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 I summarize the results of a recent 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]
Key Points
Note that these conclusions are based solely on randomized, double-blind, placebo-controlled trials (RCTs). Other types of studies show more benefits than reported here. See my commentary below.
- Men with metabolic syndrome, who were previously not addressed by the 2010 Endocrine Society Clinical Practice Guidelines, may benefit from testosterone replacement therapy based on improvements in biometrics and insulin sensitivity. Effects of testosterone replacement therapy on similar end points in men with type 2 diabetes remain inconclusive.
- Several recent clinical trials have studied the effects of testosterone replacement therapy in men with frailty, who were previously unrepresented in the 2010 Endocrine Society Clinical Practice Guidelines. Improvements in muscle strength and bone health were noted.
- Untreated sleep apnea and severe lower urinary tract symptoms may not be absolute contraindications to testosterone replacement therapy.
- Effects of testosterone replacement therapy on erectile function, even in men refractory to phosphodiesterase type 5 inhibitors, and on quality of life in men with erectile dysfunction remain inconclusive.
- There is no new level 1 evidence to support a definitive connection between testosterone replacement therapy and cardiovascular morbidity.
- There is no new level 1 evidence to support a connection between testosterone replacement therapy in men with previously treated or active prostate cancer.
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 Systematic Analysis 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 replacement 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 replacement 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 replacement 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, 10] Also 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 study [6], TIMES2 [12] 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. 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.[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 HbA1c and 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 TRT 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 studies 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.
Table 1. Effects of testosterone therapy on bone mineral density, lean body mass, and muscle strength.[5, 7, 23-25]
Study
|
Subjects
|
Treatment
|
Duration
|
Results
|
Kenny et al.[5]
|
131 men >50 yr old with hypogonadism, frailty, and osteoporosis.
|
T gel
|
12 mo
|
Lumbar spine and femoral neck BMD significant increased 3.2% and 1.4% respectively, with testosterone vs. placebo.
Total lean body mass significantly increased in testosterone group (+1.9% for testosterone vs. 0.3% for placebo) and body fat mass significant decrease.
No differences in upper- or lower extremity strength, physical performance, or frailty assessments.
No difference in adverse events between testosterone and placebo groups.
|
Srinivas-Shankar et al.[7]
Atkinson et al.[24]
|
274 hypogonadal men >65 yr old with frailty.
Same study, reporting a different outcome.
|
T gel
|
6 mo
|
Lean body mass significantly improved in T group (+1.1 kg).
Isometric knee extension and gastrocnemius muscle thickness significantly increased in T group vs. placebo.
There was a trend toward improvements in knee flexion, grip strength, and physical function.
No difference in adverse events between testosterone and placebo groups.
T treatment resulted in a preservation of muscle thickness while it decreased in the placebo group.
|
Basaria et al.[23]
The TOM trial
|
Men with mobility limitations,
>65 yr old.
|
T gel
|
6 mo
|
Leg press strength, chest press strength, and climbing power all significantly improved in T group vs. placebo.
|
Hoyos
et al [25]
|
Obese men with severe OSA.
|
TU
|
18 wk
|
Significant increased muscle mass by +1.6 kg in T group vs. placebo.
No increased in grip 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.
Summary
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]
Comments
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 (insert link here once that editorial gets published).[26] Another retrospective study found that testosterone therapy is not associated with venous thromboembolism in the general population.[27] For more, see my previous article “
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 my previous article “
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 my previous article “
Testosterone-boosting Medications and Cardiovascular Risk - a systematic review and meta-analysis”.
Final Thoughts on Medical Research – Ethical Issues
As mentioned, the gold standard research study methodology is the randomized, double-blind, placebo-controlled trial (RCT). However, when studying treatments that prove to be so effective and beneficial in the treated group – such as testosterone therapy - one may ask whether it is ethically to deprive the placebo group of a treatment they would benefit from.
A good example is the study summarized above showing significant improvements in insulin sensitivity, serum inflammatory markers, and a marker of atherosclerosis (carotid intima-media thickness, CIMT), as well as reduced prevalence of metabolic syndrome, in the testosterone treated group compared to the placebo group after 12 months.[15] Because of these important health benefits after the first year, the placebo group was put on testosterone treatment for the remaining duration of the study (year 2).
While most people would probably agree that this is appropriate, it does “break” the RCT. In this case, the Endocrine Society – and other critics - will only look at the first 12 month data and ignore the results after 24 months, as the second year there was no placebo group. This is important to bear in mind when interpreting clinical practice guidelines.
In addition to calling for more RCTs, authorities are requesting longer-term RCTs. This further aggravates the ethical problem and creates a clash between medical research methodology standards and The Declaration of Helsinki - a set of ethical principles in human experimentation, developed for the medical community by the World Medical Association.
References:
1. Bhasin, S., et al., Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010. 95(6): p. 2536-59.
2. Seftel, A.D., M. Kathrins, and C. Niederberger, Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Mayo Clin Proc, 2015. 90(8): p. 1104-15.
3. Hildreth, K.L., et al., Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab, 2013. 98(5): p. 1891-900.
4. Del Fabbro, E., et al., Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Support Care Cancer, 2013. 21(9): p. 2599-607.
5. Kenny, A.M., et al., Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc, 2010. 58(6): p. 1134-43.
6. Kalinchenko, S.Y., et al., Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf), 2010. 73(5): p. 602-12.
7. Srinivas-Shankar, U., et al., Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab, 2010. 95(2): p. 639-50.
8. Tan, W.S., et al., Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU Int, 2013. 111(7): p. 1130-40.
9. Hoyos, C.M., et al., Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin Endocrinol (Oxf), 2012. 77(4): p. 599-607.
10. Killick, R., et al., The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo-controlled trial. J Sleep Res, 2013. 22(3): p. 331-6.
11. Stout, M., et al., Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J, 2012. 164(6): p. 893-901.
12. Jones, T.H., et al., Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care, 2011. 34(4): p. 828-37.
13. Hackett, G., et al., Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. J Sex Med, 2013. 10(6): p. 1612-27.
14. Hackett, G., et al., Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med, 2014. 11(3): p. 840-56.
15. Aversa, A., et al., Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med, 2010. 7(10): p. 3495-503.
16. Gianatti, E.J., et al., Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care, 2014. 37(8): p. 2098-107.
17. Gianatti, E.J., et al., Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab, 2014. 99(10): p. 3821-8.
18. Tong, S.F., et al., Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian J Androl, 2012. 14(4): p. 604-11.
19. Amiaz, R., et al., Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. J Sex Marital Ther, 2011. 37(4): p. 243-54.
20. Buvat, J., et al., Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J Sex Med, 2011. 8(1): p. 284-93.
21. Spitzer, M., et al., Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med, 2012. 157(10): p. 681-91.
22. Spitzer, M., et al., The effect of testosterone on mood and well-being in men with erectile dysfunction in a randomized, placebo-controlled trial. Andrology, 2013. 1(3): p. 475-82.
23. Basaria, S., et al., Adverse events associated with testosterone administration. N Engl J Med, 2010. 363(2): p. 109-22.
24. Atkinson, R.A., et al., Effects of testosterone on skeletal muscle architecture in intermediate-frail and frail elderly men. J Gerontol A Biol Sci Med Sci, 2010. 65(11): p. 1215-9.
25. Hoyos, C.M., et al., Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur J Endocrinol, 2012. 167(4): p. 531-41.
26. Sharma, R., et al., Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J, 2015: p. Aug 6 [Epub ahead of print].
27. Baillargeon, J., et al., Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin Proc, 2015. 90(8): p. 1038-45.
28. Morgentaler, A., et al., Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc, 2015. 90(2): p. 224-51.
29. Corona, G., et al., Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf, 2014. 13(10): p. 1327-51.