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Cardiovascular Research 2002 53(3):597-604; doi:10.1016/S0008-6363(01)00473-4
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Copyright © 2002, European Society of Cardiology

Endothelial function, vascular reactivity and gender differences in the cardiovascular system

Mark A. Sadera,b and David S. Celermajera,b,*

aDepartment of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, 2050 NSW, Australia
bDepartment of Medicine, University of Sydney, Camperdown, 2006 NSW, Australia

* Corresponding author. Tel.: +61-2-9515-6519; fax: +61-2-9550-6262 davidc{at}card.rpa.cs.nsw.gov.au

Received 23 May 2001; accepted 21 August 2001

KEYWORDS Atherosclerosis; Endothelial function; Gender


   1. Introduction
Top
 1. Introduction
2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
 References
 
A marked gender difference exists in the prevalence and severity of cardiovascular disease, even after adjustment for traditional vascular risk factors, which are more prevalent in males [1]. This has led to an interest in the role of sex steroids themselves in the promotion or inhibition of atherogenic events. As endothelial dysfunction is an early and important event in atherogenesis [2] and appears to predict adverse coronary outcomes [3], gender differences in endothelial function and the effects of hormonal therapy on vascular function have been the focus of considerable research interest.

The normal vascular endothelium regulates arterial tone, platelet and leukocyte interactions, coagulation, fibrinolysis and vascular growth [4]. Measurement of endothelial function in the systemic arteries has become established as an important method for the detection of early (pre-symptomatic) arterial abnormalities in humans [5]. Ultrasound-detected endothelial dysfunction in peripheral arteries correlates significantly with coronary endothelial dysfunction [6], as well as with the extent and severity of coronary atherosclerosis [7]. The availability of a non-invasive method for the reproducible measurement of endothelium-dependent dilatation has facilitated the study of the interactions between sex hormones and arterial function, in both males and females.


   2. Normal endothelial function
Top
 1. Introduction
 2. Normal endothelial function
3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
 References
 
The normal vascular endothelium is only one cell layer thick, separating the blood and vascular smooth muscle. The endothelium responds to physical and chemical stimuli via the synthesis and/or release of regulatory substances affecting vascular tone and growth, thrombosis and thrombolysis and platelet and leukocyte interactions with the endothelium. Substances released by the endothelium include nitric oxide (NO), prostacyclin, endothelins, interleukins, endothelial growth factors, adhesion molecules, plasminogen inhibitors and von Willebrand factor [4,8–10].

The pivotal role of the endothelium in regulating vascular smooth muscle tone has only recently been appreciated [11]. The existence of an endothelium-derived relaxing factor (EDRF) was first postulated by Furchgott and Zawadzki [12], when it was observed that rabbit aortic rings relaxed to acetylcholine only in the presence of an intact endothelium. NO, the endothelium-derived relaxing factor, was subsequently shown to maintain a low resting arterial tone in both the peripheral [13] and pulmonary [14] circulations.

NO is synthesized from L-arginine by the enzyme, nitric oxide synthase (NOS) [15], a reaction which can be specifically blocked by arginine analogues, such as NG-monomethyl-L-arginine (L-NMMA). NO release is stimulated by increased blood flow (resulting in increased shear stress on the endothelium) [16] and by a variety of agents in the circulation, including acetylcholine, serotonin, bradykinin and thrombin, via the activation of specific endothelial cell membrane receptors. NO release results in vascular smooth muscle relaxation, through a reduction in intracellular calcium levels mediated via cyclic GMP [17].


   3. Mechanisms of hormonal regulation of endothelial function
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
 References
 
Hormonal regulation of endothelial function may be the consequence of receptor-dependent or receptor-independent mechanisms. Oestrogen receptors (ER), progesterone receptors (PR) and androgen receptors (AR) have all been identified in human vascular endothelium [18–22]. ER and AR have also been identified in smooth muscle cells, macrophages and platelets [20–25].

Gender differences in hormone receptor expression have been demonstrated in some cell lines [26], as has the hormonal regulation of hormone receptor expression [25,27]. Indeed, a man with a disruptive mutation of the oestrogen receptor gene was demonstrated to have endothelial dysfunction [28].

Oestrogen has been demonstrated to upregulate endothelial nitric oxide synthase (eNOS) activity via a receptor-mediated system [29]. Oestrogen also upregulates prostacyclin synthase and has beneficial effects in regards to the response to vascular injury and on atherosclerosis, by upregulating the expression of vascular endothelial growth factor (VEGF) and inhibiting endothelial cell apoptosis, as well as smooth muscle cell migration and proliferation [30]. Androgens have also been demonstrated to upregulate eNOS and VEGF [30,31].

Receptor-independent pathways include non-genomic, anti-oxidant effects and effects mediated by hypothalamic–pituitary feedback inhibition. Non-genomic effects occur early (within minutes) with a rapid onset and offset, occurring too quickly to be the result of altered gene expression and subsequent protein synthesis. These non-genomic effects are possibly mediated through membrane receptors or protein interactions with steroid hormone receptors [23] and involve common second messengers, such as intracellular calcium and cyclic AMP. Physiologic concentrations of oestrogen have been demonstrated to activate calcium-dependent potassium channels [32,33] and result in a rapid increase in human endothelial cell basal NO release [34]. Oestrogens are known to have anti-oxidant potential [35] and this may improve redox balance in the wall, improving local NO bioavailability and consequently enhance endothelium-dependent dilatation [36]. Natural hormone production is regulated by the hypothalamic–pituitary axis, hence exogenous hormone therapy, such as with oestrogen, will result in suppression of oestrogen and androgen production.


   4. Assessment of the effects of gender and hormones on endothelial function in vivo
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
 References
 
Gender differences and hormonal effects on endothelial function have been assessed predominantly using functional methods examining NO-dependent vasomotion, both in the coronary and peripheral circulations. The acute effects of hormones have been assessed usually using supraphysiological doses and longer-term studies have targeted specific subpopulations with natural or induced conditions of hormonal deficiency or excess, such as post-menopausal women or transsexuals.

Functional methods of assessing endothelial function examine the endothelium's ability to release NO and cause vasodilation in response to pharmacological and physiological stimuli. The majority of studies assessing the effects of hormones on endothelial function have utilised either invasive coronary artery testing or non-invasive peripheral artery ultrasound. Non-invasive techniques are more widely applicable to asymptomatic subjects, especially when assessing the effects of long-term hormonal therapy.

Invasive coronary artery testing in humans assesses coronary artery responses to intravenous endothelium-dependent (e.g., acetylcholine) and endothelium-independent (e.g., nitroprusside), using quantitative angiography and Doppler wires or catheters [37,38].

Non-invasive assessment of brachial artery endothelial function uses high resolution external vascular ultrasound [2]. Arterial diameter is measured at rest, during reactive hyperaemia (leading to flow-mediated dilatation, FMD, an endothelium-dependent response) and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Reactive hyperaemia responses are assessed following temporary brachial artery occlusion with a sphygmomanometer placed below the target artery. Arterial FMD measurements reflect endothelial vasodilator function, predominantly due to nitric oxide release [39], correlate significantly with coronary endothelial function [6] and coronary atherosclerosis [7].

Other functional methods assessing endothelial function include: plethysmography, a method requiring the intra-arterial infusion of endothelium-dependent and independent vasodilator substances; and positron emission tomography which allows the non-invasive assessment of coronary endothelial function, but is expensive and involves exposure to radiation [40].

As the endothelium influences many parameters other than vasomotor control, other methods of assessing endothelial function have been utilized, including assays for measuring NO and circulating markers of normal endothelial activity. Assays for measuring NO in plasma and urine, however, are generally not suitable for routine clinical use due to multiple non-vascular sources of nitrates [41]. Circulating markers of endothelial function (and dysfunction) include asymmetric dimethylarginine, endothelin-1, Von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor-1 and cell adhesion molecules. These assays, however, also have limitations with poor sensitivity and specificity for endothelial dysfunction, considerable overlap of normal and abnormal levels and uncertainty in regards to whether changes in circulatory markers parallel changes in other tests of endothelial function [40].


   5. Gender, hormones and endothelial function
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
 References
 
The effects of sex hormones on endothelial function may depend on subject gender, as well as the dose, duration and route of hormone delivery. Secondary effects of hormones, such as alteration in the lipid profile, may in turn alter endothelial function [42,43]. Assessment of the independent effects of hormones on endothelial function involves adjustment for known vascular risk factors, including lipids, as oestrogens in physiological doses favorably augment the lipid profile [44] and androgens in supraphysiological doses have been associated with reduced HDL levels [45].

Additionally, when considering the effects of androgens, one must remember that testosterone is converted intracellularly to dihydrotestosterone (a more potent and non-aromatizable androgen) by 5{alpha}-reductase, but also to oestrogen by aromatase, therefore may result in both androgenic and oestrogenic effects.


   6. Effects of ‘physiological’ levels of sex hormones on endothelial function
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
7. 'Pharmacological' doses of...
 8. Conclusion
 References
 
6.1. Gender
Normal ranges have been established for FMD (an endothelium-dependent) and GTN-mediated (endothelium-independent) responses of systemic arteries [46] in healthy young adults, without identifiable atherogenic risk factors. In age-matched subjects, females show significantly greater FMD and GTN values than males; however the differences in FMD and GTN responses are completely accounted for by the smaller vessel size of females, rather than due to hormonal differences.

6.2. Age
Aging is associated with progressive endothelial dysfunction in both genders [47,48]. The age-related impairment in endothelial function, however, appears to occur earlier in men than women [49]. A steep decline in FMD in women is observed, however, around the time of the menopause, consistent with a protective effect of physiological oestrogen levels on endothelial function.

6.3. Menstrual cycle
The effect of the menstrual cycle on endothelial function was assessed by Hashimoto et al., using brachial artery ultrasound during the three phases of the menstrual cycle. Endothelium-dependent vasodilatation was maximal during the follicular and luteal phases of the menstrual cycle, corresponding to elevated levels in serum oestradiol (Fig. 1) [50]. In the menstrual phase, endothelial function in the women studied was similar to that in healthy men.


Figure 1
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  		Fig. 1 The effect of the menstrual cycle on endothelial function. Endothelial function was maximal during the follicular and luteal phases of the menstrual cycle, corresponding to elevated levels in serum oestradiol, consistent with a beneficial effect of physiological levels of oestrogens on vascular reactivity (adapted from Hashimoto et al. [50]). P<0.01.

 

   7. ‘Pharmacological’ doses of sex hormones' effects on endothelial function
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
8. Conclusion
 References
 
7.1. Oestrogens in post-menopausal women
Physiologic oestrogen levels potentiate endothelium-dependent vasodilatation in both the coronary and systemic circulations (Fig. 2) [51,52] and the acute parenteral administration of high-dose oestrogen in women with coronary artery disease attenuates the acetylcholine-induced coronary artery vasoconstriction [53]. Also with sublingual administration, oestradiol has been demonstrated to have direct vasodilatory properties, with anti-ischaemic effects in older women with coronary disease [54].


Figure 2
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  		Fig. 2 Oestrogen replacement in post-menopausal women is associated with improved endothelial function (adapted from Lieberman et al. [52]). P<0.05.

 
Differential effects of oral and transdermal oestrogen replacement therapy in post-menopausal women have been observed, with oral oestrogen, but not transdermal preparations, improving endothelial function [55].

Combined hormone replacement therapy (oestrogen plus progesterone) has also been associated with beneficial effects on endothelial function [56,57], although there have been conflicting results [58], with androgenic progestagens, such as norethisterone. This raises the concern that the type of progesterone used, as well as the mode of delivery, might influence any beneficial effects of unopposed oestrogen. Recently, however, Koh et al. demonstrated no difference in the vascular effects of natural or synthetic progestagens, when combined with oestrogen, in healthy post-menopausal women [59].

Selective oestrogen receptor modulators (SERMs, including Tamoxifen and Raloxifene) are agents with high affinity for the oestrogen receptor and display a tissue-selective profile, with oestrogen-agonist activities in some tissues (such as bone) and oestrogen-antagonist in others (such as uterus and breast) [60]. Raloxifene induced coronary arterial relaxation in male and female coronary arteries by an endothelium-dependent and oestrogen receptor-dependent mechanism involving nitric oxide [61]. The influence of various SERMs on endothelial function in humans is presently being assessed, with preliminary results indicating an improvement in endothelial function in post-menopausal women on Raloxifene [62].

Phytooestrogens are plant oestrogens found mainly in soybean products, principally as isoflavanoids, and are being increasingly used to relieve menopausal symptoms. Although animal studies have indicated a protective effect of genistein [63], phytooestrogen intake by healthy post-menopausal women have not been demonstrated to have any beneficial effect on endothelial function [64].

7.2. Oestrogens in men
The short-term beneficial effects of oestrogen on endothelial function in women have not been paralleled in men. Collins et al. found that, although 17-β oestradiol attenuated the acetylcholine-induced coronary vasoconstriction in females, it did not do so in males [53]. Similarly, the transdermal application of oestradiol for 36 h improved arterial endothelium-dependent vasodilatation in women, but not in men [65], and the acute sublingual administration of oestradiol in young men did not improve FMD, despite resulting in supraphysiological serum oestradiol levels [66].

Longer-term oestrogen therapy in men has, however, been associated with improvements in endothelial function. Two cross-sectional studies assessing the effects of long-term high dose oral oestrogens in genetic males (male to female transsexuals) demonstrated enhanced arterial reactivity compared with age-matched male controls (Fig. 3) [67,68]. These unusual populations possessed several potential confounding factors, including variations in the type of castrative therapy, dose and route of oestrogen administration, use of progestins, and a high percentage of smokers in the groups studied. Nevertheless, a subsequent prospective study in healthy young men on depot subcutaneous testosterone therapy, with or without oestrogen, demonstrated an improvement in endothelial function correlating with serum oestradiol levels [69].


Figure 3
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  		Fig. 3 High-dose oestrogen use in genetic males is associated with improved arterial endothelial function (adapted from McCrohon et al. [67]). P=0.001.

 
Further support of the potential longer-term benefit of oestrogens on endothelial function in men, was the improvement in endothelial function seen following the commencement of Tamoxifen (a SERM) [70], and the cessation of testalactone treatment (an aromatase inhibitor, which inhibits the conversion of testosterone to oestradiol) in male subjects [71].

7.3. Androgens in men
Acutely administered testosterone results in arterial vasodilatation in both human and animal studies, through an endothelium-independent mechanism, probably involving ATP sensitive potassium channels on smooth muscle cells [72–74].

Regarding endothelial function, supraphysiological doses of the anabolic steroid nandrolone in an animal model resulted in impairment of both endothelium-dependent and endothelium-independent dilatation (of rabbit aortic rings) [75].

In human studies, however, androgens have had varied effects on endothelial function. Androgen deprivation therapy in elderly men with prostate cancer was associated with enhanced endothelial function, suggesting a deleterious effect of physiological levels of androgens (Fig. 4) [76]. A recent study assessing the effects of long-term androgenic anabolic steroid use in competition bodybuilders, however, did not reveal any significant difference in arterial reactivity compared to bodybuilders who had never used anabolic steroids [77]. Interestingly, both bodybuilding groups had significantly impaired arterial reactivity compared to sedentary controls, suggesting the intense exercise undertaken may have had a deleterious effect.


Figure 4
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  		Fig. 4 Androgen deprivation therapy (for prostate cancer) is associated with improved endothelial function in elderly men (adapted from Herman et al. [76]). P<0.001. FMD — flow-mediated dilatation of the brachial artery.

 
The above studies were both cross-sectional, with the potential for unknown confounding factors. We recently studied prospectively a group of otherwise healthy hypogonadal males on long-term testosterone replacement therapy, with subjects serving as their own controls, finding a significant impairment in endothelial function at peak serum testosterone levels [78]. The impairment in endothelial function occurred despite significant elevations in serum oestradiol (from testosterone aromatisation), consistent with a deleterious androgenic effect. This may vary with age, however, as dihydrotestosterone administration in older men does not appear to alter endothelium-dependent dilatation [79].

7.4. Androgens in women
The use of high dose parenteral testosterone by young genetic females (female to male transsexuals) has been associated with impaired arterial reactivity and an increase in arterial size [80], but no significant difference in FMD was demonstrated. The study power was limited, however, by a small number of subjects and a high percentage of smokers. Recently, however, low dose parenteral testosterone supplementation in post-menopausal women taking hormone replacement therapy has been associated with an improvement in endothelium-dependent and endothelium-independent vasodilatation [81]. Once again, suggesting that differences in subject age and dose/combination of sex hormones may influence the effects on endothelial function.

Polycystic ovarian syndrome is associated with endothelial dysfunction [82] and more extensive and severe coronary artery disease [83], and features mild hyperandrogenism. In addition to the effects of androgens, however, this syndrome is also characterized by other potentially pro-atherogenic metabolic abnormalities, including insulin resistance, which may confound any potential linking of endothelial dysfunction with androgens in this select subpopulation.


   8. Conclusion
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
References
 
The effect of sex hormones on vascular endothelial function and vascular reactivity is clearly influenced by gender. Oestrogens appear to have beneficial effects on endothelial function in both genders, by receptor-mediated and receptor-independent mechanisms, although this may require long-term administration in males. Androgens modulate endothelial function, usually in a deleterious manner. The direction and magnitude of the effect of androgens, however, are dependent on subject age, gender, dose and duration of administration.

Arterial reactivity and endothelium-dependent dilatation have proven to be useful markers of early vascular injury, providing insights into atherogenic risk. Arterial endothelial function is indeed related to cardiovascular outcomes, in prospective studies [84,85]. Nevertheless, the true test of benefit from hormonal therapies requires clinical end-point studies with morbidity and mortality outcome data; such studies are awaited with interest.

Nevertheless, with the advent of an increasing number of selective hormone receptor modulators and an increasing understanding of mechanisms involved in gender differences in endothelial function, future ‘gender-specific’ therapies enhancing vascular function may be on the horizon, which in turn may lead to a decreased susceptibility to occlusive arterial disease and acute vascular events.

Time for primary review 40 days.


   References
Top
 1. Introduction
 2. Normal endothelial function
 3. Mechanisms of hormonal...
 4. Assessment of the...
 5. Gender, hormones and...
 6. Effects of 'physiological'...
 7. 'Pharmacological' doses of...
 8. Conclusion
 References
 

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