Testosterone replacement therapy: What are the benefits? For which men?

Testosterone replacement therapy (TRT) is indicated as a treatment to restore normal testosterone levels in younger (< 40-year-old) hypogonadal men.1 In these men, the therapy has been shown to offer benefits over and above normalising testosterone levels. In particular, TRT has been associated with improvements to metabolic abnormalities such as insulin sensitivity and type 2 diabetes.2

Testosterone is increasingly also being prescribed to older men; however, the role of TRT for this group, whose testosterone levels decline naturally with ageing, remains controversial.³ While benefits from TRT have been demonstrated in some groups of older men,⁴ there is little evidence of benefit for the ageing male population as a whole.⁵ Safety, with regard to cardiovascular disease⁶ and prostate cancer⁷ risk, remains a concern which requires further investigation.⁵

In this context, being familiar with current evidence and professional debates is essential for practitioners facing the question: to which men should TRT be prescribed?

Testosterone replacement for hypogonadism

For younger men (< 40 years old) the indication for TRT is well defined. Men with a diagnosis of hypogonadism, based on both clinical symptoms (including the loss of secondary male sex characteristics such as deep voice and body hair) and biochemical evidence (serum testosterone levels < 8 nM) are eligible for TRT.¹ A significant proportion of men who meet this definition (20–64% depending on age) are also type 2 diabetics.⁸ 

TRT has been associated with improved insulin sensitivity in type 2 diabetic men, and proposed as a novel treatment for insulin resistance.⁹ However, TRT is not currently approved for this indication.¹ In Australia, TRT is contraindicated for treatment of men > 40 years of age,¹ those who are most likely to have comorbid chronic conditions including diabetes and the metabolic syndrome.¹⁰  This has created some debate regarding the use of TRT in ageing males.¹⁰

Testosterone and the ageing male

Testosterone levels decline gradually as men age, and also in response to chronic conditions and medication use, both of which become more prevalent with age.¹⁰ This has created controversy in the field of andrology regarding whether to view declining testosterone in ageing men as a natural process, or a treatable condition.⁶ There is also debate regarding how to define testosterone deficiency in older men, and whether clinical, biochemical or a combination of both types of evidence should be used.¹⁰

Diagnostic criteria

Australian guidelines recommend a diagnosis of testosterone deficiency be made on the basis of a combination of clinical symptoms and biochemical evidence (serum testosterone levels).¹ However, some practitioners argue that testosterone cut-off values are arbitrary, and that the requirement for combined evidence downplays the importance of clinical symptoms and is scientifically and clinically unjustified. They cite evidence of risks associated with testosterone deficiency in older men (e.g. reduced libido and an increased risk of chronic diseases such as type 2 diabetes, metabolic syndrome and cardiovascular disease) to support their claims for expanding TRT.¹⁰

Prescribing recommendation

In Australia, cut-off values for defining hypogonadism in ageing men have not been defined and prescribing testosterone to treat ageing men with declining androgen levels is only recommended in the clinical trial setting. While marketing of testosterone and its prescribing to ageing men in clinical practice has increased in the past decades, there has not been a corresponding increase in rigorous research about endocrinological changes which occur as men age, or the impact of testosterone replacement. However, ageing men with awareness of the perceived benefits of TRT may request a prescription from their doctor.¹ This creates a dilemma; to prescribe or not to prescribe?

Evidence for benefits

While testosterone has demonstrated benefits and is approved for the treatment of younger men with hypogonadism and ageing men with severely deficient testosterone levels, the evidence base for the treatment of older men with declining testosterone levels is limited. Questions remain regarding both efficacy and safety, and the associations between testosterone deficiency and inflammatory conditions such as metabolic syndrome and cardiovascular disease are poorly understood. Knowledge regarding the biological mechanisms that underpin inflammatory conditions shows a biologically plausible role for testosterone in the treatment of chronic inflammation. However, there is no empirical evidence of the impact of TRT on inflammation.⁵

Despite evidence of benefit for particular groups of ageing men (for example, those with low testosterone levels and erectile dysfunction who fail to respond to PDE-5 inhibitors)⁴ there is no objective evidence suggesting benefits for the general population of ageing men.¹ While many men perceive positive changes with TRT (e.g. improved sexual function), objective evidence of benefit in terms of improving bone or muscle quality or general wellbeing is lacking and/or controversial.¹ There are also gaps in evidence regarding the role of TRT in the treatment of chronic metabolic conditions.¹¹

TRT for the treatment of metabolic abnormalities?

Testosterone deficiency in ageing men is commonly comorbid with chronic conditions such as obesity and type 2 diabetes. These conditions require treatment to reduce the associated mortality and morbidity risk.¹² Lifestyle factors, particularly nutrition, exercise and substance abuse are associated with testosterone deficiency⁵ and chronic metabolic conditions,¹² which are in turn associated with testosterone deficiency.¹⁰ Lifestyle interventions have demonstrated considerable efficacy in resolving these chronic conditions,⁵ and when successful have a positive impact on testosterone levels.¹¹

TRT has also been trialled as a treatment for type 2 diabetes and evidence consistently shows a favourable effect on body composition. However, evidence regarding the role of TRT on other metabolic parameters such as insulin resistance and glucose metabolism are inconsistent to date and more work is required to clarify the use of TRT in this setting.¹¹

Does the benefit outweigh the risk?

The benefit of TRT for older men with severely deficient testosterone levels is unquestionable. However, controversy remains regarding the treatment of borderline cases without specific symptoms which can be monitored to assess the effectiveness of treatment (about 10% of ageing men).⁵ To date no trials have been designed to assess safety risk,⁵ and many have failed to report safety outcomes.¹³

Cardiovascular disease

A review and meta-analysis of studies investigating the cardiovascular effects of testosterone replacement reported no significant relationship between testosterone use and cardiovascular risk. However, the studies included were all short term (< 1 year duration) and results from individual studies were conflicting. The authors concluded the level of available evidence was weak, and recommended large, prospective trials be conducted amongst men with cardiovascular risk factors.¹³ Other authors have argued that evidence from observational studies as yet remains inadequate to justify research expenditure on large clinical trials investigating these questions.⁵

Prostate cancer

The development of prostate cancer is linked to endocrinological mechanisms and this knowledge has been the source of long-standing concerns vis-à-vis the potential for TRT to increase prostate cancer risk. Testosterone mediates normal prostate cell differentiation and growth and testosterone levels influence the size of the prostate gland and the differentiation and maintenance of some prostate cancer cells. Both high and low testosterone levels (compared to normal levels) have been associated with poorer treatment outcomes in prostate cancer.⁷

There is no experimental evidence linking TRT and prostate cancer; however, prostate cancer is considered a contraindication to TRT and guidelines recommend excluding prostate cancer through PSA testing and digital rectal exam prior to instituting TRT.¹⁴ In the absence of evidence excluding increased prostate cancer risk, continued screening and monitoring for prostate cancer before commencing and during TRT is essential.⁷

Conclusion

TRT has an established role in the treatment of younger men with hypogonadism. However, amongst older men, increases in prescribing testosterone have been driven by direct-to-consumer marketing rather than increasing evidence showing benefits and/or safety of TRT. There remains an urgent need for studies investigating risks and benefits in the long term, as well as for those specifically designed to assess the safety of testosterone replacement in older men.⁵ 

Until strong evidence is presented to support testosterone prescribing to older men, a prudent approach would be liberal intervention with lifestyle measures to promote weight loss and exercise. Such interventions offer great promise in not only reducing men’s risk of chronic conditions and improving general health, but also in increasing targeted men’s testosterone levels.¹¹

References

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2. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: Metabolic syndrome and erectile dysfunction. J Androl. 2009;30(1):10-22. [Abstract | Full text]
3. Handelsman DJ. Trends and regional differences in testosterone prescribing in Australia, 1991-2001. Med J Aust. 2004;181(8):419-22. [Abstract | Full text]
4. Blute M, Hakimian P, Kashanian J, et al. Erectile dysfunction and testosterone deficiency. Front Horm Res. 2009;37:108-22. [Abstract]
5. Isidori AM, Lenzi A. Testosterone replacement therapy: What we know is not yet enough. Mayo Clin Proc. 2007;82(1):11-3. [Abstract | Full text]
6. Zitzmann M. Testosterone deficiency and treatment in older men: Definition, treatment, pitfalls. Asian J Androl. 2010;12(5):623-5. [Full text]
7. Barqawi AB, Crawford ED. Testosterone replacement therapy and the risk of prostate cancer: A perspective view. Int J Impot Res. 2005;17(5):462-3. [Abstract | Full text]
8. Kalyani RR, Dobs AS. Androgen deficiency, diabetes and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes. 2007;14(3):226-34. [Abstract]
9. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol. 2008;159(5):507-14. [Abstract | Full text]
10. Carruthers M. Time for international action on treating testosterone deficiency syndrome. Aging Male. 2009;12(1):21-8. [Abstract | Full text]
11. Grossmann M. Low testosterone in men with type 2 diabetes: Significance and treatment. J Clin Endocrinol Metab. 2011;96(8):2341-53. [Abstract]
12. Allan CA, Strauss BJ, Burger HG, et al. The association between obesity and the diagnosis of androgen deficiency in symptomatic ageing men. Med J Aust. 2006;185(8):424-7. [Abstract | Full text]
13. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82(1):29-39. [Abstract | Full text]
14. Product Information: Reandron. Pymble, NSW: Bayer Australia Limited; 28 April 2011.

Testosterone deficiency

For more information on testosterone deficiency in men, including testosterone tests and testosterone replacement therapy, see Testosterone Deficiency.