© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Sex hormones and hypertension
aCenter for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
bUniversity Hospital Zurich, Department of Obstetrics and Gynecology, Clinic for Endocrinology, Frauenklinikstrasse 10, 8091 Zurich, Switzerland
cDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
dDepartment of Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
eThe Vascular Biology and Hypertension Program, University of Alabama, Birmingham, AL 35294, USA
rag{at}fhk.usz.ch
* Corresponding author. Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, CH-8051 Zurich, Switzerland. Tel.: +41-1-2555-383; fax: +41-1-2554-439
Received 8 June 2001; accepted 30 October 2001
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Abstract |
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 Top Abstract 1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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Gender has an important influence on blood pressure, with premenopausal women having a lower arterial blood pressure than age-matched men. Compared with premenopausal women, postmenopausal women have higher blood pressures, suggesting that ovarian hormones may modulate blood pressure. However, whether sex hormones are responsible for the observed gender-associated differences in arterial blood pressure and whether ovarian hormones account for differences in blood pressure in premenopausal versus postmenopausal women remains unclear. In this review, we provide a discussion of the potential blood pressure regulating effects of female and male sex hormones, as well as the cellular, biochemical and molecular mechanisms by which sex hormones may modify the effects of hypertension on the cardiovascular system.
KEYWORDS Blood pressure; Endothelial function; Gender; Growth factors; Hypertension; Smooth muscle
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1. Introduction |
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TopAbstract1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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Sexual dimorphism in arterial blood pressure appears in adolescence and persists throughout adulthood [1,2]. Average systolic and diastolic blood pressures in men less than 60 years-of-age are higher than in age-matched women by 6–7 and 3–5 mmHg, respectively [3–5]. After that time, blood pressure (particularly systolic blood pressure) increases in women so that hypertension becomes more prevalent [4] or at least as prevalent in women as men. Inasmuch as gender-associated differences in hypertension prevalence either disappear or cross over after women enter menopause, ovarian hormones may be responsible in part for lower blood pressure in premenopausal women and for the increase in blood pressure in postmenopausal women. Similar to humans, sex-associated differences in blood pressure also exist in animals. For example, compared with females, male spontaneously hypertensive rats (SHR; [6–9]), Dahl salt-sensitive rats [10,11], deoxycorticosterone acetate-salt hypertensive rats [12], and New Zealand genetically hypertensive rats [13] have higher blood pressures. In these animal models of hypertension, blood pressure is reduced in males by castration [6–9,14,15], but is not increased in females by ovariectomy [16,17]. Thus, sex-associated differences in blood pressure also may be due to changes in testicular hormones. In the sections that follow, we examine the evidence for and against the involvement of female and male sex hormones in the pathogenesis of hypertension.
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2. Estrogens and hypertension |
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TopAbstract1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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2.1. Effects of estrogens on blood pressure
Cross sectional [18–20], but not longitudinal [21–23], studies show a significant increase in systolic and diastolic blood pressure following the onset of menopause. Staessen et al. [18] reported a four-fold increase in the incidence of hypertension in postmenopausal women (40% in postmenopausal women vs. 10% in premenopausal women). In a subsequent prospective evaluation of blood pressure (conventional and ambulatory) in women who were premenopausal, perimenopausal or postmenopausal, the authors reported that postmenopausal women had a higher systolic blood pressure (4–5 mmHg) compared with premenopausal or perimenopausal women [20]. Also, the rise in systolic blood pressure per decade was 5 mmHg greater in perimenopausal and postmenopausal women compared with premenopausal women [20]. Because menopause is associated with decreased synthesis of estradiol, it is likely that changes in blood pressure induced by menopause may be due in part to reductions in estradiol production.
Support for the conclusion that estradiol has a blood pressure lowering effect in women is provided by the observation that during the menstrual cycle, blood pressure is lower during the luteal phase (when estradiol levels peak) than during the follicular phase [24–26]. Observations made during pregnancy provide additional circumstantial evidence for a blood pressure lowering effect of estradiol. Estradiol levels increase 50–180-fold during pregnancy [27], and these increases are associated with substantial reductions in blood pressure [28]. The timing of maximal decreases in blood pressure and maximal increases in estradiol levels does not coincide completely, however. In the first, second and third trimesters of pregnancy, estradiol levels increase by 8-, 15- and 186-fold [27], respectively. In contrast, ambulatory blood pressure is lowest in the first (systolic 103±7 mmHg) and second (systolic 101±9 mmHg) trimesters and rises in the third trimester (systolic 111±9 mmHg) of pregnancy [28]. This suggests that factors in addition to estradiol modulate blood pressure in pregnancy [29] and/or that other hormones or local modulators generated during pregnancy abrogate the blood pressure lowering effects of estradiol during the third trimester of pregnancy.
If endogenous estradiol does lower blood pressure, administration of estrogenic preparations to women might also be expected to reduce blood pressure. However, data on the effects of estrogenic preparations on blood pressure are inconsistent, and include reports of blood pressure lowering [30–45], blood pressure elevating [46–51], and blood pressure neutral effects [37,52–54]. Evidence for blood pressure elevating effects of estrogen preparations comes primarily from studies conducted between 1970 and the early 1980s that used conjugated estrogens or contraceptive estrogens (different from natural estradiol) and conventional rather than ambulatory blood pressure measurements. For example, in several studies, PremarinTM (a mixture of conjugated estrogens isolated from urine of pregnant mares) increased blood pressure [46,50,51], and various synthetic contraceptive estrogens increased the risk of hypertension [55–60]. Of five women who developed hypertension after using Premarin (1.25 mg/day) for 3 months to 5 years, four became normotensive from 1 to 7 months after they cessation of therapy [46]. Similarly, of 27 women who developed hypertension while taking Premarin (1.25 mg/day), 13 became normotensive within 3.6 months after Premarin was discontinued, and of five women who restarted Premarin, blood pressure was again elevated within 6 weeks to 6 months [50]. In a prospective study of 160 postmenopausal women taking either Premarin (n=73) or piperazine estrone sulphate (Ogen; n=87), development of hypertension was observed only in women taking Premarin [51]. It should be noted that in the above studies, conjugated estrogens (Premarin) were administered orally. Since conjugated estrogens administered via patches have been shown to have largely neutral or marginally blood pressure lowering effects, the route of administration may have a decisive role in defining the effects of conjugated estrogens on blood pressure.
With regard to contraceptive estrogens, in 22 patients who developed hypertension on oral contraceptive pills, the blood pressure was normalized after oral contraceptives were discontinued (blood pressures before, during and after administration of oral contraceptives were 125/76, 183/110, and 130/82 mmHg, respectively [46]). Similar reversals in oral contraceptive-induced hypertension were observed in eight out of 14 women within 3.6 months of discontinuing the contraceptive estrogen [50], and seven of the eight became hypertensive again 3–6 months after resuming therapy. In a prospective cohort study of 68 297 female nurses, compared with women who had never used oral contraceptives, the age adjusted relative risk of hypertension was 1.5 (95% CI=1.5 to 1.8) for current use and 1.1 (95% CI=0.9 to 1.2) for past use [59]. After adjusting for age, body mass index, hormones, cigarette smoking, family history of hypertension, parity, physical activity, alcohol intake, and ethinicity, current users of oral contraceptives had an increased risk of development of hypertension [relative risk (RR)=1.8; 95% CI=1.5–2.3]. The risk of hypertension associated with oral contraceptives increased with age, duration of use, body mass and progestin potency [56]. It is important to note that the estrogens used in contraceptive pills (e.g., ethinyl estradiol) are different than the natural estrogen estradiol; moreover, the doses for contraceptive estrogens and estrogens used for hormone replacement therapy vary considerably. This underscores the principle that the blood pressure effects of estrogenic preparations cannot be equated just because the preparations belong to the same pharmacological class.
More recent studies indicate that postmenopausal estrogen replacement therapy either does not affect or reduces blood pressure. For example, tibolone, a synthetic estrogen with both androgenic and gestagenic properties, had no effect on blood pressure [61]. In the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI), no change in blood pressure was observed in 875 normotensive postmenopausal women receiving conjugated equine estrogens in combination with a variety of progestins [52]. In smaller placebo-controlled, randomized crossover studies, administration of conjugated estrogens to normotensive postmenopausal women had blood pressure lowering or neutral effects (Table 1).
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Administration of estradiol (oral or transdermal patches) to normotensive postmenopausal women either reduced or had no effect on blood pressure (Table 1). For example, in a placebo-controlled, double-blind, crossover study with 24-h ambulatory blood pressure measurements, transdermal estradiol (50 µg/day; achieves physiological levels of estradiol) treatment for 2 months was reported to decrease nocturnal blood pressure (systolic, diastolic and mean), but not daytime (office) blood pressure [40]. Several other studies utilizing 24-h ambulatory blood pressure measurement reported blood pressure lowering effects of estradiol (Table 1). In a non-randomized, non-placebo-controlled study, nocturnal blood pressure was decreased in normotensive women treated chronically with estradiol (transdermal) [41]. Twenty four-hour ambulatory blood pressure was also lowered in postmenopausal women who were treated with estradiol sequentially with the progestin dydrogesterone (5 or 10 mg) for 1 year [32].
Blood pressure lowering effects of estradiol were also observed by Seely et al. [42] who evaluated in healthy postmenopausal women the effects of transdermal estradiol (0.1 mg patches administered twice per week to attain physiologic estradiol levels) administered in combination with intravaginal progesterone (300 mg). Significant decreases in nighttime systolic, diastolic, and mean blood pressure were observed in the group treated with estradiol and estradiol/progesterone. Similar to the findings of Cagnacci et al. [40] and the data from the PEPI trial [52], there were trends toward lower daytime or office systolic and diastolic blood pressures in patients on estradiol or estradiol/progestin compared to placebo; however, the changes were not significant. Since women, in particular may be vulnerable to white coat hypertension [62], it is possible that nocturnal blood pressure may be more sensitive to estradiol and progesterone. Moreover, this may be a potential reason for the lack of decrease in office/daytime blood pressure observed in the PEPI trial [52]. This also reaffirms the importance and superiority of 24-h ambulatory blood pressure measurements for ascertaining blood pressure changes accurately and without missing some subtle but potentially important effects of estrogen replacement therapy on blood pressure. Indeed, decreases in nighttime ambulatory blood pressure in response to hormone replacement therapy have been observed in other clinical studies [32,41].
Results from several small clinical trials suggest that estrogen replacement therapy also lowers blood pressure in hypertensive postmenopausal women (Table 1). In a randomized, double-blind crossover trial carried out in 30 postmenopausal women with mild hypertension who were receiving estradiol (transdermal; delivery rate 100 mg/day), the 24-h ambulatory blood pressure was lowered significantly [31]. A significant decrease in blood pressure was also observed in postmenopausal women with mild to moderate hypertension who were receiving transdermal estradiol [33]. In a prospective study conducted in 34 postmenopausal women with treated hypertension, administration of estradiol plus the progestin norgestrel for 19 weeks lowered 24-h ambulatory blood pressure [36]. In 13 postmenopausal women with ongoing treatment for hypertension, acute administration of transdermal estradiol reduced 24-h ambulatory day time systolic blood pressure and nocturnal systolic and diastolic blood pressure [43]. In a follow up study of 75 hypertensive postmenopausal women on estradiol replacement therapy for 36 months, no significant changes in blood pressure were observed [53], a negative result that may have been due to the lack of ambulatory blood pressure measurements.
Estradiol also lowers blood pressure in several animal models of hypertensive, including SHR [63], stroke prone SHR (SHRSP; [64]), rats with deoxycortisterone acetate-salt induced hypertension [65], Dahl salt-sensitive rats [66] and rats with pulmonary hypertension [67,68]. In contrast, ovariectomy does not affect the development of hypertension in SHRs [6], suggesting that the effects of estradiol on blood pressure in rats are pharmacological rather than physiological. Unlike the natural estrogen estradiol, the synthetic estrogen ethinyl estradiol increases blood pressure [55], suggesting that the effects of natural and synthetic estrogens differ markedly and may influence distinct mechanisms involved in the regulation of blood pressure. For example, even though contraceptive estrogens are administered at a lower dose (30–200 µg) than estrogens (0.625–2 mg) used for hormone replacement therapy, contraceptive estrogens increase blood pressure [55].
In summary, although the literature on the effects of estrogens on blood pressure is confusing and inconsistent, several general trends can be gleaned from existing reports. Whether blood pressure is decreased, increased or unchanged in response to estrogen treatment depends primarily on three factors: (1) the type of estrogenic preparation; (2) the dose of estrogens; and (3) how blood pressure is monitored. Contraceptive estrogenic preparations tend to increase blood pressure; conjugated equine estrogens appear to have little effect on blood pressure, and estradiol tends to lower blood pressure. The blood pressure lowering effects of estradiol are more readily observed if 24-h ambulatory blood pressure monitoring is employed. The effects of estradiol on the cardiovascular system and kidneys are discussed below from the perspective of how these effects may contribute to the blood pressure lowering actions of estradiol.
2.2. Effects of estradiol on vascular tone
Functional estrogen receptors (ERs) of the 
and β subtypes are expressed in vascular endothelial [60,70] and smooth muscle cells [60,70], and it is well established that estradiol can cause vasodilation by both ER-dependent and ER-independent mechanisms. Acute administration of estradiol in vitro and in vivo induces rapid dilation of coronary arteries of cholesterol-fed ovariectomized animals [69–73]. Exogenous estradiol also dilates coronary and brachial arteries in postmenopausal women and men [74–77]. Long-term treatment with estradiol abrogates the vasoconstrictor effects of U46619
[GenBank]
(thromboxane mimetic), phenylepinephrine, 5-HT, calcium, potassium and acetylcholine on vascular tissues such as aortic rings and coronary arteries [69,78–81]. Compared with premenopausal women, vasodilator effects of estradiol are decreased in postmenopausal women and are normalized by estrogen replacement therapy [69]. The vasodilator effect of estradiol replacement therapy is diminished by co-administration of synthetic progestins such as medroxyprogesterone and cyproterone acetate [82,83].
Both the acute and long-term vasodilator effects of estradiol are mediated in part via generation of endothelium-derived NO and are attenuated by NO synthesis inhibitors [84,85]. Estradiol induces an increase in intracellular free calcium concentration in endothelial cells [69,86], which could contribute to the increase in endothelial-derived NO. Since inhibition of NO synthesis promotes arterial hypertension [87], it is conceivable that estradiol protects against hypertension by increasing NO synthesis. Long-term administration of estradiol increases acetylcholine-mediated coronary vasodilation in non-human primates [71,72], male-to-female transsexuals [88], and postmenopausal women [89], particularly those with angina and normal coronary arteries [90]. The ability of estradiol to increase endothelium-dependent vasodilation in the forearm of hypertensive postmenopausal women is shared by conjugated equine estrogens [91]. Progestins inhibit estradiol-induced synthesis of endothelium-derived NO [92,93], and this may contribute to the diminished vasodilator effects of estrogen observed in postmenopausal women receiving estradiol plus progestins.
Other mechanisms also contribute to estradiol-induced vasodilation. Estradiol causes coronary vasodilation by opening calcium-activated K+ channels and relaxes endothelium-denuded porcine coronary arteries by opening large conductance calcium-activated and voltage-activated K+ channels [86,94]. Estradiol inhibits voltage-dependent L-type calcium currents in vascular smooth muscle cells and has potent stimulatory effects on large-conductance, calcium- and voltage-activated K+ channels in coronary artery vascular smooth muscle cells [95]. Since the vasodilator effects of estradiol in intact arteries are abrogated by blockers of calcium-activated, large conductance K+ channels and inhibitors of cyclic GMP-dependent protein kinase, estradiol may exert its vasodilator effects by opening calcium-activated, large conductance K+ channels via NO and cGMP-dependent pathways [94–98].
Additionally, estradiol activates adenylyl cyclase activity and increases the synthesis of cyclic AMP, a vasodilator second messenger [99]. Moreover, estradiol stimulates the production of adenosine in vascular smooth muscle cells via the cyclic AMP-adenosine pathway [99]. Estradiol also increases the synthesis of the vasodilator prostacyclin by inducing the expression of prostacyclin synthase and cyclooxygenase [100,101]. Finally, estradiol reduces the synthesis of potent vasoconstrictors such as angiotensin II (Ang II), endothelin-1 and catecholamines [102–104].
In summary, estradiol is a vasodilator that decreases vascular resistance by multiple mechanisms. Increased production of NO plays a prominent role, and increased synthesis of other endogenous vasodilators, decreased synthesis of endogenous vasoconstrictors and activation of K+ channels also contribute to the vasodilatory actions of estradiol.
2.3. Effects of estradiol on vascular growth
The elevated total peripheral resistance characteristic of hypertension is due in part to accelerated growth of vascular smooth muscle cells [105]. Vascular remodeling in hypertension involves interactions among multiple cell types, such as endothelial cells, smooth muscle cells, adventitial fibroblasts, monocytes, macrophages and leukocytes, and among multiple growth inducers, including local growth factors, circulating growth factors and mechanical forces [106]. The processes that lead to increased vascular resistance involve endothelial cell damage/dysfunction, increased generation of chemotactic and mitogenic factors at injury sites, migration of smooth muscle cells into the intima, proliferation of the migrated cells, hypertrophy of smooth muscle cells (increase in cell size) and deposition of extracellular matrix proteins [106]. In addition to smooth muscle cells, migration of adventitial fibroblasts into the neointima and fibroblast proliferation also play a major role in the vascular remodeling process [107]. The sequence of events in vascular remodeling may vary depending on the type of vascular challenge (mechanical, immunologic, lipid-induced), but the abnormal growth of smooth muscle cells is the final process that leads to increased vascular resistance. In vivo studies conducted in several species using various models (balloon injury-induced neointima formation, allograft-induced dysplasia, cholesterol/lipid-induced atherosclerosis and vascular narrowing-induced neointima formation) provide convincing evidence that estradiol prevents the vascular remodeling processes [69,70].
Estradiol engages key cellular/molecular components of the vascular remodeling process. Specifically, estradiol: (1) protects against endothelial damage caused by mechanical injury, oxidized-low-density lipoprotein (LDL), homocysteine, free radicals and immunological factors; (2) blocks vascular inflammation and decreases the expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1) at sites of vascular damage; (3) inhibits neointima formation by attenuating/inhibiting the recruitment of circulating macrophages, lymphocytes and thrombocytes to the site of injury, thus reducing the secretion of cytokines, eicosanoids and growth factors; (4) inhibits the vascular remodeling processes in atherosclerosis by stopping the migration of macrophages into the subendothelial spaces and preventing them from accumulating LDL and becoming foam cells; (5) prevents foam cell-induced inflammatory processes such as platelet adhesion and the release of multiple platelet-derived growth factors and cytokines; and (6) inhibits the mitogenic effects of multiple factors generated at the site of endothelial injury/dysfunction and which trigger a cascade of biochemical events that stimulate hyperplastic and/or hypertrophic growth of vascular smooth muscle cells [69,70,108].
In summary, there is no doubt that estradiol profoundly inhibits the vascular response to injury. This important effect of estradiol is mediated by numerous mechanisms, and this is an active area of contemporary research. The vasculoprotective effects of estradiol may attenuate the development of hypertension and may protect the vasculature from the injurious effects of high blood pressure.
2.4. Effects of estradiol on circulating factors
Estradiol modulates the synthesis of circulating factors known to influence vascular tone and structure. For example, estradiol increases bradykinin levels and may lower blood pressure by increasing bradykinin synthesis [124]. Estradiol down-regulates the expression of angiotensin converting enzyme (ACE) in serum as well as in the vasculature [103,109–111] and decreases renin release and Ang II formation [103]. These effects are in some respects paradoxical since estradiol stimulates angiotensinogen expression in the liver [50]. Ang II is a potent mitogen for vascular smooth muscle cells [112,113] and induces vascular remodeling processes associated with hypertension. Therefore, the inhibitory effects of estradiol on the renin–angiotensin system may lead to reduced vascular growth. Estradiol also down-regulates the expression of Ang II type 1 receptors in smooth muscle cells [114]. Since these receptors mediate the mitogenic effects of Ang II, estradiol may abrogate the effects of Ang II in part via this mechanism. Our own studies show that estradiol inhibits Ang II-induced growth of human smooth muscle cells in vitro [115], thus supporting this concept. Additionally, estradiol induces the synthesis of Ang 1–7, a vasodilator and smooth muscle cell growth inhibitor [116].
Homocysteine contributes to vascular disease by inducing endothelial cell damage, inhibiting endothelial cell growth and inducing smooth muscle cell growth [117,118]. Clinical studies provide evidence that estradiol reduces circulating levels of homocysteine in postmenopausal women [119]. In women-to-men transsexuals, homocysteine levels increase with androgen treatment, whereas in men-to-women transsexuals, homocysteine levels decrease with estrogen substitution [120]. Thus, estrogen may protect the vasculature in part by lowering homocysteine levels.
Endothelin-1 is a vasoconstrictor and mitogenic peptide that is thought to play a role in the pathogenesis of various forms of vascular disease. The synthesis and biological activity of endothelin-1 are regulated by estradiol. Estradiol inhibits serum- and Ang II-stimulated synthesis of endothelin-1 [121] in endothelial cells via ER-receptor dependent mechanisms [122]. Estradiol also blocks the mitogenic effects of endothelin-1 on smooth muscle cells and inhibits endothelin-1 induced MAP kinase activation [123]. Compared with premenopausal women, plasma endothelin-1 levels are increased in postmenopausal women not taking estradiol, and are reduced following estradiol replacement therapy [104,119]. These findings suggest that estradiol may have anti-mitogenic effects on the vasculature in part by reducing endothelin-1 levels.
Estradiol influences the synthesis of a number of factors associated with coagulation and fibrinolysis. For example, estradiol decreases plasma concentrations of clottable fibrinogen, soluble thrombomodulin, plasminogen activator inhibitor 1, antithrombin III and protein S [125–127]. Moreover, most studies report that estradiol decreases levels of von Willebrand factor [128]. Importantly, the effects of estradiol on coagulation and fibrinolytic factors are not the same as those of the oral contraceptive ethinyl estradiol [129]. Even though ethinyl estradiol is administered at a much lower dose than is used for estrogen replacement therapy, it increases coagulation factors such as factor VII, VIII, VIII:Ag, VIII:C, IX and X. Ethinyl estradiol also increases beta-thromboglobulin, plasminogen, fibrinogen antigen and euglobulin lysis activity [130–132], and decreases antithrombin levels and the sensitivity to activated protein C, a process that could increase the risk of thrombosis. Moreover, ethinyl estradiol has a greater ability to induce hepatic synthesis of angiotensinogen than does estradiol, and ethinyl estradiol tends to cause sodium and fluid retention [132]. Unlike the natural estrogens, ethinyl estradiol increases triglycerides and total cholesterol and is associated with impaired glucose tolerance [132].
The clinical significance of the aforementioned effects of estradiol and oral contraceptives on circulating factors is underscored by the well established fact that oral contraceptives induce disorders of coagulation and increase blood pressure, whereas estradiol when used for hormone replacement therapy tends to lower blood pressure and have neutral effects on the coagulation system. In this context, following the early reports in 1960s that blood pressure is elevated in women on oral contraceptives [55], multiple clinical studies have provided evidence that contraceptive estrogens increase blood pressure [55–60]. In a study of 83 women using oral contraceptives for 3 years, increases in both systolic and diastolic blood pressure (9.2 and 5.0 mmHg, respectively) were observed. In a subgroup of these subjects, the mean increases in systolic and diastolic blood pressure were 14.2 and 8.5 mmHg, respectively [133]. Moreover, the blood pressure returned to pretreatment levels within 3 months of stopping the contraceptives [133]. In a longitudinal study of 13 358 women on oral contraceptives, a significant rise in blood pressure was observed, and this increase could be reversed by discontinuing oral contraceptives [134]. The Nurses Health study found that current users of contraceptive estrogens had significantly increased (RR=1.8; 95% CI=1.5–2.3) risk of hypertension compared with never users [59].
The adverse effects of contraceptive estrogens in the past can be attributed to the high doses (
150 µg) of contraceptive estrogens (ethinyl estradiol) used. Indeed, with the current regimen of 30 µg, the blood pressure elevating effects of contraceptive estrogens have been considerably reduced [132]. Briggs and Briggs [135] reported no rise in blood pressure in women taking 30 µg contraceptive estrogens for 3 years, while there was an increase in women taking 50 µg contraceptive estrogens. Lack of blood pressure elevating effects of 30 µg contraceptive estrogens was also observed in a three year study of 1000 women [136]. Although the lower doses may be safer, contraceptive estrogens still can elevate blood pressure and oral contraceptive-induced hypertension is still the most frequent form of secondary hypertension in younger women [137].
Apart from the blood pressure elevating effects of contraceptive estrogens, clinical studies provide evidence that oral contraceptives can disturb glucose metabolism, and induce glucose intolerance, procoagulant effects, hypercholesterolemia and unfavorable effects on the plasma lipoprotein [high-density lipoprotein (HDL) and LDL] profile [132]. High, but not low, doses of oral contraceptive estrogens were associated with increased risk of ischaemic stroke and venous thromboembolism [132]. Taken together, this once again illustrates the concept that all estrogenic compounds are not created equal.
In summary, the direct vasodilator and vasoprotective effects of estradiol are likely reinforced by the ability of estradiol to modify several important humoral systems and circulating factors, including the renin–angiotensin system, homocysteine, endothelin-1, the coagulation cascade and the fibrinolytic system. As discussed above, in contrast to estradiol, the oral contraceptives, such as ethinyl estradiol, induce unfavorable effects on coagulation, fibrinolysis, as well as on hepatic angiotensinogen synthesis, sodium and fluid balance, triglycerides and total cholesterol levels, and glucose tolerance.
2.5. Effects of estradiol on the heart
Hypertension is importantly associated with a remodeling process that leads to cardiac hypertrophy and abnormal growth and function of cardiac fibroblasts and myocytes. Cardiac fibroblasts contribute to pathological changes in the hypertensive heart by proliferating, depositing extracellular proteins and replacing myocytes with fibrotic scar tissue. Estradiol and progesterone inhibit mitogen-induced proliferation of cardiac fibroblasts and extracellular matrix (collagen) synthesis by cardiac fibroblasts [138], suggesting that these sex hormones may attenuate the structural changes in the heart that are usually associated with hypertension. The direct effects of estradiol on the heart may be amplified by estradiol-induced changes in circulating and local factors such as Ang II, endothelin, NO, prostacyclin, adenosine and bradykinin.
Many studies provide evidence that estradiol ameliorates ischemia/reperfusion-induced myocardial injury and ventricular arrhythmias [139–143]. Estradiol may induce these protective effects by: (1) upregulating NO synthesis and opening calcium-activated potassium channels [139]; (2) inhibiting TNF- production and limiting the deleterious ICAM-1 mediated binding of leukocytes to injured myocardium [140]; (3) regulating endothelin-1 synthesis and expression of endothelin type-B receptors [141]; and (4) activating mitochondrial ATP-dependent potassium channels in myocardium [142]. Importantly, the protective effects of estradiol on exercise-induced myocardial ischemia in postmenopausal women are enhanced by the naturally occurring progestin, progesterone, but not by the synthetic progestin, medroxyprogesterone [143].
Female sex hormones have other protective effects on cardiac myocytes. For instance, apoptosis causes loss of cardiac myocytes in heart failure [144], and estradiol prevents programmed cell death in cardiac myocytes [144]. In addition, estradiol and progesterone, but not testosterone, upregulate the expression of heat shock factor-1, and overexpression of this factor attenuates cardiac damage [145]. Other protective mechanisms induced by estradiol in cardiac myocytes include induction of NO synthesis (inducible NOS and endothelial NOS; [146]), reduction in L-type calcium channel current and density [147] and inhibition of K+ currents [148].
The above findings indicate that estradiol has favorable effects on both cardiac myocytes and fibroblasts. The cardioprotective effects of estradiol may attenuate hypertension-induced cardiac damage, as well as ischemia/reperfusion injury of the heart.
2.6. Effects of estradiol on the kidney
The kidneys play a major role in the regulation of blood pressure, and renal abnormalities are involved in the development and maintenance of hypertension. As pointed out repeatedly by Guyton et al. [149], the common defect in hypertension is a shift to the right in the pressure-natriuresis relationship [150]. This contention is strongly supported by the experimental evidence that transplantation of prehypertensive kidneys from SHR to Wistar–Kyoto rats and from Dahl salt-sensitive to salt-resistant rats produces hypertension [150]. Moreover, blood pressure is normalized in hypertensive humans transplanted with kidneys from normotensive donors [151].
Gender-associated differences in renal hemodynamics [single nephron glomerular filtration rate (GFR), glomerular plasma flow, preglomerular resistance, glomerular pressure] and renal responses to Ang II are well established. In single nephrons, GFR and glomerular plasma flow are higher and preglomerular resistance is lower in male compared with female rats despite similar numbers of glomeruli per kidney [16,17]. A reduction in preglomerular resistance is associated with increased glomerular injury, particularly if there is a concomitant increase in systemic BP.
Premenopausal women are protected against the progression of renal disease [16,152,153], and evidence from epidemiological studies, clinical trials and experimental studies with animal models of renal injury suggests that ovarian hormones are responsible for this renoprotection. A meta-analysis has shown that men are predisposed to the rapid progression of multiple non-diabetic chronic renal diseases, including idiopathic membranous nephropathy and autosomal dominant polycystic kidney disease [153]. Further, aged male rats of various strains exhibit decreased GFR and develop glomerular injury, including glomerulosclerosis, at an earlier age than females rats [16,152]. Moreover, estradiol treatment reduces glomerulosclerosis, cellular infiltration, and expression of adhesion and extracellular matrix molecules and prevents tubular damage in animal models with chronic renal allograft rejection or unilateral nephrectomy [154,155]. Since healthy glomeruli are critical for normal renal hemodynamics and blood pressure, the above findings suggest that estradiol helps maintain a normal blood pressure by protecting the kidney.
Estradiol down-regulates the synthesis of multiple factors known to induce glomerulosclerosis and elevate blood pressure. Of particular relevance to the kidney, estradiol decreases: (1) the local synthesis of Ang II within the kidney [109]; (2) the production of endothelin-1 [121], a strong mitogen for glomerular mesangial cells [106]; (3) plasma levels of homocysteine [119], another endogenous factor that causes glomerular damage and induces glomerulosclerosis; (4) IGF-1, a potent mitogen for mesangial cells [106] and IGF-1 receptors [156]; (5) PAI-1, a mesangial cell mitogen that is decreased by almost 50% by estradiol [126]; (6) free radicals [106,157]; (7) oxidized-LDL [158]; (8) cholesterol [158]; and (9) lipid peroxides [159].
Increased generation and deposition of extracellular matrix proteins is an initial step in the development of glomerular obsolescence and progressive loss of renal function. Estradiol suppresses collagen (types I and IV) synthesis in mesangial cells [70,92], suggesting that it may limit the development of glomerulosclerosis by reducing matrix accumulation after glomerular injury. In particular, estradiol inhibits collagen synthesis induced by Ang II and TGFβ, growth factors implicated in the pathophysiology of progressive renal injury in various experimental models of kidney disease [160–162]. Moreover, estradiol inhibits serum-induced collagen synthesis in mesangial cells by down-regulating TGFβ expression [161]. Since endothelin-1 and Ang II induce proliferation of mesangial cells via TGFâ [163], it is likely that estradiol attenuates the deleterious effects of endothelin-1 and Ang II on the kidney by modulating TGFβ. Thus, there is strong evidence that estradiol protects the kidney in part by abrogating the mitogenic effects of multiple growth factors that participate in the pathophysiology of glomerulosclerosis.
In addition to increased production and deposition of extracellular matrix proteins, increased proliferation of mesangial cells play a key role in glomerulosclerosis. Estradiol inhibits mitogen-induced proliferation of human glomerular mesangial cells [92], suggesting that it may protect against glomerular remodeling by inhibiting mesangial cell growth.
Other mechanisms that may contribute to the renoprotective effects of estradiol include: (1) up-regulation of anti-aggregatory pathways by induction of ecto-ADPase in glomeruli and the vessel wall [164]; (2) up-regulation of renal oxytocin receptor gene expression responsible for regulating renal fluid dynamics [165]; (3) prevention of urinary stone formation with inhibition of crystal deposition and calcium content in renal tissue; (4) decrease in urinary excretion of oxalate; (5) down-regulation of the expression of osteopontin mRNA in renal tissue [166]; (6) up-regulation of the synthesis of anti-mitogenic prostaglandins [100]; (7) attenuation of IgA-induced nephropathy [167]; (8) up-regulation of adenosine synthesis [99]; and (9) increases in NO synthesis by glomerular endothelial cells [92].
Injury to glomerular endothelial cells (ECs) also contributes to glomerulopathies [168], and growth of glomerular ECs participates in capillary repair in glomerulonephritis. Since estradiol induces growth of aortic ECs, it may also facilitate the glomerular repair process by inducing growth of glomerular ECs. It is important to note that estradiol induces VEGF synthesis [169], and VEGF is known to repair glomerular EC injury [170]. This suggests that estradiol may protect the glomeruli by inducing VEGF synthesis in glomerular ECs. Estradiol prevents TNF and LPS-induced apoptosis of vascular ECs [171]. Thus it is likely that estradiol also protects against the deleterious effects of TNF and LPS on glomerular ECs.
In summary, estradiol engages multiple mechanisms to protect the kidney from injury. Thus, estradiol-induced renoprotection may importantly contribute to the ability of estradiol to maintain the normotensive state.
2.7. Effects of estradiol on the sympathetic nervous system
In 12 perimenopausal women randomized to receive estradiol valerate (n=7) or placebo (n=5), Sudhir et al. [172] demonstrated that estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover. Vogpatanasin et al. [173] recently conducted a randomized, crossover, placebo-controlled study in 12 normotensive postmenopausal women who were treated for 8 weeks with either transdermal estradiol, oral conjugated estrogens or placebo. Measured parameters included 24-h ambulatory blood pressure and sympathetic nerve discharge. Transdermal estradiol, but not conjugated estrogens, decreased sympathetic nerve discharge and blood pressure. Hunt et al. [174] examined the effects of conjugated estrogens administered for 6 months to 11 healthy, postmenopausal women on baroreflex function. In this study, conjugated estrogens did not affect blood pressure or cardiac-vagal baroreflex gain, but significantly increased sympathetic baroreflex gain. The effects of estrogen on sympathetic baroreflex reflexes are also supported by two other studies in postmenopausal women [175,176]. Moreover, in menopausal women, acute administration of estradiol and progesterone attenuated mental stress-induced cardiovascular responses and increases in plasma catecholamines [177], and muscle sympathetic nerve activity measured by microneurography is reduced in women compared with age-matched men [178].
There is also evidence that estradiol inhibits the sympathetic nervous system in animal models of hypertension. In this regard, Fang et al. recently demonstrated that in SHR endogenous estradiol, as well as phytoestrogens (genistein, an ERβ ligand), attenuate NaCl-induced hypertension by inhibiting NaCl-induced activation of the sympathetic nervous system [179]. These findings are consistent with the sexually dimorphic response to dietary NaCl supplementation observed in SHR and WKY rats [180,181].
In summary, it appears that estradiol, but not conjugated estrogens, decreases basal sympathetic tone, and that estrogenic preparations may augment sympathetic baroreflex gain. These effects would reinforce the antihypertensive actions of estradiol.
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3. Progestins and hypertension |
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TopAbstract1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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3.1. Effects of progestins on blood pressure
Data from both human and animal studies indicate that progesterone, the natural progestin, has either neutral or depressor effects on blood pressure. For example, decreases in blood pressure with the progression of pregnancy are positively correlated with increases in progesterone [182]. Moreover, oral administration of natural progesterone significantly lowered blood pressure in six men and four postmenopausal women with mild to moderate hypertension who were not receiving antihypertensive drugs [183]. In contrast, administration of natural progesterone (200 mg, orally) to seven postclimacteric women failed to influence blood pressure [184]. In animal studies, acute administration of progesterone did not alter mean arterial blood pressure in rats [185].
Most studies conducted with synthetic progestins for contraception or hormone replacement therapy have shown a blood pressure elevating effect [132]. Contraceptive progestins have androgenic activity, whereas natural progesterone are non-androgenic. The blood pressure elevating effects of contraceptive progestins may therefore depend on the androgenicity of the individual progestin [186].
In theory, synthetic progestins increase blood pressure by stimulating sodium retention [187]. However, data from small well controlled clinical studies (Table 1) provide evidence that sequential administration of the non-androgenic progestogen medroxyprogesterone acetate (MPA) or the androgenic progestogen norethisterone acetate (NETA) either does not alter or enhances the blood pressure lowering effects of estrogens. In a randomized double-blind crossover study of 53 postmenopausal women treated for 4 weeks with conjugated equine estrogen (0.625 mg daily) and sequentially with either 2.5, 5 and 10 mg MPA during the last 14 days [186], there was a dose-dependent decrease in daytime ambulatory diastolic and mean arterial blood pressure with the MPA treatment [186]. Similar to MPA, the progestin NETA was shown to significantly enhance the blood pressure lowering effects of estradiol in a placebo-controlled randomized crossover study in 16 normotensive postmenopausal women [38]. In summary, based on the human data it is evident that at least some progestins given in the cyclic regimens of hormone replacement therapy have blood pressure neutral or lowering effects.
3.2. Effects of progestins on vascular tone
Similar to estradiol, progesterone induces endothelium-dependent vascular relaxation. In coronary arteries from dogs pretreated with estradiol, endothelium-dependent relaxation is enhanced by progesterone [188]. These findings suggest that natural progesterone has beneficial or neutral, but not adverse, effects on blood pressure. On the other hand, synthetic progestins seem to antagonize the beneficial effects of estradiol on the vasculature. In vitro studies provide evidence that estradiol-induced NO synthesis is inhibited by synthetic progestins [92,93], and in women the vasodilator effects of estradiol are diminished by co-administration of synthetic progestins such as MPA and cyproterone acetate [93]. In atherosclerotic monkeys, estradiol induces coronary artery dilation and increases blood flow reserve, and co-administration of MPA results in a 50% reduction in the dilator response to estradiol [189]. Moreover, estradiol-induced NO synthesis in postmenopausal women is significantly reduced by MPA, as well as by other synthetic progestins such as norethisterone acetate and cyproterone acetate [83,84]. Moreover, MPA can abrogate the antivasoocclusive effects of estradiol following vascular injury ([190]; Fig. 1).
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In summary, natural progesterone augments and some synthetic progestins abrogate the beneficial effects of estradiol on vascular tone and the vascular injury response. Nonetheless, synthetic progestins may augment the antihypertensive effects of estradiol. The aforementioned studies teach that like estrogens, not all progestins have the same pharmacological effects.
3.3. Effects of progestins on vascular growth
Similar to estradiol, progesterone inhibits mitogen induced growth and proliferation of cardiac fibroblasts [138], vascular smooth muscle cells [191] and glomerular mesangial cells [106], which contribute to the vascular and glomerular remodeling associated with hypertension, atherosclerosis and glomerulosclerosis. Little is know regarding the effects of synthetic progestins on vascular growth.
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4. Androgens and hypertension |
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TopAbstract1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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4.1. Effects of androgens on blood pressure
Relatively little is known regarding the influence of androgens on blood pressure and cardiovascular disease. There are reports of lower circulating testosterone [192–194] and androstenedione [194] levels in hypertensive men [192–194], and circulating testosterone levels in men with coronary artery disease [195] or myocardial infarction [196] are either unchanged or decreased. These studies suggest that decreased, rather than increased, androgen levels are associated with hypertension, myocardial infarction and coronary artery disease. An important caveat is that the lower testosterone levels observed in the aforementioned studies may merely reflect increased stress. Testosterone levels decrease in response to stress induced by recent myocardial infarction, surgery, head trauma, burns, hypoxia, sleep deprivation and psychological stressors [196]. Thus, the lower levels of testosterone in men with hypertension and cardiovascular disease may not indicate that testosterone reduces blood pressure and protects the cardiovascular system. In support of this conclusion is the low prevalence of coronary disease among men with hypotestosteronemia plus hyperestrogenemia [195]. Also, women suffering from chronic anovulation and exhibiting hypertestosteronemia have an increased risk of coronary artery disease and myocardial infarction [196]. Moreover, men with testosterone deficiency following orchiectomy have a slightly lower mortality from heart disease [196], suggesting that lower testosterone may protect against cardiovascular disease.
In summary, clinical studies are needed to directly define the effects of testosterone on the cardiovascular system in human subjects. Studies should be conducted in men with Klinefelter disease who have testosterone deficiency and require testosterone supplementation. Results from these studies could provide data on the dose-dependent effects of testosterone on cardiovascular function.
Studies in animals strongly suggest that testosterone is a pro-hypertensive hormone. Blood pressure is higher in male SHR, Dahl salt-sensitive rats, deoxycorticosterone acetate-salt hypertensive rats and New Zealand genetically hypertensive rats compared to females [6–13]. The association between testosterone and high blood pressure in these animals is supported by the observation that castration at a young age (3–5 weeks) attenuates the development of hypertension in SHR and Dahl salt-sensitive rats [6–9,14,15]. Furthermore, treatment of ovariectomized normotensive females or castrated males with testosterone increases blood pressure to levels similar to those in intact males [7,9], and testosterone increases blood pressure in ovariectomized female SHRs [7,9]. Moreover, irreversible increases in arterial blood pressure are observed in normotensive, uninephrectomized female rats treated chronically with testosterone [197,198].
Use of anabolic steroids that are synthetic derivatives of testosterone is temporally associated with hypertension, ventricular remodeling, myocardial ischemia and sudden cardiac death [199]. Moreover, in a double blind placebo-controlled study in 21 men, treatment with testosterone enanthate (3.5 mg/kg body weight) for 12 weeks significantly increased systolic blood pressure by 10 mmHg [200]. In contrast, administration of testosterone to 20 male subjects (mean age 70.6±6.2 years) to achieve physiologic and superphysiologic serum testosterone concentrations did not increase blood pressure [201], and no changes in blood pressure were observed in men receiving testosterone undecanoate (120 mg/day for 5 days; [202]). The different outcomes in the above studies may have been due to the age group of the subjects tested (young vs. old) or the duration of treatment (acute vs. long-term). Importantly, the blood pressure elevating effects were observed in subjects who were undergoing regular weight training. In contrast, the subjects with no increase in blood pressure did not exercise. Therefore, it is possible that the effects of testosterone on blood pressure are modulated by exercise.
A number of mechanisms by which testosterone can elevate blood pressure and damage blood vessels have been elucidated. Testosterone increases circulating levels of homocysteine. Homocysteine induces endothelial damage, thus leading to the development of atherosclerosis, and may adversely influence renal function by damaging glomerular endothelial cells [120]. In contrast to estradiol, testosterone increases endothelin-1 levels in subjects undergoing a sex change, providing a humoral mechanism by which it may elevate blood pressure [120]. Finally, in male SHR, elevated levels of catecholamines are associated with high blood pressure [203], and castration reduces catecholamine levels to those observed in normotensive controls [204], suggesting that testosterone can also directly induce catecholamine synthesis [204]. This effect may be explained by the observation that testosterone stimulates tyrosine hydroxylase, the rate limiting enzyme for catecholamine synthesis [203,204]. Thus, testosterone may elevate blood pressure and contribute to the pathogenesis of cardiovascular disease by altering a number of humoral factors, including homocysteine, endothelin-1 and catecholamines.
4.2. Effects of androgens on vascular tone
Androgen receptors are expressed in vascular cells [108], and androgens may have a functional role in modulating vascular tone. Testosterone relaxes precontracted rabbit coronary arteries and aortas in vitro, with or without endothelium [108,205]. Short-term intracoronary infusions of testosterone dilate male and female canine coronary arteries in vivo and increase coronary blood flow. These vasodilator effects of testosterone are largely mediated via ATP-sensitive K+ channels [206]. Via similar mechanisms, short-term intracoronary administration of physiological concentrations of testosterone induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease [207]. Androgen receptor blockers do not alter these rapid onset acute vasorelaxing effects of testosterone. Therefore, the acute vascular effects of testosterone are most likely androgen-receptor independent and non-genomic.
In porcine coronary arteries, testosterone, progesterone and estradiol induce concentration-dependent relaxation of both prostaglandin F2-induced and KCl-induced contraction [208,209]. In contrast to estradiol, testosterone and progesterone have greater relaxing effects on vessels precontracted with prostaglandin F2. Estradiol inhibits Ca2+ entry, and progesterone and testosterone cause coronary relaxation by inhibiting other contractile mechanisms [208,209]. Estradiol induces NO synthesis in endothelial cells, and this effect is accompanied by translocation of membrane-associated eNOS [210]. In contrast to estradiol, neither progesterone nor testosterone modulates NO synthesis [210]. Testosterone improves post-exercise ST-segment depression in patients with angina [196,211,212], and short-term administration of testosterone induces beneficial effects on exercise-induced myocardial ischemia in men with coronary artery disease, an effect that may be due to the direct coronary-relaxing actions of testosterone [213].
In contrast to the direct vasodilator and vasorelaxing effects discussed above, testosterone may block the effects of other vasodilator agents. In this regard, coronary vascular perfusion with testosterone blocks adenosine-mediated vasodilation via a rapid non-genomic mechanism [214]. Treatment of cultured cells with testosterone, but not estradiol, significantly increases thromboxane A2 receptor density. This effect is inhibited by the testosterone receptor blocker hydroxyflutamide, suggesting the involvement of androgen receptors. The testosterone precursor androstenedione also increases thromboxane A2 receptor density [215,216]. Several lines of evidence support the functional significance of this androgen-induced increase in thromboxane A2 receptor density. The aortas of male rats show increased (compared to females) contractile responses to thromboxane A2 [215]. Further, testosterone enhances coronary artery constriction induced by a thromboxane A2 mimetic in vitro and in vivo [217]. Thromboxane A2 is implicated as a risk factor for cardiovascular diseases, and it is possible that the contrasting effects of estradiol and testosterone on thromboxane A2 signaling may, in part, be responsible for some of their differential effects on the cardiovascular system.
Testosterone has additional pro-hypertensive effects. In SHR, testosterone enhances the activity of tyrosine hydroxylase, the rate limiting enzyme in norepinephrine synthesis, and the resultant increase in norepinephrine levels may contribute to the development of hypertension in male animals with this form of genetically-determined hypertension [204]. Moreover, testosterone up-regulates the release of the potent vasoconstrictor neuropeptide Y [218]. Testosterone also enhances, whereas estradiol attenuates, the contractile effects of endothelin-1 in porcine coronary artery rings [219].
These findings indicate that testosterone can activate mechanisms that cause both vasoconstriction and vasorelaxation. The balance between the vasodilating and vasoconstricting effects of testosterone determines its net effect on vascular tone and, perhaps, blood pressure. Thus, the inconsistent effects of testosterone on blood pressure discussed above may be due to its variable effects on vascular tone, in part dependent on the pretreatment condition of the vasculature.
4.3. Effects of androgens on vascular growth and atherogenesis
There is evidence that testosterone can protect against the response to vascular injury and the development of atherosclerosis [205,220,221]. In cholesterol fed rabbits [221], testosterone is anti-atherosclerotic by a mechanism independent of changes in plasma lipids. Testosterone also protects against post-injury-induced plaque development [205]. Despite its anti-atherosclerotic effects in rabbits, testosterone does not inhibit smooth muscle cell proliferation [220]. Testosterone is also ineffective in inhibiting mitogen-induced smooth muscle cell migration [222] and proliferation in vitro [157,223]. These findings suggest that the vasoprotective effects of testosterone are not mediated by inhibition of vascular smooth muscle cell growth.
In contrast, a number of other observations suggest that testosterone is pro-atherosclerotic. Testosterone: (1) exacerbates diet-induced atherosclerosis and has adverse effects on atherosclerosis-related arterial remodeling in female monkeys [224]; (2) induces vascular plaque formation in chicks [225]; (3) increases monocyte adhesion to vascular endothelial cells and increases the expression of vascular cell adhesion molecule-1 in humans [226]; (4) lowers HDL and raises LDL [227]; (5) up-regulates the release of neuropeptide Y [219] which can induce pro-atherosclerotic actions and local vasoconstriction; (6) has a pro-mitogenic effect on vascular smooth muscle cells [228]; and (7) increases the synthesis of Ang II, a vasoconstrictor and mitogen known to induce hypertension and atherosclerosis [6]. Thus, whether testosterone inhibits or accelerates atherosclerosis appears to be model dependent.
4.4. Effects of androgens on cardiac mechanisms
Testosterone and its metabolite dihydrotestosterone (DHT) induce cardiac hypertrophy in part by activating androgen receptors that are expressed in cardiac myocytes [229]. In baroreceptor-denervated rats, left ventricular hypertrophy is gender-dependent; estradiol inhibits, whereas testosterone stimulates, cardiac hypertrophy [230]. Moreover, in vitro studies provide evidence that androgens induce hypertrophic growth in cultured myocytes [229], suggesting that the growth promoting effect is direct. The hypertrophic effects of DHT, but not testosterone, are associated with increased synthesis of atrial natriuretic peptide [229], suggesting that these androgens may induce hypertrophy via different mechanisms.
4.5. Effects of androgens on renal mechanisms
Reckelhoff and Granger have described several mechanisms by which androgens can induce renal injury and precipitate hypertension [231]. Studies in rat models provide evidence that, compared with females, ageing males exhibit decreased glomerular filtration rate and develop glomerular injury, glomerulosclerosis, proteinuria and increased blood pressure [16,152,231]. Castration at an early age attenuates renal injury and prevents the development of hypertension; whereas, administration of exogenous testosterone to castrated animals increases blood pressure to levels similar to those found in intact males [7,152,231]. These findings suggest testosterone can adversely influence renal function and blood pressure, eventually leading to hypertension.
The kidneys express androgen receptors [231,232], and studies have examined whether the effects of testosterone on blood pressure are androgen-receptor mediated. Administration of flutamide, an androgen receptor antagonist, to intact male SHRs lowers blood pressure to levels found in female or castrated male SHRs [232], suggesting that the effects of androgens are receptor mediated. Furthermore, sodium-induced increases in blood pressure in Wistar–Kyoto and SHR are suppressed by androgen-receptor blockade [233], confirming the androgen-receptor dependence of salt sensitive hypertension in this animal model.
Disruption of the CYP4A14 gene (arachidonic acid 
-1-hydroxylase) in mice results in hypertension that is more severe in males and is androgen sensitive, i.e., increases in blood pressure are reduced upon castration and restored upon testosterone supplementation [234]. Renal vascular resistance is dramatically increased in these mice, suggesting that lack of functional CYP4A14 in the kidney may have several interrelated metabolic and regulatory effects whose functional manifestations are increased renal vascular resistance, impaired renal hemodynamics and hypertension. It has been suggested that the final mediator for the blood pressure enhancing effects of androgens in CYP4A14 knockout mice is 20-HETE [234], which is known to alter renal hemodynamics and function.
Another key mechanism by which androgens tilt the cardiovascular system toward a pro-hypertensive state is by shifting the pressure-natriuresis relationship to the right [149,150,152]. At comparable renal perfusion pressures, intact SHR males and ovariectomized females receiving chronic testosterone treatment excrete significantly less sodium and water than intact females, ovariectomized females or castrated males [7,231]. These effects may be mediated by the renin–angiotensin system because testosterone increases plasma renin activity (PRA) [7,152,231], castration of male rats decreases PRA, and administration of testosterone to ovariectomzied female rats increases PRA [7,152,231]. The effect of testosterone on PRA is dose-dependent [7,152,231]; suggesting that the blood pressure regulating effects of testosterone may be concentration-dependent [7,152,231]. Angiotensinogen mRNA levels are also higher in male rats than in females, and castration reduces these levels [235,236]. Thus, animal studies provide convincing evidence that testosterone diminishes the ability of the kidneys to excrete salt, and thereby predisposes to hypertension. Whether this occurs in humans is unknown.
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5. Gender independent factors and role of hormone metabolism |
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TopAbstract1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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Both estradiol and testosterone are present in both sexes, albeit in different concentrations and ratios [196]. Endogenous androgens (dehydroepiandrosterone, androstenedione, and testosterone) are readily converted to estradiol by the sequential actions of 17β-hydroxysteroid dehydrogenase (17β-HSD) and aromatase. Thus, some of the beneficial effects of testosterone observed in males may be due to its conversion to estradiol and estradiol metabolites. This hypothesis is supported by the recent finding that the inhibitory effects of dehydroepiandrosterone, a precursor of androstenedione, on atherosclerosis are blocked by the aromatase inhibitor fadrozole [237]. This finding suggests that the sequential conversion of androgens to estradiol is responsible for their anti-atherosclerotic actions, but whether estradiol is the ultimate mediator remains unclear.
Findings from our laboratory provide evidence that sequential metabolism of estradiol to catecholestradiols and ultimately methoxyestradiols is responsible for the anti-mitogenic effects of estradiol on vascular smooth muscle cells [238], cardiac fibroblasts [239] and glomerular mesangial cells [240]. Importantly, these effects of estradiol on cell growth appear to be ER-independent [92,238]. Increased proliferation of these cell types leads to hypertension, vascular disease, left ventricular hypertrophy and glomerulosclerosis. Thus, some of the cardiovascular and renal protective effects of both testosterone and estradiol may be mediated via their conversion to methoxyestradiols, which have anti-mitogenic effects on multiple cell types (Fig. 2). The importance of estradiol metabolites in vasoprotection is further supported by our finding that in male obese ZSF1 rats that exhibit the metabolic syndrome (i.e., hypertension, obesity, diabetes and hyperlipidemia) and have left ventricular, renal and vascular dysfunction, treatment with 2-hydroxyestradiol decreases body weight, improves vascular endothelial function, decreases nephropathy, exerts antidiabetic actions and lowers blood pressure and blood cholesterol [241].
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The hypothesis that estradiol metabolites are responsible for the anti-mitogenic effects of estradiol is supported by several recent findings. Estradiol prevents neointima formation in mice lacking functional ER-
and ER-β, suggesting that the protective effects of estradiol on the cardiovascular system may be ER independent. Estradiol prevents neointima formation in gonadectomized, but not intact male rats, even though male rats express ER- and ER-β. In female rats the inhibitory effects of estradiol are abrogated by medroxyprogesterone, a synthetic progestin [190]. Since both androgens and medroxyprogesterone are potent inhibitors of the enzyme responsible for the formation of 2-hydroxyestradiol ([242], Dubey et al. unpublished data), these steroids may abrogate the anti-vasoocclusive effects of estradiol by blocking its metabolism to hydroxyestradiols and methoxyestradiols. This hypothesis merits further direct testing. Lifestyle factors, such as dietary habits and stress, may participate in the development of cardiovascular diseases. Since life style factors can interfere with estradiol metabolism, it is feasible that they may induce their adverse effects in part by preventing methoxyestradiol formation. In this regard, it is important to note that metabolism of 2-hydroxestradiol to 2-methoxyestradiol is mediated by catechol-O-methyltransferase (COMT), the enzyme that metabolizes catecholamines to methoxy metabolites. Our recent studies show that catecholamines can abrogate the anti-mitogenic effects of estradiol and 2-hydroxyestradiol on vascular smooth muscle cells, cardiac fibroblasts and glomerular cells, and that these effects are associated with the inhibition of 2-methoxyestradiol formation [243,244].
Although catecholamines may not normally interfere with the metabolism of estradiol to 2-methoxyestradiol, production of 2-methoxyestradiol may be seriously compromised under pathological conditions associated with increased release of catecholamines. As illustrated in Fig. 2, under normal conditions, testosterone is metabolized by aromatase to estradiol; estradiol is metabolized by hydroxylases (CYP1A1, CYP1A2 and CYP1B1) to catecholestradiols (e.g., 2-hydroxyestradiol), and catecholestradiols are metabolized by COMT to methoxyestradiols [245], which induce anti-vasoocclusive effects [238,244]. However, when catecholamine release is increased, catecholamines compete with catecholestradiols and inhibit their metabolism to methoxyestradiols. This results in increased accumulation of catecholestradiols, inhibition of hydroxylases and therefore accumulation of estradiol. Since estradiol inhibits testosterone synthesis by negatively regulating FSH/LH synthesis [246], the net result is a decrease in levels of testosterone. The general principle illustrated by this hypothesis is that the metabolism of estradiol and testosterone may play a critical role in determining the overall effects of sex hormones on the cardiovascular system.
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6. Conclusion |
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TopAbstract1. Introduction2. Estrogens and hypertension3. Progestins and hypertension4. Androgens and hypertension5. Gender independent factors...6. ConclusionAcknowledgmentsReferences |
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Compared to men and postmenopausal women, premenopausal women are relatively protected against hypertension and its sequelae. Animal studies provide strong evidence that estradiol is an antihypertensive sex hormone, whereas testosterone is pro-hypertensive. As summarized in Fig. 3, the mechanisms by which both estradiol and testosterone affect blood pressure are multifaceted and involve direct effects on vascular, renal and heart cells, as well as indirect effects mediated by humoral factors. It is not yet possible to arrive at any firm conclusions regarding the role of progesterone in hypertension.
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