Alleged concerns regarding risk of cardiovascular disease with testosterone replacement therapy (TRT) have been promulgated recently. However, a large and growing number of intervention studies show to the contrary that TRT reduces cardiovascular risk factors and confers multiple beneficial health effects. Thus, fears promoted by some recent flawed studies need to be critically re-evaluated.
This article gives an overview of studies that have investigated health effects and safety of TRT. As outlined here, the position that testosterone deficiency (TD) should be regarded as a risk factor for cardiovascular disease is supported by a rapidly expanding body of evidence.[2-4]
In a previous article I outlines all detrimental health consequences of hypogonadism, aka testosterone deficiency or low-T:
In this article I will describe the effects of testosterone therapy (TRT) on a wide range of risk factors (some of which are relatively unknown).
Key effects of testosterone replacement therapy
* TRT has beneficial effects on body composition:
Increased muscle mass (size) / fat-free mass / lean body mass [5-20]
* TRT has beneficial effects on lipid profile:
Reduced TC / HDL ratio 
Reduced Lp(a) 
* TRT has beneficial effects on cardiovascular function:
Reduced CIMT (carotid intima media thickness) 
Increased circulating endothelial progenitor cell (EPC) number 
Decreased levels of osteoprotegerin (a novel independent marker of cardiovascular risk) 
* TRT has beneficial effects on glucose metabolism, which reduce risk of diabetes:
* TRT has beneficial effects on inflammatory parameters:
Increase in anti-inflammatory cytokines (IL-10) 
* TRT has beneficial effects on the skeleton:
* TRT has beneficial effects on longevity:
* TRT has beneficial effects on sexual function:
* TRT has beneficial effects on quality of life:
- TRT effectively restores physiological T levels within the first 12 months and these restored T levels are maintained with T therapy throughout the entire study period, which at this point is up to 6 years.
- Long-term TRT results in a marked and sustained reduction in body weight, waist circumference, BMI, CRP (C-reactive protein; an inflammatory biomarker), HbA1c and improves the lipid profile by reducing total cholesterol, LDL and triglycerides while increasing HDL.
- It is especially notable that the long-term reductions in body weight, waist circumference and HbA1c keep progressing throughout 5 years, and further improve after each year of TRT.
* Safety of TRT
- The most common side effects of TRT are increases in hematocrit and PSA.[42, 68] However, these elevations occur within the first 12 months, and thereafter remain stable with continued TRT for up to 5 years. This corroborates findings from a previous 3 year-long study which demonstrated that elevations (within the reference range) of hemacocrit and PSA plateau at 12 months and 6 months respectively, after initiation of TRT.
- 5 years of TRT also does not change the International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) rate, post-void residual (PVR) volume, or prostate size. Thus, long-term TRT does not impact negatively on lower urinary tract symptoms (LUTS) and prostate volume.
What is known
Testosterone deficiency (TD), a.k.a hypogonadism, is a common clinical condition, affecting almost 40% of men aged 45 years and older. Observational studies report associations of lower testosterone levels with poorer health outcomes in ageing men, including frailty, reduced sexual activity, insulin resistance, cognitive decline, cardiovascular events and mortality [71, 72]. Decreased testosterone levels also are associated with increased risks of osteoporosis, metabolic syndrome, type 2 diabetes. 
Men with the metabolic syndrome have lower testosterone levels than age-matched men without the metabolic syndrome [22, 74-78], and risk of developing the metabolic syndrome is lower in men with higher testosterone levels.[79-83] Similarly, men with type 2 diabetes have lower testosterone levels than men without a history of diabetes [84-90], and risk of type 2 diabetes is lower in men with high testosterone levels.[91-94] Likewise, men with coronary artery disease have lower testosterone levels than age-matched men without coronary artery disease [95, 96], and risk of cardiovascular events  and cardiovascular death  is lower in men with high testosterone levels.
What new studies show
A comprehensive review of TRT interventions confirms that TRT is safe if treatment and monitoring are appropriately executed. The evidence available to date does not support recently raised concerns about potential detrimental cardiovascular effects of testosterone therapy. Instead, a growing number of interventions studies show that TRT has multiple beneficial effects, as outlined above.
It is notable that TRT also has beneficial effects on novel risk factors like osteoprotegerin  and circulating (in the blood stream) endothelial progenitor cells (EPCs). There is now emerging evidence that osteoprotegerin contributes to the development of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors, such as dyslipidemia, endothelial dysfunction, diabetes and hypertension. This is supported by studies showing that severity of atherosclerosis is significantly associated with higher osteoprotegerin levels, and findings that osteoprotegerin is an independent predictor of cardiovascular events [99, 100] and heart disease. [99, 101] This being that case, it is interesting that TRT reduces osteoprotegerin levels. Endothelial progenitor cells number is another relatively unknown health indicator.
The level of circulating endothelial progenitor cells, which play a critical role in repair of blood vessel injuries, has been shown to predict the occurrence of future cardiovascular events and death from cardiovascular causes. In line with this, a reduced number of circulating endothelial progenitor cells is an independent predictor of atherosclerosis progression.  Low levels of testosterone are associated with a low number of circulating endothelial progenitor cells  and testosterone replacement therapy has been demonstrated to induce an increase in circulating endothelial progenitor cell number, possibly via a direct effect on the bone marrow.[53, 104] Emerging research shows that testosterone an important role in the development and maturation of endothelial progenitor cells, and regulates vascular (endothelial) function. Because of the critical role of the inner lining of blood vessels (aka endothelium) in regulating erectile function, a better understanding of the function of endothelial progenitor cells may pave the way to development of new therapeutic approaches for the treatment of erectile dysfunction.
Thus, there is now ample evidence to argue that TD should be an element in the definition of the metabolic syndrome. In the long run, the beneficial effects of TRT on the metabolic parameters outlined above would protect against development of the main killers; cardiovascular disease and type-2 diabetes. There is a high prevalence of TD in type-2 diabetics [84-90], and because multiple studies demonstrate metabolic benefits of TRT in type-2 diabetic patients [24, 30, 31, 45, 49, 107] it has been suggested that testosterone supplementation be regarded as a new therapy for diabetes. There is also mounting data to support use of TRT in treatment of obesity. [23, 33, 35-37, 41, 67, 109, 110]
Low testosterone levels together with standard risk factors can be used to improved health risk prediction, and may represent a valuable biomarker for indication of cardiovascular disease risk. Due to the strong associations of low testosterone levels with detrimental health outcomes, it is likely that TD contributes, at least partly, to aging related health deterioration. It has therefore been suggested that testosterone deficiency should be regarded as a risk factor for cardiovascular disease.[2-4]
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