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 Observational studies report strong associations of lower testosterone levels with worse health outcomes in men, including reduced sexual activity, obesity, insulin resistance, inflammation, dyslipidemia, metabolic syndrome, atherosclerosis, cardiovascular events 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 coronary artery disease incidence and severity, carotid intima-media thickness, atherosclerosis, and mortality are inversely correlated with 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 clinicians 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 be evaluated for cardiovascular disease risk factors.33
In primary care/screening-based studies, the prevalence of testosterone deficiency in men aged 53-62 years is up to 39%34. Among men with the metabolic syndrome or diabetes, around 45% have testosterone deficiency.35 Similarly, up to 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 the skeletal muscle.43
Testosterone therapy increases insulin sensitivity, ameliorates components of the metabolic syndrome and reduces risk of type 2 diabetes
Long-term observational real-life studies have shown that testosterone therapy for up to 10 years ameliorates components of metabolic syndrome and improves the lipid profile, blood glucose and HbA1c, insulin sensitivity, inflammation, as well as systolic and diastolic blood pressure.48-61
Meta-analyses show that testosterone therapy reduces fasting plasma glucose, HbA1c, fat mass, insulin resistance (HOMA-IR), waist circumference and triglycerides in men with the metabolic syndrome or type 2 diabetes.62,63 In men with the metabolic syndrome, an increase in HDL levels has also been observed.63
A randomized controlled trial showed that treatment with testosterone undecanoate injections for 24 months reduced insulin resistance (HOMA-IR), carotid intima media thickness (CIMT) and high-sensitivity C-reactive protein (hsCRP) levels.64
Testosterone therapy improves sexual function
Considering that testosterone plays a key role in male sexual function, it is not surprising that both observational4,5,51,61,65 and placebo-controlled randomized clinical trials66-69 show that testosterone therapy results in significant improvements in most - if not all - domains of sexual function in men with testosterone deficiency. 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 included 14 placebo-controlled randomized clinical trials with a total of 2298 men with a mean age of 60 year.3 The mean testosterone treatment duration was 40 weeks and the IIEF-erectile function domain (IIEF-EFD) was used as outcome measure. Results showed that testosterone treatment significantly improved erectile function compared with placebo. Patients 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 life70, and that testosterone treatment improves quality of life and mood parameters in both clinical trials68,71,72 and observational studies.4,5 Mood parameters and sexual function improve relatively rapidly and improvements are maintained throughout the testosterone treatment period.4,5,73 Testosterone treatment also has been found to improve global cognition74 and reduce fatigue.75
Testosterone therapy improves bone mineral density (BMD)
Several clinical trials76-78 and observational studies51,79,80 have demonstrated that testosterone treatment improves BMD. A significant increase in structural and mechanical properties of trabecular bone in response to testosterone treatment was reported in the Testosterone Trials.78 Increases in vertebral and hip BMD over 36 months was seen both when testosterone was administered alone and when combined with finasteride.81 This suggests that dihydrotestosterone is not essential for the beneficial effects of testosterone on BMD.81
Long-term testosterone treatment with testosterone undecanoate injections for 3 years in hypogonadal obese patients with metabolic syndrome resulted in a significant improvement in lumbar BMD and femoral BMD, with a 5%/year increase.80 A direct relationship between testosterone level and BMD increments was found.80 Treatment with testosterone undecanoate injections for 6 years in hypogonadal men with osteoporosis resulted in a progressive improvement of BMD throughout the treatment period.79 After 6 years, 40 of 45 treated men (89%) no longer fulfilled criteria for osteoporosis at the last measurement.79 In a third long-term study, treatment with testosterone undecanoate injections for 8 years significantly increased T scores of vertebral and femoral BMD.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 a pathophysiological mechanism connecting lower urinary tract symptoms and the metabolic syndrome in men.82 One study reported that endogenous T levels correlate negatively with severity of LUTS (in other words; lower testosterone levels were associated with greater severity of LUTS and higher testosterone levels with less severe LUTS).82 Another study found no consistent associations were seen for circulating testosterone, free testosterone, or SHBG. However, circulating androstanediol glucuronide, a metabolite of dihydrotestosterone, and estradiol were associated with an increased risk of LUTS.83 Nevertheless, it has been suggested that testosterone deficiency is an important risk factor for LUTS/BPH.84
The data on the effect of testosterone therapy on LUTS is more consistent than the associations of endogenous testosterone levels and LUTS. Contrary to old beliefs, numerous observational and small, randomized trials have pointed to a possible improvement in male LUTS in patients treated with testosterone.85 The exact mechanism of this improvement is still debated but may have a close relationship to metabolic syndrome.85 Support for this comes from a study showing concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of testosterone levels in hypogonadal elderly men.86
Evidence for lack of worsening of LUTS during long-term testosterone treatment comes from a “real life” registry study in which men were treated with testosterone undecanoate injections for 5 years.87 A meta-analysis of 14 clinical trials provides further evidence that testosterone therapy does not worsen lower urinary tract symptoms.88 Even more impressively, in another registry study, treatment with testosterone undecanoate injections 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.89
Testosterone therapy ameliorates anemia, including unexplained anemia
In one-third of older adults with anemia no known cause can be found.90-93 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.94,95 and testosterone treatment of men with low testosterone increases hemoglobin levels68,73,96-98, 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.99 In line with the consequences of anemia in elderly - such as fatigue, weakness, reduced muscular strength and physical performance, impaired cognitive function, dementia, and depression100 - 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.99 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
A large number of observational studies have investigated the relation between mortality and testosterone levels.101-123 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 (hazard ratio = 1.35).124
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 myocardial infarction, stroke, deep venous thrombosis events or overall mortality.125 Two notable studies showed that testosterone therapy reduced mortality by half in Veterans121 and in men with type 2 diabetes117, compared with men with testosterone deficiency from each population who remained untreated.
The largest systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCT) showed that testosterone therapy is not related to any increase in cardiovascular risk.126 In RCTs performed in subjects with metabolic derangements testosterone therapy reduced cardiovascular risk.126
An especially notable real-life long-term study showed that treatment with testosterone undecanoate 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.127 The testosterone-group had an estimated reduction in mortality between 66% and 92% compared to non-treated men.127 Another long-term real-life study showed that testosterone undecanoate treatment of testosterone deficient men with a history of cardiovascular disease for up to 8 years resulted in sustained improvements in numerous cardiometabolic risk factors; weight loss, reduced waist circumference and improved lipid profile, glycemic control, blood pressure, heart rate and pulse pressure).128 No patient suffered a major adverse cardiovascular event during the full observation time.128 It was suggested that testosterone therapy may be effective as an add-on treatment for secondary prevention of cardiovascular events in testosterone deficient men with a history of cardiovascular disease.128 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