Monday, June 27, 2011

Testosterone Replacement Therapy

Testosterone Replacement Therapy. A Fresh Look Perhaps.
Andrew Rynne.
June 2011.

It has to be admitted, the word itself, “testosterone” does not usually evoke positive feelings or responses. In the popular press, the term testosterone is too often associated with reports about boy racers, reckless driving, male aggression, dodgy bodybuilding techniques, commercial dominance, sexual misbehaviour and cheating in competitive sports. All pretty negative stuff.
In the medical press the word “testosterone” does not fare much better. Mention of testosterone replacement therapy (TRT) to your average doctor is likely to elicit vague objections to do with increased cancer risks, it being not natural, it being unnecessary and other generally negative and ill-defined resistance to the suggestion. This may be a pitty.
No, let’s face it; testosterone replacement therapy was never going to be an easy sell. But are things changing? I for one very much hope that they are. I have been at this for almost ten years now, quietly promoting the notion of TRT. To summarily dismiss TRT as unnecessary, unnatural or even dangerous, might be to deny some older men a chance for a better quality of life and a chance for a reduced risk of contracting some of the less savoury side effects associated with the ageing process including premature death.
In the next five minutes, if you will allow me to, I hope to convince you to look afresh at TRT for older and for perhaps not so much older men and to consider recent research findings that cast this treatment in an entirely different and more positive light. Here are the bones of three recent studies that have been published this year alone:
 (1) Low serum testosterone and increased mortality in men with coronary artery disease.
In a large study conducted through the Department of Cardiology, Royal Hallamshire Hospital in Sheffield on 930 consecutive men with proven coronary artery disease recruited between June 2000 and June 2002 and followed up for a mean of 6.9 years the Authors concluded:

In patients with coronary disease Testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of Testosterone replacement are needed to assess the effect of treatment on survival. (1)

(2) Effects of Testosterone Undecanoate (Nebido) on Cardiovascular Risk Factors and Arteriosclerosis in middle aged men with late onset Hypogonadism and Metabolic Syndrome.
This was a randomised double-blind placebo-controlled study on 50 men with mean age of 57 + or – 8 years who received 1,000 mg of Testosterone Undecanoate every 12 weeks or placebo.
Conclusion. Testosterone Undecanoate reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with Metabolic Syndrome. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in Metabolic Syndrome without significant haematological and prostate adverse events.

(3) Effects of Testosterone Replacement Therapy on Depressive Symptoms and Sexual Dysfunction in Hypogonadal men with Metabolic Syndrome.
This was a multi-centred, placebo controlled, study directed from the Department of Psychiatry, Leiden University Medical Centre in the Netherlands. In it 184 men suffering from Metabolic Syndrome and Hypogonadism were treated for thirty weeks with either Testosterone  Undecanoate or placebo.  
Conclusions. Testosterone Undecanoate administration may improve depressive symptoms, aging male symptoms and sexual dysfunction
in hypogonadal men with the Metabolic Syndrome. The beneficial effects of testosterone were most evident in men with the lowest baseline total testosterone levels.
                                       *                *             *

Traditionally, doctors resistant to the notion that testosterone replacement therapy might be good for one, used to cite the lack of scientific evidence to support their negative views. This is no longer a tactic open to them. Here we have just a sample of some of the clinical studies showing benefit from TRT. Some of them may be small studies but they are peer review, published and conducted in line with strict scientific criteria. They are moreover ongoing. As time goes on you may expect to see further positive evidence for the beneficial effects of TRT.
What are the delivery systems now for testosterone replacement?
Two other points worth considering at this stage are testosterone delivery systems and the clinical criteria now applied when assessing a potential candidate for therapy:
Up to a few short years ago testosterone delivery systems were cumbersome, problematic, erratic and fraught. There were injections that tended to deliver the hormone in bursts that bore no relationship to the levels found in the physiological state. There were implants that were time consuming to insert under the skin and their use carried all the risks common to any minor surgical procedures. They also had a disconcerting tendency to be rejected. And then there were transdermal patches famous for giving rise to local skin reactions and dubious blood hormone levels.
All of these have now largely been replaced by either a transdermal gel – Testogel, Testim, Androderm etc or a long-acting deep intramuscular injection called Nebido and containing 1,000 mg of Testosterone Undecanoate in 4ml oily suspension. This is given every twelve weeks although in practise this is usually increased to be given once every ten weeks. Also, in practise, I find it easiest to prescribe the gel for the first two months before moving on to the intramuscular version, given at 0,6 and then every 10 weeks.
Do I need to run a battery of expensive and unreliable hormonal assays?
The second thing that has changed, or at least that is changing, is the criteria used to decide if a man needs or is likely to benefit from TRT. Heretofore the practise was to order up a battery of hormonal assays including free and total testosterone, sex hormone binding globulin and luteinising hormone to mention only a few. These tests are not just very expensive they are also notoriously unreliable; vary from hour to hour during the day and from laboratory to laboratory on split samples. In a study conducted in 2007 the authors concluded as follows:        
Though laboratory assays can support a diagnosis of androgen deficiency in men, they
should not be used to exclude it. It is suggested that there needs to be greater reliance on the history and clinical features, together with careful evaluation of the symptomatology, and where necessary a therapeutic trial of androgen treatment given. (4)

This has made things a lot easier, not to mention a lot less expensive, for general practitioners considering TRT for certain patients. Today, doctors rely much less on hormone assay when deciding who and who should not be considered for testosterone supplementation. Nowadays I tend to take the pragmatic or empirical approach. If a sixty-three year old man comes to me complaining of mild depression and erectile dysfunction not fixed by Viagra then I would immediately think of TRT.
Or, if a seventy-two year old man attends with Type 2 diabetes and loss of libido, TRT will at the very least cross my mind such that I will  discuss the ins and out of this suggestion with the client. The same holds true for the Metabolic Syndrome. Presented with an overweight, hypertensive, and hyperlipidemic man in his seventies, with a strong family history of coronary artery disease, I would, with very little hesitation, strongly consider TRT as a wise choice for him. In any of these situations, I would consider PSA as the only blood test necessary to do and even at that reluctantly.

As for gauging the clinical indications or efficacy of TRT, in the absence of blood androgen levels, we have the self-assessment tool known as the ADAM test. Here the client, not the doctor, scores himself against a series of graded questions to do mostly with his quality of life. If this score is low then perhaps TRT is worth considering. If after a few weeks on TRT his score remains low then perhaps discontinuation of TRT might be equally meritorious. This is pragmatic medicine. It can be as simple as that.
Does testosterone therapy cause prostate cancer?
There is no evidence that raised testosterone levels causes or increases the risk of prostate cancer. Prostate cancer is a disease of older men with reduces testosterone levels. It is not a disease of younger men with high testosterone levels. So, if anything, testosterone would appear to be protective of the prostate gland against malignancy. I am not making that case here though. 
It has been observed in peer review study that by significantly reducing testosterone levels with the use of finasteride this can reduce the incidence of prostate cancer by some 25%. Does this not therefore strongly suggest that the increase of testosterone levels would have the opposite effect and increase the incidence of prostate cancer?
Yes indeed it does. But such a proposition is no more than a corollary and as with all corollaries it has to be accepted without any supporting evidence. You must accept it as “logical” and leave the field of clinical science and evidence based medicine behind you.
Corollaries work very nicely in religion and philosophy. God is good. If you don’t believe in God then clearly you do not believe in goodness. But do they work in medicine? I hardly think so. It is a tad annoying to see that the very people shuffling on the high moral ground of peer review science and baying for evidence based medicine only, can themselves so readily abandon such lofty principles when it suites them. There is a double standard at play here and it is not equitable. 
Does testosterone therapy not risk accelerating the growth of a pre-existing yet to be detected prostate cancer?   

This might be your Becher’s Brook when it comes to supporting TRT. But that’s all it is, a jump and like most jumps you can get over it. Castration, surgical or pharmaceutical, causes prostate cancer to regress albeit temperately. Therefore, watch the slight of hand here now, increased testosterone levels will or might fan the flames of an existing small and contained prostate cancer. Isn’t that only logical?
Indeed it is only logical. Note the imagery often used – fan the flames. Logical and emotional even. But is it scientific? Is it peer review and evidence based? No it is not. It is another corollary for which there is not one shred of clinical or scientific foundation to support. Indeed, what few studied there have been to date have all failed to demonstrate any correlation between raise testosterone levels and prostate cancer. And yet, when considering a man for TRT we still consider it necessary to apply that monkey-wrench of an instrument called PSA.
Summery. Debate and controversy continue to rage around the subject of testosterone replacement therapy. Clinical trials are ongoing and so far have delivered good news and even hint at an expanding potential range of disease processes related to ageing where TRT may be indicated.
Certainly, in the last ten years, we have moved a long was from thinking of TRT as a mere bedroom fodder, libido booster and adjunct to ED treatments. Evidence is slowly emerging to support the proposition that testosterone has a role to play in the reduction of dementias – senile and Alzheimer’s, the management of type two diabetes, hyperlipidemia, coronary artery disease, metabolic syndrome and osteoporosis.
The academic naysayers and detractors remain alive and well of course although the firmness of the high moral ground upon which they once stood maybe crumbling somewhat.       

(1) Chris J Malkin,1 Peter J Pugh,1 Paul D Morris,1 Sonia Asif,1 T Hugh Jones,2,3
Kevin S Channer1   

(2) Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, and
men with late onset Hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7:3495–3503.

(3) Giltay EJ, Tishova YA, Mskhalaya GJ, Gooren LJG, Saad F, and Kalinchenko
SY. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med 2010;7:2572–2582.

(4) The validity of androgen assays
Malcolm Carruthers,1 Tom R. Trinick,2 and Michael J. Wheeler3
1Centre for Men's Health, London, UK
2Department of Chemical Pathology, The Ulster Hospital, Belfast, UK
3Department of Chemical Pathology, St. Thomas' Hospital, London, UK
Correspondence: Malcolm Carruthers, Centre for Men's Health, 20/20 Harley Street, London W1G 9PH, UK. Tel: +44(0)2076368283. Fax: +44(0)2076368292.

Doctor Rynne