A fresh look at testosterone therapy

To mark Men’s Health Week, which runs until June 19, Kildare GP Dr Andrew Rynne takes a look at some of the benefits associated with testosterone replacement therapy.

It has to be admitted, the word ‘testosterone’ does not usually evoke positive feelings or responses. In the popular press, the word 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 testosterone replacement therapy (TRT) to your average doctor and it 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 pity.

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 quietly promoting the notion of TRT for almost ten years now. 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 less savoury side-effects associated with the ageing process, including premature death.

In the next few 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, 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 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 1,000mg of testosterone undecanoate every 12 weeks or placebo. The authors concluded:
“Testosterone undecanoate reduced fasting glucose and waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with metabolic syndrome. Resumption and maintenance of testosterone 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.” (2)

(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, some 184 men suffering from metabolic syndrome and hypogonadism were treated for thirty weeks with either testosterone undecanoate or placebo. It concluded:
“Testosterone undecanoate administration may improve depressive symptoms, ageing-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.” (3)

Traditionally, doctors who were resistant to the notion that testosterone replacement therapy might be good for a person used to cite the lack of scientific evidence to support their negative views. This is no longer a tactic open to them. Above, we have just a sample of some of the clinical studies showing the benefits from TRT. Some of them may be small studies, but they are peer reviewed, 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.

Delivery systems
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 — such as Testogel, Testim, Tostran or Androderm — or a long-acting, deep intramuscular injection called Nebido and containing 1,000mg of testosterone undecanoate in 4ml oily suspension. This is given every 12 weeks, although in practice, this is usually increased to be given once every ten weeks.

Also, in practice, I find it easiest to prescribe the gel for the first two months before moving on to the intramuscular version, given at zero, six and then every 10 weeks.

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.

Dr Andrew Rynne

Heretofore, the practice was to order 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 – they 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 assays when deciding who should or should not be considered for testosterone supplementation.

Nowadays, I tend to take the pragmatic or empirical approach. If a 63-year-old man comes to me complaining of mild depression and erectile dysfunction not fixed by Viagra, then I would immediately think of initiating TRT.

Or, if a 72-year-old man attends with type II 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 hyperlipidaemic 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 prostate-specific antigen (PSA) as the only blood test necessary to do — and even reluctantly, at that.

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.

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 reduced 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 per cent. 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 suits them. There is a double standard at play here and it is not equitable.

Regarding the issue of whether testosterone therapy risks 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 sleight of hand here), 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 reviewed 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 studies 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.

Summary
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 past ten years, we have moved a long way from thinking of TRT as a mere bedroom fodder, libido booster and adjunct to erectile dysfunction treatments. Evidence is slowly emerging to support the proposition that testosterone has a role to play in the reduction of dementias, senility and Alzheimer’s disease, the management of type II diabetes, hyperlipidaemia, 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 may be crumbling somewhat.

References:
(1) Malkin et al. Heart 2010;96:1821-1825.
(2) Aversa et al. J Sex Med 2010;7:3495–3503.
(3) Giltay et al. J Sex Med 2010;7:2572–2582.
(4) Carruthers et al. Aging Male 2007; 10(03):165-72.