This early in the evaluation: but testosterone therapy in those men with CHF is of considerable benefit. This would improve the catabolic:anabolic state, reduce inflammation, improve strength/endurance and reduce CVD risk
Patients with ventricular tachycardia demonstrated significantly lower serum values of FT3 and FT3/FT4, and significantly higher values of rT3. Serum thyroid hormone levels can provide a quantitative index for evaluating the severity of chronic heart failure and predicting ventricular tachycardia.
Diet is a language that interacts with out DNA. Study finds that Mediterranean diet + extra virgin olive oil alters genetic expression to reduce cardiovascular risk.
Testosterone has beneficial
effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves
cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart
failure.
testosterone is an L-calcium channel blocker and induces potassium
channel activation in vascular smooth muscle cells
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
Studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally [39] and to produce modest but consistent improvement in exercise-induced angina and reverse associated ECG changes [40]. The mechanism of action is via blockade of calcium channels with effect of similar magnitude to nifedipine
Testosterone acts as a calcium channel blocker inducing vasodilation.
men with chronic stable angina pectoris, the ischaemic threshold increased after 4 weeks of TRT and a recent study demonstrates improvement continuing beyond 12 months [
Exercise capacity in men with chronic heart failure increased after 12 weeks
Studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels
Medications such as chronic analgesics, anticonvulsants, 5ARIs, and androgen ablation therapy are associated with increased risk of testosterone deficiency and insulin resistance
Women with T2D or metabolic syndrome characteristically have low SHBG and high free testosterone
Hypogonadism is a common feature of the metabolic syndrome
The precise interaction between insulin resistance, visceral adiposity, and hypogonadism is, as yet, unclear but the important mechanisms are through increased aromatase production, raised leptin levels, and increase in inflammatory kinins
levels of testosterone are reduced in proportion to degree of obesity
Men should be encouraged to combine aerobic exercise with strength training. As muscle increases, glucose will be burned more efficiently and insulin levels will fall. A minimum of 30 minutes exercise three times weekly should be advised
Testosterone increases levels of fast-twitch muscle fibres
By increasing testosterone, levels of type 2 fibres increase and glucose burning improves
Weight loss will increase levels of testosterone
studies now clearly show that low testosterone leads to visceral obesity and metabolic syndrome and is also a consequence of obesity
In the case of MMAS [43], a baseline total testosterone of less than 10.4 nmol/L was associated with a greater than 4-fold incidence of type 2 diabetes over the next 9 years
There is high level evidence that TRT improves insulin resistance
Low testosterone predicts increased mortality and testosterone therapy improves survival in 587 men with type 2 diabetes
A similar retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% (
) in the treated group with the greatest effect in younger men and those with type 2 diabetes
the presence of ED has been shown to be an independent risk factor, particularly in hypogonadal men, increasing the risk of cardiac events by over 50%
A recent online publication on ischaemic heart disease mortality in men concluded optimal androgen levels are a biomarker for survival
inverse associations between low TT or FT (Table 2) and the severity of CAD
A recent 10 year study from Western Australia involving 3690 men followed up from 2001–2010 concluded that TT and FT levels in the normal range were associated with decreased all-cause and cardiovascular mortality, for the first time suggesting that both low and DHT are associated with all-cause mortality and higher levels of DHT reduced cardiovascular risk
TDS is associated with increased cardiovascular and all-cause mortality
The effect of treatment with TRT reduced the mortality rate of treated cohort (8.4%) to that of the eugonadal group whereas the mortality for the untreated remained high at 19.2%
hypogonadal men had slightly increased triglycerides and HDL
Men with angiographically proven CAD (coronary artery disease) have significantly lower testosterone levels [29] compared to controls (
) and there was a significant inverse relationship between the degree of CAD and TT (total testosterone) levels
TRT has also been shown to reduce fibrinogen to levels similar to fibrates
men treated with long acting testosterone showed highly significant reductions in TC, LDL, and triglycerides with increase in HDL, associated with significant reduction in weight, BMI, and visceral fat
Low androgen levels are associated with an increase in inflammatory markers
In the Moscow study, C-reactive protein was reduced by TRT at 30 weeks versus placebo
In some studies, a decline in diastolic blood pressure has been observed, after 3–9 months [24, 26] and in systolic blood pressure
A decline was noted in IL6 and TNF-alpha
No studies to date show an increase in LUTS/BPH symptoms with higher serum testosterone levels
TRT has been shown to upregulate PDE5 [65] and enhance the effect of PDE5Is (now an accepted therapy for both ED and LUTS), it no longer seems logical to advice avoidance of TRT in men with mild to moderate BPH.
What about just starting with normalization of Testosterone levels first.
Several meta-analyses have failed to show a link between TRT and development of prostate cancer [66] but some studies have shown a tendency for more aggressive prostate cancer in men with low testosterone
And if one would have looked at their estrogen levels, I guarantee they would have been found to be elevated.
low bioavailable testosterone and high SHBG were associated with a 4.9- and 3.2-fold risk of positive biopsy
Current EAU, ISSAM, and BSSM guidance [1, 2] is that there is “no evidence TRT is associated with increased risk of prostate cancer or activation of subclinical cancer.”
Men with prostate cancer, treated with androgen deprivation, develop an increase of fat mass with an altered lipid profile
Erectile dysfunction is an established marker for future cardiovascular risk and the major presenting symptom leading to a diagnosis of low testosterone
Low T3 post MI is associated with increased CHF, morbidity and mortality. Article discusses thyroid hormones and cardiac function/remodeling post infarct. The article also lays the ground work for a new study of T3 in patients post MI to be followed for 6 months.
BNP and NT-proBNP associated with HF and worsening HF. Also, in the same setting, elevated BNP and NT-proBNP is found to be associated with increased cardiovascular events and mortality.
This is the first paper to show that CRP values increase with progressive thyroid failure and may count as an additional risk factor for the development of coronary heart disease in hypothyroid patient
overall mortality and CV mortality were inversely associated with serum T concentrations.
men with low serum T, defined as < 8.7 nmol l−1 (250 ng dl−1 ), demonstrated significantly greater all-cause mortality than men with higher serum T (hazard ratio [HR]: 2.24; 95% CI: 1.41-3.57), as well as greater CV mortality
lower T levels were significantly associated with the presence of any CV disease
more than 30 years of studies suggesting that low levels of T represent an increased risk for CV and overall mortality,
lower serum T concentrations also are associated with CV disease, including incident coronary artery disease [17],[18],[19] and atherosclerosis,
the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk = 10.1%) as in the untreated group (1587 events in 7486 men = 21.2%)
The study by Vigen et al. [7] has already undergone two published corrections,
29 medical societies have called for retraction of the article, asserting "gross data mismanagement and contamination," that rendered the study "no longer credible
Mortality in T-treated men was reduced by approximately half in treated men compared with untreated men, at 10.3% versus 20.7%, respectively
The mortality rate for men who received TTh was 3.4 deaths per 100 person-years, and 5.7 deaths per 100 person-years in untreated men
HR of 0.61 (95%CI: 0.42-0.88; P = 0.008), indicating a significant reduction in mortality with TTh
men in the highest prognostic MI risk quartile, treatment with TTh was associated with reduced risk
tripling in T prescriptions in the US over the last decade
a majority of observational studies have found that low endogenous serum T levels are associated with increased mortality.
Men who received TTh were able to exercise significantly longer without ischemia compared with men who received placebo
In men with congestive heart failure, those who received T demonstrated greater walking distance and other functional endpoints compared with those who received placebo
TTh has been shown uniformly and repeatedly to improve several known CV risk factors, including reduced fat mass, body fat percent, and waist circumference, and increased lean mass
improved glycemic control
reductions in insulin resistance.
the evidence strongly points to improved CV status with normal serum T or treatment with TTh in men with TD
analysis of health insurance claims data that reported a 36% increased rate of nonfatal MI in the 90d following receipt of a T prescription compared with the 12 prior months.
Comparison with men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) revealed no increased rate of MI following the prescription
Great review by Morgentaler of Testosterone and CVD. He highlights the significant flaws in the JAMA and the NEJM articles of Testosterone therapy risks. Morgentaler highlights the significant evidence that points to low T and increased risk of CVD.
On contention I have, is Morgantaler seems to flip aside the massive uptick of Testosterone use in the US as compared to other countries. The evidence definitely points to Testosterone therapy as being safe in those with low T, but there is definitely a problem of significant Testosterone doping that is taking place as well.
Another study regarding reverse T3 that many Endocrinologists need to read. In this study, the authors find that significantly higher reverse T3 levels were associated with myocardial function impairment (MFI) class IV. This MFI class IV was also found associated with a decreased fT3/rT3.
Les chirurgiens de l'insuffisance cardiaque en Inde veillent à ce que les patients reçoivent un traitement médical de haute qualité à une fraction du coût dans les pays occidentaux.