Adverse health effects of testosterone deficiency in men

Adverse health effects of testosterone deficiency (TD) in men. Traish AM. Steroids. 2014 Jun 2. pii: S0039-128X(14)00122-6. doi: 10.1016/j.steroids.2014.05.010. [Epub ahead of print]

Testosterone deficiency, also known as hypogonadism, is a state with sub-optimal circulating levels of testosterone concomitant with clinical signs and symptoms attributed to low physiological testosterone levels.1-3

Sexual dysfunction is the most commonly recognized symptom of testosterone deficiency. However, testosterone also plays a broader role in men's health. A growing body of evidence has established associations between low testosterone levels and multiple risk factors and diseases including the metabolic syndrome, obesity, type 2 diabetes, sarcopenia (loss of muscle mass), frailty, mobility limitations, osteoporosis, cognitive impairment, depression, cardiovascular disease, and reduced longevity.3-12

This summary gives an overview of a comprehensive review of studies that have investigated the detrimental impact of testosterone deficiency on a wide range of health outcomes.13

Key Points

Adverse effects of testosterone deficiency (TD) on men’s health.13

Impact on: Adverse effect:
Glycemic control and diabetes Increased insulin resistance
increased blood glucose levels
increased HbA1c levels (glycated hemoglobin)
increased risk of diabetes
Inflammatory responses Increased activities of liver enzymes
Increased levels of CRP (an inflammatory marker)
Increased levels of inflammatory cytokines
Lipid profile Increased total cholesterol levels
Increased LDL-cholesterol levels
Increased triglyceride (TG) levels
Body composition Reduced muscle mass
Increased visceral fat mass
Increased total fat mass
Muscle mass / fat mass Reduced muscle mass
Increased visceral fat mass
Bone mineral density Reduced bone mineral density
Blood pressure Increased hypertension
Endothelial function Increased endothelial (blood vessel) dysfunction
Cardiovascular function Increased risk of cardiovascular disease
Increased risk of intima media thickness
(an indicator of atherosclerosis)
Increased risk of coronary artery disease
Mortality Increased risk of mortality
Sexual function Decreased libido
Increased erectile dysfunction
Diminished ejaculatory function
Quality of Life Diminished physical activity
Diminished energy
Depressed mood
Decreased vitality

What is known

Testosterone deficiency is characterized by either deficiency in total serum testosterone (TT) levels or low calculated free testosterone levels (below the young healthy adult male reference range), coupled with signs and symptoms indicative of sup-optimal testosterone levels.1-3 While there is no universal agreement on the specific signs and symptoms of testosterone deficiency, reduced sexual desire and sexual dysfunction are thought to be strong indications of testosterone deficiency.1-3, 14-18 More specifically, the three sexual symptoms most significantly related to low testosterone levels are decreased frequency of morning erection, decreased frequency of sexual thoughts, and erectile dysfunction.18 Other signs and symptoms include reduced physical performance (an inability to engage in vigorous activity [e.g., running, lifting heavy objects, or participating in strenuous sports], an inability to walk more than 1 km, and an inability to bend, kneel, or stoop), and psychological malaise (loss of energy, sadness [“downheartedness” on questionnaire], and fatigue).18

It is Important to note that low testosterone levels even within the normal range negatively impact risk of cardiovascular events and mortality. For example, the MrOS (Osteoporotic Fractures in Men) Study found that men aged 69 to 81 years in the highest quartile of testosterone, 550 ng/dL (approximately 19.1 nmol/L) and above, had a lower risk of cardiovascular events compared with age-matched men in the 3 lower quartiles.19 More specifically, men having testosterone levels of 550 ng/dl and above had a 30% lower risk of experiencing cardiovascular events during a 5 year follow-up compared to men with levels below 550 ng/dL.19 This association remained after adjustment for traditional CV risk factors and was not materially changed in analyses excluding men with known CV disease at baseline.

The EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk) Prospective Population Study demonstrated in men aged 40 to 79 years that increasing endogenous testosterone levels are inversely related to mortality due to all causes, cardiovascular causes, and cancer during a 7 year follow-up.20 Men in the highest (over 19.6 nmol/L = 565 ng/dL) compared with the lowest quartile (below 12.5 nmol/L = 361 ng/dL) of testosterone level had a 25-30% lower risk of total mortality.20 The EPIC-Norfolk Study also found that for every 6-nmol/L (173 ng/dL) increase in serum testosterone there was a 14% lower risk of mortality. The magnitude of effect was similar for deaths due to cardiovascular causes and those due to cancer and was little changed after adjustment for cardiovascular risk factors and sex hormone binding globulin or after the exclusion of deaths within 2 years.20 Also in men with pre-existing coronary artery disease low testosterone levels within the normal range negatively impact survival, with a cut-off of total testosterone of 15.1 nmol/L (436 ng/dL) being related to increased mortality.21

It should be underscored that all these thresholds represent cut-offs that are higher than most currently accepted definitions of hypogonadism. In many laboratories, the lower limit of the normal range for total testosterone levels is 280-300 ng/dl (9.8–10.4 nmol/L).1 Thus, even men who have not been diagnosed with hypogonadim and therefore are being denied testosterone therapy may be at unnecessarily increased risk for negative health outcomes, which may be prevented with testosterone therapy.

What this study adds

The review outlined here clearly shows that testosterone deficiency, which is a common clinical condition, is associated with many adverse health effects and a significant deterioration in quality of life. Testosterone deficiency increases risk for obesity, type 2 diabetes, metabolic syndrome, cardiovascular disease, dyslipidemia (abnormal blood cholesterol and fats), inflammation, endothelial dysfunction, hypertension, and loss of lean body mass, muscle volume and strength, and bone mineral density. Testosterone deficiency is also associated with diminished sexual desire and erectile function, decline in cognitive and intellectual function, reduced energy, increased fatigue, depressed mood and vitality, and depression.
Figure 1: Testosterone deficiency in men contributes to a host of co-morbidities.
Figure 1: Testosterone deficiency in men contributes to a host of co-morbidities. These include, inflammation, insulin resistance, diabetes, dyslipidemia, hypertension, metabolic syndrome, vascular stiffness, atherosclerosis, cardiovascular disease, sexual dysfunction and mortality.

From Traish 2014, Steroids
Men with erectile or ejaculatory dysfunction, reduced sexual desire, as well as those with visceral obesity and metabolic diseases, should be screened for testosterone deficiency and, if found hypogonadal, treated, regardless of age.3, 14 Because testosterone therapy in testosterone deficient men with these co-morbidities may reverse or delay their progression22, it is imperative that clinicians become more aware of the wide ranging impact of suboptimal testosterone levels on men's health and well-being.

References

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2. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Journal of andrology. 2009;30(1):1-9.
3. Buvat J, Maggi M, Guay A, et al. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. The journal of sexual medicine. 2013;10(1):245-284.
4. Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes/metabolism research and reviews. 2012;28 Suppl 2:52-59.
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7. Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male ageing? Critical reviews in clinical laboratory sciences. 2012;49(5-6):168-182.
8. Traish AM, Guay A, Feeley R, et al. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. Journal of andrology. 2009;30(1):10-22.
9. Traish AM, Saad F, Feeley RJ, et al. The dark side of testosterone deficiency: III. Cardiovascular disease. Journal of andrology. 2009;30(5):477-494.
10. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. Journal of andrology. 2009;30(1):23-32.
11. Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis: The lipid link. Vascular pharmacology. 2009;51(5-6):303-313.
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13. Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. 2014.
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16. Yassin AA, Saad F. Treatment of sexual dysfunction of hypogonadal patients with long-acting testosterone undecanoate (Nebido). World journal of urology. 2006;24(6):639-644.
17. Yassin AA, Saad F. Improvement of sexual function in men with late-onset hypogonadism treated with testosterone only. The journal of sexual medicine. 2007;4(2):497-501.
18. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. The New England journal of medicine. 2010;363(2):123-135.
19. Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. Journal of the American College of Cardiology. 2011;58(16):1674-1681.
20. Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007;116(23):2694-2701.
21. Malkin CJ, Pugh PJ, Morris PD, et al. Low serum testosterone and increased mortality in men with coronary heart disease. Heart. 2010;96(22):1821-1825.
22. Traish AM, Miner MM, Morgentaler A, et al. Testosterone deficiency. The American journal of medicine. 2011;124(7):578-587.
Last updated: 2017
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