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

Clinically, testosterone deficiency is divided into primary hypogonadism (testicular dysfunction), secondary hypogonadism (pituitary or hypothalamic failure) or mixed hypogonadism (a combination of testicular failure and pituitary-hypothalamic failure).³ A significant proportion of older men have high gonadotropins (LH and FSH) and testosterone within the normal range.^19-21 This indicates a state of compensated, or subclinical, hypogonadism that may eventually develop into overt primary hypogonadism.²² Thus, by coupling testosterone levels with LH levels clinicians can detect impending testosterone deficiency. Measuring LH together with testosterone can also strengthen symptomatic diagnosis as sexual symptoms are more prevalent in secondary and primary hypogonadism, whereas physical symptoms are more likely in compensated hypogonadism.²² Obese men are especially prone to secondary hypogonadism, while in older men primary hypogonadism predominates.²² Testosterone deficiency may also result from an impairment of testosterone action because of decreased bioavailability of the hormone (due to SHBG elevations) or because of androgen receptor alterations.³

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.²³ 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.²³ 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.²⁴ 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.²⁴ 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.²⁴ 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.²⁵

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, 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 below illustrates how testosterone deficiency contributes to development or progression of multiple risk factors, which in turn increase the risk of mortality.