Testosterone deficiency syndrome: safety fears and treatment

Claude Schulman
MD PhD
Brussels University
Erasme Hospital
Brussels
Belgium

With prolonged life expectancy, men and women can expect to live one-third of their lives with some form of hormone deficiency. Men, in particular, have the added problem of ­developing urological diseases, such as benign prostatic hyperplasia, prostate cancer, continence ­disorders and erectile dysfunction. Testosterone deficiency syndrome (TDS) is a clinical and ­biochemical syndrome which results in significant detriment in the quality of life and adversely affects the function of multiple organ systems (see Figure 1).(1) TDS is characterised by a decrease in testosterone and other hormones and is associated with changes in body mass index, obesity, osteoporosis, sleep and mood disorders.(2) Obesity appears to be a driving factor since adipose cells secrete leptin, which results in a decrease of testosterone (see Figure 2). The metabolic syndrome, which is an association of ­hypertension, hyperlipidaemia and increased insulin resistance (glucose intolerance – diabetes type II) is interlinked with obesity and TDS. In addition, obesity, and its associated decrease in testosterone, is linked to an increased risk of more aggressive prostate cancer.

[[HHE07_fig1_P45]]

[[HHE07_fig2_P45]]

Testosterone deficiency is a serious medical condition
Men with total testosterone levels below 200 ng/dl (6.9 nmol/l) have a twofold higher risk of death, a threefold higher risk of cancer-related death and a twofold higher risk of cardiovascular-related death over 17 years than men with testosterone levels of 410–509 ng/dl (14.2–17.7 nmol/l).(3)

Recent analyses from the clinical database of the Veterans Administration showed that, during a follow-up of eight years, low testosterone levels were associated with increased mortality in male ­veterans.(4) Therefore, there is good evidence to show that TDS has serious consequences but it is often considered an inevitable part of ageing, with attention limited to sexual function.(1)

Fears on safety are unfounded
Fears about the effects of testosterone substitution, particularly on the prostate, are a barrier to its use, but it is time for a re-evaluation, since these concerns are historical and do not withstand scientific scrutiny.(5) Huggins and Hodges reported in 1941 that marked reductions in testosterone by castration or oestrogen treatment caused metastatic prostate cancer (CaP) to regress and administration of exogenous testosterone caused CaP incidence to rise. Remarkably, this latter conclusion was based on results from only one patient who showed elevated but fluctuating acid phosphatase levels after testosterone injection.

Multiple subsequent reports revealed no CaP progression with testosterone administration, and some men even experienced subjective improvement, such as resolution of bone pain. More recent data have shown no apparent increase in CaP rates in clinical trials of testosterone supplementation, neither in normal men nor in men at increased risk for CaP with high-grade prostatic intraepithelial neoplasia or ­following radical prostatectomy.(6) No relationship between CaP risk and serum ­testosterone levels was found in multiple longitudinal studies. The apparent paradox in which castration causes CaP to regress yet higher testosterone levels fail to cause CaP to grow is solved by a saturation model, in which maximal stimulation of CaP is reached at relatively low levels of testosterone.(5) Although ­testosterone levels decrease with age in men, the incidence of prostate cancer increases significantly. In prostate cancer, men with more aggressive disease (Gleason score of 8 or greater) have lower levels of serum ­testosterone. These perspectives do not support a scientific basis for the belief that testosterone causes CaP to develop. Discarding this modern myth will allow exploration of alternative hypotheses regarding the relationship between testosterone and CaP that may be scientifically and clinically rewarding, shedding new light on a challenging concept.

Benefits of testosterone therapy outweigh risks
A clear indication based on a clinical picture together with biochemical evidence of low serum ­testosterone should exist prior to the initiation of testosterone treatment (TRT).(2) The typical ­contraindications are presence of a carcinoma of the prostate or breast.(6) Testosterone substitution has wide-ranging benefits on muscle mass and fat distribution, mood and behaviour, bone density, some cardiovascular risk factors and increasing libido and erectile function (alone or in combination with phosphodiesterase 5-inhibitors) in men with TDS.

Most of the available preparations of testosterone, intramuscular, transdermal, oral and buccal, are safe and effective if used correctly. However, short-acting (transdermal, oral, ­buccal) preparations should be preferred over long-acting ones. Preparations avoiding supraphysiological ­concentrations and releasing steady testosterone levels should be preferred. In all cases, the choice of the preparation should be a joint decision between patient and physician. Before initiation of TRT, prostate health has to be checked, by determining serum prostate-specific antigen (PSA) together with digital rectal examination (DRE). Transrectal ultrasound-guided biopsies of the prostate are indicated only if DRE or serum PSA levels are abnormal, as in usual good clinical practice.(2,6) Men on testosterone therapy should be monitored at three-month intervals during the first year of use and thereafter at one-year intervals.(2,6) Careful monitoring of men receiving testosterone supplementation should be a shared responsibility, with the urologist having a major role to play.

Conclusion
The benefits of TRT in men presenting with TDS far outweigh the safety risks, which can be largely avoided by following the most appropriate recommendations.(2,6) Larger-scale and long-term studies are needed on the effects of testosterone treatment in men regarding risks and benefit. Although there is a need for more evidence, testosterone therapy has many benefits and few risks.

References

1. Morales A, et al. Testosterone d­eficiency syndrome (TDS) needs to be named ­appropriately – the importance of accurate terminology. Eur Urol 2006;50:407-9.
2. Nieschlag E, et al.  Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations.  Eur Urol 2005;48:1.
3. Araujo AB, et al.  Total testosterone as a predictor of mortality in men: results from the Massachusetts Male Aging Study. ­Presented at: The Endocrine ­Society Annual Meeting. San Diego, California, USA; 4–7 June 2005.
4. Shores MM, et al.  Low serum testosterone and mortality in male veterans. Arch Intern Med 2006;166:1660-5.
5. Morgentaler A.  Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 2006;50:935-9.
6. Rhoden E, et al. Risk of testosterone-replacement therapy and recommendations for monitoring. NEJM 2004;350:482-92.