Effects of testosterone therapy in men with hypogonadism

05 September 2014

STUDY: Traish AM. Outcomes of testosterone therapy in men with testosterone deficiency (TD): part II. Steroids. 2014;88:117-126.

Alleged concerns regarding risk of cardiovascular disease with testosterone therapy have been promulgated recently. However, a large and growing number of intervention studies show to the contrary that testosterone therapy 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 summary gives an overview of a comprehensive review of studies that have investigated health effects and safety of testosterone therapy.1 As outlined here, the position that hypogonadism (also known as testosterone deficiency) should be regarded as a risk factor for cardiovascular disease is supported by a rapidly expanding body of evidence.2-4

KEY POINTS

  • Testosterone therapy has beneficial effects on body composition:
    1. Increased muscle mass
    2. Reduced visceral fat mass
    3. Reduced total body fat mass
  • Testosterone therapy has beneficial effects on lipid profile:
    1. Reduced Total cholesterol (TC)
    2. Reduced LDL cholesterol
    3. Reduced triglycerides (TGs)
    4. Increased HDL levels
  • Testosterone therapy has beneficial effects on cardiovascular function:
    1. Reduced arterial stiffness
    2. Reduced CIMT (carotid intima media thickness)
    3. Reduced blood pressure
  • Testosterone therapy has beneficial effects on glucose metabolism, which reduce risk of diabetes:
    1. Increased insulin sensitivity
    2. Reduced glucose levels
    3. Reduced HbA1c levels
  • Testosterone therapy has beneficial effects on inflammatory parameters:
    1. Decreased levels of liver enzymes
    2. Decreased CRP levels
    3. Reduction in inflammatory cytokines
  • Testosterone therapy has beneficial effects on longevity:
    1. Reduced risk of mortality and improved survival
  • Testosterone therapy has beneficial effects on sexual function:
    1. Increased libido, improved erectile function and ejaculatory function
  • Testosterone therapy has beneficial effects on quality of life:
    1. Less fatigue and improvement in energy, mood, vitality
  • This review in addition highlights results from multiple long-term registry studies which demonstrate the following key results:5-11
    1. Testosterone therapy effectively restores physiological testosterone levels within the first 12 months and these restored testosterone levels are maintained with testosterone therapy throughout the entire study period, which at this point is up to 6 years.
    2. Long-term testosterone therapy results in a marked and sustained reduction in body weight and waist circumference (figure 1), BMI, CRP, HbA1c and improves the lipid profile by reducing total cholesterol, LDL and triglycerides while increasing HDL.
    3. 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 testosterone therapy.
  • Safety of testosterone therapy
    1. The most common side effects of testosterone therapy are increases in hematocrit and PSA. However, these elevations occur within the first 12 months, and thereafter remain stable with continued testosterone therapy 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 testosterone therapy.
    2. 5 years of testosterone therapy 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 testosterone therapy does not impact negatively on lower urinary tract symptoms (LUTS) and prostate volume.
Effects of long-term testosterone therapy on weight loss (WL) (Panel A), waist circumference (WC) (Panel B)

Figure 1: Effects of long-term testosterone therapy on weight loss (WL) (Panel A), waist circumference (WC) (Panel B). Marked and progressive decrease in weight (WL) (Panel A) and reduction in WC (Pane B) were observed in men with TD who were treated with T for a 5 year period.

From Traish 2014

What is known

Hypogonadism is a common clinical condition. Observational studies report associations of lower testosterone levels with poorer health outcomes in aging men, including frailty, reduced sexual activity, insulin resistance, cognitive decline, cardiovascular events and mortality.15,16 Decreased testosterone levels also are associated with increased risks of osteoporosis, metabolic syndrome, type 2 diabetes.17

Men with the metabolic syndrome have lower testosterone levels than age-matched men without the metabolic syndrome18-23, and risk of developing the metabolic syndrome is lower in men with higher testosterone levels.24-28 Similarly, men with type 2 diabetes have lower testosterone levels than men without a history of diabetes29-35, and risk of type 2 diabetes is lower in men with high testosterone levels.36-39 Likewise, men with coronary artery disease have lower testosterone levels than age-matched men without coronary artery disease,40, 41 and risk of cardiovascular events42 and cardiovascular death41 is lower in men with high testosterone levels.

What this study adds

A comprehensive review of testosterone therapy interventions confirms that testosterone therapy 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 testosterone therapy has multiple beneficial effects.

Thus, there is now ample evidence to argue that hypogonadism should be an element in the definition of the metabolic syndrome.43 In the long run, the beneficial effects of testosterone therapy 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 hypogonadism in type 2 diabetics,29-35 and because multiple studies demonstrate metabolic benefits of testosterone therapy in type 2 diabetic patients44-49 it has been suggested that testosterone supplementation should be considered when treating type 2 diabetes in hypogonadal men.50 There also are mounting data to support use of testosterone therapy in treatment of obesity.5-11, 51,52

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.53 Due to the strong associations of low testosterone levels with detrimental health outcomes, it is likely that hypogonadism 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 The mechanism of action of testosterone therapy is summarized in figure 2.

What this study shows

In non-obese men with low-normal testosterone levels, testosterone treatment significantly improved fat-free mass and skeletal muscle mass compared with placebo. The dropout rate was high (30%), as in other studies with the testosterone patch. This, and the small cohort size, was a limitation of this study.

Beneficial effects of testosterone therapy on physiological and metabolic function in men, which contribute to a reduced risk of cardiovascular disease and mortality.

Figure 2: Beneficial effects of testosterone therapy on physiological and metabolic function in men, which contribute to a reduced risk of cardiovascular disease and mortality.

From Traish 2014

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