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Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis

there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)

bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors

Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function

It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years

no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.

free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD

Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans

Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)

Testosterone shares the same molecular binding site as nifedipine

Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production

Testosterone also inhibited the Ca2+ influx response to PGF2α

one of the major actions of testosterone is on NO and its signalling pathways

In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger

the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development

Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone

t long-term testosterone treatment reduced CIMT in men with low testosterone levels and angina

neither intracellular nor membrane-associated ARs are required for the rapid vasodilator effect

acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription

Testosterone and DHT increased the expression of eNOS in HUVECs

oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner

Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition

non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle

increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells

Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy

Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism

patients with the highest IL1β concentrations had lower endogenous testosterone levels

TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD

testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo

parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly men

Higher levels of serum adiponectin have been shown to lower cardiovascular risk

Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone

Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells

decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT

The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.

testosterone functions through the AR to modulate adhesion molecule expression

pre-treatment with DHT reduced the cytokine-stimulated inflammatory response

DHT inhibited NFκB activation

DHT could inhibit an LPS-induced upregulation of MCP1

Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other

As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription

prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone

DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes

(Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol

TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs

3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)

This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.

The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell

There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality

The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm

trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months

Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action

The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.

the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms

hypogonadal–obesity–adipocytokine hypothesis

The presence of estradiol and the adipocytokines TNF-α, IL6, and leptin (as a result of leptin resistance in obesity) inhibits the hypothalamic–pituitary–testicular axis response to decreasing androgen levels

An increasing number of studies have illustrated the potential for applying metabolomics to the field of androgen research

As early as the 1940s, the therapeutic use of testosterone was reported to improve angina pectoris in men with coronary artery disease

most of the epidemiological studies reported increased cardiovascular risk and mortality in men with low testosterone levels

long-term testosterone replacement appears to be a safe and effective means of treating hypogonadal elderly men

a recent interventional trial showed that testosterone treatment was associated with decreased mortality when compared with no testosterone treatment in an observational cohort of men with low testosterone levels

a number of short-term studies conducted support the notion that testosterone therapy reduces the cardiovascular risk

The majority of animal studies support the hypothesis that the actions of testosterone on vascular relaxation are both endothelium-dependent and -independent vasodilatory effects

Endothelial-dependent actions of testosterone increase the expression or activity of endothelial nitric oxide synthase and enhance nitric oxide production, which in turn activates cyclic guanosine monophosphate to induce vasorelaxation in smooth muscle cells

Endothelial-independent mechanisms of testosterone are believed to occur primarily via inhibition of voltage-operated Ca2+ channels and/or activation of K+ channels in smooth muscle cells

Testosterone may also inhibit intracellular Ca2+ influx via store-operated Ca2+ channels by blocking the response to prostaglandin F2α

testosterone has demonstrated anti-inflammatory effects to protect against atherogenesis in animal studies

both genomic AR activation to modulate gene transcription and non-genomic activation to modulate the rapid intracellular signaling pathways of ion channels may mediate testosterone effects on vascular function and inflammation.

Butenandt & Ruzicka first showed how testosterone is synthesized and responsible for masculine characteristics in the early 1930s

Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure

E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution

ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake

It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.

Both ERs have been identified in the ARC

Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.

Both ERs have been identified in the LH

both ERs have been identified in this nucleus

The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive

The VMH is ERα regulated

Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body

GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake

data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance

In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane

It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.

E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue

In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue

decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin

Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance

Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs

Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue

suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue

Testosterone has a known age-related decline, and total levels typically drop by approximately 1.6% per year beginning for most men in their 30s

As estrogen levels rise, they prompt the body to produce more SHBG, which in turn has a higher binding affinity for testosterone, and drives the unbound fraction of the testosterone pool down even further

When the increase in SHBG is taken into account, the age-related decline in the level of hormone that can be used by the body is closer to 2% to 3% per year.

Stinging nettle (Urtica dioica), an herb commonly used for allergies, can also be employed to bind to SHBG, which leaves more testosterone available to tissues

Leptin, an adipose-derived peptide hormone that regulates appetite and metabolism, has been shown to directly inhibit testosterone production in animal models

tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) further inhibit Leydig cell testosterone production

Natural aromatase inhibitors include the bioflavonoids chrysin and luteolin

Zinc deficiency causes an upregulation of the aromatase enzyme

Testosterone reduces lipoprotein lipase (LPL) activity

there are several herbs that can work to boost testosterone levels, including longjack (Eurycoma longifolia), horny goat weed (Epimedium grandiflorum), and tribulus (Tribulus terrestris).

the majority of the hormone is bound to carrier proteins including sex hormone binding globulin (SHBG) and albumin