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testosterone therapy causes a shift in the skeletal muscle of CHF patients toward a higher concentration of type I muscle fibers

Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics26,68–69 and to lower the BMI in obese patients.

Lower levels of endogenous testosterone have been associated with longer duration of the QTc interval

testosterone replacement has been shown to shorten the QTc interval

negative correlation has been demonstrated between endogenous testosterone levels and IMT of the carotid arteries, abdominal aorta, and thoracic aorta

These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.

Current guidelines from the Endocrine Society make no recommendations on whether patients with heart disease should be screened for hypogonadism and do not recommend supplementing patients with heart disease to improve survival.

The Massachusetts Male Aging Study also projects ≈481 000 new cases of hypogonadism annually in US men within the same age group

since 1993 prescriptions for testosterone, regardless of the formulation, have increased nearly 500%

Testosterone levels are lower in patients with chronic illnesses such as end‐stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus (T2DM), obesity, and several genetic conditions such as Klinefelter syndrome

A growing body of evidence suggests that men with lower levels of endogenous testosterone are more prone to develop CAD during their lifetimes

There are 2 major potential confounding factors that the older studies generally failed to account for. These factors are the subfraction of testosterone used to perform the analysis and the method used to account for subclinical CAD.

The biologically inactive form of testosterone is tightly bound to SHBG and is therefore unable to bind to androgen receptors

The biologically inactive fraction of testosterone comprises nearly 68% of the total testosterone in human serum

The biologically active subfraction of testosterone, also referred to as bioavailable testosterone, is either loosely bound to albumin or circulates freely in the blood, the latter referred to as free testosterone

It is estimated that ≈30% of total serum testosterone is bound to albumin, whereas the remaining 1% to 3% circulates as free testosterone

it can be argued that using the biologically active form of testosterone to evaluate the association with CAD will produce the most reliable results

English et al14 found statistically significant lower levels of bioavailable testosterone, free testosterone, and free androgen index in patients with catheterization‐proven CAD compared with controls with normal coronary arteries

patients with catheterization‐proven CAD had statistically significant lower levels of bioavailable testosterone

In conclusion, existing evidence suggests that men with CAD have lower levels of endogenous testosterone,13–18 and more specifically lower levels of bioavailable testosterone

low testosterone levels are associated with risk factors for CAD such as T2DM25–26 and obesity

In a meta‐analysis of these 7 population‐based studies, Araujo et al41 showed a trend toward increased cardiovascular mortality associated with lower levels of total testosterone, but statistical significance was not achieved (RR, 1.25

the authors showed that a decrease of 2.1 standard deviations in levels of total testosterone was associated with a 25% increase in the risk of cardiovascular mortality

the relative risk of all‐cause mortality in men with lower levels of total testosterone was calculated to be 1.35

higher risk of cardiovascular mortality is associated with lower levels of bioavailable testosterone

Existing evidence seems to suggest that lower levels of endogenous testosterone are associated with higher rates of all‐cause mortality and cardiovascular mortality

studies have shown that lower levels of endogenous bioavailable testosterone are associated with higher rates of all‐cause and cardiovascular mortality

It may be possible that using bioavailable testosterone to perform mortality analysis will yield more accurate results because it prevents the biologically inactive subfraction of testosterone from playing a potential confounding role in the analysis

The earliest published material on this matter dates to the late 1930s

the concept that testosterone replacement therapy improves angina has yet to be proven wrong

In more recent studies, 3 randomized, placebo‐controlled trials demonstrated that administration of testosterone improves myocardial ischemia in men with CAD

The improvement in myocardial ischemia was shown to occur in response to both acute and chronic testosterone therapy and seemed to be independent of whether an intravenous or transdermal formulation of testosterone was used.

testosterone had no effect on endothelial nitric oxide activity

There is growing evidence from in vivo animal models and in vitro models that testosterone induces coronary vasodilation by modulating the activity of ion channels, such as potassium and calcium channels, on the surface of vascular smooth muscle cells

Experimental studies suggest that the most likely mechanism of action for testosterone on vascular smooth muscle cells is via modulation of action of non‐ATP‐sensitive potassium ion channels, calcium‐activated potassium ion channels, voltage‐sensitive potassium ion channels, and finally L‐type calcium ion channels

Corona et al confirmed those results by demonstrating that not only total testosterone levels are lower among diabetics, but also the levels of free testosterone and SHBG are lower in diabetic patients

Laaksonen et al65 followed 702 Finnish men for 11 years and demonstrated that men in the lowest quartile of total testosterone, free testosterone, and SHBG were more likely to develop T2DM and metabolic syndrome.

Vikan et al followed 1454 Swedish men for 11 years and discovered that men in the highest quartile of total testosterone were significantly less likely to develop T2DM

authors demonstrated a statistically significant increase in the incidence of T2DM in subjects receiving gonadotropin‐releasing hormone antagonist therapy. In addition, a significant increase in the rate of myocardial infarction, stroke, sudden cardiac death, and development of cardiovascular disease was noted in patients receiving antiandrogen therapy.67

Several authors have demonstrated that the administration of testosterone in diabetic men improves the homeostatic model of insulin resistance, hemoglobin A1c, and fasting plasma glucose

Existing evidence strongly suggests that the levels of total and free testosterone are lower among diabetic patients compared with those in nondiabetics

insulin seems to be acting as a stimulant for the hypothalamus to secret gonadotropin‐releasing hormone, which consequently results in increased testosterone production. It can be argued that decreased stimulation of the hypothalamus in diabetics secondary to insulin deficiency could result in hypogonadotropic hypogonadism

BMI has been shown to be inversely associated with testosterone levels

This interaction may be a result of the promotion of lipolysis in abdominal adipose tissue by testosterone, which may in turn cause reduced abdominal adiposity. On the other hand, given that adipose tissue has a higher concentration of the enzyme aromatase, it could be that increased adipose tissue results in more testosterone being converted to estrogen, thereby causing hypogonadism. Third, increased abdominal obesity may cause reduced testosterone secretion by negatively affecting the hypothalamus‐pituitary‐testicular axis. Finally, testosterone may be the key factor in activating the enzyme 11‐hydroxysteroid dehydrogenase in adipose tissue, which transforms glucocorticoids into their inactive form.

increasing age may alter the association between testosterone and CRP. Another possible explanation for the association between testosterone level and CRP is central obesity and waist circumference

Bai et al have provided convincing evidence that testosterone might be able to shorten the QTc interval by augmenting the activity of slowly activating delayed rectifier potassium channels while simultaneously slowing the activity of L‐type calcium channels

consistent evidence that supplemental testosterone shortens the QTc interval.

Intima‐media thickness (IMT) of the carotid artery is considered a marker for preclinical atherosclerosis

Studies have shown that levels of endogenous testosterone are inversely associated with IMT of the carotid artery,126–128,32,129–130 as well as both the thoracic134 and the abdominal aorta

1 study has demonstrated that lower levels of free testosterone are associated with accelerated progression of carotid artery IMT

another study has reported that decreased levels of total and bioavailable testosterone are associated with progression of atherosclerosis in the abdominal aorta

These findings suggest that normal physiologic testosterone levels may help to protect men from the development of atherosclerosis

Czesla et al successfully demonstrated that the muscle specimens that were exposed to metenolone had a significant shift in their composition toward type I muscle fibers

Type I muscle fibers, also known as slow‐twitch or oxidative fibers, are associated with enhanced strength and physical capability

It has been shown that those with advanced CHF have a higher percentage of type II muscle fibers, based on muscle biopsy

Studies have shown that men with CHF suffer from reduced levels of total and free testosterone.137 It has also been shown that reduced testosterone levels in men with CHF portends a poor prognosis and is associated with increased CHF mortality.138 Reduced testosterone has also been shown to correlate negatively with exercise capacity in CHF patients.

Testosterone replacement therapy has been shown to significantly improve exercise capacity, without affecting LVEF

the results of the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not cause an increase in the rate of adverse cardiovascular events

Data from 3 meta‐analyses seem to contradict the commonly held belief that testosterone administration may increase the risk of developing prostate cancer

One meta‐analysis reported an increase in all prostate‐related adverse events with testosterone administration.146 However, when each prostate‐related event, including prostate cancer and a rise in PSA, was analyzed separately, no differences were observed between the testosterone group and the placebo group

the existing data from the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not increase the risk of adverse cardiovascular events

the authors correctly point out the weaknesses of their study which include retrospective study design and lack of randomization, small sample size at extremes of follow‐up, lack of outcome validation by chart review and poor generalizability of the results given that only male veterans with CAD were included in this study

the studies that failed to find an association between testosterone and CRP used an older population group

low testosterone may influence the severity of CAD by adversely affecting the mediators of the inflammatory response such as high‐sensitivity C‐reactive protein, interleukin‐6, and tumor necrosis factor–α

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

The presence of symptoms was more closely linked to increasing age than to testosterone levels

Findings similar to type 2 diabetes were reported for men with the metabolic syndrome, which were associated with reductions in total testosterone of −2.2 nmol/l (95% CI −2.41 to 1.94) and in free testosterone

low testosterone is more predictive of the metabolic syndrome in lean men

Cross-sectional studies uniformly show that 30–50% of men with type 2 diabetes have lowered circulating testosterone levels, relative to references based on healthy young men

In a recent cross-sectional study of 240 middle-aged men (mean age 54 years) with either type 2 diabetes, type 1 diabetes or without diabetes (Ng Tang Fui et al. 2013b), increasing BMI and age were dominant drivers of low total and free testosterone respectively.

both diabetes and the metabolic syndrome are associated with a modest reduction in testosterone, in magnitude comparable with the effect of 10 years of ageing

In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone with anaemia

In men, low testosterone is a marker of poor health, and may improve our ability to predict risk

low testosterone identifies men with an adverse metabolic phenotype

Diabetic men with low testosterone are significantly more likely to be obese or insulin resistant

increased inflammation, evidenced by higher CRP levels

Bioavailable but not free testosterone was independently predictive of mortality

It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker, co-existing because of in-common risk factors.

In prospective studies, reviewed in detail elsewhere (Grossmann et al. 2010) the inverse association of low testosterone with metabolic syndrome or diabetes is less consistent for free testosterone compared with total testosterone

In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident metabolic syndrome

low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes

In cross-sectional studies of men with (Grossmann et al. 2008) and without (Bonnet et al. 2013) diabetes, SHBG but not testosterone was inversely associated with worse glycaemic control

SHBG may have biological actions beyond serving as a carrier protein for and regulator of circulating sex steroids

In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced

Low free testosterone remains inversely associated with insulin resistance, independent of SHBG (Grossmann et al. 2008). This suggests that the low testosterone–dysglycaemia association is not solely a consequence of low SHBG.

Experimental evidence reviewed below suggests that visceral adipose tissue is an important intermediate (rather than a confounder) in the inverse association of testosterone with insulin resistance and metabolic disorders.

testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes

testosterone regulates the metabolic functions of mature adipocytes (Xu et al. 1991, Marin et al. 1995) and myocytes (Pitteloud et al. 2005) in ways that reduce insulin resistance.

Pre-clinical evidence (reviewed in Rao et al. (2013)) suggests that at the cellular level, testosterone may improve glucose metabolism by modulating the expression of the glucose-transported Glut4 and the insulin receptor, as well as by regulating key enzymes involved in glycolysis.

More recently testosterone has been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis

Interestingly, a reciprocal feedback also appears to exist, given that not only chronic (Cameron et al. 1990, Allan 2013) but also, as shown more recently (Iranmanesh et al. 2012, Caronia et al. 2013), acute hyperglycaemia can lower testosterone levels.

There is also evidence that testosterone regulates insulin sensitivity directly and acutely

In men with prostate cancer commencing androgen deprivation therapy, both total as well as, although not in all studies (Smith 2004), visceral fat mass increases (Hamilton et al. 2011) within 3 months

More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several large observational registry studies

Testosterone has also been shown to reduce the concentration of pro-inflammatory cytokines in some, but not all studies, reviewed recently in Kelly & Jones (2013). It is not know whether this effect is independent of testosterone-induced changes in body composition.

the observations discussed in this section suggest that it is the decrease in testosterone that causes insulin resistance and diabetes. One important caveat remains: the strongest evidence that low testosterone is the cause rather than consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor.

Several large prospective studies have shown that weight gain or development of type 2 diabetes is major drivers of the age-related decline in testosterone levels

there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in testosterone

Circulating testosterone, on an average 30%, is lower in obese compared with lean men

increased visceral fat is an important component in the association of low testosterone and insulin resistance

The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone levels

obesity is a dominant risk factor

men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat mass is already present before puberty

Only 5% of men with type 2 diabetes have elevated LH levels

inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity

Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH) secretion from GNRH neurons situated in the preoptic area

kisspeptin has emerged as one of the most potent secretagogues of GNRH release

hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes

A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects

suppression of the diabesity-associated HPT axis is functional, and may hence be reversible

Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis

weight gain and development of diabetes accelerate the age-related decline in testosterone

Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone levels than age alone

55% of symptomatic androgen deficiency reverted to a normal testosterone or an asymptomatic state after 8-year follow-up, suggesting that androgen deficiency is not a stable state

Weight loss can reactivate the hypothalamic–pituitary–testicular axis

Leptin treatment resolves hypogonadism in leptin-deficient men

The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men

Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes

change in BMI was associated with the change in testosterone (Corona et al. 2013a,b).

weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression

There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis

in men who improved their glycaemic control over time, testosterone levels increased. By contrast, in those men in whom glycaemic control worsened, testosterone decreased

testosterone levels should be measured after successful weight loss to identify men with an insufficient rise in their testosterone levels. Such men may have HPT axis pathology unrelated to their obesity, which will require appropriate evaluation and management.

both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems

In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation

fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet

testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation

fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.

testosterone status did not significantly affect body weight

testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis

Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone

it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth

Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β

Testosterone status also affected metabolic and neural measures

many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression

neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation

testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions

glia are the primary sources of proinflammatory molecules in the CNS

poorer survival of neurons grown on glia from mice maintained on high-fat diet

Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group

significantly increased expression of TNFα and IL-1β in glia cultures derived from obese mice

testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions

IL-1β treatment has been shown to induce synapse loss and inhibit differentiation of neurons

Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration

testosterone prevented and/or restored thermal nociception in both diet groups

a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS

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

During the I/R period, testosterone replacement in ORX rats exerted the beneficial effects as indicated by (1) improved left ventricular pressure; (2) markedly decreased infarct size; (3) reduced fatal cardiac arrhythmias by increased time to 1st VT/VF onset and reduced arrhythmia scores; and (4) attenuated cardiac mitochondrial dysfunction caused by I/R injury by reducing ROS production, cardiac mitochondrial swelling and mitochondria membrane depolarization.

Chronic testosterone replacement also ameliorates left ventricular dysfunction, and reduces the infarct size and cardiac arrhythmias impaired by I/R injury under testosterone-deprived conditions

The mechanisms responsible for these beneficial effects of testosterone could be due to its ability to attenuate cardiac mitochondrial dysfunction and cardiomyocyte apoptosis

An association between testosterone and WBC count was not observed

These findings are consistent with the hypothesis that in men higher androgen concentration is anti-inflammatory, and higher estrogen concentration is pro-inflammatory.

the probability of elevated CRP concentrations (≥ 3 mg/L) decreased with higher total and calculated free testosterone concentrations, while the probability increased with higher total and calculated free estradiol concentrations

there is ample evidence supporting the immunosuppressive effect of androgens

The incidence of autoimmune diseases is higher in androgen-deficient men

Studies have shown that the induction of hypogonadism in older men is followed by a significant increase in IL-6 concentrations (Khosla et al. 2002), a potent stimulator of inflammation, and that activation of the androgen receptor exerts a direct anti-inflammatory effect

It has been suggested that the mechanisms for the immunosuppressive effect of androgens could be either a direct effect on the expression of inflammatory genes (Bellido et al. 1995; Asirvatham et al. 2006), or an indirect effect through inhibition of nuclear factor-kB activation

Estradiol is the major biologically active estrogen, and about 80% is formed in adult men from the aromatization of testosterone primarily in the adipose tissue

estrogen can stimulate the transcription factor C/EBP-β, which is involved in CRP transcription

Most prior cross-sectional studies have observed inverse associations between androgen concentrations and inflammatory biomarkers

A recent study in Chinese men showed that lower concentrations of total and calculated free testosterone were associated with higher CRP concentration

Data from the Boston Area Community Health Survey also reported inverse associations between testosterone and CRP concentrations

Total testosterone was inversely associated with WBC count (Tang et al. 2007; Schneider et al. 2009; Brand et al. 2012), but calculated free testosterone was not associated with WBC

The first trial found a decrease in CRP, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα) but no changes in IL-6 and IL-10 concentrations between the active treatment and placebo arms

the majority of studies in the literature have not observed statistically significant associations between estradiol and inflammatory biomarkers in men, although several of them observed point estimates in the positive direction

total testosterone and estradiol compete for binding to SHBG, and seem to have opposite effects on the concentration of inflammatory biomarkers

A small randomized controlled trial of estrogen replacement therapy in prostate cancer patients showed an increase in CRP in the active treatment group versus the comparator group

Obese men are known to have lower androgen concentrations compared to their normal-weight counterparts

The strongest suggestion of an interaction was the inverse association between androstanediol glucuronide and CRP concentrations in obese participants, while the association was positive in the non-obese

A recent Chinese cross-sectional study observed stronger inverse associations between total testosterone and CRP concentrations in individuals with a BMI of 27.5 kg/m2 or greater

our results suggest that total and calculated free testosterone are modestly inversely associated with CRP concentrations, and that total and calculated free estradiol are modestly positively associated with CRP and WBC

Testosterone deficiency has a high prevalence in men with T2DM, and it is also associated with impaired insulin sensitivity, increased percentage body fat, central obesity, dyslipidemia, hypertension and cardiovascular diseases (CVD)

A meta-analysis of four randomized controlled trials (RCTs) showed that TRT seemed to improve glycemic control as well as fat mass in T2DM subjects with low testosterone levels and sexual dysfunction.

testosterone administration could increase muscle mass and strength

Insulin stimulates glucose uptake into muscle and adipose tissue via the Glut4 glucose transporter isoform. When insulin activates signaling via the insulin receptor, Glut4 interacts with insulin receptor substrate 1 to initialize intracellular signaling and facilitate glucose transportation into the cell

The benefits of TRT on glucose metabolism can mainly be explained by its influence on the insulin signaling pathway

Insulin resistance as assessed by, which is calculated from the equation (If*Gf/22.5, where If is fasting insulin and Gf is fasting glucose), was definitely improved by TRT after testosterone administration in three studies

Testosterone was observed to elevate the expression levels and stimulate translocation of Glut4 in cultured skeletal muscle cells and to upregulate Glut4 by activating insulin receptor signaling pathways in neonatal rats

These effects were inhibited by a dihydrotestosterone (DHT) blocker, indicating that glucose uptake may correlate with conversion of testosterone to DHT and activation of the androgen receptor.

TRT reduced triglyceride levels

TRT has been reported to have a positive effect in the decrease of total and LDL cholesterol levels and triglycerides in hypogonadal men

a recent meta-analysis showed that statins could significantly lower testosterone concentrations.

Epidemiological studies have found a negative relationship between testosterone levels and typical cardiovascular risk markers, such as body mass index, waist circumference, visceral adiposity and carotid intima-media thickness.

Testosterone treatment was shown to raise hemoglobin, hematocrit and thromboxane, all of which might give rise to CVD

testosterone concentrations should be checked 2–3 months after initiation of therapy and after adjusting the dose

the recommendation for injectable testosterone esters is to check the serum concentration midway between injections

it is recommended for serum testosterone to be evaluated 3 to 12 hours after application of the transdermal patch

Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)

a study from 1989 utilizing testosterone transdermally containing 5, 10, or 15 mg of testosterone showed that peak concentrations of testosterone were achieved 3 to 8 hours after scrotal application in hypogonadal men

measure serum testosterone any time after the patient has been on treatment with gel for at least 1 week

evaluate serum testosterone at the end of the dosing interval for testosterone pellets

increased amount of fat leads to increased extragonadal aromatase activity, resulting in increased concentrations of estradiol. High circulating concentrations of estradiol down regulate the HPG axis and decrease the amount of circulating testosterone

Up to 80% of plasma estradiol originates from aromatization of testosterone and less than 20% of estradiol in the circulation is secreted by the testes

A PSA concentration, digital rectal examination, and hematocrit should be performed at baseline and at 3 months, 6 months, then yearly after TRT is initiated.

It is used for many medications and has the advantage of high bioavailability, absence of hepatic first pass metabolism, increased therapeutic efficacy, and steadiness of plasma concentrations of the drug

If the hematocrit rises above 54%, treatment should be discontinued

elderly men having higher estradiol serum concentrations than postmenopausal women

none of the men stopped testosterone supplementation due to prostate cancer recurrence, and none demonstrated cancer progression

PSA level did transiently rise in one patient; however, none exceeded a PSA of 1.5 ng ml−1 to raise concern for biochemical recurrence

after 19 months on TRT, 10 hypogonadal patients with a history of undergoing a radical retropubic prostatectomy for prostate cancer had no PSA recurrence and had statistically significant improvements in serum total testosterone and hypogonadal symptoms

Similarly, Kaufman and Graydon14 examined case records of seven hypogonadal men who had undergone curative RP with symptoms of hypogonadism and low serum testosterone levels treated with testosterone replacement. No biochemical or clinical evidence of cancer recurrence was noted

In a much larger case series, Khera et al.15 reviewed the records of 57 men who received TRT following RP. After an average of 36 months following RP, testosterone replacement was initiated and followed for an average of 13 months. Mean testosterone values rose significantly and once again, there was no increase in PSA values and, therefore, no diagnosed biochemical recurrence

Four of the patients in the treatment group were found to have cancer recurrence, compared with eight in the control group

All biochemical recurrences were seen in individuals with high-risk disease

Cherrier et al [17] evaluated a sample of 32 subjects, which included 17 men with mild cognitive impairment and 15 with Alzheimer's disease. At the 6-week follow-up, patients who received TRT showed significantly better scores regarding spatial memory, constructional abilities, and verbal memory compared to those noted in the placebo group. Taken together, these results suggest that TRT has a beneficial effect on cognitive function

TRT improved mood and well-being, and reduced fatigue and irritability in hypogonadal men

The study by Pope et al [20] involved men with depression refractory to standard anti-depressants, and found that TRT lowered the Hamilton Depression score,

depression tends to increase as testosterone levels decrease [21], it is highly likely that TRT improved symptoms of depression by increasing testosterone levels.

Low TT and SHBG levels also are prevalent in Chinese [7],[8] and Korean [9] men with the MetS

Normally 40%-50% of TT is bound to SHBG, so reducing SHBG levels will decrease TT.

Hyperinsulinism suppresses SHBG synthesis and secretion by the liver

significant increase in SHBG levels occurred after acutely lowering insulin levels in obese men

Estradiol levels are increased in men with the MetS, and they are positively correlated with the number of abnormal components of the MetS.

Although it is known that estrogen will increase SHBG levels, apparently the hyperinsulinism associated with obesity has a greater effect on SHBG levels

Estradiol also can inhibit luteinizing hormone (LH) secretion

Inflammatory cytokines are thought to have a direct effect on the pituitary to reduce LH secretion [15] and also a direct effect on Leydig cell secretion of testosterone

Low TT Levels have been shown to predict development of the MetS in men with normal BMI

Men in the lowest quartiles of serum TT, calculated free testosterone (cFT) and SHBG at baseline had the highest odds ratios for developing the MetS or DM during the 11 years follow-up

More recently, investigators conducting population-based studies have reported that only SHBG is associated with future development of the MetS

Additional evidence that low TT increases the risk of MetS comes from androgen deprivation treatment of prostate cancer

Low TT and low bioavailable testosterone (bT) were each significantly associated with elevated 20 years risk of CVD mortality in an older population in which cause-specific mortality was age, adiposity, and lifestyle-adjusted.

combination of low bT and ATP III-defined MetS is associated with increased cardiovascular mortality in men aged 40 years and above

in elderly men, testosterone may weakly protect against CVD. Alternatively, low TT may indicate poor general health

Muraleedharan and Jones [27] concluded that there is convincing evidence that low T is a biomarker for disease severity and mortality.

The evidence that TRT improves insulin sensitivity and glucose control is conflicted

It is widely recognized that testosterone treatment can reduce fat mass and increase lean body mass; however, until recently most reports have not been associated with much weight loss

Changes in body composition and weight loss are considered potential mechanisms by which testosterone treatment improves insulin sensitivity and glucose control in patients with diabetes. Effects on inflammatory cytokines [38] and changes in oxidative metabolism [39] also have been reported to improve glucose metabolism.

Testosterone replacement therapy has been reported to improve some or all of the components of the MetS.

The MVC and PTmax were significantly improved in TRT patients but remained unchanged in the placebo group

handgrip strength improved significantly with testosterone treatment

According to EF assessed by echocardiography, no differences were observed between the patients who were prescribed testosterone and those who received placebo

There were no differences between the groups in circulating levels of NT pro-BNP, and inflammatory markers were unchanged, except for a decrease in TNF-α from baseline in the placebo group

Testosterone supplementation therapy appeared to be safe, and the subjects who accepted testosterone treatment did not appear any obvious adverse reactions.