Results of two new trials will drive further research into the “andropause hypothesis”
Two important research articles, published in a recent issue of the New England Journal of Medicine (NEJM), bracket the topic of prescribing testosterone for older men.1,2 Testosterone treatment for older men is based on considering male ageing as analogous to either menopause or pathologically based hypogonadism. The former is a false analogy — menopause has a unique natural history featuring complete failure of female reproductive hormones in mid-adult life, contrary to all other human hormonal systems which decline gradually and modestly with ageing. The latter is based on the superficial resemblance of non-specific symptoms in ageing men with those of most hormonal deficiencies or chronic diseases. This “andropause hypothesis” is not well substantiated, with the 2004 United States Institute of Medicine’s authoritative review3 concluding that available evidence did not justify a major study of testosterone replacement in older men comparable to the Women’s Health Initiative (WHI) study of oestrogen replacement in menopause. Nevertheless, the past two decades have seen an approximately 20-fold increase in testosterone prescribing despite no proven new indications. This is largely confined to the US, with minimal changes in Australia4 and other regional markets; however, that bandwagon could certainly be viewed as having left the station, fuelled by heavy direct-to-public drug advertising in the US.
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- 1. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010; 363: 123-135.
- 2. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109-122.
- 3. Liverman CT, Blazer DG, editors. Testosterone and aging: clinical research directions. Washington, DC: Institute of Medicine, The National Academies Press, 2004.
- 4. Handelsman DJ. Trends and regional differences in testosterone prescribing in Australia: 1991–2001. Med J Aust 2004; 181: 419-422. <MJA full text>
- 5. Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab 2004; 89: 3813-3817.
- 6. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006; 91: 4335-4343.
- 7. Travison TG, Shackelton R, Araujo AB, et al. The natural history of symptomatic androgen deficiency in men: onset, progression, and spontaneous remission. J Am Geriatr Soc 2008; 56: 831-839.
- 8. Travison TG, Araujo AB, Hall SA, McKinlay JB. Temporal trends in testosterone levels and treatment in older men. Curr Opin Endocrinol Diabetes Obes 2009; 16: 211-217.
- 9. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95: 2560-2575.
- 10. Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006; 27: 57-64.
- 11. Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev 2003; 24: 313-340.
- 12. Conway AJ, Handelsman DJ, Lording DW, et al. Use, misuse and abuse of androgens: the Endocrine Society of Australia consensus guidelines for androgen prescribing. Med J Aust 2000; 172: 220-224. <MJA full text>
- 13. 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. J Androl 2009; 30: 1-9.
- 14. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559.
- 15. Sikaris K, McLachlan RI, Kazlauskas R, et al. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J Clin Endocrinol Metab 2005; 90: 5928-5936.
- 16. Sartorius G, Ly LP, Sikaris K, et al. Predictive accuracy and sources of variability in calculated free testosterone estimates. Ann Clin Biochem 2009; 46: 137-143.
I have received consultancy fees from Clarus Therapeutics and Radius for advising United States companies on androgens. My institution has received funding from Bayer Schering Pharma and Ascend for investigator-initiated research.