an excess of steroid hormones such as mineralocorticoids has been linked to heart hypertrophy , arrhythmias , inflammation , fibrosis , and apoptosis as well as to endothelial and smooth muscle vascular dysfunctions . benefits of antagonizing aldosterone action in patients with cardiovascular diseases ( cvd ) have demonstrated a causal relationship between steroid hormones and cvd ( 1 ) . on the other hand , putatively protective steroid hormones such as dehydroepiandrosterone ( dhea ) decrease with aging . dhea , and particularly its sulfated derivative , dhea sulfate ( dhea - s ) , are among the most abundant circulating steroid hormones . these two hormones are derived from cholesterol and are principally produced by the adrenal cortex ; however , small amounts of them have been proposed to be produced by other organs such as the heart . since the discovery of dhea and its sulfated metabolite during the first half of the 20th century , many publications have hypothesized that the development of dhea deficiencies with age might play a key role in the degradation of many functions and contribute to the genesis of several disorders , including cardiovascular defects ( 2 ) . other studies have reported a beneficial role for dhea ( s ) in various physiologic or pathophysiologic conditions such as brain development , aging , osteoporosis , immune system - mediated rheumatologic diseases , diabetes mellitus ( dm ) , obesity , chronic heart failure ( particularly when linked with oxidative stress ) , and recently , vascular remodeling as occurring in pulmonary arterial hypertension ( 3 ) . nevertheless , only few marked beneficial effects have been clearly reported with dhea supplementation in human and therefore , this subject is still controversial . in the present article , we aimed at providing a short review of recently published works showing the inverse correlation between the circulating levels of dhea and dhea - s and the degree of illness in several pathophysiologic situations . we focused our attention on cvd and on the beneficial effects of counteracting dhea ( s ) deficiency by supplementation . we also discussed the putative mechanisms of action exerted by the hormone in several cardiovascular target organs and tissues . all references have been searched using pubmed and the following strategy : our initial selection included all articles in english language and we sorted them with the keywords  dhea or dhea - s  and  heart or vascular or endothelium or cardiovascular disease  . the final selection was made according to the relevance of the article content to the aims of the review . according to these criteria , correlation between dhea or dhea - s plasma levels and ageing - related pathologies has been widely explored during the last twenty years . indeed , dhea ( s ) levels in circulation decrease with ageing more markedly than those of other hormones . numerous studies have shown a negative correlation between the levels of these hormones and ageing , as defined by the occurrence of several disorders including cvd as well as more definitive entities such as mortality . however , the predictive value is influenced by factors such as sex and smoking habits . in a cohort of elderly subjects , it was demonstrated that dhea - s levels inversely correlated with men mortality whereas there was no association with women mortality ( 4 ) . in addition , only one published work has clearly mentioned physiologic differences between dhea and dhea - s to relate their respective concentrations to various pathologies ( 5 ) . they highlighted the difficulty to properly correlate dhea concentration with diseases , probably due to the different hormone distribution throughout life , compared to its sulfated form . the authors also reported that dhea - s levels are much more often measured in studies than dhea levels , which are often not reported at all . the cvd encompass numerous and diverse kinds of pathologies related to peripheral vessels as well as to the heart . have demonstrated that mean dhea - s concentrations decreases in men with age and are significantly lower in those with a history of heart disease ( 6 ) . after adjustment for age and other cvd risk factors , they found that men with lower dhea - s levels ( < 3.8 mol / l ) had a 1.5-fold higher risk to die of any cause ( which was not statistically significant ) , but a 3.3-fold higher risk to die of cvd ( p < 0.05 ) , and particularly from ischemic heart disease ( ihd ) . clinical and demographic parameters are relevant to drawing any conclusion about causal relationship between dhea ( s ) and cvd . for example , concerning the sex , studies are more consistent for men , and when looking at women cohorts , the relationship between dhea - s and mortality from all causes , including from cvd , is often less obvious . nevertheless , in the wise ( women s ischemia syndrome evaluation ) study , including 270 postmenopausal women undergoing coronary angiography for suspected ischemia , a positive correlation between dhea - s levels and cvd outcome was reported , which was potentially explained by a better atherosclerosis state of patients with higher dhea - s levels ( 7 ) . another study demonstrated that the decrease of dhea - s concentrations observed in elderly women is significantly more pronounced in case of coronary heart diseases , osteoporosis or depression ( 8) . in contrast , prospectively investigating the longitudinal patterns of sex steroids in a cohort of 254 elderly men on a ten - year follow - up did not reveal any significant association between sex steroids ( testosterone and dhea - s ) and the incidence of cvd or all - cause mortality risk ( 9 ) . in conclusion , dhea - s levels are variably good markers not perfect for predicting cvd in the general population probably because many additional important factors have to be integrated in these predictions . the role of dhea and dhea - s has been studied in the context of endothelial function in postmenopausal women with coronary risks factors . results have shown that lower levels of dhea - s are associated with endothelial dysfunction as assessed by a positive correlation between dhea - s and percentage of flow - mediated dilatation ( % fmd ) , a marker of endothelial function ( 10 ) . this correlation was independent of other coronary risk factors such as age , body mass index , blood pressure , total and high - density lipoprotein cholesterol ( hdl - c ) , fasting glucose levels , or smoking habits . recent studies evaluated whether dhea ( s ) is associated with development of carotid atherosclerosis , a situation predicting cardiovascular complications . for example , measurement of intima media thickness ( imt ) , blood flow volume , and endothelial function ( % fmd ) has been performed by ultrasonography of carotid arteries in 419 japanese patients of both sexes with cardiovascular risk factors , and imt appeared to be inversely correlated with dhea - s levels in males , but not in females . in contrast , dhea - s was a positive factor for predicting blood flow volume in females , but not in males , and no significant correlation could be demonstrated in this study between dhea - s and % fmd regardless of sex ( 11 ) . the association between androgen levels , including dhea - s and total and bioavailable testosterone , with aortic atherosclerosis has been also investigated in 1032 nonsmoking dutch men and women aged 55 years or older . intimal atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta ; however , no clear association between levels of dhea - s and presence of severe aortic atherosclerosis was found in men or women ( 12 ) . in order to examine the association between dhea and coronary atherosclerosis , plasma dhea and dhea - s levels had been previously determined in 206 middle - aged patients undergoing coronary angiography . the dhea - s level was significantly lower in subjects with stenosis and was inversely associated with the number of affected coronary vessels and the extent of coronary atherosclerosis ( 13 ) . another part of the same study also investigated the putative protection of dhea against the development of vasculopathy after cardiac allograft . in a cohort of 61 cardiac allograft recipients , it has been found that dhea levels inversely correlated with the development of accelerated coronary vasculopathy , which appeared earlier in patients with low levels of the hormone , suggesting that high levels of dhea could retard the development of coronary atherosclerosis and coronary allograft vasculopathy . in a prospective study ( massachusetts male aging study ) on 1167 males aged 40 to 70 years at baseline followed for over ten years , low serum dhea ( s ) was predictive of later ihd independent of other risk factors . mol / l ) were significantly more likely to develop ihd with an adjusted odds ratio of 1.6 ( 95% ci , 1.07 - 2.39 ) ( 14 ) . the risk of ischemic stroke might be influenced by dhea - s levels , as suggested by another study based on a cohort of 32 826 women ( nurses health study ) following patients for cardiovascular events ( 15 ) . matching 461 cases of ischemic strokes confirmed by medical records , with controls of the same age , race , menopausal status , hormone use , and smoking status demonstrated that lower dhea - s levels were associated with a greater risk of stroke . association of atrial fibrillation and its prevalence with dhea - s levels were investigated in 436 men and 544 women aging 65 to 97 years old . interestingly , a low dhea - s concentration was significantly associated with cardiac arrhythmias in men , while occlusive arterial diseases , chronic obstructive lung disease , or osteoporosis were more frequent in women with low dhea - s . however , only the association with osteoporosis remained significant after controlling for differences in lifestyle and general health status parameters ( 16 ) . the authors concluded that in the elderly , low serum dhea - s levels are more a nonspecific indicator of aging and health status rather than a risk marker of specific diseases . diabetes mellitus is frequently associated with cvd , and significantly lower dhea - s concentrations were observed in 51 diabetic patients with a specific subtype of type 2 dm in comparison with 49 healthy controls ( 17 ) . the putative cardioprotective effect of dhea has been investigated in 62 male patients with type 2 dm by determining the association between the hormone levels and the activated protein c , c - reactive protein , and the imt of the carotid artery . the study concluded that lower circulating levels of dhea are associated with decreased activated protein c generation and higher imt in patients type 2 dm ( 18 ) . finally , testosterone and dhea were determined in 153 men with dm ( age , 65  9 years ) with coronary artery disease ( cad ) . androgen deficiency , defined as serum levels below the 10th percentile of healthy peers , was common in men with dm with stable cad and predicted increased cardiovascular mortality ( 19 ) . several early supplementation studies have been done before any clinical studies aimed at measuring dhea or dhea - s levels . this fact led to many misunderstandings as supplementation was not always provided for correcting dhea ( s ) deficiencies in patients . systemic vascular remodeling , as occurring during restenosis after injury , is characterized by the presence of proliferative and apoptosis - resistant smooth muscle cells with activated akt pathway . because dhea has been previously proposed to inhibit this pathway in cancer , bonnet et al . investigated a putative role for dhea in remodeling vessel wall both in vitro , using cultured human carotid vascular smooth muscle cells and saphenous vein grafts challenged with pdgf , and in vivo , with a rat carotid injury model . in each case , dhea reduced proliferation and increased apoptosis of smooth muscle cells through the inhibition of the akt pathway . dhea effect was unaffected by androgen or estrogen antagonists , suggesting a steroid receptor - independent mechanism . the authors concluded that orally available dhea might be attractive for treating systemic vascular remodeling , including restenosis ( 20 ) . in order to mimic the metabolic dysregulation often occurring in the elderly , these animals develop inflammatory processes and cardiomyopathies linked to their diabetic state . in this context , dhea seems to be beneficial for counteracting cardiac disturbances such as unbalanced oxidative status , impairment of cardiac myogenic factors , and contractility dysfunction ( 21 ) . in a model of rabbits fed with a high fat diet and displaying hyperglycemia , insulin resistance , dyslipidemia , increased oxidative stress , and proinflammatory insults , the impairment of cardiac contractility was observed by measuring the switch of myosin heavy chain ( mhc ) isoforms expression . in these animals , low dose of dhea supplementation , which did not affect glucose levels or insulin resistance , restored the oxidative balance and lowered lipid levels and inflammation , preventing alteration of the cardiac function and delaying the onset of cardiac tissue damage . a similar effect of dhea has been observed by the same authors in rats with streptozocin - induced dm ( 22 ) . the hyperglycemia - induced oxidative stress increases advanced glycated end - products ( ages ) and triggers a cascade of signaling involving nfb ( 23 ) , finally leading to interstitial fibrosis . the dhea treatment , by improving the oxidative balance , counteracts the age action and restores the contractility of the ventricular tissue by preventing the fibrotic response . dhea also improved the right ventricular function and remodeling in rats upon reoxygenation after 21 days of hypoxia ( 24 ) . ex vivo investigations demonstrated that the presence of dhea during the reoxygenation phase increased myocytes proliferation through cyclic amp response element binding protein ( creb ) and pgc1 activation , prevented mitochondrial fragmentation , and improved the respiratory chain activity . dhea supplementation ( 25 mg / day ) in asymptomatic , normotensive , non - diabetic and nonsmoker men with hypercholesterolemia ( mean age , 54 years ) increased plasma levels of dhea - s and significantly ameliorated the % fmd of arteries ( 25 ) . this observation points out that for this specific dhea ( s ) action , results are in good agreement in both sexes , as previously discussed for postmenopausal women ( 10 ) . this was confirmed in another study , where supplementation of 36 healthy postmenopausal women with dhea ( 100 mg / day ) for three months also increased the % fmd and the laser doppler velocimetry parameters , and significantly reduced total plasma cholesterol concentration ( 26 ) . in contrast , dhea - s supplementation ( 50 mg / day ) appeared to have beneficial effect on neither insulin action , determined by euglycemic hyperinsulinemic clamp , nor the quality of life , measured by extensive parameters in female patients with hypopituitary hypoadrenalism ( with very low dhea - s levels ) and following standard replacement therapy ( 27 ) . however , the quality of life in this study was not assessed in term of cardiovascular health , which has been clearly shown to be associated with metabolic diseases . the benefits of dhea supplementation in the aging population is highly controversial within the literature and therefore , published studies have been recently reviewed in a meta - analysis to determine whether there is a potential therapeutic role of dhea in postmenopausal women ( 28 ) . in spite of several observational studies showing that lower dhea levels were associated with increased cardiovascular risk in women , interventional trials did not demonstrate improvement atherosclerosis or cardiovascular risk factors by dhea supplementation . the dhea even appears to be responsible for lowering hdl - c levels , a putative cardioprotective marker , probably through an androgen - dependent mechanism ; however , it is not clear how much this action of dhea is detrimental to the cardiovascular function . the authors conclude that there was no strong current evidence in favor of dhea supplementation in healthy postmenopausal women . several reports also suggest that high doses of dhea ( > 25 mg / day ) could be potentially pro - arrhythmogenic ( 29 ) and in most cases , palpitations or tachycardia disappear when the drug is stopped . whether this deleterious effect of dhea is related to its in vivo transformation into androgens , or to a direct action of the hormone on cardiomyocytes , remains to be determined . when assessing the cellular and molecular mechanism of dhea ( s ) action , it is important to realize that because of their quite different chemical properties , dhea and dhea - s may act differently on their targets cells in terms of both efficiency and specificity of the involved signaling pathways . moreover , both genomic and non - genomic mechanisms can be recruited by these hormones with divergent consequences for the cell function . several effects of dhea ( and not always mimicked by dhea - s ) on the endothelium have been extensively described ( table 1 ) . the formation of the atheroma plaque , for example , requires the adhesion of monocytes to vascular endothelium through binding of endothelial neural cell adhesion molecule ( ncam ) to monocyte ncam . this interaction is prevented by sialylation of ncam . when administered to cultured human coronary artery endothelial cells , dhea inhibited monocyte adhesion by increasing the expression of polysialylated ncam , a response sensitive to androgen receptor ( ar ) and estrogen receptor ( er ) antagonists in a sex - dependent manner ( 30 ) . interestingly , the expression of polysialylated ncam was completely abolished in the presence of trilostane , an inhibitor of 3-hydroxysteroid dehydrogenase , suggesting that dhea acts via its end metabolites , estradiol and testosterone . abbreviations : dhea ( s ) , dehydroepiandrosterone ( sulfate ) ; ar , androgen receptor ; er , estrogen receptor ; ncam , neural cell adhesion molecule ; huvec , human umbilical vein endothelial cell ; tnf , tumor necrosis factor ; n / d , not determined ; nfb , nuclear factor kappa - light - chain - enhancer of activated b cells ; ppar , peroxisome proliferator - activated receptor alpha ; il-8 , interleukin 8 ; icam-1 , intercellular adhesion molecule 1 ; ros , reactive oxygen species ; vcam-1 , vascular cell adhesion molecule 1 ; erk , extracellular signal - regulated kinase ; enos , endothelial no synthase ; gpcr , g protein - coupled receptor ; pah , pulmonary arterial hypertension ; stat3 , signal transducer and activator of transcription 3 ; nfat , nuclear factor of activated t cells ; and creb , response element binding protein . the protective action of dhea against atherosclerosis has been further investigated in human umbilical vein endothelial cells ( huvec ) , where the hormone ( 100 mol / l ) appeared to inhibit in vitro tnf-induced inflammatory response including nfb translocation , icam-1 and e - selectin expression , reactive oxygen species ( ros ) production , and u937 monocyte adhesion ( 31 ) . the same group previously showed that dhea was able to inhibit huvec proliferation by arresting the cell cycle in the g1 phase , a process that is over - activated in pathologic inflammatory and angiogenic conditions ( 34 ) . it is noteworthy that the antiproliferative action of dhea was not inhibited by ar or er antagonists , was not mimicked by estradiol or testosterone , and more surprisingly , was not mimicked either by the sulfated ester , dhea - s . this effect of dhea on the reduction of endothelial proliferation is in contrast with the observation by others that like estradiol and testosterone , dhea increased the proliferation of bovine aortic endothelial cells and huvec ( 26 ) . in this case , while the proliferative effect of estradiol and testosterone were abolished by the er antagonist ( ici 182780 ) and ar antagonist ( flutamide ) none of them blocked the proliferative action of dhea . the reasons for the existing discrepancy between this finding and the previous study in term of endothelial cell proliferation are not known . high complexity of this system was suggested by an independent observation that testosterone induced the growth of human vascular endothelial cells via ar - independent mechanisms , while dihydrotestosterone ( dht ) inhibited the growth of the same cells through an ar - dependent mechanism ( 35 ) . moreover , both testosterone and dht enhanced vascular smooth muscle cell proliferation in a same way and erk1/2 activation via ar - dependent and ar - independent pathways , respectively . a protective action of dhea on human vascular endothelial cells against superoxide injury has been also reported , and this effect appeared to be through ar - independent mechanisms ( 35 ) , reminding the antioxidant properties of the dhea molecule . among other beneficial effects attributed to dhea , its ability to stimulate nitric oxide ( no ) release from endothelial cells is noteworthy . indeed , dhea stimulates no release within five minutes exposure of intact bovine aortic endothelial or huvec ( 36 ) . increased no release is due to activation of enos and leads to an elevation of cgmp within the cell . tamoxifen , an er antagonist , has been shown to block estrogen - stimulated no release , but not the acute dhea effect , which was abolished by pertussis toxin . interestingly , albumin - conjugated dhea also stimulated no release , comforting the hypothesis that dhea exerts its action through a plasma membrane - initiated mechanism , possibly involving a g protein . platelets in patients with type 2 dm are more sensitive to aggregation , which has been attributed to a reduced ability of these cells to produce no . recently , dhea was shown to reduce platelet adp - induced aggregation by 40% in plasma obtained from postmenopausal women with type-2 dm . using several pharmacologic agents , the authors determined that dhea action on the platelets was mediated by the activation of the pkc/enos / no / cgmp pathway ( 44 ) . similarly , the increased adhesion of u937 monocytes on huvec , induced by high glucose concentrations in vitro , as well as the concomitant overexpression of several adhesion molecules was abolished by dhea ( 32 ) . moreover , dhea completely blocked the oxidative stress and decreased the translocation of nf-b induced by glucose in these cells , suggesting that dhea could be useful for preventing some complications of dm and hyperglycemia . pulmonary arterial hypertension is a severe disease of the pulmonary vasculature , which is defined by an increased arterial pressure and is characterized by proliferation and resistance to apoptosis of arterial smooth muscle cells . this last phenotype is partly due to the activation by growth factors and inflammatory cytokines of neoplastic pathways involving the transcription factor stat3 under the control of the protein src . similar to cancer cells , src / stat3 stimulation leads to the activation of nfat signaling , itself responsible for both proliferation and resistance to apoptosis . the dhea ( s ) has been reported to be a pulmonary vasodilator that prevent acute hypoxic pulmonary vasoconstriction by opening potassium channels ( 38 ) and upregulating the no - modulated soluble guanylyl cyclase ( 39 ) , both mechanisms leading to relaxation of vascular smooth muscle cells . recently , dhea was shown to reduce the activity of voltage - activated t - type calcium channels within various cell types , including pulmonary artery smooth muscle cells . the modifications of the electrophysiologic properties of the calcium channels observed upon dhea challenge resulted in the inhibition of kcl - induced contraction of pulmonary artery rings . they were independent of ar and er and a pertussis toxin - sensitive gi protein pathway is implicated for these effects ( 40 ) . in addition , dhea reverses human vascular remodeling by inhibiting src / stat3 constitutive activation ( 41 ) . this in vitro inhibition by dhea was shown to be associated with a reduced activity of nfat , a mitochondrial membrane depolarization ( sensitizing the cell to apoptosis ) , and a decrease of intracellular calcium concentrations , all these factors contributing to a reduction of cell proliferation . the response to dhea was similar to that observed upon molecular inhibition of stat3 , suggesting stat3 as a main target for the hormone in smooth muscle cells . the putative cardioprotective action of dhea , which was suggested by several epidemiologic observational studies , was tested in vitro using a neonatal rat cardiomyocyte culture system . it was found that the presence of dhea significantly inhibited the increase in myocyte cell size and bnp mrna levels upregulated by endothelin-1 ( 42 ) . interestingly , in the same study , the authors reported that dhea levels in humans , measured at the coronary sinuses and aortic roots during cardiac catheterization , were suppressed in patients with heart failure in contrast to controls . they postulated that dhea or its metabolites exert a cardioprotective action through their anti - hypertrophic effects . recently , another study investigated the ability of dhea to counteract the chronotropic and hypertrophic actions of aldosterone and glucocorticoids ( 43 ) . freshly isolated neonate rat cardiomyocytes contract spontaneously in culture and their beating frequency is markedly increased upon stimulation of the mineralocorticoid or the glucocorticoid receptors ( mr and gr , respectively ) . dhea was found to reduce this chronotropic response by decreasing the t - type calcium channel expression and activity within cardiomyocytes . in the same model , dhea also prevented mr- and gr - mediated myocyte hypertrophy as well as the expression of anp and bnp . the kinetics of the negative chronotropic action of dhea and its sensitivity to actinomycin d revealed the presence of both genomic and non - genomic mechanism of action . while the genomic action was mostly related to mr inhibition , the rapid non - genomic response appeared to be due to dhea antioxidant properties . the reduction of myocyte hypertrophy and spontaneous beating frequency by dhea is clearly beneficial for the heart function ; however , epiandrosterone , a metabolite of dhea , has been reported to reduce l - type calcium channel activity in ventricular myocytes and therefore , inhibits myocardial contractility ( 45 ) . correlation between dhea or dhea - s plasma levels and ageing - related pathologies has been widely explored during the last twenty years . indeed , dhea ( s ) levels in circulation decrease with ageing more markedly than those of other hormones . numerous studies have shown a negative correlation between the levels of these hormones and ageing , as defined by the occurrence of several disorders including cvd as well as more definitive entities such as mortality . however , the predictive value is influenced by factors such as sex and smoking habits . in a cohort of elderly subjects , it was demonstrated that dhea - s levels inversely correlated with men mortality whereas there was no association with women mortality ( 4 ) . in addition , only one published work has clearly mentioned physiologic differences between dhea and dhea - s to relate their respective concentrations to various pathologies ( 5 ) . they highlighted the difficulty to properly correlate dhea concentration with diseases , probably due to the different hormone distribution throughout life , compared to its sulfated form . the authors also reported that dhea - s levels are much more often measured in studies than dhea levels , which are often not reported at all . the cvd encompass numerous and diverse kinds of pathologies related to peripheral vessels as well as to the heart . have demonstrated that mean dhea - s concentrations decreases in men with age and are significantly lower in those with a history of heart disease ( 6 ) . after adjustment for age and other cvd risk factors , they found that men with lower dhea - s levels ( < 3.8 mol / l ) had a 1.5-fold higher risk to die of any cause ( which was not statistically significant ) , but a 3.3-fold higher risk to die of cvd ( p < 0.05 ) , and particularly from ischemic heart disease ( ihd ) . clinical and demographic parameters are relevant to drawing any conclusion about causal relationship between dhea ( s ) and cvd . for example , concerning the sex , studies are more consistent for men , and when looking at women cohorts , the relationship between dhea - s and mortality from all causes , including from cvd , is often less obvious . nevertheless , in the wise ( women s ischemia syndrome evaluation ) study , including 270 postmenopausal women undergoing coronary angiography for suspected ischemia , a positive correlation between dhea - s levels and cvd outcome was reported , which was potentially explained by a better atherosclerosis state of patients with higher dhea - s levels ( 7 ) . another study demonstrated that the decrease of dhea - s concentrations observed in elderly women is significantly more pronounced in case of coronary heart diseases , osteoporosis or depression ( 8) . in contrast , prospectively investigating the longitudinal patterns of sex steroids in a cohort of 254 elderly men on a ten - year follow - up did not reveal any significant association between sex steroids ( testosterone and dhea - s ) and the incidence of cvd or all - cause mortality risk ( 9 ) . in conclusion , dhea - s levels are variably good markers not perfect for predicting cvd in the general population probably because many additional important factors have to be integrated in these predictions . the role of dhea and dhea - s has been studied in the context of endothelial function in postmenopausal women with coronary risks factors . results have shown that lower levels of dhea - s are associated with endothelial dysfunction as assessed by a positive correlation between dhea - s and percentage of flow - mediated dilatation ( % fmd ) , a marker of endothelial function ( 10 ) . this correlation was independent of other coronary risk factors such as age , body mass index , blood pressure , total and high - density lipoprotein cholesterol ( hdl - c ) , fasting glucose levels , or smoking habits . recent studies evaluated whether dhea ( s ) is associated with development of carotid atherosclerosis , a situation predicting cardiovascular complications . for example , measurement of intima media thickness ( imt ) , blood flow volume , and endothelial function ( % fmd ) has been performed by ultrasonography of carotid arteries in 419 japanese patients of both sexes with cardiovascular risk factors , and imt appeared to be inversely correlated with dhea - s levels in males , but not in females . in contrast , dhea - s was a positive factor for predicting blood flow volume in females , but not in males , and no significant correlation could be demonstrated in this study between dhea - s and % fmd regardless of sex ( 11 ) . the association between androgen levels , including dhea - s and total and bioavailable testosterone , with aortic atherosclerosis has been also investigated in 1032 nonsmoking dutch men and women aged 55 years or older . intimal atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta ; however , no clear association between levels of dhea - s and presence of severe aortic atherosclerosis was found in men or women ( 12 ) . in order to examine the association between dhea and coronary atherosclerosis , plasma dhea and dhea - s levels had been previously determined in 206 middle - aged patients undergoing coronary angiography . the dhea - s level was significantly lower in subjects with stenosis and was inversely associated with the number of affected coronary vessels and the extent of coronary atherosclerosis ( 13 ) . another part of the same study also investigated the putative protection of dhea against the development of vasculopathy after cardiac allograft . in a cohort of 61 cardiac allograft recipients , it has been found that dhea levels inversely correlated with the development of accelerated coronary vasculopathy , which appeared earlier in patients with low levels of the hormone , suggesting that high levels of dhea could retard the development of coronary atherosclerosis and coronary allograft vasculopathy . in a prospective study ( massachusetts male aging study ) on 1167 males aged 40 to 70 years at baseline followed for over ten years , low serum dhea ( s ) was predictive of later ihd independent of other risk factors . mol / l ) were significantly more likely to develop ihd with an adjusted odds ratio of 1.6 ( 95% ci , 1.07 - 2.39 ) ( 14 ) . the risk of ischemic stroke might be influenced by dhea - s levels , as suggested by another study based on a cohort of 32 826 women ( nurses health study ) following patients for cardiovascular events ( 15 ) . matching 461 cases of ischemic strokes confirmed by medical records , with controls of the same age , race , menopausal status , hormone use , and smoking status demonstrated that lower dhea - s levels were associated with a greater risk of stroke . association of atrial fibrillation and its prevalence with dhea - s levels were investigated in 436 men and 544 women aging 65 to 97 years old . interestingly , a low dhea - s concentration was significantly associated with cardiac arrhythmias in men , while occlusive arterial diseases , chronic obstructive lung disease , or osteoporosis were more frequent in women with low dhea - s . however , only the association with osteoporosis remained significant after controlling for differences in lifestyle and general health status parameters ( 16 ) . the authors concluded that in the elderly , low serum dhea - s levels are more a nonspecific indicator of aging and health status rather than a risk marker of specific diseases . diabetes mellitus is frequently associated with cvd , and significantly lower dhea - s concentrations were observed in 51 diabetic patients with a specific subtype of type 2 dm in comparison with 49 healthy controls ( 17 ) . the putative cardioprotective effect of dhea has been investigated in 62 male patients with type 2 dm by determining the association between the hormone levels and the activated protein c , c - reactive protein , and the imt of the carotid artery . the study concluded that lower circulating levels of dhea are associated with decreased activated protein c generation and higher imt in patients type 2 dm ( 18 ) . finally , testosterone and dhea were determined in 153 men with dm ( age , 65  9 years ) with coronary artery disease ( cad ) . androgen deficiency , defined as serum levels below the 10th percentile of healthy peers , was common in men with dm with stable cad and predicted increased cardiovascular mortality ( 19 ) . correlation between dhea or dhea - s plasma levels and ageing - related pathologies has been widely explored during the last twenty years . indeed , dhea ( s ) levels in circulation decrease with ageing more markedly than those of other hormones . numerous studies have shown a negative correlation between the levels of these hormones and ageing , as defined by the occurrence of several disorders including cvd as well as more definitive entities such as mortality . however , the predictive value is influenced by factors such as sex and smoking habits . in a cohort of elderly subjects , it was demonstrated that dhea - s levels inversely correlated with men mortality whereas there was no association with women mortality ( 4 ) . in addition , only one published work has clearly mentioned physiologic differences between dhea and dhea - s to relate their respective concentrations to various pathologies ( 5 ) . they highlighted the difficulty to properly correlate dhea concentration with diseases , probably due to the different hormone distribution throughout life , compared to its sulfated form . the authors also reported that dhea - s levels are much more often measured in studies than dhea levels , which are often not reported at all . the cvd encompass numerous and diverse kinds of pathologies related to peripheral vessels as well as to the heart . have demonstrated that mean dhea - s concentrations decreases in men with age and are significantly lower in those with a history of heart disease ( 6 ) . after adjustment for age and other cvd risk factors , they found that men with lower dhea - s levels ( < 3.8 mol / l ) had a 1.5-fold higher risk to die of any cause ( which was not statistically significant ) , but a 3.3-fold higher risk to die of cvd ( p < 0.05 ) , and particularly from ischemic heart disease ( ihd ) . clinical and demographic parameters are relevant to drawing any conclusion about causal relationship between dhea ( s ) and cvd . for example , concerning the sex , studies are more consistent for men , and when looking at women cohorts , the relationship between dhea - s and mortality from all causes , including from cvd , is often less obvious . nevertheless , in the wise ( women s ischemia syndrome evaluation ) study , including 270 postmenopausal women undergoing coronary angiography for suspected ischemia , a positive correlation between dhea - s levels and cvd outcome was reported , which was potentially explained by a better atherosclerosis state of patients with higher dhea - s levels ( 7 ) . another study demonstrated that the decrease of dhea - s concentrations observed in elderly women is significantly more pronounced in case of coronary heart diseases , osteoporosis or depression ( 8) . in contrast , prospectively investigating the longitudinal patterns of sex steroids in a cohort of 254 elderly men on a ten - year follow - up did not reveal any significant association between sex steroids ( testosterone and dhea - s ) and the incidence of cvd or all - cause mortality risk ( 9 ) . in conclusion , dhea - s levels are variably good markers not perfect for predicting cvd in the general population probably because many additional important factors have to be integrated in these predictions . the role of dhea and dhea - s has been studied in the context of endothelial function in postmenopausal women with coronary risks factors . results have shown that lower levels of dhea - s are associated with endothelial dysfunction as assessed by a positive correlation between dhea - s and percentage of flow - mediated dilatation ( % fmd ) , a marker of endothelial function ( 10 ) . this correlation was independent of other coronary risk factors such as age , body mass index , blood pressure , total and high - density lipoprotein cholesterol ( hdl - c ) , fasting glucose levels , or smoking habits . recent studies evaluated whether dhea ( s ) is associated with development of carotid atherosclerosis , a situation predicting cardiovascular complications . for example , measurement of intima media thickness ( imt ) , blood flow volume , and endothelial function ( % fmd ) has been performed by ultrasonography of carotid arteries in 419 japanese patients of both sexes with cardiovascular risk factors , and imt appeared to be inversely correlated with dhea - s levels in males , but not in females . in contrast , dhea - s was a positive factor for predicting blood flow volume in females , but not in males , and no significant correlation could be demonstrated in this study between dhea - s and % fmd regardless of sex ( 11 ) . the association between androgen levels , including dhea - s and total and bioavailable testosterone , with aortic atherosclerosis has been also investigated in 1032 nonsmoking dutch men and women aged 55 years or older . intimal atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta ; however , no clear association between levels of dhea - s and presence of severe aortic atherosclerosis was found in men or women ( 12 ) . in order to examine the association between dhea and coronary atherosclerosis , plasma dhea and dhea - s levels had been previously determined in 206 middle - aged patients undergoing coronary angiography . the dhea - s level was significantly lower in subjects with stenosis and was inversely associated with the number of affected coronary vessels and the extent of coronary atherosclerosis ( 13 ) . another part of the same study also investigated the putative protection of dhea against the development of vasculopathy after cardiac allograft . in a cohort of 61 cardiac allograft recipients , it has been found that dhea levels inversely correlated with the development of accelerated coronary vasculopathy , which appeared earlier in patients with low levels of the hormone , suggesting that high levels of dhea could retard the development of coronary atherosclerosis and coronary allograft vasculopathy . in a prospective study ( massachusetts male aging study ) on 1167 males aged 40 to 70 years at baseline followed for over ten years , low serum dhea ( s ) was predictive of later ihd independent of other risk factors . mol / l ) were significantly more likely to develop ihd with an adjusted odds ratio of 1.6 ( 95% ci , 1.07 - 2.39 ) ( 14 ) . the risk of ischemic stroke might be influenced by dhea - s levels , as suggested by another study based on a cohort of 32 826 women ( nurses health study ) following patients for cardiovascular events ( 15 ) . matching 461 cases of ischemic strokes confirmed by medical records , with controls of the same age , race , menopausal status , hormone use , and smoking status demonstrated that lower dhea - s levels were associated with a greater risk of stroke . association of atrial fibrillation and its prevalence with dhea - s levels were investigated in 436 men and 544 women aging 65 to 97 years old . interestingly , a low dhea - s concentration was significantly associated with cardiac arrhythmias in men , while occlusive arterial diseases , chronic obstructive lung disease , or osteoporosis were more frequent in women with low dhea - s . however , only the association with osteoporosis remained significant after controlling for differences in lifestyle and general health status parameters ( 16 ) . the authors concluded that in the elderly , low serum dhea - s levels are more a nonspecific indicator of aging and health status rather than a risk marker of specific diseases . diabetes mellitus is frequently associated with cvd , and significantly lower dhea - s concentrations were observed in 51 diabetic patients with a specific subtype of type 2 dm in comparison with 49 healthy controls ( 17 ) . the putative cardioprotective effect of dhea has been investigated in 62 male patients with type 2 dm by determining the association between the hormone levels and the activated protein c , c - reactive protein , and the imt of the carotid artery . the study concluded that lower circulating levels of dhea are associated with decreased activated protein c generation and higher imt in patients type 2 dm ( 18 ) . finally , testosterone and dhea were determined in 153 men with dm ( age , 65  9 years ) with coronary artery disease ( cad ) . androgen deficiency , defined as serum levels below the 10th percentile of healthy peers , was common in men with dm with stable cad and predicted increased cardiovascular mortality ( 19 ) . several early supplementation studies have been done before any clinical studies aimed at measuring dhea or dhea - s levels . this fact led to many misunderstandings as supplementation was not always provided for correcting dhea ( s ) deficiencies in patients . systemic vascular remodeling , as occurring during restenosis after injury , is characterized by the presence of proliferative and apoptosis - resistant smooth muscle cells with activated akt pathway . because dhea has been previously proposed to inhibit this pathway in cancer , bonnet et al . investigated a putative role for dhea in remodeling vessel wall both in vitro , using cultured human carotid vascular smooth muscle cells and saphenous vein grafts challenged with pdgf , and in vivo , with a rat carotid injury model . in each case , dhea reduced proliferation and increased apoptosis of smooth muscle cells through the inhibition of the akt pathway . dhea effect was unaffected by androgen or estrogen antagonists , suggesting a steroid receptor - independent mechanism . the authors concluded that orally available dhea might be attractive for treating systemic vascular remodeling , including restenosis ( 20 ) . in order to mimic the metabolic dysregulation often occurring in the elderly , these animals develop inflammatory processes and cardiomyopathies linked to their diabetic state . in this context , dhea seems to be beneficial for counteracting cardiac disturbances such as unbalanced oxidative status , impairment of cardiac myogenic factors , and contractility dysfunction ( 21 ) . in a model of rabbits fed with a high fat diet and displaying hyperglycemia , insulin resistance , dyslipidemia , increased oxidative stress , and proinflammatory insults , the impairment of cardiac contractility was observed by measuring the switch of myosin heavy chain ( mhc ) isoforms expression . in these animals , low dose of dhea supplementation , which did not affect glucose levels or insulin resistance , restored the oxidative balance and lowered lipid levels and inflammation , preventing alteration of the cardiac function and delaying the onset of cardiac tissue damage . a similar effect of dhea has been observed by the same authors in rats with streptozocin - induced dm ( 22 ) . the hyperglycemia - induced oxidative stress increases advanced glycated end - products ( ages ) and triggers a cascade of signaling involving nfb ( 23 ) , finally leading to interstitial fibrosis . the dhea treatment , by improving the oxidative balance , counteracts the age action and restores the contractility of the ventricular tissue by preventing the fibrotic response . dhea also improved the right ventricular function and remodeling in rats upon reoxygenation after 21 days of hypoxia ( 24 ) . ex vivo investigations demonstrated that the presence of dhea during the reoxygenation phase increased myocytes proliferation through cyclic amp response element binding protein ( creb ) and pgc1 activation , prevented mitochondrial fragmentation , and improved the respiratory chain activity . dhea supplementation ( 25 mg / day ) in asymptomatic , normotensive , non - diabetic and nonsmoker men with hypercholesterolemia ( mean age , 54 years ) increased plasma levels of dhea - s and significantly ameliorated the % fmd of arteries ( 25 ) . this observation points out that for this specific dhea ( s ) action , results are in good agreement in both sexes , as previously discussed for postmenopausal women ( 10 ) . this was confirmed in another study , where supplementation of 36 healthy postmenopausal women with dhea ( 100 mg / day ) for three months also increased the % fmd and the laser doppler velocimetry parameters , and significantly reduced total plasma cholesterol concentration ( 26 ) . in contrast , dhea - s supplementation ( 50 mg / day ) appeared to have beneficial effect on neither insulin action , determined by euglycemic hyperinsulinemic clamp , nor the quality of life , measured by extensive parameters in female patients with hypopituitary hypoadrenalism ( with very low dhea - s levels ) and following standard replacement therapy ( 27 ) . however , the quality of life in this study was not assessed in term of cardiovascular health , which has been clearly shown to be associated with metabolic diseases . the benefits of dhea supplementation in the aging population is highly controversial within the literature and therefore , published studies have been recently reviewed in a meta - analysis to determine whether there is a potential therapeutic role of dhea in postmenopausal women ( 28 ) . in spite of several observational studies showing that lower dhea levels were associated with increased cardiovascular risk in women , interventional trials did not demonstrate improvement atherosclerosis or cardiovascular risk factors by dhea supplementation . the dhea even appears to be responsible for lowering hdl - c levels , a putative cardioprotective marker , probably through an androgen - dependent mechanism ; however , it is not clear how much this action of dhea is detrimental to the cardiovascular function . the authors conclude that there was no strong current evidence in favor of dhea supplementation in healthy postmenopausal women . several reports also suggest that high doses of dhea ( > 25 mg / day ) could be potentially pro - arrhythmogenic ( 29 ) and in most cases , palpitations or tachycardia disappear when the drug is stopped . whether this deleterious effect of dhea is related to its in vivo transformation into androgens , or to a direct action of the hormone on cardiomyocytes , remains to be determined . systemic vascular remodeling , as occurring during restenosis after injury , is characterized by the presence of proliferative and apoptosis - resistant smooth muscle cells with activated akt pathway . because dhea has been previously proposed to inhibit this pathway in cancer , bonnet et al . investigated a putative role for dhea in remodeling vessel wall both in vitro , using cultured human carotid vascular smooth muscle cells and saphenous vein grafts challenged with pdgf , and in vivo , with a rat carotid injury model . in each case , dhea reduced proliferation and increased apoptosis of smooth muscle cells through the inhibition of the akt pathway . dhea effect was unaffected by androgen or estrogen antagonists , suggesting a steroid receptor - independent mechanism . the authors concluded that orally available dhea might be attractive for treating systemic vascular remodeling , including restenosis ( 20 ) . in order to mimic the metabolic dysregulation often occurring in the elderly , these animals develop inflammatory processes and cardiomyopathies linked to their diabetic state . in this context , dhea seems to be beneficial for counteracting cardiac disturbances such as unbalanced oxidative status , impairment of cardiac myogenic factors , and contractility dysfunction ( 21 ) . in a model of rabbits fed with a high fat diet and displaying hyperglycemia , insulin resistance , dyslipidemia , increased oxidative stress , and proinflammatory insults , the impairment of cardiac contractility was observed by measuring the switch of myosin heavy chain ( mhc ) isoforms expression . in these animals , low dose of dhea supplementation , which did not affect glucose levels or insulin resistance , restored the oxidative balance and lowered lipid levels and inflammation , preventing alteration of the cardiac function and delaying the onset of cardiac tissue damage . a similar effect of dhea has been observed by the same authors in rats with streptozocin - induced dm ( 22 ) . the hyperglycemia - induced oxidative stress increases advanced glycated end - products ( ages ) and triggers a cascade of signaling involving nfb ( 23 ) , finally leading to interstitial fibrosis . the dhea treatment , by improving the oxidative balance , counteracts the age action and restores the contractility of the ventricular tissue by preventing the fibrotic response . dhea also improved the right ventricular function and remodeling in rats upon reoxygenation after 21 days of hypoxia ( 24 ) . ex vivo investigations demonstrated that the presence of dhea during the reoxygenation phase increased myocytes proliferation through cyclic amp response element binding protein ( creb ) and pgc1 activation , prevented mitochondrial fragmentation , and improved the respiratory chain activity . dhea supplementation ( 25 mg / day ) in asymptomatic , normotensive , non - diabetic and nonsmoker men with hypercholesterolemia ( mean age , 54 years ) increased plasma levels of dhea - s and significantly ameliorated the % fmd of arteries ( 25 ) . this observation points out that for this specific dhea ( s ) action , results are in good agreement in both sexes , as previously discussed for postmenopausal women ( 10 ) . this was confirmed in another study , where supplementation of 36 healthy postmenopausal women with dhea ( 100 mg / day ) for three months also increased the % fmd and the laser doppler velocimetry parameters , and significantly reduced total plasma cholesterol concentration ( 26 ) . in contrast , dhea - s supplementation ( 50 mg / day ) appeared to have beneficial effect on neither insulin action , determined by euglycemic hyperinsulinemic clamp , nor the quality of life , measured by extensive parameters in female patients with hypopituitary hypoadrenalism ( with very low dhea - s levels ) and following standard replacement therapy ( 27 ) . however , the quality of life in this study was not assessed in term of cardiovascular health , which has been clearly shown to be associated with metabolic diseases . the benefits of dhea supplementation in the aging population is highly controversial within the literature and therefore , published studies have been recently reviewed in a meta - analysis to determine whether there is a potential therapeutic role of dhea in postmenopausal women ( 28 ) . in spite of several observational studies showing that lower dhea levels were associated with increased cardiovascular risk in women , interventional trials did not demonstrate improvement atherosclerosis or cardiovascular risk factors by dhea supplementation . the dhea even appears to be responsible for lowering hdl - c levels , a putative cardioprotective marker , probably through an androgen - dependent mechanism ; however , it is not clear how much this action of dhea is detrimental to the cardiovascular function . the authors conclude that there was no strong current evidence in favor of dhea supplementation in healthy postmenopausal women . several reports also suggest that high doses of dhea ( > 25 mg / day ) could be potentially pro - arrhythmogenic ( 29 ) and in most cases , palpitations or tachycardia disappear when the drug is stopped . whether this deleterious effect of dhea is related to its in vivo transformation into androgens , or to a direct action of the hormone on cardiomyocytes , remains to be determined . when assessing the cellular and molecular mechanism of dhea ( s ) action , it is important to realize that because of their quite different chemical properties , dhea and dhea - s may act differently on their targets cells in terms of both efficiency and specificity of the involved signaling pathways . moreover , both genomic and non - genomic mechanisms can be recruited by these hormones with divergent consequences for the cell function . several effects of dhea ( and not always mimicked by dhea - s ) on the endothelium have been extensively described ( table 1 ) . the formation of the atheroma plaque , for example , requires the adhesion of monocytes to vascular endothelium through binding of endothelial neural cell adhesion molecule ( ncam ) to monocyte ncam . this interaction is prevented by sialylation of ncam . when administered to cultured human coronary artery endothelial cells , dhea inhibited monocyte adhesion by increasing the expression of polysialylated ncam , a response sensitive to androgen receptor ( ar ) and estrogen receptor ( er ) antagonists in a sex - dependent manner ( 30 ) . interestingly , the expression of polysialylated ncam was completely abolished in the presence of trilostane , an inhibitor of 3-hydroxysteroid dehydrogenase , suggesting that dhea acts via its end metabolites , estradiol and testosterone . abbreviations : dhea ( s ) , dehydroepiandrosterone ( sulfate ) ; ar , androgen receptor ; er , estrogen receptor ; ncam , neural cell adhesion molecule ; huvec , human umbilical vein endothelial cell ; tnf , tumor necrosis factor ; n / d , not determined ; nfb , nuclear factor kappa - light - chain - enhancer of activated b cells ; ppar , peroxisome proliferator - activated receptor alpha ; il-8 , interleukin 8 ; icam-1 , intercellular adhesion molecule 1 ; ros , reactive oxygen species ; vcam-1 , vascular cell adhesion molecule 1 ; erk , extracellular signal - regulated kinase ; enos , endothelial no synthase ; gpcr , g protein - coupled receptor ; pah , pulmonary arterial hypertension ; stat3 , signal transducer and activator of transcription 3 ; nfat , nuclear factor of activated t cells ; and creb , response element binding protein . the protective action of dhea against atherosclerosis has been further investigated in human umbilical vein endothelial cells ( huvec ) , where the hormone ( 100 mol / l ) appeared to inhibit in vitro tnf-induced inflammatory response including nfb translocation , icam-1 and e - selectin expression , reactive oxygen species ( ros ) production , and u937 monocyte adhesion ( 31 ) . the same group previously showed that dhea was able to inhibit huvec proliferation by arresting the cell cycle in the g1 phase , a process that is over - activated in pathologic inflammatory and angiogenic conditions ( 34 ) . it is noteworthy that the antiproliferative action of dhea was not inhibited by ar or er antagonists , was not mimicked by estradiol or testosterone , and more surprisingly , was not mimicked either by the sulfated ester , dhea - s . this effect of dhea on the reduction of endothelial proliferation is in contrast with the observation by others that like estradiol and testosterone , dhea increased the proliferation of bovine aortic endothelial cells and huvec ( 26 ) . in this case , while the proliferative effect of estradiol and testosterone were abolished by the er antagonist ( ici 182780 ) and ar antagonist ( flutamide ) none of them blocked the proliferative action of dhea . the reasons for the existing discrepancy between this finding and the previous study in term of endothelial cell proliferation are not known . high complexity of this system was suggested by an independent observation that testosterone induced the growth of human vascular endothelial cells via ar - independent mechanisms , while dihydrotestosterone ( dht ) inhibited the growth of the same cells through an ar - dependent mechanism ( 35 ) . moreover , both testosterone and dht enhanced vascular smooth muscle cell proliferation in a same way and erk1/2 activation via ar - dependent and ar - independent pathways , respectively . a protective action of dhea on human vascular endothelial cells against superoxide injury has been also reported , and this effect appeared to be through ar - independent mechanisms ( 35 ) , reminding the antioxidant properties of the dhea molecule . among other beneficial effects attributed to dhea , its ability to stimulate nitric oxide ( no ) release from endothelial cells is noteworthy . indeed , dhea stimulates no release within five minutes exposure of intact bovine aortic endothelial or huvec ( 36 ) . increased no release is due to activation of enos and leads to an elevation of cgmp within the cell . tamoxifen , an er antagonist , has been shown to block estrogen - stimulated no release , but not the acute dhea effect , which was abolished by pertussis toxin . interestingly , albumin - conjugated dhea also stimulated no release , comforting the hypothesis that dhea exerts its action through a plasma membrane - initiated mechanism , possibly involving a g protein . platelets in patients with type 2 dm are more sensitive to aggregation , which has been attributed to a reduced ability of these cells to produce no . recently , dhea was shown to reduce platelet adp - induced aggregation by 40% in plasma obtained from postmenopausal women with type-2 dm . using several pharmacologic agents , the authors determined that dhea action on the platelets was mediated by the activation of the pkc/enos / no / cgmp pathway ( 44 ) . similarly , the increased adhesion of u937 monocytes on huvec , induced by high glucose concentrations in vitro , as well as the concomitant overexpression of several adhesion molecules was abolished by dhea ( 32 ) . moreover , dhea completely blocked the oxidative stress and decreased the translocation of nf-b induced by glucose in these cells , suggesting that dhea could be useful for preventing some complications of dm and hyperglycemia . pulmonary arterial hypertension is a severe disease of the pulmonary vasculature , which is defined by an increased arterial pressure and is characterized by proliferation and resistance to apoptosis of arterial smooth muscle cells . this last phenotype is partly due to the activation by growth factors and inflammatory cytokines of neoplastic pathways involving the transcription factor stat3 under the control of the protein src . similar to cancer cells , src / stat3 stimulation leads to the activation of nfat signaling , itself responsible for both proliferation and resistance to apoptosis . the dhea ( s ) has been reported to be a pulmonary vasodilator that prevent acute hypoxic pulmonary vasoconstriction by opening potassium channels ( 38 ) and upregulating the no - modulated soluble guanylyl cyclase ( 39 ) , both mechanisms leading to relaxation of vascular smooth muscle cells . recently , dhea was shown to reduce the activity of voltage - activated t - type calcium channels within various cell types , including pulmonary artery smooth muscle cells . the modifications of the electrophysiologic properties of the calcium channels observed upon dhea challenge resulted in the inhibition of kcl - induced contraction of pulmonary artery rings . they were independent of ar and er and a pertussis toxin - sensitive gi protein pathway is implicated for these effects ( 40 ) . in addition , dhea reverses human vascular remodeling by inhibiting src / stat3 constitutive activation ( 41 ) . this in vitro inhibition by dhea was shown to be associated with a reduced activity of nfat , a mitochondrial membrane depolarization ( sensitizing the cell to apoptosis ) , and a decrease of intracellular calcium concentrations , all these factors contributing to a reduction of cell proliferation . the response to dhea was similar to that observed upon molecular inhibition of stat3 , suggesting stat3 as a main target for the hormone in smooth muscle cells . the putative cardioprotective action of dhea , which was suggested by several epidemiologic observational studies , was tested in vitro using a neonatal rat cardiomyocyte culture system . it was found that the presence of dhea significantly inhibited the increase in myocyte cell size and bnp mrna levels upregulated by endothelin-1 ( 42 ) . interestingly , in the same study , the authors reported that dhea levels in humans , measured at the coronary sinuses and aortic roots during cardiac catheterization , were suppressed in patients with heart failure in contrast to controls . they postulated that dhea or its metabolites exert a cardioprotective action through their anti - hypertrophic effects . recently , another study investigated the ability of dhea to counteract the chronotropic and hypertrophic actions of aldosterone and glucocorticoids ( 43 ) . freshly isolated neonate rat cardiomyocytes contract spontaneously in culture and their beating frequency is markedly increased upon stimulation of the mineralocorticoid or the glucocorticoid receptors ( mr and gr , respectively ) . dhea was found to reduce this chronotropic response by decreasing the t - type calcium channel expression and activity within cardiomyocytes . in the same model , dhea also prevented mr- and gr - mediated myocyte hypertrophy as well as the expression of anp and bnp . the kinetics of the negative chronotropic action of dhea and its sensitivity to actinomycin d revealed the presence of both genomic and non - genomic mechanism of action . while the genomic action was mostly related to mr inhibition , the rapid non - genomic response appeared to be due to dhea antioxidant properties . the reduction of myocyte hypertrophy and spontaneous beating frequency by dhea is clearly beneficial for the heart function ; however , epiandrosterone , a metabolite of dhea , has been reported to reduce l - type calcium channel activity in ventricular myocytes and therefore , inhibits myocardial contractility ( 45 ) . several effects of dhea ( and not always mimicked by dhea - s ) on the endothelium have been extensively described ( table 1 ) . the formation of the atheroma plaque , for example , requires the adhesion of monocytes to vascular endothelium through binding of endothelial neural cell adhesion molecule ( ncam ) to monocyte ncam . this interaction is prevented by sialylation of ncam . when administered to cultured human coronary artery endothelial cells , dhea inhibited monocyte adhesion by increasing the expression of polysialylated ncam , a response sensitive to androgen receptor ( ar ) and estrogen receptor ( er ) antagonists in a sex - dependent manner ( 30 ) . interestingly , the expression of polysialylated ncam was completely abolished in the presence of trilostane , an inhibitor of 3-hydroxysteroid dehydrogenase , suggesting that dhea acts via its end metabolites , estradiol and testosterone . abbreviations : dhea ( s ) , dehydroepiandrosterone ( sulfate ) ; ar , androgen receptor ; er , estrogen receptor ; ncam , neural cell adhesion molecule ; huvec , human umbilical vein endothelial cell ; tnf , tumor necrosis factor ; n / d , not determined ; nfb , nuclear factor kappa - light - chain - enhancer of activated b cells ; ppar , peroxisome proliferator - activated receptor alpha ; il-8 , interleukin 8 ; icam-1 , intercellular adhesion molecule 1 ; ros , reactive oxygen species ; vcam-1 , vascular cell adhesion molecule 1 ; erk , extracellular signal - regulated kinase ; enos , endothelial no synthase ; gpcr , g protein - coupled receptor ; pah , pulmonary arterial hypertension ; stat3 , signal transducer and activator of transcription 3 ; nfat , nuclear factor of activated t cells ; and creb , response element binding protein . the protective action of dhea against atherosclerosis has been further investigated in human umbilical vein endothelial cells ( huvec ) , where the hormone ( 100 mol / l ) appeared to inhibit in vitro tnf-induced inflammatory response including nfb translocation , icam-1 and e - selectin expression , reactive oxygen species ( ros ) production , and u937 monocyte adhesion ( 31 ) . the same group previously showed that dhea was able to inhibit huvec proliferation by arresting the cell cycle in the g1 phase , a process that is over - activated in pathologic inflammatory and angiogenic conditions ( 34 ) . it is noteworthy that the antiproliferative action of dhea was not inhibited by ar or er antagonists , was not mimicked by estradiol or testosterone , and more surprisingly , was not mimicked either by the sulfated ester , dhea - s . this effect of dhea on the reduction of endothelial proliferation is in contrast with the observation by others that like estradiol and testosterone , dhea increased the proliferation of bovine aortic endothelial cells and huvec ( 26 ) . in this case , while the proliferative effect of estradiol and testosterone were abolished by the er antagonist ( ici 182780 ) and ar antagonist ( flutamide ) none of them blocked the proliferative action of dhea . the reasons for the existing discrepancy between this finding and the previous study in term of endothelial cell proliferation are not known . high complexity of this system was suggested by an independent observation that testosterone induced the growth of human vascular endothelial cells via ar - independent mechanisms , while dihydrotestosterone ( dht ) inhibited the growth of the same cells through an ar - dependent mechanism ( 35 ) . moreover , both testosterone and dht enhanced vascular smooth muscle cell proliferation in a same way and erk1/2 activation via ar - dependent and ar - independent pathways , respectively . a protective action of dhea on human vascular endothelial cells against superoxide injury has been also reported , and this effect appeared to be through ar - independent mechanisms ( 35 ) , reminding the antioxidant properties of the dhea molecule . among other beneficial effects attributed to dhea , its ability to stimulate nitric oxide ( no ) release from endothelial cells is noteworthy . indeed , dhea stimulates no release within five minutes exposure of intact bovine aortic endothelial or huvec ( 36 ) . increased no release is due to activation of enos and leads to an elevation of cgmp within the cell . tamoxifen , an er antagonist , has been shown to block estrogen - stimulated no release , but not the acute dhea effect , which was abolished by pertussis toxin . interestingly , albumin - conjugated dhea also stimulated no release , comforting the hypothesis that dhea exerts its action through a plasma membrane - initiated mechanism , possibly involving a g protein . platelets in patients with type 2 dm are more sensitive to aggregation , which has been attributed to a reduced ability of these cells to produce no . recently , dhea was shown to reduce platelet adp - induced aggregation by 40% in plasma obtained from postmenopausal women with type-2 dm . using several pharmacologic agents , the authors determined that dhea action on the platelets was mediated by the activation of the pkc/enos / no / cgmp pathway ( 44 ) . similarly , the increased adhesion of u937 monocytes on huvec , induced by high glucose concentrations in vitro , as well as the concomitant overexpression of several adhesion molecules was abolished by dhea ( 32 ) . moreover , dhea completely blocked the oxidative stress and decreased the translocation of nf-b induced by glucose in these cells , suggesting that dhea could be useful for preventing some complications of dm and hyperglycemia . pulmonary arterial hypertension is a severe disease of the pulmonary vasculature , which is defined by an increased arterial pressure and is characterized by proliferation and resistance to apoptosis of arterial smooth muscle cells . this last phenotype is partly due to the activation by growth factors and inflammatory cytokines of neoplastic pathways involving the transcription factor stat3 under the control of the protein src . similar to cancer cells , src / stat3 stimulation leads to the activation of nfat signaling , itself responsible for both proliferation and resistance to apoptosis . the dhea ( s ) has been reported to be a pulmonary vasodilator that prevent acute hypoxic pulmonary vasoconstriction by opening potassium channels ( 38 ) and upregulating the no - modulated soluble guanylyl cyclase ( 39 ) , both mechanisms leading to relaxation of vascular smooth muscle cells . recently , dhea was shown to reduce the activity of voltage - activated t - type calcium channels within various cell types , including pulmonary artery smooth muscle cells . the modifications of the electrophysiologic properties of the calcium channels observed upon dhea challenge resulted in the inhibition of kcl - induced contraction of pulmonary artery rings . they were independent of ar and er and a pertussis toxin - sensitive gi protein pathway is implicated for these effects ( 40 ) . in addition , dhea reverses human vascular remodeling by inhibiting src / stat3 constitutive activation ( 41 ) . this in vitro inhibition by dhea was shown to be associated with a reduced activity of nfat , a mitochondrial membrane depolarization ( sensitizing the cell to apoptosis ) , and a decrease of intracellular calcium concentrations , all these factors contributing to a reduction of cell proliferation . the response to dhea was similar to that observed upon molecular inhibition of stat3 , suggesting stat3 as a main target for the hormone in smooth muscle cells . the putative cardioprotective action of dhea , which was suggested by several epidemiologic observational studies , was tested in vitro using a neonatal rat cardiomyocyte culture system . it was found that the presence of dhea significantly inhibited the increase in myocyte cell size and bnp mrna levels upregulated by endothelin-1 ( 42 ) . interestingly , in the same study , the authors reported that dhea levels in humans , measured at the coronary sinuses and aortic roots during cardiac catheterization , were suppressed in patients with heart failure in contrast to controls . they postulated that dhea or its metabolites exert a cardioprotective action through their anti - hypertrophic effects . recently , another study investigated the ability of dhea to counteract the chronotropic and hypertrophic actions of aldosterone and glucocorticoids ( 43 ) . freshly isolated neonate rat cardiomyocytes contract spontaneously in culture and their beating frequency is markedly increased upon stimulation of the mineralocorticoid or the glucocorticoid receptors ( mr and gr , respectively ) . dhea was found to reduce this chronotropic response by decreasing the t - type calcium channel expression and activity within cardiomyocytes . in the same model , dhea also prevented mr- and gr - mediated myocyte hypertrophy as well as the expression of anp and bnp . the kinetics of the negative chronotropic action of dhea and its sensitivity to actinomycin d revealed the presence of both genomic and non - genomic mechanism of action . while the genomic action was mostly related to mr inhibition , the rapid non - genomic response appeared to be due to dhea antioxidant properties . the reduction of myocyte hypertrophy and spontaneous beating frequency by dhea is clearly beneficial for the heart function ; however , epiandrosterone , a metabolite of dhea , has been reported to reduce l - type calcium channel activity in ventricular myocytes and therefore , inhibits myocardial contractility ( 45 ) . dhea ( s ) is the hormone not only circulating at the highest concentration in blood , but it is also displaying the most extensive decrease upon aging . therefore , it has been tempting to correlate the reduction of the hormone levels with several types of age - related dysfunctions including cvd . many observational studies performed over decades , demonstrated the existence of a significant inverse association between levels of dhea ( s ) and cardiovascular risk , morbidity , and mortality , even after correcting for usual confounding factors . nevertheless , a strong correlation is not a proof of causality . in order to discriminate between a hormonal deficiency directly responsible for the observed disease or the hormone acting as a simple marker of the biologic age ( possibly the main cause of the increased frequency of pathologies ) in other words , the question addressed here was whether dhea ( s ) was the anti - aging hormone . unfortunately , supplementation studies were much less conclusive than expected and the benefit of dhea ( s ) on the outcome of cvd is still highly controversial . discrepancies among results can be due to several factors such as insufficient duration of treatment , heterogeneity of the tested population , irreversibility of investigated pathologies , or even economic concerns . indeed , because dhea ( s ) is a cheap , not patentable molecule , already on the free market for a long time in the united states , there is poor motivation in the industry for conducting rigorous and expensive clinical trials . therefore , it is not surprising that the strongest information on dhea ( s ) action has been obtained from in vitro studies . however , strong limitation in the discovery of the molecular mechanisms of dhea ( s ) action are the lack of a specific receptor , which can be clearly identified as responsible for the hormone response , as well as the ability of dhea ( s ) to be converted into androgens and estrogens . moreover , similar to other steroid hormones , dhea ( s ) appears to exert its effect through genomic and non - genomic pathways , the latter of which included simple antioxidant properties . nevertheless , a better comprehension of the basic mechanisms leading to the multiple actions of dhea ( s ) on its various target cells will be certainly useful for developing new strategies and better apprehending cvd , which is still killing too many people in western countries .
context : dehydroepiandrosterone ( dhea ) and its sulfate ester , dehydroepiandrosterone sulfate ( dhea - s ) have been considered as putative anti - aging hormones for many years . 
 indeed , while dheas is the most abundant circulating hormone , its concentration is markedly decreased upon aging and early epidemiologic trials have revealed a strong inverse correlation between the hormone concentrations and the occurrence of several dysfunctions frequently encountered in the elderly . naturally , hormonal supplementation has been rapidly suggested to prevent dhea ( s ) deficiency and therefore , age - related development of these pathologies , using the same strategy as estrogen replacement therapy proposed in postmenopausal women.evidence acquisition : all references were searched using pubmed and the following strategy : our initial selection included all articles in english and we sorted them with the following keywords :  dhea or dhea - s  and  heart or vascular or endothelium or cardiovascular disease  . 
 the search was limited to neither the publication date nor specific journals . 
 the final selection was made according to the relevance of the article content with the aims of the review . according to these criteria , fewer than 10% of the articles retrieved at the first step 
 were discarded.results:in this short review , we have focused on the cardiovascular action of dhea . 
 we started by analyzing evidences in favor of a strong inverse association between dhea ( s ) levels and the cardiovascular risk as demonstrated in multiple observational epidemiologic studies for several decades . 
 then we discussed the different trials aimed at supplementing dhea ( s ) , both in animals and human , for preventing cardiovascular diseases and we analyzed the possible reasons for the discrepancy observed among the results of some studies . 
 finally , we presented putative molecular mechanisms of action for dhea ( s ) , demonstrated in vitro in different models of vascular and cardiac cells , highlighting the complexity of the involved signaling pathways.conclusions:the identification of the beneficial cardiovascular effects of dhea ( s ) and a better understanding of the involved mechanisms should be helpful to develop new strategies or pharmacologic approaches for many lethal diseases in western countries .