What is known about testosterone deficiency
Testosterone deficiency is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.10-16 Large population studies report strong associations of lower testosterone levels with worse health outcomes in men, including reduced sexual activity, obesity, insulin resistance, inflammation, cholesterol abnormalities, metabolic syndrome, atherosclerosis, heart complications and mortality, as well as depressed mood, reduced motivation, fatigue, frailty, anemia, bone loss and decreased quality of life.17-27
Testosterone deficiency is associated with an adverse cardiovascular risk profile and increased atherosclerotic burden.28-30 A substantial body of evidence indicates that atherosclerosis, heart disease incidence and death are increased in men with low testosterone levels.31 Consistent with this, men with low testosterone levels have an increased number and severity of multiple cardiovascular risk markers.32 Hence, there is a need for greater awareness of the impact of testosterone deficiency on general health and particularly on cardiovascular risk. The 2018 American Urological Association (AUA) guideline urges doctors to inform patients who have testosterone deficiency that low testosterone is a risk factor for cardiovascular disease, and recommends that all testosterone deficient patients should have their cardiovascular disease risk factors checked.33
In the general population, up to 39% of men aged 53-62 have testosterone deficiency.34 Among men with the metabolic syndrome or diabetes, around 45% have testosterone deficiency.35 Similarly, half of men with erectile dysfunction are testosterone deficient.36 In men over 40 years of age with abdominal obesity and erectile dysfunction, 68% have low testosterone levels.37 In obese men, up to 78% have testosterone deficiency.38,39 Among men with a waist circumference of >120 cm, 87% have low testosterone levels.40 Considering that the prevalence of obesity is close to 40% in the general male population41, testosterone deficiency has become a global public health concern.10
What this review adds about the effects of testosterone therapy
Testosterone therapy improves body composition by increasing lean body (muscle) mass and decreasing fat mass
It is well documented that testosterone treatment dose-dependently increases lean body (muscle) mass and decreases body fat mass.42-47 Notably, older men are as responsive as young men to the anabolic effects of graded doses of testosterone on muscle.43
Testosterone therapy increases insulin sensitivity, ameliorates components of the metabolic syndrome and reduces risk of type 2 diabetes
Long-term real-life studies have shown that testosterone therapy for up to 10 years ameliorates components of metabolic syndrome and improves the cholesterol profile, blood sugar levels, insulin sensitivity, inflammation, as well as blood pressure.48-61
Testosterone therapy improves sexual function
Considering that testosterone plays a key role in male sexual function, it is not surprising that a large number of medical research studies show that testosterone therapy results in significant improvements in most - if not all - domains of sexual function in men with testosterone deficiency.4,5,51,61-66 An 8-year long study showed that testosterone therapy significantly improved 5-item and 15-item International Index of Erectile Function (IIEF) scores.51
A meta-analysis of 14 studies of men with a mean age of 60 years showed that testosterone treatment significantly improved erectile function compared with placebo.3 Men with more severe hypogonadism (total testosterone level 8 nmol/L) reported greater changes in final IIEF-EF score when compared with those with a milder testosterone deficiency (total testosterone levels 12 nmol/L). The magnitude of the effect was lower in the presence of metabolic derangements, such as obesity and diabetes. Other aspects of sexual function (as evaluated by IIEF subdomains) were also improved, including libido, intercourse satisfaction, orgasm, and overall sexual satisfaction.3 The meta-analysis argued that sexual dysfunction should be considered a hallmark manifestation of testosterone deficiency, since those symptoms can be significantly improved with normalization of testosterone levels with testosterone treatment.3
Testosterone therapy improves mood and depressive symptoms, energy, and quality of life
It is well documented that testosterone deficiency significantly impairs quality of life67, and that testosterone treatment improves quality of life and mood parameters4,5,65,68,69 Mood parameters and sexual function improve relatively rapidly and improvements are maintained throughout the testosterone treatment period.4,5,70 Testosterone treatment also has been found to improve global cognition71 and reduce fatigue.72
Testosterone therapy improves bone mineral density (BMD)
Another well documented effect of testosterone treatment is improvement in BMD, which is important because men with testosterone deficiency often have a low BMD and osteoporosis.51,73-77
Long-term testosterone treatment for 3 years in obese patients with metabolic syndrome resulted in a significant improvement in BMD in the spine and legs, with a 5%/year increase.77 A direct relationship between testosterone level and BMD increments was found.77 Treatment with testosterone for 6 years in men with osteoporosis resulted in a progressive improvement of BMD throughout the treatment period.76 After 6 years, 40 of 45 treated men (89%) no longer fulfilled criteria for osteoporosis at the last measurement.76 In a third long-term study, treatment with testosterone for 8 years significantly increased BMD in the back and legs.51
Testosterone therapy attenuates lower urinary tract symptoms (LUTS)
It has been suggested that testosterone has a beneficial effect on lower urinary tract function and that testosterone deficiency may be the link connecting lower urinary tract symptoms and the metabolic syndrome in men.78 One study reported that lower testosterone levels were associated with greater severity of LUTS and higher testosterone levels with less severe LUTS78, and it has been suggested that testosterone deficiency is an important risk factor for LUTS/BPH.79
Contrary to old beliefs, numerous observational and small, randomized trials have pointed to a possible improvement in male LUTS in patients treated with testosterone.80 Interestingly, testosterone therapy results in simultaneous improvement of the metabolic syndrome and LUTS as testosterone levels increase during treatment of testosterone deficient elderly men.81
In an impressive real-life study, treatment with testosterone for up to 10 years resulted in significant improvements in urinary and sexual function, and quality of life. Notably, in untreated hypogonadal men, voiding and erectile function deteriorated over time.5 Improvements in voiding symptoms and lower IPSS irritative sub-scale scores were also reported in testosterone treated men compared to untreated men in the RHYME study.82
Testosterone therapy ameliorates anemia, including unexplained anemia
In one-third of older adults with anemia no known cause can be found.83-86 Currently there is no established treatment for this unexplained anemia. One possible cause of unexplained anemia in older men is testosterone deficiency, because low testosterone levels are significantly associated with unexplained anemia.87,88 and testosterone treatment of men with low testosterone increases hemoglobin levels65,70,89-91, and thereby resolves unexplained anemia.
The Anemia Trial of the Testosterone Trials showed that testosterone treatment for 12 months significantly increased hemoglobin levels and reduced the prevalence of both unexplained anemia and anemia of known cause.92 In line with the consequences of anemia in elderly - such as fatigue, weakness, reduced muscular strength and physical performance, impaired cognitive function, dementia, and depression93 - increases in hemoglobin levels with testosterone treatment were associated with improvement in walking and vitality, as well as with men’s impression of change in overall health and energy.92 This, combined with large magnitude of the changes and the correction of anemia in most men suggests that the amelioration of anemia with testosterone treatment is clinically meaningful.
Testosterone therapy reduces all-cause and cardiovascular mortality
Many population studies have investigated the relation between mortality and testosterone levels.94-116 The majority reported a significant association of low testosterone with increased mortality among men in the general population, as well as in clinical populations of men with diabetes, erectile dysfunction and renal disease. A large meta-analysis, which investigated 16,184 subjects from the general population with a mean follow-up of 9.7 years, found that low testosterone levels were associated with a significant 35% increased risk of cardiovascular related mortality.117
Contrary to widespread concern about testosterone therapy and cardiovascular risk, an overwhelming body of evidence is showing that testosterone therapy does not increase risk of heart attack, stroke, blood clots, or overall mortality.118 Two notable studies showed that testosterone therapy reduced mortality by half in Veterans114 and in men with type 2 diabetes110, compared with men with testosterone deficiency from each population who remained untreated.
An especially notable real-life long-term study showed that testosterone treatment for up to 10 years in obese men with testosterone deficiency reduced deaths and non-fatal heart attacks and strokes, compared to men not receiving testosterone therapy.119 The testosterone-group had an estimated reduction in death between 66% and 92% compared to non-treated men.119 Another long-term real-life study showed that testosterone treatment of testosterone deficient men with a history of heart disease for up to 8 years resulted in sustained improvements in several cardiometabolic risk factors; including weight loss, reduced waist circumference and improved cholesterol profile, blood sugar metabolism and blood pressure.120 No patient had any heart problems.120 These two long-term studies provide excellent evidence for the safety of testosterone treatment in a real-life scenario of men seeking treatment for urological complaints.
The research summarized here clearly provide evidence that that testosterone is not a “niche” hormone confined to reproduction or sexual functions, but a multi‑system hormone with wide range of physiological effects, as summarized in the figure.8