has been hypothesised, therefore, that the hypo-oestrogenic state may be associated with greater hypertrophy as compared to premenopausal women. A recent report has suggested that the dose of oestrogen used may determine whether it has an inhibitory or facilitatory influence on hypertrophy in response to cyclical strain [152].

In an isolated working rat heart apparatus, oestrogen (2 mg/day S.C.) was found to restore ventricular function to normal following gonadectomy [123]. Progesterone alone did not normalise function. There was a parallel shift in myosin isoenzyme expression towards V₃ (usually seen in pressure overload states or hypertrophy) following gonadectomy, which was blocked by oestrogen, but again not by progesterone. Gonadectomy had a more pronounced detrimental effect on male rat cardiac function and testosterone replacement was consequently more potent than other sex steroids. Interestingly, testosterone had more marked beneficial effects on systolic function than oestrogen, even in female rats. Acute in vivo effects of oestradiol have also been studied in thoracotomised rats [153]. This showed no significant effect on contractility (assessed by isovolumic dP/dt), though there were significant decreases in peripheral vascular resistance and increasing cardiac output with increasing doses (50–200 ng/kg I.V.). A study in the isolated rabbit heart has shown that acute oestrogen appears to have a significant negative inotropic effect (assessed by peak systolic pressure), consistent with a calcium blockade mechanism [154]. This was seen at concentrations above 1 µM. This effect on contraction was independent of gender. Similar results have been obtained for testosterone and progesterone using the same experimental preparation [155]. In a comparable isolated rat heart study, however, no inotropic effect was demonstrated at concentrations up to 5 µM [156]. A further negative inotropic effect of oestradiol was seen in isolated guinea pig myocytes. Jiang found that 17β-oestradiol (10–30 µM) prolonged action potential duration, decreased shortening and decreased peak inward calcium current, similar to dihydropyridine calcium antagonists [157]. These effects were reversible within minutes of washout. Comparison and integration of all these studies is difficult because of the different species studied, the different methods used to characterise ventricular function, and the different concentrations and mode of delivery of oestrogen used.

6.3 Hormone replacement therapy and vascular function
A range of alternate mechanisms explaining the large non-lipid related cardiovascular benefit attributable to HRT have been proposed, ranging from alteration in the fibrinolytic balance [158,159]; induction of prostacyclin [160]; improvement or restoration of endothelial function [161–166]; NO release [167–169]; attenuation of endothelin effect [170]; calcium blockade [141,157,169,171]; by direct effects on vascular depolarisation [172] and smooth muscle relaxation [173,174]; as well as through modulation of autonomic function [175]. Early reports of increase in renin or renin substrate may have been related to the higher of oestrogen doses used previously [176], as recent work suggests that oestrogen replacement therapy is associated with decreased plasma renin substrate [177].

A common endpoint of many of these mechanisms explaining oestrogen's beneficial effect involves vasodilatation. Systemic vasodilatation due to HRT has been associated with increased cardiac output and diminished systemic vascular resistance both in experimental animals [153,173] and in humans [147,149]. Coronary vascular reactivity has also been used as a surrogate marker for beneficial cardiovascular effect. Numerous studies have documented improvement in coronary diameter in response to oestrogen [163,178–181] and to hormone replacement therapy [180], particularly in the presence of atherosclerotic disease [182]. Clinical studies have also shown decreases in exercise induced-ischaemia and angina due either to improved haemodynamics or direct coronary vasomotion [183,184].

It has been suggested that the mechanism of oestrogen's action may vary according to the concentration of oestrogen present, with low concentrations relying on induction of NO release from the endothelium, and higher concentrations being associated with smooth muscle relaxation due to endothelium-independent mechanisms [185]. A number of studies have confirmed improved endothelial function in postmenopausal women receiving HRT, both oestrogen alone [162] and oestrogen in combination with progesterone [186]. While recent studies in transsexual males have found enhanced brachial endothelial function under the influence of oestrogen [187,188], coronary vasomotion in patients with ischaemic heart disease is only improved by oestrogen in women [168].

The mechanism by which oestrogen alters vascular function has received extensive study. It is now accepted that the classical oestrogen receptor () is found on vascular smooth muscle cells [132] as well as the endothelial cell [189]. A study of human coronary arterial smooth muscle cells found oestrogen receptors were more likely to be expressed on normal, rather than atherosclerotic, arteries [190]. This may help to explain why the oestrogen receptor has not been identified in other studies [191]. Oestrogen has also recently been shown to have non-genomic activity via the classical oestrogen receptor () on the cell surface [142], helping to explain acute vascular effects of oestrogen found in numerous studies. Other (non-classical or β) oestrogen receptors have also been suggested to explain oestrogenic action on both vascular smooth muscle and endothelial cell activity in oestrogen receptor a deficient mice [192].

Beyond the acute smooth muscle effects in the vascular wall, sex hormones have also been shown to influence large arterial structure. In the Cardiovascular Health Study, oestrogen users were found to have lower intima-media wall thickness than non-users [193]. A consistent problem as with this study, is that oestrogen use itself is often associated with a beneficial risk profile limiting definitive interpretation. In the larger ARIC study, HRT use was not associated with any decrease in intima-media thickness [126]. Oestrogen replacement has also been shown to limit intimal hyperplasia induced by ovarian ablation in a sheep model of vascular remodeling [194]. One possible mechanism demonstrated in this study was through decreased production of basic fibroblast growth factor. In animal studies oestrogen has been shown to increase the rate of collagen and elastin degradation, leading to a net increase in the elastin:collagen ratio [195]. This has the effect of decreasing the stiffness of the vessel wall. Such limitation of accumulation of collagen by oestrogen was also seen in hypertensive rat aortae [196]. Contrary to these findings, a human study has suggested that combined HRT may increase type III collagen synthesis, as assessed by production by-products, similar to anabolic steroids and be associated with increased arterial stiffness [197]. Direct comparison of these studies is difficult and may merely reflect differences in species.

Apart from oestrogen, other sex hormones have also been shown to have significant vascular effects. Because oestrogen is prescribed in combination with a progestin in women with an intact uterus, recent work has examined the modulating effect that this might have on cardiovascular function. Importantly, while the beneficial fibrinolytic [158] and lipid effects [198] of oestrogens do not appear to be impaired with concurrent medroxyprogesterone use, it has been shown to reverse beneficial vascular effects of oestrogen in experimental [199] and clinical studies [200], which may be important in understanding results of the recent large prospective Heart and Estrogen/progestin Replacement Study (HERS) Research Group Study (HERS) [201].

Acute decreases in aortic stiffness due to oestrogen have been demonstrated using simultaneous high fidelity intravascular ultrasonic dimension crystals and aortic pressure recordings [202]. In a non-invasive study of the effect of tibolone (which has both oestrogenic and androgenic effects) no effect was seen on aortic compliance [203], and in a prospective, randomised study of 3 months combined HRT using magnetic resonance imaging of the aorta with calibrated carotid pressure waveforms, again no difference in aortic compliance was found [204]. There was an increase in size of the aorta noted with oestrogen in the latter study, but not in the combined group. In the ARIC Study, no change in carotid artery dimensions or wall thickness was found in response to hormone replacement therapy [126]. Arterial compliance was not assessed. One recent study has shown improved arterial compliance and decreased PWV in response to HRT in postmenopausal women [205]. We have found that although indices of arterial stiffness were not improved in a cross-sectional study of postmenopausal women, pulsatile vascular load was lower in women receiving HRT [206].

6.4 Hormone replacement therapy and hypertension
Because hypertension is so prevalent in postmenopausal women, and even the low-dose contraceptive pills continue to be associated with excess hypertension [207,208], there has been controversy over whether HRT may be beneficial or detrimental [209,210]. While most studies do not show an increase in blood pressure in response to HRT [198,201,210–214], occasional patients do have idiosyncratic increases in blood pressure in response to oestrogen [215–217]. This may well be related to excessive renin activation in those subjects [215]. Most such case reports date from an era of higher oestrogen dose and it may be that current regimens would not incite such a response. A recent study, using a current HRT regimen, found that, in general, there is a decrease in plasma renin substrate associated with treatment [177]. It has also been recognised that the type and dose of supplemental oestrogen may be important in determining blood pressure response [218].

A well conducted cross-over study of two doses of oestrogen found a small, but significant, decrease in systolic and diastolic blood pressure largely due to a prominent fall in peripheral resistance [219]. The decrease in blood pressure was likely contributed to by a prominent decrease in heart rate [148,219]. Preliminary results from a small blinded, placebo-controlled study in newly diagnosed hypertensive women show a marked improvement in clinic blood pressure, prompting the authors to recommend HRT as an early therapeutic option in menopausal hypertensive women [220]. Initial concerns that progestins, prescribed as part of combined HRT, may reverse blood pressure lowering in response to oestrogen, appear to be unfounded [198,214,221]. Hypertensives seem to have similar blood pressure reduction to normotensives in those studies with a mixed population [221], though the decrease in peripheral resistance seen in one study was less than that for normotensives [219]. In a retrospective cohort study, a lower rate of development of hypertension was found in women taking oestrogen replacement therapy, though it is of note that at the time of commencement of follow-up, a greater percentage of the control group were already hypertensive, suggesting some bias [212]. A beneficial effect of oestrogen on the development of hypertension is consistent with a study in spontaneously hypertensive rats, which found that oestrogen therapy from a young age was associated with an attenuation of the normal increase in blood pressure [222]. Oestrogen therapy was also associated with a limitation of weight gain. In a further group of rats, starved to achieve the same weight, blood pressure increased as expected, suggesting that the inhibitory effect of oestrogen on the development of hypertension could not be explained by changes in body mass [222].

6.5 Hormone replacement therapy and cardiovascular function — summary
There is extensive concordant physiological evidence supporting an important role of HRT in the modulation of vascular function. This is particularly true in acute and chronic endothelial-dependent effects, both in the periphery and in the coronary arteries. Apart from effects on responsiveness, structural remodeling changes due to oestrogen are suggested by animal models but have not been universally supported by large human cross-sectional studies. Clinical studies of aortic compliance have also led to inconsistent results. Studies of ventricular function are limited and inconclusive. A consistent problem is the lack of prospective studies. Interpretation of those studies which have been suggested a positive effect of HRT is limited by the fact that they were in relatively small number and unrandomised or unblinded. The only prospective, blinded examination of the effect of HRT on cardiac function found no apparent effect. It should be noted, however, that where the clinical studies appeared to support a positive inotropic effect of oestrogen, animal studies have either been neutral or demonstrated negative inotropism. The literature can therefore only be considered inconclusive for any effect of oestrogen on cardiac function.

	7 Supplemental androgens in men

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
Androgen receptors are widespread, having been found within aortic, peripheral vascular, ventricular and atrial mammalian cells [135] and more recently in normal male and female left ventricles [131]. It is not surprising therefore, that supplemental androgens have been shown to have cardiovascular effects. Non-medical androgen supplementation has been associated with an adverse cardiovascular profile, ranging from increased sudden death, LV hypertrophy, cardiomyopathy and increased myocardial infarction related to both vascular spasm as well as platelet and haemostatic activation [223]. It has been shown however, that many steroid hormones, testosterone included, have dose-dependent effects ranging from inhibition to stimulation of vascular and endothelial cell proliferation [224]. Similar dose-dependent effects are implied by contrary findings in response to non-medical androgen use compared to controlled experiments with respect to either cholesterol levels (increased LDL [225]; decreased LDL [226]), or vasomotor function (impaired [227] or enhanced [228]).

This variability in response extends to clinical studies. While low endogenous levels of testosterone in men have been associated with an atherogenic lipid profile [229,230] and an increase in coronary artery disease [231,232], other studies have not found such a relation [233,234]. In women, however, in both clinical and experimental studies, increasing endogenous androgen levels are associated with increased coronary risk factors [235] and coronary disease [236–238]. This complex hormone–sex interaction has also been demonstrated in an animal study showing decreased intimal thickening in male cholesterol-fed rabbits given testosterone and in corresponding female rabbits given oestrogen [239]. It has been hypothesised that the sexual dimorphism of the endogenous hormone dehydroepiandrosterone may be related to androgen-related oestrogen antagonism in women and oestrogenic effects in men [240].

7.1 Testosterone and ventricular function
The anabolic effect of androgens on skeletal muscle is also evident in the heart. In experimental studies, gonadectomy is associated with a decrease in heart weight and contractile function which is corrected following testosterone replacement [123]. As with oestrogen, testosterone increases V₁ myosin heavy chain isoenzyme expression independent of loading conditions [241,242]. Such isoform switching is associated with alterations in activated tension development in isolated myocytes [243], which may contribute to such effects. While further studies have suggested that testosterone does not exaggerate normal physiologic hypertrophy [244], anabolic abuse in weight lifters is associated with excessive LV hypertrophy and diastolic dysfunction [245]. Myocyte preparations have also been shown to respond to testosterone exposure with cellular hypertrophy mediated by a specific androgen receptor [131]. Even without inducing hypertrophy, 3 months of nandrolone decreased ventricular compliance in rats without affecting contractility possibly due to increased collagen or impaired relaxation [246]. An intriguing, but reproducible effect of testosterone has been shown following significant trauma and haemorrhage in mice. Male mice have been shown to have depressed immune function associated with impaired cardiac function which is not seen in female mice [247]. Subsequent studies have shown that testosterone blockade has been able to improve cardiac function in haemodynamic stress situations [248].

7.2 Testosterone and vascular function
Similar to oestrogen, testosterone has been shown to limit aortic atheroma formation [249]. Again, as with oestrogen, only a portion of such benefit appears attributable to changes in lipoprotein fractions, suggesting direct vascular activity both at the endothelium as well as the vascular smooth muscle cell [224]. Studies of androgenic effects on endothelial function have revealed marked gender disparity. Whereas high-dose androgens in women impaired vascular reactivity [227], acute high-dose testosterone was associated with an improvement in endothelial function in men [228]. Despite this, hypotestosteronaemic men undergoing a variety of treatments for prostate cancer have been found to have worse endothelial function than age- and risk-matched men [250]. Early clinical studies suggesting a beneficial effect of testosterone in coronary disease have recently been confirmed in a number of studies showing a beneficial effect of testosterone on exercise capacity in men with coronary artery disease [251,252].

Animal studies have shown that testosterone may relax vascular smooth muscle by endothelium-dependent [253] or independent mechanisms [254]. These findings have recently been extended to the human coronary circulation [255]. A recent animal study found that testosterone impaired coronary vasodilatation in response to adenosine in an isolated perfused rat heart protocol [256]. Such effects were mediated acutely and most likely through thromboxane release. Any vascular effect of testosterone, therefore, is likely to be a balance of vasodilatation by endothelial and non-endothelial effects and vasoconstriction due to thromboxane and possibly other mediators. There have not been any studies examining androgenic effects on the function of large arteries.

	8 Conclusions and recommendations

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
Table 4 summarises the strength of clinical and animal evidence for a contributory role for gender, menopause and hormone replacement on cardiovascular physiology endpoints discussed in this paper. Despite anatomic similarities, there is strong evidence of significant gender differences in cardiovascular structure and function. Many of these differences are not completely accounted for by differences in stature, suggesting gender-related hormonal differences as important modulators of cardiovascular physiology. Some changes are only apparent in the effect of ageing or in the adaptation to a stimulus such as pressure overload. These differences are significant because they uncover for the first time, gender differences in cardiac gene expression not apparent in health. The modulatory role of sex hormones on such gene expression remains to be examined. Menopause, while shown to be associated with increased cholesterol, is only associated with minor changes in cardiovascular function after accounting for the dominant effect of age. Studies of the role of the menopause on cardiovascular structure and function are hampered by a lack of longitudinal data in humans.

View this table: [in this window] [in a new window]   Table 4 Evidence for contributory role for gender, menopause and hormone replacement on cardiovascular physiology endpoints

 
Hormone replacement therapy has been shown convincingly to improve vascular function and may have a role in vascular remodeling. Data concerning ventricular structure and function is limited by the lack of prospective studies, and by the lack of rigorous randomisation in the smaller studies. Large HRT trials should incorporate physiological sub-studies to allow the determination of the role of HRT in modulating physiology including the effects on LV mass, systolic and diastolic LV function and vascular wall properties including structure and compliance, as well as the important mortality endpoints. Investigation of the effect of physiologic testosterone supplementation in men is in its infancy, and further studies are needed in view of extensive literature demonstrating adverse effects from non-medical use. A number of clinical studies suggest beneficial cardiovascular effects of testosterone on vascular parameters though the important question of whether low-dose testosterone may contribute to left ventricular hypertrophy has not yet been answered.

Time for primary review 22 days.

	Acknowledgments

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 
Dr Hayward is supported by grants from the National Heart Foundation of Australia and the Royal Australasian College of Physicians.

	References

Top 1 Introduction 2 Gender and cardiovascular... 3 Gender and cardiac... 4 Gender and vascular... 5 Menopause 6 Hormone replacement therapy... 7 Supplemental androgens in... 8 Conclusions and... Acknowledgments References

 

1. Kannel W.B., Wilson P.W.F. Risk factors that attenuate the female coronary disease advantage. Arch Int Med (1995) 155:57–61.[Abstract/Free Full Text]
2. Wenger N.K., Speroff L., Packard B. Cardiovascular health and disease in women. N Engl J Med (1993) 329:247–256.[Free Full Text]
3. Wenger N.K. Women's heart research: it's about time. J Women Health (1995) 4:459–460.
4. Dittrich H., Gilpin E., Nicod P., et al. Acute myocardial infarction in women: influence of gender on mortality and prognostic variables. Am J Cardiol (1988) 62:1–7.[Web of Science][Medline]
5. Greenland P., Reicher-Reiss H., Goldbourt U., Behar S. In-hospital and 1-year mortality in 1524 women after myocardial infarction. Comparison with 4315 men. Circulation (1991) 83:484–491.[Abstract/Free Full Text]
6. Shapira I., Isakov A., Burke M., Almog C. Cardiac rupture in patients with acute myocardial infarction. Chest (1987) 92:219–223.[CrossRef][Web of Science][Medline]
7. Vaccarino V., Krumholz H.M., Berkman L.F., Horwitz R.I. Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women? Circulation (1995) 91:1861–1871.[Abstract/Free Full Text]
8. Kostis J.B., Wlison A.C., O’Dowd K. MIDAS Study Group. Sex differences in the management and long-term outcome of acute myocardial infarction. A state-wide study. Myocardial Infarction Data Acquisition System. Circulation (1994) 90:1715–1730.[Abstract/Free Full Text]
9. Bueno H., Vidan T., Almazan A., Lopez-Sendon J.L., Delcan J.L. Influence of sex on the short-term outcome of elderly patients with a first acute myocardial infarction. Circulation (1995) 92:1133–1140.[Abstract/Free Full Text]
10. Greenberg M.A., Mueller H.S. Why the excess mortality in women after PTCA? Circulation (1993) 87:1030–1032.[Free Full Text]
11. Bell M.R., Holmes D.R., Berger P.B., et al. The changing in-hospital mortality of women undergoing percutaneous transluminal coronary angioplasty. J Am Med Assoc (1993) 269:2091–2095.[Abstract/Free Full Text]
12. Kelsey S.F., James M., Holubkov A.L. NHLBI Investigators. Results of percutaneous transluminal coronary angioplasty in women. 1985–6 NHLBI Coronary Angioplasty Registry. Circulation (1993) 87:720–727.[Abstract/Free Full Text]
13. Acinapura A.J., Cane J., Robertazzi R.R., et al. The relationship of gender to cardiac surgery mortality: is female gender alone an operative risk factor. Circulation (1997) 96(8):1–371. Abstract.
14. Khan S.S., Nessim S., Gray R., Czer L.S., Chaux A., Matloff J. Increased mortality of women in coronary artery bypass surgery: evidence for a referral bias. Ann Intern Med (1990) 112:561–567.[Abstract/Free Full Text]
15. O’Connor G.T., Morton J.R., Diehl M.J., et al. Differences between men and women in hospital mortality associated with coronary artery bypass graft surgery. Circulation (1993) 88:2104–2110.[Abstract/Free Full Text]
16. Adams J.N., Jamieson M., Rawles J.M., Trent R.J., Jennings K.P. Women and myocardial infarction: agism rather than sexism. Br Heart J (1995) 73:87–91.[Abstract/Free Full Text]
17. Kudenchuk P.J., Maynard C., Martin J.S., Wirkus M., Weaver W.D., et al. MITI Project of presentation, treatment, and outcome of acute myocardial infarction in men versus women (The Myocardial Infarction Triage and Intervention Registry). Am J Cardiol (1996) 78:9–14.[Web of Science][Medline]
18. Wenger N.K. Gender, coronary artery disease and coronary bypass surgery. Ann Intern Med (1990) 112:557–558.[CrossRef][Web of Science][Medline]
19. Demirovic J., Blackburn H., McGovern P.G., et al. Sex differences in early mortality after acute myocardial infarction (The Minnesota Heart Survey). Am J Cardiol (1995) 75:1096–1101.[CrossRef][Web of Science][Medline]
20. Kimmelstiel C.D., Konstam M.A. Heart failure in women. Cardiology (1995) 86:304–309.[Web of Science][Medline]
21. Batts K.P., Ackermann D.M., Edwards W.D. Postinfarction rupture of the left ventricular free wall: Clinicopathologic correlates in 100 consecutive autopsy cases. Hum Pathol (1990) 21:530–535.[CrossRef][Web of Science][Medline]
22. Becker R.C., Gore J.M., Lambrew C., et al. A composite view of cardiac rupture in the United States National Registry of Myocardial Infarction. J Am Coll Cardiol (1996) 27:1321–1326.[Abstract]
23. Shub C., Klein A.L., Zachariah P.K., Basey K.R., Tajik A.J. Determination of left ventricular mass by echocardiography in a normal population: Effect of age and sex in addition to body size. Mayo Clin Proc (1994) 69:205–211.[Web of Science][Medline]
24. Carroll J.D., Carroll E.P., Feldman T., et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation (1992) 86:1099–1107.[Abstract/Free Full Text]
25. Krumholz H.M., Larson M., Levy D. Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol (1993) 72(3):310–313.[CrossRef][Web of Science][Medline]
26. Levy D., Garrison R.J., Savage D.D., Kannel W.B., Castelli W.P. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med (1990) 322:1561–1566.[Abstract]
27. Ganau A., Devereaux R.B., Roman M.J., et al. Patterns of left ventricular hypertrophy and geometric remodelling in essential hypertension. J Am Coll Cardiol (1992) 19:1550–1558.[Abstract]
28. Krumholz H.M., Larson M., Levy D. Prognosis of left ventricular geometric patterns in the Framingham Heart Study. J Am Coll Cardiol (1995) 25(4):879–884.[Abstract]
29. Devereux R.B., de Simone G., Pickering T.G., Schwartz J.E., Roman M.J. Relation of left ventricular midwall function to cardiovascular risk factors and arterial structure and function. Hypertension (1998) 31(4):929–936.[Abstract/Free Full Text]
30. Lauer M.S., Anderson K.M., Larson M.G., Levy D. A new method for indexing left ventricular mass for differences in body size. Am J Cardiol (1994) 74:487–491.[CrossRef][Web of Science][Medline]
31. Vasan R.S., Larson M.G., Levy D., Evans J.C., Benjamin E.J. Distribution and categorization of echocardiographic measurements in relation to reference limits. The Framingham Heart Study: Formulation of a height- and sex-specific classification and its prospective validation. Circulation (1997) 96:1863–1873.[Abstract/Free Full Text]
32. Devereux R.B., Lutas E.M., Casale P.N., et al. Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol (1984) 4:1222–1230.[Abstract]
33. Verdecchia P., Schillaci G., Borgioni C., et al. Adverse prognostic significance of concentric remodeling of the left ventricle in hypertensive patients with normal left ventricular mass. J Am Coll Cardiol (1995) 25(4):871–878.[Abstract]
34. Gardin J.M., Henry W.L., Savage D.D., Ware J.H., Burn C., Borer J.S. Echocardiographic measurements in normal subjects: evaluation of an adult population without clinically apparent heart disease. J Clin Ultrasound (1979) 7:439–447.[Web of Science][Medline]
35. Batterham A.M., George K.P., Mullineaux D.R. Allometric scaling of left ventricular mass by body dimensions in males and females. Med Sci Sports Exerc (1997) 29(2):181–186.
36. Dannenberg A.L., Levy D., Garrison R.J. Impact of age on echocardiographic left ventricular mass in a healthy population (The Framingham Study). Am J Cardiol (1989) 64:1066–1068.[CrossRef][Web of Science][Medline]
37. Marcus R, Krause L, Weder AB, Dominguez-Mejia, Schork NJ, Julius S. Sex-specific determinants of increased left ventricular mass in the Tecumseh Blood Pressure Study. Circulation 1994;90:928–936.
38. Olivetti G., Giorgano G., Corradi D., et al. Gender differences and ageing: effects on the human heart. J Am Coll Cardiol (1995) 26:1068–1079.[Abstract]
39. de Simone G., Devereux R.B., Kimball T.R., et al. Interaction between body size and cardiac workload: influence on left ventricular mass during body growth and adulthood. Hypertension (1998) 31(5):1077–1082.[Abstract/Free Full Text]
40. Verdecchia P., Schillaci G., Boldrini F., Guerreri M., Porcellati C. Sex, cardiac hypertrophy and diurnal blood pressure variations in essential hypertension. J Hypertens (1992) 10:683–692.[Web of Science][Medline]
41. de Simone G., Devereaux R.B., Roman M.J., Alderman M.H., Laragh J.H. Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults. Hypertension (1994) 23:600–606.[Abstract/Free Full Text]
42. Chen C.-H., Ting C.-T., Lin S.-L., et al. Which arterial and cardiac parameters best predict left ventricular mass? Circulation (1998) 98:422–428.[Abstract/Free Full Text]
43. Devereux R.B., Roman M.J., de Simone G., et al. Relations of left ventricular mass to demographic and hemodynamic variables in American Indians. The Strong Heart Study. Circulation (1997) 96:1416–1423.[Abstract/Free Full Text]
44. Levy D., Anderson K.M., Savage D.D., et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. Ann Int Med (1988) 108:7–13.[Abstract/Free Full Text]
45. Devereux R.B. Detection of left ventricular hypertrophy by M-mode echocardiography: anatomic validation, standardization, and comparison to other methods. Hypertension (1987) 9(Suppl_2):1136–1139.
46. Devereux R.B., Pickering T.G., Alderman M.H., et al. Left ventricular hypertrophy in hypertension. Prevalence and relationship to pathophysiologic variables. Hypertension (1987) 9(Suppl 2):1153–1160.
47. Aurigemma G.P., Silver K.H., McLaughlin M., Mauser J., Gaasch W.H. Impact of chamber geometry and gender on left ventricular systolic function in patients >60 years of age with aortic stenosis. Am J Cardiol (1994) 74:794–798.[CrossRef][Web of Science][Medline]
48. de Simone G., Devereux R.B., Roman M.J., et al. Gender differences in left ventricular anatomy, blood viscosity and volume regulatory hormones in normal adults. Am J Cardiol (1991) 68:1704–1708.[CrossRef][Web of Science][Medline]
49. Topol E.J., Traill T.A., Fortuin N.J. Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med (1985) 312:277–283.[Abstract]
50. Pearson A.C., Gudipati C.V., Labovitz A. Systolic and diastolic flow abnormalities in elderly patients with hypertensive hypertrophic cardiomyopathy. J Am Coll Cardiol (1988) 12:989–995.[Abstract]
51. Lewis J.F., Maron B.J. Elderly patients with hypertrophic cardiomyopathy: a subset with distinctive left ventricular morphology and progressive clinical course late in life. J Am Coll Cardiol (1989) 13:36–45.[Abstract]
52. Teare D. Asymmetric hypertrophy of the heart in young adults. Br Heart J (1958) 20:1–8.[Free Full Text]
53. Domanski M.J., Davis B.R., Pfeffer M.A., Kastantin M., Mitchell G.F. Isolated systolic hypertension: prognostic information provided by pulse pressure. Hypertension (1999) 34(3):375–380.[Abstract/Free Full Text]
54. Villari B., Campbell S.E., Schneider J., Vassalli G., Chiarello M., Hess O.M. Sex-dependent differences in left ventricular function and structure in chronic pressure overload. Eur Heart J (1995) 16:1410–1419.[Abstract/Free Full Text]
55. Buonanno C., Arbustini E., Rossi L., et al. Left ventricular function in men and women. Another difference between sexes. Eur Heart J (1982) 3(6):525–528.[Abstract/Free Full Text]
56. Bommer W.J., Shamanski L., Fried L., et al. Left ventricular systolic function in the cardiovascular health study. Circulation (1995) 92(I):335–336. Abstract.[Web of Science]
57. Bogaert J., Marchal G., Herregods M.-C., Van de Werf F., Rademakers F.E. Gender-related differences in myocardial function and morphology. Circulation (1996) 94:1–421. Abstract.[Free Full Text]
58. Hayward CS. The effect of age and gender on ventriculo-vascular coupling in humans. Doctor of Medicine Thesis. Sydney: University of New South Wales, 1998, 323 p.
59. Mendelson M.A., Hendel R.C. Myocardial infarction in women. Cardiology (1995) 86:272–285.[CrossRef][Web of Science][Medline]
60. Lindenfeld J., Krause-Steinrauf H., Salerno J. Where are all the women with heart failure? J Am Coll Cardiol (1997) 30(6):1417–1419.[Abstract]
61. Mosterd A., Hoes A.W., de Bruyne M.C., et al. Prevalence of heart failure and left ventricular dysfunction in the general population; The Rotterdam Study. Eur Heart J (1999) 20(6):447–455.[Abstract/Free Full Text]
62. Schocken D.D., Arrieta M.I., Leaverton P.E., Ross E.A. Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol (1992) 20:301–306.[Abstract]
63. Adams K.F., Dunlap S.H., Sueta C.A., et al. Relation between gender, etiology and survival in patients with symptomatic heart failure. J Am Coll Cardiol (1996) 28:1781–1788.[Abstract]
64. Adams K.F. Jr., Sueta C.A., Gheorghiade M., et al. Gender differences in survival in advanced heart failure: Insights from the FIRST study. Circulation (1999) 99(14):1816–1821.[Abstract/Free Full Text]
65. Tofler G.H., Stone P.H., Muller J.E., et al. Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, especially black women. J Am Coll Cardiol (1987) 9:473–482.[Abstract]
66. Mendes L.A., Davidoff R., Cupples L.A., Ryan T.J., Jacobs A.K. Congestive heart failure in patients with coronary artery disease: the gender paradox. Am Heart J (1997) 134(2 Pt 1):207–212.[CrossRef][Web of Science][Medline]
67. Hoffman R.M., Psaty B.M., Kronmal R.A. Modifiable risk factors for incident heart failure in the Coronary Artery Surgery Study. Arch Intern Med (1994) 154:417–423.[Abstract/Free Full Text]
68. Davis K.B., Chaitman B., Ryan T., Bittner V., Kennedy J.W. Comparison of 15 year survival for men and women after initial medical or surgical treatment for coronary artery disease; a CASS registry study. J Am Coll Cardiol (1995) 25:1000–1009.[Abstract]
69. Becker R.C. Coronary thrombolysis in the treatment of women with acute myocardial infarction. Cardiology (1995) 86:299–303.[Web of Science][Medline]
70. Vasan R.S., Larson M.G., Benjamin E.J., et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol (1999) 33(7):1948–1955.[Abstract/Free Full Text]
71. Benjamin E.J., Levy D., Anderson K.M., et al. Determinants of doppler indexes of left ventricular diastolic function in normal subjects (The Framingham Heart Study). Am J Cardiol (1992) 70:508–515.[CrossRef][Web of Science][Medline]
72. Spirito P., Maron B.J. Influence of ageing on doppler echocardiographic indices of left ventricular diastolic function. Br Heart J (1988) 59:672–679.[Abstract/Free Full Text]
73. Voutilainen S., Kupari M., Hippelainen M., et al. Factors influencing doppler indexes of left ventricular filling in healthy persons. Am J Cardiol (1991) 68:653–659.[CrossRef][Web of Science][Medline]
74. Capasso J.M., Remily R.M., Smith R.H., Sonnenblick E.H. Sex differences in the myocardial contractility in the rat. Basic Res Cardiol (1983) 78:156–171.[CrossRef][Web of Science][Medline]
75. Wang S.N., Wyeth R.P., Kennedy R.H. Effects of gender on the sensitivity of rat cardiac muscle to extracellular Ca²⁺. Eur J Pharmacol (1998) 361(1):73–77.[CrossRef][Web of Science][Medline]
76. Schaible T.F., Scheuer J. Comparison of heart function in male and female rats. Basic Res Cardiol (1984) 79:402–412.[CrossRef][Web of Science][Medline]
77. Pfeffer J.M., Pfeffer M.A., Fletcher P., Fishbein M.C., Braunwald E. Favorable effects of therapy on cardiac performance in spontaneously hypertensive rats. Am J Physiol (1982) 242(5):H776–H784.[Web of Science][Medline]
78. Douglas P.S., Katz S.E., Weinberg E.O., et al. Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload. J Am Coll Cardiol (1998) 32(4):1118–1125.[Abstract/Free Full Text]
79. Tamura T., Said S., Gerdes A.M. Gender-related differences in myocyte remodeling in progression to heart failure. Hypertension (1999) 33(2):676–680.[Abstract/Free Full Text]
80. Pelzer T., Shamim A., Schumann M., Stimpel M., Wolfges S., Neyses L. Gender specific differences in the hypertrophic response of cardiomyocytes. Circulation (1997) 96(8):1–630. Abstract.
81. Weinberg E.O., Thienelt C.D., Katz S.E., et al. Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol (1999) 34(1):264–273.[Abstract/Free Full Text]
82. Lorell B.H., Weinberg E.O. Gender effects on ace expression during cardiac growth. Circulation (1997) 96(8):1–630. Abstract.
83. O’Rourke M.F. Steady and pulsatile energy losses in the systemic circulation under normal conditions and in simulated arterial disease. Cardiovasc Res (1967) 1(4):312–326.
84. Furchgott R.F., Zawadzki J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (1980) 288(5789):373–376.[CrossRef][Medline]
85. Friedman R.J., Moore S., Singal D.P. Repeated endothelial injury and induction of atherosclerosis in normolipemic rabbits by human serum. Lab Invest (1975) 32(3):404–415.[Web of Science][Medline]
86. Celermajer D.S., Sorensen K.E., Bull C.M., Robinson J., Deanfield J.E. Endothelium dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol (1994) 24:468–474.
87. Celermajer D.S., Sorensen K.E., Spiegelhalter D.J., et al. Ageing is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol (1994) 24:471–476.[Abstract]
88. Sarabi M., Millgard J., Lind L. Effects of age, gender and metabolic factors on endothelium-dependent vasodilation: a population-based study. J Intern Med (1999) 246(3):265–274.[CrossRef][Web of Science][Medline]
89. Forte P., Kneale B.J., Milne E., et al. Evidence for a difference in nitric oxide biosynthesis between healthy women and men. Hypertension (1998) 32(4):730–734.[Abstract/Free Full Text]
90. Hashimoto M., Akishita M., Eto M., et al. Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation (1995) 92(12):3431–3435.[Abstract/Free Full Text]
91. English J.L., Jacobs L.O., Green G., Andrews T.C. Effect of the menstrual cycle on endothelium-dependent vasodilation of the brachial artery in normal young women. Am J Cardiol (1998) 82(2):256–258.[CrossRef][Web of Science][Medline]
92. Rosselli M., Imthurm B., Macas E., Keller P.J., Dubey R.K. Circulating nitrite/nitrate levels increase with follicular development: indirect evidence for estradiol mediated NO release. Biochem Biophys Res Commun (1994) 202(3):1543–1552.[CrossRef][Web of Science][Medline]
93. Kawano H., Motoyama T., Kugiyama K., et al. Gender difference in improvement of endothelium-dependent vasodilation after estrogen supplementation. J Am Coll Cardiol (1997) 30(4):914–919.[Abstract]
94. Adams M.R., Robinson J., McCredie R., et al. Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis. J Am Coll Cardiol (1998) 32(1):123–127.[Abstract/Free Full Text]
95. Laogun A.A., Gosling R.G. In vivo arterial compliance in man. Clin Phys Physiol Meas (1982) 3:201–212.[CrossRef][Medline]
96. Schimmler W. Correlation between the pulse wave velocity in the aorto-iliac vessel and age, sex and blood pressure. Angiology (1966) 17:314–322.[Free Full Text]
97. London G.M., Guerin A.P., Pannier B., Marchais S.J., Stimpel M. Influence of sex on arterial hemodynamics and blood pressure. Role of body height. Hypertension (1995) 26:514–519.[Abstract/Free Full Text]
98. Sonesson B., Hansen F., Stale H., Lanne T. Compliance and diameter in the human abdominal aorta — the influence of age and sex. Eur J Vasc Surg (1993) 7:690–697.[CrossRef][Web of Science][Medline]
99. de Simone G., Roman M.J., Daniels S.R., et al. Age-related changes in total arterial capacitance from birth to maturity in a normotensive population. Hypertension (1997) 29(6):1213–1217.[Abstract/Free Full Text]
100. London G.M., Guerin A.P., Pannier B.M., Marchais S.J., Metivier F. Body height as a determinant of carotid pulse contour in humans. J Hypertens (1992) 10(Suppl 6):93–95.[CrossRef][Web of Science][Medline]
101. Schreiner P.J., Heiss G., Tyroler H.A., et al. Race and gender differences in the association of Lp(a) with carotid artery wall thickness. Arterioscler Thromb Vasc Biol (1996) 16(3):471–478.[Abstract/Free Full Text]
102. Hayward C.S., Kelly R.P. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol (1997) 30(7):1863–1871.[Abstract]
103. Poppas A., Shroff S.G., Korcarz C.E., et al. Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load. Circulation (1997) 95(10):2407–2415.[Abstract/Free Full Text]
104. Kojda G., Husgen B., Hacker A., et al. Impairment of endothelium-dependent vasorelaxation in experimental atherosclerosis is dependent on gender. Cardiovasc Res (1998) 37(3):738–747.[Abstract/Free Full Text]
105. Holm P., Andersen H.O., Arroe G., Stender S. Gender gap in aortic cholesterol accumulation in cholesterol-clamped rabbits. Role of the endothelium and mononuclear-endothelial cell interaction. Circulation (1998) 98:2731–2737.[Abstract/Free Full Text]
106. Matsuzaki M., Kobayashi S., Kohno M., et al. Cardiac-vascular remodelling and functional interaction. Maruyama Y.H.M, Janicki J.S., eds. (1997) Tokyo: Springer-Verlag. 203–216.
107. Colditz G.A., Willett W.C., Stampfer M.J., et al. Menopause and the risk of coronary heart disease in women. N Engl J Med (1987) 316:1105–1110.[Abstract]
108. Barrett-Connor E.L., Bush T.L. Estrogen and coronary heart disease in women. J Am Med Assoc (1991) 265:1861–1867.[Abstract/Free Full Text]
109. Matthews K.A., Meilahn E., Kuller L.H., et al. Menopause and risk factors for coronary heart disease. N Engl J Med (1989) 312:641–646.
110. Kannel W.B., Hjortland M.C., McNamara P.M. Menopause and risk of cardiovascular disease. The Framingham Study. Ann Int Med (1976) 85:447–452.[Abstract/Free Full Text]
111. Akahoshi M., Soda M., Nakashima E., et al. Effects of menopause on trends of serum cholesterol, blood pressure and body mass index. Circulation (1996) 94:61–66.[Abstract/Free Full Text]
112. Davis C.E., Pajak A., Rywik S., et al. Natural menopause and cardiovascular disease risk factors: The Poland and US collaborative study on cardiovascular disease epidemiology. Ann Epidemiol (1994) 4–6:445–448.
113. Lindquist O. Intraindividual changes of blood pressure, serum lipids, and body weight in relation to menstrual state: results from a prospective population study of women in Goteberg. Sweden Prev Med (1982) 11:162–172.
114. Staessen J., Bulpitt C., Fagard R., Lijnen R., Amery A. The influence of menopause on blood pressure. J Hum Hypertens (1989) 3:427–433.[Web of Science][Medline]
115. Owens J.F., Stoney C.M., Matthews K.A. Menopausal status influences ambulatory blood pressure levels and blood pressure changes during mental stress. Circulation (1993) 88:2794–2802.[Abstract/Free Full Text]
116. Pines A., Fisman E.Z., Drory Y., et al. Menopause-induced changes in Doppler derived parameters of aortic flow in healthy women. Am J Cardiol (1992) 69:1104–1106.[CrossRef][Web of Science][Medline]
117. Pines A., Fisman E.Z., Shemesh J., et al. Menopause-related changes in left ventricular function in healthy women. Cardiology (1992) 80:413–416.[Web of Science][Medline]
118. Pines A., Fisman E.Z., Levo Y., et al. Menopause-induced changes in left ventricular wall thickness. Am J Cardiol (1993) 72:240–241.[CrossRef][Web of Science][Medline]
119. Prelevic G.M., Beljic T. The effect of oestrogen and progestogen replacement therapy on systolic flow velocity in healthy postmenopausal women. Maturitas (1994) 20:37–44.[CrossRef][Web of Science][Medline]
120. Karpanou E.A., Vyssoulis G.P., Papakyriakou S.A., Toutouza M.G., Toutouzas P.K. Effects of menopause on aortic root function hypertensive women. J Am Coll Cardiol (1996) 28:1562–1566.[Abstract]
121. Eckstein N., Pines A., Fisman E.Z., et al. The effect of the hypoestrogenic state, induced by gondaotropin-releasing hormone agonist, on Doppler derived parameters of aortic flow. J Clin Endocrinol Metab (1993) 77:910–912.[Abstract]
122. Schaible T.F., Malhotra A., Ciambrone G., Scheuer J. The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats. Circ Res (1984) 54:38–49.[Abstract/Free Full Text]
123. Scheuer J., Malhotra A., Schaible T.F., Capasso J. Effects of gonadectomy and hormonal replacement on rat hearts. Circ Res (1987) 61:12–19.[Abstract/Free Full Text]
124. Taddei S., Virdis A., Ghiadoni L., et al. Menopause is associated with endothelial dysfunction in women. Hypertension (1996) 28:576–582.[Abstract/Free Full Text]
125. Westendorp I.C., Bots M.L., Grobbee D.E., et al. Menopausal status and distensibility of the common carotid artery. Arterioscler Thromb Vasc Biol (1999) 19(3):713–717.[Abstract/Free Full Text]
126. Nabulsi A.A., Folsom A.R., Szklo M. Investigators ftAS. Atherosclerosis Risk in Communities (ARIC) Study Investigators. No association of menopause and hormone replacement therapy with carotid artery intima-media thickness. Circulation (1996) 94(8):1857–1863.[Abstract/Free Full Text]
127. Taquet A., Bonithon-Kopp C., Simon A., et al. Relations of cardiovascular risk factors to aortic pulse wave velocity in asymptomatic middle-aged women. Eur J Epidemiol (1993) 9(3):298–306.[CrossRef][Web of Science][Medline]
128. Gangar K.F., Vyas S., Whitehead M., et al. Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet (1991) 338:839–842.[CrossRef][Web of Science][Medline]
129. Barr D.P., Russ E.M., Ha E. Influence of oestrogen on lipoproteins in atherosclerosis. Transactions of the Association of American Physicians (1952) 65:102–111.[Web of Science][Medline]
130. Bush T.L., Barrett-Connor E., Cowan L., et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation (1987) 75:1102–1109.[Abstract/Free Full Text]
131. Marsh J.D., Lehmann M.H., Ritchie R.H., et al. Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation (1998) 98(3):256–261.[Abstract/Free Full Text]
132. Karas R.H., Patterson B.L., Mendelsohn M.E. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation (1994) 89:1943–1950.[Abstract/Free Full Text]
133. Mashiah A., Berman V., Thole H.H., et al. Estrogen and progesterone receptors in normal and varicose saphenous veins. Cardiovasc Surg (1999) 7(3):327–331.[CrossRef][Web of Science][Medline]
134. Stumpf W.E., Sar M., Aumuller G. The heart: a target organ for estradiol. Science (1977) 196:319–321.[Abstract/Free Full Text]
135. McGill H.C., Sheridan P.J. Nuclear uptake of sex steroid hormones in the cardiovascular system of the baboon. Circ Res (1981) 48:238–244.[Abstract/Free Full Text]
136. Ingegno M.D., Money S.R., Thelmo W., et al. Progesterone receptors in the human heart and great vessels. Lab Invest (1988) 59:353–356.[Web of Science][Medline]
137. Klangkalya B., Chan A. The effects of ovarian hormones on beta-adrenergic and muscarinic receptors in rat heart. Life Sci (1988) 42:2307–2314.[CrossRef][Web of Science][Medline]
138. Baksi S.N., Hughes M.J. Modulation by estradiol of rabbit atrial chronotropic response to histamine. Basic Res Cardiol (1983) 78:505–509.[CrossRef][Web of Science][Medline]
139. Schumacher M. Rapid membrane effects of steroid hormones: an emerging concept in neuroendocrinology. Trends Neurosci (1990) 13:359–362.[CrossRef][Web of Science][Medline]
140. Aronica S.M., Kraus W.L., Katzenellenbogen B.S. Estrogen action via the cAMP signalling pathway: Stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA (1994) 91:8517–8521.[Abstract/Free Full Text]
141. Freay A.D., Curtis S.W., Korach K.S., Rubanyi G.M. Mechanism of vascular smooth muscle relaxation by estrogen in depolarized rat and mouse aorta. Role of nuclear estrogen receptor and Ca²⁺ uptake. Circ Res (1997) 81(2):242–248.[Abstract/Free Full Text]
142. Chen Z., Yuhanna I.S., Galcheva-Gargova Z., et al. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest (1999) 103(3):401–406.[Web of Science][Medline]
143. Mendelsohn M.E., Karas R.H. Estrogen and the blood vessel wall. Curr Opin Cardiol (1994) 9:619–626.[Web of Science][Medline]
144. Snabes M.C., Payne J.P., Kopelen H.A., et al. Physiologic estradiol replacement therapy and cardiac structure and function in normal postmenopausal women: a randomized, double-blind, placebo-controlled, crossover trial. Obstet Gynecol (1997) 89(3):332–339.[CrossRef][Web of Science][Medline]
145. Kuch B., Hense H.W., Muscholl M., et al. Postmenopausal hormone replacement therapy and left ventricular mass and geometry. J Am Coll Cardiol (1997) 29:297A. Abstract.
146. Lim W.K., Wren B., Jepson N., Roy S., Caplan G. Effect of hormone replacement therapy on left ventricular hypertrophy. Am J Cardiol (1999) 83(7):1132–1134.[CrossRef][Web of Science][Medline]
147. Pines A., Fisman E.Z., Levo Y., et al. The effects of hormone replacement therapy in normal postmenopausal women: Measurements of Doppler derived parameters of aortic flow. Am J Obstet Gynecol (1991) 164:806–812.[Web of Science][Medline]
148. Luotola H., Pyorala T., Lohteehake P., Toivanen J. Haemodynamic and hormonal effects of short-term oestradiol treatment in postmenopausal women. Maturitas (1979) 1:287–294.[CrossRef][Web of Science][Medline]
149. Slater A.J., Gude N., Clarke I.J., Walters W.A.W. Haemodynamic changes and left ventricular performance during high dose oestrogen administration to male transsexuals. Br J Obstet Gynaecol (1986) 93:532–538.[Web of Science][Medline]
150. Cabral A.M., Vasquez E.C., Moyses M.R., Antonio A. Sex hormone modulation of ventricular hypertrophy in sino-aortic denervated rats. Hypertension (1988) 11(2 Pt 2):93–97.[Web of Science]
151. Vargas R., Wreblewska B., Rego A., Hatch J., Ramwell P.W. Oestradiol inhibits smooth muscle cell proliferation of pig coronary artery. Br J Pharmacol (1993) 109:612–617.[Web of Science][Medline]
152. Sudhir K., Ling S., Chou T.M., Ives H.E., Chatterjee K. Interactions between estradiol and mechanical strain in human vascular smooth muscle cells in culture. J Am Coll Cardiol (1997) 29:484A. Abstract.
153. Beyer M.E., Yu G., Hoffmeister H.M. Hemodynamic and inotropic effects of estrogen in vivo. Circulation (1996) 94:1–278. Abstract.[Free Full Text]
154. Raddino R., Manca C., Poli E., Bolognesi R., Visioli O. Effects of 17 β-estradiol on the isolated rabbit heart. Arch Int Pharmacodyn (1986) 281:57–65.[Medline]
155. Raddino R., Poli E., Pela G., Manca C. Action of steroid sex hormones on the isolated rabbit heart. Pharmacology (1989) 38(3):185–190.[CrossRef][Web of Science][Medline]
156. Eckstein N., Nadler E., Barnea O., Shavit G., Ayalon D. Acute effects of 17β-estradiol on the rat heart. Am J Obstet Gynecol (1994) 171:844–848.[Web of Science][Medline]
157. Jiang C., Poole-Wilson P.A., Sarrel P.M., et al. Effect of 17β-oestradiol on contraction calcium current and intracellular free calcium in guinea pig isolated myocytes. Br J Pharmacol (1992) 106:739–745.[Web of Science][Medline]
158. Shahar E., Folsom A.R., Salomaa V.V. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Relation of hormone-replacement therapy to measures of plasma fibrinolytic activity. Circulation (1996) 93(11):1970–1975.[Abstract/Free Full Text]
159. Koh K.K., Mincemoyer R., Bui M.N., et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med (1997) 336(10):683–690.[Abstract/Free Full Text]
160. Chang W.-C., Nakao J., Orimo H., Murota S.-I. Stimulation of prostaglandin cyclooxygenase and prostacyclin synthetase activities by estradiol in rat aortic smooth muscle cells. Biochem Biophys Acta (1980) 620:472–482.[Medline]
161. Gisclard V., Miller V.M., Vanhoutte P.M. Effect of 17β-estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Ther (1988) 244:19–22.[Abstract/Free Full Text]
162. Lieberman E.H., Gerhard M.D., Uehata A., et al. Estrogen improves endothelium-dependent, flow mediated vasodilation in postmenopausal women. Ann Intern Med (1994) 121:936–941.[Abstract/Free Full Text]
163. Gilligan D.M., Badar D.M., Panza J.A., Quyyumi A.A., Cannon R.O. Acute vascular effects of estrogen in postmenopausal women. Circulation (1994) 90:786–791.[Abstract/Free Full Text]
164. Keaney J.F., Shwaery C.T., Xu A., et al. 17β-estradiol preserves endothelial vasodilator function and limits low density lipoprotein oxidation in hypercholesterolemic swine. Circulation (1994) 89:2251–2259.[Abstract/Free Full Text]
165. McCrohon J.A., Adams M.R., McCredie R.J., et al. Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women. Clin Endocrinol (Oxf) (1996) 45(4):435–441.[CrossRef][Medline]
166. White C.R., Shelton J., Chen S.-J., et al. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation (1997) 96(5):1624–1630.[Abstract/Free Full Text]
167. Hayashi T., Fukuto J.M., Ignarro L.J., Chaudhuri G. Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci USA (1992) 89:11259–11263.[Abstract/Free Full Text]
168. Collins P., Rosano G.M.C., Sarrel P.M., et al. 17β-estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation (1995) 92:24–30.[Abstract/Free Full Text]
169. Weiner C.P., Lizasoain I., Baylis S.A., et al. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA (1994) 91:5212–5216.[Abstract/Free Full Text]
170. Jiang C., Sarrel P.M., Poole-Wilson P.A., Collins P. Acute effect of 17β-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol (1992) 263:H271–H275.[Web of Science][Medline]
171. Collins P., Rosano G.M.C., Jiang G., et al. Cardiovascular protection by oestrogen — a calcium antagonist effect. Lancet (1993) 341:1264–1265.[CrossRef][Web of Science][Medline]
172. Harder D.R., Coulson P.B. Estrogen receptors and effects of estrogen on membrane electrical properties of coronary vascular smooth muscle. J Cell Physiol (1979) 100:375–382.[CrossRef][Web of Science][Medline]
173. Magness R.R., Rosenfeld C.R. Local and systemic estradiol-17β: effects on uterine and systemic vasodilatation. Am J Physiol (1989) 256:E536–E542.[Web of Science][Medline]
174. Mugge A., Riedel M., Barton M., Kuhn M., Lichtlen P.R. Endothelium independent relaxation of human coronary arteries by 17β-oestradiol in vitro. Cardiovasc Res (1993) 27:1939–1942.[Abstract/Free Full Text]
175. Du X.-J., Riemersma R.A., Dart A.M. Cardiovascular protection by oestrogen is partly mediated through modulation of autonomic nervous function. Cardiovasc Res (1995) 30:161–165.[Abstract/Free Full Text]
176. Shionoiri H., Eggena P., Barrett J.D., et al. An increase in high molecular weight renin substrate associated with estrogenic hypertension. Biochem Med (1983) 29:14–22.[CrossRef][Web of Science][Medline]
177. Schunkert H., Danser A.H.J., Hense H.-W., et al. Effects of estrogen replacement therapy on the Renin-Angiotensin System in postmenopausal women. Circulation (1997) 95:39–45.[Abstract/Free Full Text]
178. Williams J.K., Adams M.R., Lopfenstein H.S. Estrogen modulates responses of atherosclerotic coronary arteries. Circulation (1990) 81:1680–1687.[Abstract/Free Full Text]
179. Williams J.K., Adams M.R., Herrington D.M., Clarkson T.B. Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries. J Am Coll Cardiol (1992) 20:452–457.[Abstract]
180. Williams J.K., Honore E.K., Washburn S.A., Clarkson T.B. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol (1994) 24:1757–1761.[Abstract]
181. Gilligan D.M., Quyyumi A.A., Cannon R.O. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation (1994) 89:2545–2551.[Abstract/Free Full Text]
182. Reis S.E., Gloth S.T., Blumenthal R.S., et al. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation (1994) 89:52–60.[Abstract/Free Full Text]
183. Rosano G.M.C., Sarrel P.M., Poole-Wilson P.A., Collins P. Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease. Lancet (1993) 342:133–136.[CrossRef][Web of Science][Medline]
184. Webb C.M., Rosano G.M., Collins P. Oestrogen improves exercise-induced myocardial ischaemia in women. Lancet (1998) 351(9115):1556–1557.[CrossRef][Web of Science][Medline]
185. Williams J.K., Adams M.R., Clarkson M.R. Effects of oestrogen on vascular tone. J Cardiovasc Pharmacol (1996) 28(Suppl 5):S29–S33.
186. Gerhard M., Walsh B.W., Tawakol A., et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation (1998) 98(12):1158–1163.[Abstract/Free Full Text]
187. McCrohon J.A., Walters W.A., Robinson J.T., et al. Arterial reactivity is enhanced in genetic males taking high dose estrogens. J Am Coll Cardiol (1997) 29(7):1432–1436.[Abstract]
188. New G., Timmins K.L., Duffy S.J., et al. Long-term estrogen therapy improves vascular function in male to female transsexuals. J Am Coll Cardiol (1997) 29(7):1437–1444.[Abstract]
189. Venkov C.D., Rankin A.B., Vaughan D.E. Identication of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function. Circulation (1996) 94:727–733.[Abstract/Free Full Text]
190. Losordo D.W., Kearney M., Kim E.A., Jekanowski J., Isner J.M. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation (1994) 89:1501–1510.[Abstract/Free Full Text]
191. Collins P., Sheppard M., Beale C.M., Dowsett M. The classical estrogen receptor is not found in human coronary arteries. Circulation (1995) 92(8):38–38. Abstract.[Web of Science]
192. Iafrati M.D., Karas R.H., Aronovitz M., et al. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med (1997) 3(5):545–548.[CrossRef][Web of Science][Medline]
193. Manolio T.A., Furberg C.D., Shemanski L. The CHS Collaborative Research Group. Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. Circulation (1993) 88:2163–2171.[Abstract/Free Full Text]
194. Selzman C.H., Gaynor J.S., Turner A.S., et al. Ovarian ablation alone promotes aortic intimal hyperplasia and accumulation of fibroblast growth factor. Circulation (1998) 98(19):2049–2054.[Abstract/Free Full Text]
195. Fischer G.M. In vivo effects of estradiol on collagen and elastin dynamics in rat aorta. Endocrinology (1972) 91:1227–1232.[Abstract/Free Full Text]
196. Wolinsky H. Effects of estrogen and progestogen treatment on the response of the aorta of male rats to hypertension. Morphological and chemical studies. Circ Res (1972) 30(3):341–349.[Abstract/Free Full Text]
197. Hassager C., Jensen L.T., Podenphant J., Riis B.J., Christiansen C. Collagen synthesis in postmenopausal women during therapy with anabolic steroid or female sex hormones. Metabolism (1990) 39:1167–1169.[CrossRef][Web of Science][Medline]
198. Writing Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. J Am Med Assoc (1995) 273:199–208.[Abstract/Free Full Text]
199. Miyagawa K., Rosch J., Stanczyk F., Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary spasm. Nature Med (1997) 3:324–327.[CrossRef][Web of Science][Medline]
200. Rosano G.M.C., Sarrel P.M., Chierchia S.L., et al. Medroxyprogesterone, but not natural progesterone, reverses the beneficial effect of estradiol 17beta upon exercise-induced myocardial ischemia. Circulation (1996) 94:1–18. Abstract.[Free Full Text]
201. Hulley S., Grady D., Bush T. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc (1998) 280(7):605–613.[Abstract/Free Full Text]
202. Stefanadis C., Tsiamis E., Dernellis J., Toutouzas P. Effect of estrogen on aortic function in postmenopausal women. Am J Physiol (1999) 276(2 Pt 2):H658–H662.[Web of Science][Medline]
203. Lehmann E.D., Hopkins K.D., Parker J.R., et al. Aortic distensibility in postmenopausal women receiving Tibolone. Br J Radiol (1994) 67:701–705.[Abstract/Free Full Text]
204. Giraud G.D., Morton M.J., Wilson R.A., Burry K.A., Speroff L. Effects of estrogen and progestin on aortic size and compliance in postmenopausal women. Am J Obstet Gynecol (1996) 174:1708–1718.[CrossRef][Web of Science][Medline]
205. Rajkumar C., Kingwell B.A., Cameron J.D., et al. Hormonal therapy increases arterial compliance in postmenopausal women. J Am Coll Cardiol (1997) 30(2):350–356.[Abstract]
206. Hayward C.S., Knight D.C., Wren B.G., Kelly R.P. Effect of hormone replacement therapy on noninvasive cardiovascular haemodynamics. J Hypertension (1997) 15:987–993.[CrossRef][Web of Science][Medline]
207. Kovacs L., Bartfai G., Apro G., et al. The effect of the contraceptive pill on blood pressure: a randomised controlled trial of three progesterone–oestrogen combinations in Szeged, Hungary. Contraception (1986) 33:69–77.[CrossRef][Web of Science][Medline]
208. Chasan-Taber L., Willett W.C., Manson J.E., et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation (1996) 94:483–489.[Abstract/Free Full Text]
209. Mashchak C.A., Lobo R.A. Estrogenic replacement therapy and hypertension. J Reprod Med (1985) 30(10):805–810.[Web of Science][Medline]
210. Lip G.Y.H., Beevers M., Churchill D., Beevers D.G. Hormone replacement therapy and blood pressure in hypertensive women. J Human Hypert (1994) 8:491–494.
211. Lind T., Cameron E.C., Hunter W.M., et al. A prospective, controlled trial of six forms of hormone replacement therapy given to postmenopausal women. Br J Obstet Gynaecol (1979) 86(Suppl 3):1–30.[Web of Science][Medline]
212. Hammond C.B., Jelovsek F.R., Lee K.L., Creasman W.T., Parker R.T. Effects of long term estrogen replacement therapy. I. Metabolic effects. Am J Obstet Gynecol (1979) 133:525–536.[Web of Science][Medline]
213. Conard J., Basdevant A., Thomas J.-L., et al. Cardiovascular risk factors and combined estrogen–progestin replacement therapy: a placebo-controlled study with noegestrol acetate and estradiol. Fertil and Steril (1995) 64:957–962.
214. Khoo S.-K., Coglan M.J., Wright G.R., DeVoss K.N., Battistutta D. Hormone therapy in women in the menopause transition. Randomised, double blind, placebo controlled trial of effects on body weight, blood pressure, lipoprotein levels, antithrombin III activity, and the endometrium. Med J Aust (1998) 168:216–220.[Web of Science][Medline]
215. Crane M.G., Harris J.J., Winsor III W. Hypertension, oral contraceptive agents and conjugated estrogens. Ann Intern Med (1971) 74:13–21.[Abstract/Free Full Text]
216. Notelovitz M. Effect of natural oestrogens on blood pressure and weight in postmenopausal women. S Afr Med J (1975) 49:2251–2254.[Web of Science][Medline]
217. Utian W.H. Effect of postmenopausal estrogen therapy on diastolic blood pressure and weight. Maturitas (1978) 1:3–8.[CrossRef][Web of Science][Medline]
218. Wren B.G., Routledge A.D. The effect of type and dose of oestrogen on the blood pressure of postmenopausal women. Maturitas (1983) 5:135–142.[CrossRef][Web of Science][Medline]
219. Luotola H. Blood pressure and hemodynamics in postmenopausal women during estradiol-17β substitution. Ann Clin Res (1983) 15(Suppl 38):9–112.
220. Rosano G.M.C., Sposato B., Leonardo F., et al. Chronic transdermal 17β-oestradiol therapy lowers blood pressure in newly diagnosed hypertensive postmenopausal women. Eur Heart J (1999) 20(Suppl):544. Abstract.
221. Jespersen C.M., Arnung K., Hagen C., et al. Effects of natural oestrogen therapy on blood pressure and renin angiotensin system in normotensive and hypertensive menopausal women. J Hypertension (1983) 1:361–364.[CrossRef][Medline]
222. Hoeg J.M., Willis I.R., Weinberger M.H. Estrogen attenuation of the development of hypertension in spontaneously hypertensive rats. Am J Physiol (1977) 233(3):H369–H373.[Web of Science][Medline]
223. Sullivan M.L., Martinez C.M., Gennis P., Gallagher E.J. The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis (1998) 41(1):1–15.[Web of Science][Medline]
224. Somjen D., Kohen F., Jaffe A., et al. Effects of gonadal steroids and their antagonists on DNA synthesis in human vascular cells. Hypertension (1998) 32(1):39–45.[Abstract/Free Full Text]
225. Hurley B.F., Seals D.R., Hagberg J.M., et al. High-density-lipoprotein cholesterol in bodybuilders v powerlifters. Negative effects of androgen use. J Am Med Assoc (1984) 252(4):507–513.[Abstract/Free Full Text]
226. Uyanik B.S., Ari Z., Gumus B., Yigitoglu M.R., Arslan T. Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study. Jpn Heart J (1997) 38(1):73–82.[Medline]
227. McCredie R.J., McCrohon J.A., Turner L., et al. Vascular reactivity is impaired in genetic females taking high-dose androgens. J Am Coll Cardiol (1998) 32(5):1331–1335.[Abstract/Free Full Text]
228. Ong P.J.L., Patrizi G., Chong W.C.F., et al. Testosterone enhances flow-mediated brachial artery reactivity in men with coronary artery disease. Am J Cardiol (2000) 85:14–17.
229. Khaw K.T., Barrett-Connor E. Endogenous sex hormones, high density lipoprotein cholesterol, and other lipoprotein fractions in men. Arterioscler Thromb (1991) 11(3):489–494.[Abstract/Free Full Text]
230. Zmuda J.M., Cauley J.A., Kriska A., et al. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol (1997) 146(8):609–617.[Abstract/Free Full Text]
231. Barrett-Connor E.L., Khaw K.T., Yen S.S. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med (1986) 315:1519–1524.[Abstract]
232. Phillips G.B., Pinkernell B.H., Jing T.Y. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb (1994) 14(5):701–706.[Abstract/Free Full Text]
233. Duell P.B., Bierman E.L. The relationship between sex hormones and high-density lipoprotein cholesterol levels in healthy adult men. Arch Intern Med (1990) 150(11):2317–2320.[Abstract/Free Full Text]
234. Barrett-Connor E., Khaw K.T. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation (1988) 78(3):539–545.[Abstract/Free Full Text]
235. Haffner S.M., Mykkanen L., Valdez R.A., Katz M.S. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab (1993) 77(6):1610–1615.[Abstract]
236. Adams M.R., Williams J.K., Kaplan J.R. Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arterioscler Thromb Vasc Biol (1995) 15(5):562–570.[Abstract/Free Full Text]
237. Barrett-Connor E., Khaw K.T. Absence of an inverse relation of dehydroepiandrosterone sulfate with cardiovascular mortality in postmenopausal women [letter]. N Engl J Med (1987) 317(11):711.[Medline]
238. Birdsall M.A., Farquhar C.M., White H.D. Association between polycystic ovaries and extent of coronary disease in women having cardiac catheterisation. Ann Intern Med (1997) 126(1):32–35.[Abstract/Free Full Text]
239. Bruck B., Brehme U., Gugel N., et al. Gender-specific differences in the effects of testosterone and estrogen on the development of atherosclerosis in rabbits. Arterioscler Thromb Vasc biol (1997) 17:2192–2199.[Abstract/Free Full Text]
240. Ebeling P., Koivisto V.A. Physiological importance of dehydroepiandrosterone. Lancet (1994) 343(8911):1479–1481.[CrossRef][Web of Science][Medline]
241. Lengsfeld M., Morano I., Ganten U., Ganten D., Ruegg J.C. Gonadectomy and hormonal replacement changes systolic blood pressure and ventricular myosin isoenzyme pattern of spontaneously hypertensive rats. Circ Res (1988) 63(6):1090–1094.[Abstract/Free Full Text]
242. Morano I., Gerstner J., Ruegg J.C., et al. Regulation of myosin heavy chain expression in the hearts of hypertensive rats by testosterone. Circ Res (1990) 66(6):1585–1590.[Abstract/Free Full Text]
243. Metzger J.M., Wahr P.A., Michele D.E., Albayya F., Westfall M.V. Effects of myosin heavy chain isoform switching on Ca²⁺ activated tension development in single adult cardiac myocytes. Circ Res (1999) 84(11):1310–1317.[Abstract/Free Full Text]
244. Malhotra A., Buttrick P., Scheuer J. Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. Am J Physiol (1990) 259(3 Pt 2):H866–H871.[Web of Science][Medline]
245. Urhausen A., Holpes R., Kindermann W. One- and two-dimensional echocardiography in bodybuilders using anabolic steroids. Eur J Appl Physiol (1989) 58(6):633–640.[CrossRef][Web of Science]
246. Trifunovic B., Norton G.R., Duffield M.J., Avraam P., Woodiwiss A.J. An androgenic steroid decreases left ventricular compliance in rats. Am J Physiol (1995) 268(3 Pt 2):H1096–H1105.[Web of Science][Medline]
247. Wichmann M.W., Zellweger R., DeMaso C.M., Ayala A., Chaudry I.H. Enhanced immune responses in females, as opposed to decreased responses in males following haemorrhagic shock and resuscitation. Cytokine (1996) 8(11):853–863.[CrossRef][Web of Science][Medline]
248. Remmers D.E., Wang P., Cioffi W.G., Bland K.I., Chaudry I.H. Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males. Am J Physiol (1997) 273(6 Pt 2):H2919–H2925.[Web of Science][Medline]
249. Alexandersen P., Haarbo J., Byrjalsen I., Lawaetz H., Christiansen C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ Res (1999) 84(7):813–819.[Abstract/Free Full Text]
250. Herman S.M., Robinson J.T.C., McCredie R.J., et al. Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men. Arterioscl Thromb Vasc Biol (1997) 17:2004–2009.[Abstract/Free Full Text]
251. Rosano G.M., Leonardo F., Pagnotta P., et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation (1999) 99(13):1666–1670.[Abstract/Free Full Text]
252. Webb C.M., Adamson D.L., de Zeigler D., Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol (1999) 83(3):437–439.[CrossRef][Web of Science][Medline]
253. Chou T.M., Sudhir K., Hutchison S.J., et al. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation (1996) 94(10):2614–2619.[Abstract/Free Full Text]
254. Yue P., Chatterjee K., Beale C., Poole-Wilson P.A., Collins P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation (1995) 91(4):1154–1160.[Abstract/Free Full Text]
255. Webb C.M., McNeill J.G., Hayward C.S., de Zeigler D., Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary artery disease. Circulation (1999) 100:1690–1696.[Abstract/Free Full Text]
256. Ceballos G., Figueroa L., Rubio I., et al. Acute and nongenomic effects of testosterone on isolated and perfused rat heart. J Cardiovasc Pharmacol (1999) 33(5):691–697.[CrossRef][Web of Science][Medline]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				W. Lieb, V. Xanthakis, L. M. Sullivan, J. Aragam, M. J. Pencina, M. G. Larson, E. J. Benjamin, and R. S. Vasan Longitudinal Tracking of Left Ventricular Mass Over the Adult Life Course: Clinical Correlates of Short- and Long-Term Change in the Framingham Offspring Study Circulation, June 23, 2009; 119(24): 3085 - 3092. [Abstract] [Full Text] [PDF]

				C. Donaldson, S. Eder, C. Baker, M. J. Aronovitz, A. D. Weiss, M. Hall-Porter, F. Wang, A. Ackerman, R. H. Karas, J. D. Molkentin, et al. Estrogen Attenuates Left Ventricular and Cardiomyocyte Hypertrophy by an Estrogen Receptor-Dependent Pathway That Increases Calcineurin Degradation Circ. Res., January 30, 2009; 104(2): 265 - 275. [Abstract] [Full Text] [PDF]

				R. Matyal Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management: A Core Review Anesth. Analg., July 1, 2008; 107(1): 37 - 50. [Abstract] [Full Text] [PDF]

				S. H. Han, J. H. Bae, D. R. Holmes Jr, R. J. Lennon, E. Eeckhout, G. W. Barsness, C. S. Rihal, and A. Lerman Sex differences in atheroma burden and endothelial function in patients with early coronary atherosclerosis Eur. Heart J., June 1, 2008; 29(11): 1359 - 1369. [Abstract] [Full Text] [PDF]

This Article Extract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Hayward, C. S. Articles by Collins, P. Search for Related Content PubMed PubMed Citation Articles by Hayward, C. S. Articles by Collins, P. Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics