The Role of Steroids in Endothelial Function in the Aging Male
men with symptoms of androgen deficiency are at risk of increased carotid intima media thickness (IMT) and suggested that normal testosterone levels may offer protection against the development of atherosclerosis in middle-aged men. Malkin et al.37
hypothesised that the
immune-modulating properties of testosterone are important in inhibiting atheroma formation and progression to acute coronary syndrome. The authors demonstrated that significant reduction in total cholesterol was recorded with testosterone therapy and demonstrated a shift in the cytokine balance to a state of reduced inflammation.38
Estrogens in the male can be synthezised locally from testosterone by the CYP3A aromatase enzyme in many tissues. Estrogens may act via their classic nuclear receptors or via rapid membrane actions.39
The rate
of whole-body aromatization is higher in older men, but the precise mechanisms are unclear.40
have been reported variously as declining41 the aging process.42
The age trends of estrogen levels in men or remaining steady during
Massachusetts male aging study (MMAS).38
Estrogens were invariant with age in the The ability of estrogen to
enhance endothelium-dependent vasodilator function has been well described in females.43
However, endogenous estrogen also influences
In healthy young men, inhibition of aromatase by administration of anastrozole impaired FMD, suggesting that endogenous estrogen production directly affects endothelial function;45 moreover, the suppression of endogenous estrogens determined an impairment of FMD without significant changes in lipoproteins, homocysteine or CRP,45
vascular function in males. For example, a young man with an estrogen receptor-α (ORα) mutation showed both CAD and endothelial dysfunction.44
suggesting that endogenous estrogens play a
direct regulatory role in endothelial function. 17β−oestradiol (E2) regulates NO synthase in the hypothalamus,46
and
E2 has an immediate action on median eminence endothelial cells via non-genomic signaling pathways, leading to NO-stimulated
modulates vascular endothelial growth/permeability factor in normal and tumor tissue47 barrier.48,49
gonadotropin-releasing hormone (GnRH) release.50 Vascular endothelial
growth factor (VEGF) expression is higher in the neural lobe than in the anterior lobe and is undetectable in the intermediate lobe; it is rapidly
upregulated by E2 in the anterior pituitary, but remains unchanged in the posterior pituitary.51
increased eNOS activity and protein levels.52 eNOS may contribute to the neuroprotective effects of estrogens. Galea
In vivo estrogen treatment leads to a 100 % increase in eNOS mRNA copy number and increases eNOS protein levels by 47 % in mouse cerebral blood vessels,54
suggesting that estrogen modulates
eNOS at the transcriptional level in blood vessels in vivo. Low E2 results in reduced nNOS and eNOS expression in the hippocampus and E2 substitution reverses these effects,55
and eNOS expression and activity in the hippocampus and improves hippocampal function. Tivesten et al.56
predictor of progression of carotid artery IMT in middle-aged men.
Only a few studies have addressed the relation between endogenous E2 levels and atherosclerosis in men.36
US ENDOCRINOLOGY In a recent four-year longitudinal showed that circulating E2 is a suggesting that E2 increases nNOS
et al. hypothesized that the protective effects of E2 in cerebral ischemia may be attributed to the blockade of leucocyte adhesion in cerebral endothelial cells.53
ORα activation in cerebrovascular tissue resulted in Increased NO production by
and glucose transporter-1 expression in the blood–brain
study on the relation between baseline E2 levels and progression of carotid artery IMT in men, Muller et al.57
found a tendency toward a
positive association between serum E2 and IMT, but the data did not reach statistical significance. Further studies are needed to investigate
the role of endogenous E2 for incident CVD events.
The circulating adrenal androgen dehydroepiandrosterone (DHEA) represents a pathway that may be of increasing importance with age. In fact, it is a precursor for intracellular production of androgens and estrogens in non-reproductive tissues. Studies agree that levels of DHEA and its sulphate (DHEA-S), the most plentiful steroid in serum, decline with age more markedly than other hormones. The adrenal steroid androstenedione follows a similarly sharp decline.58
The MMAS data show
DHEA, DHEA-S, and androstenedione declining by 2–3 % per year, both cross-sectionally and longitudinally.59
importance as a biomarker and protective factor against aging.60
DHEA-S is thought to be of potential Clinical
and experimental studies have shown that DHEA-S in humans and other mammals is a multifunctional steroid implicated in a broad range of biological effects, including obesity, diabetes, bone metabolism, neuroprotection, and antitumorigenesis, and that plasma or serum DHEA-S levels are independently and inversely associated with the incidence of coronary heart disease and mortality in males.61,62
DHEA is
thought to be associated with life expectancy and anti-aging. However, its biological significance in atherosclerosis remains controversial. DHEA supplementation restored aortic eNOS levels and activity, suggesting that DHEA has direct genomic and non-genomic effects on the vascular wall.63,64 Liu and Dillon65
demonstrated that physiological concentrations of DHEA acutely increase NO release from intact vascular endothelial cells by a plasma membrane-dependent mechanism. This action of DHEA is mediated by a steroid-specific, G-protein-coupled receptor mechanism, which activates eNOS in both bovine and human endothelial cells.66
This
cellular mechanism may underlie some of the cardiovascular protective effects proposed for DHEA. According to other studies, there was no significant relationship between plasma or serum DHEA-S levels and atherosclerotic diseases, including coronary heart disease and carotid atherosclerosis, in males.67,68
Thus the clinical significance of
DHEA-S in the prevention of atherosclerosis and cardiovascular diseases has not been fully elucidated in either males or females. However, in a recent study, Yoshida et al. showed that, although DHEA-S is not involved in endothelial function, it is inversely associated with sex-dependent signs of carotid atherosclerosis: increased maximum and mean IMT in males and decreased common carotid artery blood flow volume in females.69
Aldosterone is a steroid hormone that controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, and regulates genes that play a role in salt and water homoeostasis in the kidney. The dysregulation of the mineralocorticoid system reveals its crucial role in various human diseases, including hypertension, atherosclerosis, cardiac failure, mineralocorticoid resistance, and disorders of the nervous system. Recently, experimental animal models of mineralocorticoid/salt-induced hypertension and atherosclerosis have revealed an epithelial, pro-inflammatory role for MR activation. Extensive investigation has begun to elucidate the mechanisms underlying the vascular effects of MR activation, which involve its direct role in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. More specifically, in patients with cardiovascular risk factors and disease,
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