Critical update of the 2010 endocrine society guidelines for hypogonadism
Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Seftel AD, Kathrins M, Niederberger C. Mayo Clin Proc. 2015; 90(8): 1104-1115.
In 2010, the Endocrine Society published a Clinical Practice Guideline “Testosterone Therapy in Adult Men With Androgen Deficiency Syndromes”, which addressed important issues regarding the diagnosis and treatment of male hypogonadism.1
Since publication of this Guideline, several high-quality trials have been conducted, warranting an update of the 2010 recommendations in several areas, especially that of testosterone therapy in men with the metabolic syndrome, type 2 diabetes, sexual dysfunction, and frailty. In addition, many of the previously stated contraindications to testosterone therapy – including severe lower urinary tract symptoms (LUTS) and untreated obstructive sleep apnea (OSA) - have been reexamined in recent trials.
Here we summarize the results of a systematic analysis of the latest high-quality studies, which call for some important updates of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism.2
What is known
Testosterone deficiency and its treatment is an evolving medical field, supported by a rapidly accumulating amount of research. The 2010 Endocrine Society Clinical Practice Guideline is a high-impact report that guides physicians in clinical practice regarding diagnosis and evaluation of men with suspected hypogonadism, indications for treatment, information on various available treatment modalities, and recommended monitoring of regimens.
Since the publication of the 2010 guidelines, several randomized, double-blind, placebo-controlled trials (RCTs) – the gold standard research study methodology, also known as evidence level 1 – have been published. This new research evidence calls for some important updates to the 2010 Guideline.
What this review adds
New studies published since 2010 reinforce the positive effects of testosterone therapy on quality of life. What follows is a summary of new research that challenges the 2010 Guidelines or adds new findings that were not previously addressed.
Lower urinary tract symptoms, obstructive sleep apnea, and chronic heart failure
The 2010 Endocrine Society Clinical Practice Guideline cautioned against the use of testosterone therapy in patients with severe lower urinary tract symptoms, untreated severe obstructive sleep apnea, or uncontrolled/severe chronic heart failure. Multiple recent studies show that these conditions may not be absolute contraindications.
Six new RCTs all show that testosterone therapy in patients with lower urinary tract symptoms (LUTS) does not worsen LUTS symptoms - measured by the validated International Prostate Symptom Score (IPSS) questionnaire - compared to placebo.3-8 Even in men with severe LUTS, no differences in IPSS were seen in men receiving testosterone therapy vs. placebo.8 Notably, there was actually a small improvement in IPSS scores in the testosterone treated group.8
Regarding untreated severe obstructive sleep apnea, three new RCTs show no worsening in sleep related parameters after testosterone therapy vs. placebo.9,10Also in healthy men without obstructive sleep apnea, testosterone therapy does not cause any adverse sleep related effects.3
The Guidelines also cited severe, uncontrolled, or poorly controlled congestive heart failure as a relative contraindication to testosterone therapy. A placebo controlled trial of 41 hypogonadal men with stable congestive heart failure treated with injectable testosterone along with a standardized exercise regimen found significant improvements in peak oxygen uptake and leg strength in the testosterone treated group.11 This study suggests that testosterone therapy is beneficial for men with well-controlled congestive heart failure. However, the specific contraindication against testosterone therapy in men with uncontrolled congestive heart failure remains unexamined.
Benefits of testosterone therapy in men with the metabolic syndrome
The 2010 Endocrine Society Clinical Practice Guideline did not specifically comment on the effect of testosterone therapy in men with the metabolic syndrome.1 Regarding type 2 diabetes, while encouraging screening for hypogonadism in men with type 2 diabetes, the 2010 Guidelines cited conflicting evidence of the effects of testosterone therapy on insulin sensitivity and sexual / erectile function.1
Since 2010 several multicenter, high-quality trials have been published addressing effects of testosterone therapy in men with metabolic syndrome and type 2 diabetes; The Moscow study6, TIMES212 and BLAST trials.13,14
The Moscow study treated 184 hypogonadal men with the metabolic syndrome with injectable testosterone undecanoate for 30 weeks.6 Their results showed significant reductions in body weight, BMI, waist circumference, and serum inflammatory markers. Notably, waist circumference decreased significantly by - 6.02 cm in the testosterone group. Insulin sensitivity and lipid profiles were not significantly improved after 30 weeks compared with baseline.6
TIMES2 study (Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome) treated 220 symptomatic hypogonadal men with type 2 diabetes or metabolic syndrome with testosterone gel for 12 months.12 After the first 6-month fixed testosterone dose phase, insulin sensitivity was significantly improved only in patients with type 2 diabetes (HOMA-IR reduction of 16.0% P=049). After 9 months, glycemic control was significantly better (as indicated by a reduction in HbA1c) in the testosterone group compared to the placebo group. Testosterone treatment had a number of beneficial effects on the lipid profile. In the metabolic syndrome group, testosterone therapy was associated with significantly greater reductions in plasma levels of Lp(a) and LDL cholesterol than placebo. Testosterone treatment also reduced Lp(a) in diabetic men. In both groups combined, testosterone therapy resulted in a minor decrease in HDL from 1.19 mmol/L to 1.12 mmol/L, however at 12 months the difference from baseline was no longer significant. At 6 months, there were no significant effects of testosterone therapy on triglycerides, abdominal obesity, percentage body fat, BMI, or waist circumference. However, after 12 months there was a significant reduction in waist circumference in type 2 diabetic patients. In both groups combined, there was a significant improvement in overall IIEF (International Index of Erectile Function) scores (but no change in AMS scale scores).12
The BLAST study (Birmingham, Lichfield, Atherstone, Sutton Coldfield, and Tamworth) treated 190 symptomatic hypogonadal men with type 2 diabetes with injectable testosterone over 30 weeks.13,14 The testosterone group demonstrated improvements in BMI, weight (-1.2 kg), and waist circumference (-1.9 cm ).13 Sexual function and symptoms associated with hypogonadism, as measured by the international Index of Erectile Function (IIEF) erectile function domain and the Aging Males’ Symptoms (AMS) scale scores, respectively, were significantly improved at 30 weeks.13 Another report from the BLAST study showed significant reductions in HbA1cand waist circumference -2.5cm after 30 weeks testosterone therapy. There were also marked improvements in insulin sensitivity vs. placebo.14
Smaller single-center RCTs have also examined the effects of testosterone therapy on patients with metabolic syndrome and type 2 diabetes. One trial treated 50 men with symptomatic hypogonadism and metabolic syndrome or type 2 diabetes with injectable testosterone undecanoate for 24 months.15 After 12 months of testosterone treatment, insulin sensitivity, serum inflammatory markers, and a marker of atherosclerosis (carotid intima-media thickness, CIMT) were significantly improved. In addition, the prevalence of metabolic syndrome was reduced.15 Notable about this study is that blinding was terminated early at 12 months; because such beneficial significant effects were seen in the testosterone treated group, the placebo group was put on testosterone treatment. Also, the reduction in CIMT (a surrogate of atherosclerosis) is a remarkable finding.
In contrast, one other single-center RCT of 88 hypogonadal men with type 2 diabetes found no improvement in insulin sensitivity, HbA1c, waist circumference or BMI after treatment with testosterone undecanoate for 40 weeks.16,17 This lack of effect is likely due to the short treatment duration, as the baseline total testosterone level was not very low at 10.6 nmol/L (306 ng/dL), and the increase in total and calculated free testosterone across 40 weeks – although significant - was only +5.9 nmol/L (+170 ng/dL) and +183 pmol/L (+53 pg/mL), respectively. Nevertheless, there was a significant increase in lean body mass and reduction in abdominal subcutaneous fat volume.16,17 It is likely that improvements in insulin sensitivity, HbA1c, waist circumference would have occurred if this study had been conducted for a longer duration.
Effects on sexual function, well-being, and quality of life
The 2010 Endocrine Society Clinical Practice Guideline recommended Testosterone therapy for men with concomitant hypogonadism, low libido, and erectile dysfunction (ED) after evaluation and treatment with established therapies.
Recent studies reinforce the positive effects of testosterone therapy on quality of life.18 In depressed men testosterone therapy was found to improve sexual function.19
Regarding the effect of testosterone therapy on PDE5i efficacy in men with erectile dysfunction, the evidence is still conflicting. One trial – the TADTEST study - found that hypogonadal men with testosterone levels below 300 ng/dL who did not respond to the PDE5 inhibitor tadalafil, benefit when testosterone is added to tadalafil in the treatment of erectile dysfunction.20 However, one other study investigating the effect of adding testosterone therapy to sildenafil treatment in men with erectile dysfunction, did not report any benefit of sildenafil + testosterone vs. sildenafil alone.21,22 However, this study did not investigate the effect of testosterone alone on erectile dysfunction.
Effect on bone mineral density, lean body mass, and muscle strength
The 2010 Endocrine Society Clinical Practice Guideline noted a modest improvement in bone mineral density at the lumbar spine in men receiving testosterone therapy.1 However, it stated that the effects of testosterone therapy on physical function and lower-extremity strength were inconsistent, based on studies primarily including men without functional limitations.1
Since then, four new trials have investigated the effects of testosterone therapy on bone mineral density, lean body mass, and muscle strength, outlined in table 1.5,7,23-25
Table 1. Effects of testosterone therapy on bone mineral density, lean body mass, and muscle strength.
T = testosterone; TU = testosterone undecanoate; BMD = bone mineral density; OSA = obstructive sleep apnea; mo = months; wk = weeks
Thus, trials published since 2010 reinforce the positive effects of testosterone therapy on bone mineral density, and in addition show increases in muscle mass and strength in frail men.
This systematic analysis of level 1 evidence trials examining the safety and efficacy of testosterone therapy published since 2010 largely reinforces the 2010 Endocrine Society Guidelines, such as the positive effects by testosterone treatment on quality of life. The impact of testosterone therapy on men with erectile dysfunction refractory to PDE5i therapy remains conflicting.
Notable new research findings published since the 2010 guideline are that severe LUTS and untreated OSA may not be contraindications to testosterone therapy. Also, a growing number of high-quality studies shows that testosterone therapy improves insulin sensitivity in men with the metabolic syndrome, and reduces waist circumference and body fat. Testosterone therapy may also be beneficial for men with frailty and / or osteoporosis, in whom it increases bone mineral density, lean body mass, and some strength and power parameters. Testosterone replacement in intermediate-frail and frail elderly men is associated with preservation of muscle thickness, which suggests that testosterone protects against sarcopenia in aging men.24
There are currently no high-quality prospective trials examining the effects of testosterone therapy on cardiovascular disease outcomes. However, recently published retrospective studies have shown reassuring results. Compared to non-treated men, testosterone treated men who achieved normalization of their testosterone levels had a major and significant reduction in heart attack, stroke and all-cause mortality by 24%, 36% and 56%, respectively.26 Another retrospective study found that testosterone therapy is not associated with venous thromboembolism in the general population.27 For more, see our previous editorial “Risk of venous thromboembolism in men receiving testosterone therapy”.
A comprehensive literature review of all available studies published on testosterone therapy and cardiovascular outcomes showed that there is no convincing evidence of increased cardiovascular risks with testosterone therapy; on the contrary, there appears to be a strong beneficial relationship between normal testosterone and cardiovascular health that has not yet been widely appreciated.28 For more, see our previous editorial “Testosterone therapy and cardiovascular risk - advances and controversies”.
Further, the largest systematic review and meta-analysis does not support a causal role between testosterone therapy and adverse cardiovascular events, and concluded that research accumulated during the last 20 years supports treatment of hypogonadal men with testosterone therapy, which is a valuable strategy in improving a patient's metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease.29 For more, see our previous editorial “Testosterone-boosting medications and cardiovascular risk - a systematic review and meta-analysis”.