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The end of testosterone? -

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Norman Swan: Hello, and welcome to the Health Report with me, Norman Swan. Today we will get beyond the hype on medicinal cannabis. A follow-up on the rotten fish oil capsule debate. Beating heart surgery, the question to ask your cardiac surgeon before she does your bypass grafts.

And is testosterone the elixir of youth for men? The latest in a series of trials of testosterone supplementation in older men has been reported. And if you or someone you know is thinking of testosterone, they need to listen to this.

The person who wrote the commentary that went with the papers is Australian researcher and international authority on testosterone Professor David Handelsman who is director of the Anzac Research Institute at Concord Hospital in Sydney. Welcome to the Health Report.

David Handelsman: Pleasure.

Norman Swan: Tell me about these studies that were published recently in the Journal of the American Medical Association.

David Handelsman: These studies go back about a decade. It is known that testosterone levels fall a bit variably over men's ageing, and the question was whether if that was restored whether that would improve men's health in all sorts of ways, including sexual function, but other functions as well. NIH funded seven studies out of a common core protocol with seven different endpoints.

Norman Swan: So they recruited a bunch of men and you got thrown into different parts of the study.

David Handelsman: People could participate in between one and seven of the different studies, all at the same time, depended upon what was being observed as they were going through 12 months of treatment with either testosterone or placebo. So that's a high quality randomised control trial.

Norman Swan: And these were men who didn't have abnormally low testosterone levels, they didn't have what's called hypogonadism.

David Handelsman: They didn't have pathological disorders of the reproductive system, which is the classic indication for using testosterone treatment. These were men who had a reduction in testosterone for unknown reasons but not due to reproductive disorders, and that could be anything from being obese, from being unfit, from having cardiovascular disease, being depressed. There are many, many conditions which lower your testosterone, because testosterone is like a barometer of health. So the question was, if testosterone is lowered for any reason, not disorders of the reproductive system, does replacing it make a difference, does it improve health.

Norman Swan: So some of the studies have reported beforehand, and these were into thinking ability.

David Handelsman: The ones that had reported last year were actually sexual function, physical activity and energy levels, and those show that there was a transient short-term effect on improving sexual function, but it wore off during the study, and there was no effect on vitality or on physical activity. That was reported in 2016…

Norman Swan: And you and I spoke about it then.

David Handelsman: Yes indeed. And these studies are the other four, so there were three endpoints reported in 2016. These four endpoints were reported now in February, and essentially they showed that very convincingly a large proportion of all the men in the combined studies were in the study looking at cognitive function, that is thinking or ability to reason and so on, and that was a clear negative. It was overwhelmingly negative, and I think…

Norman Swan: When you say negative, there was no result, it didn't make it worse.

David Handelsman: They didn't make it better, didn't make it worse, and it more or less settles the idea that testosterone could make such an improvement. The two other studies that were reported that showed side benefits, small increases in haemoglobin…

Norman Swan: So less likely to be anaemic.

David Handelsman: Less likely to be anaemic, but the difference was smaller than the difference between men and women. And there was also an improvement in bone density, but again a very small effect. But the real headline out of these studies was the cardiovascular endpoint which was looking at coronary artery plaque. That is the plaque which is the reason why coronary arteries get blocked or any arteries get blocked actually, and they were able to measure that and accurately measure it for the first time, and they showed that over the 12-month period the testosterone actually made the plaques worse. It caused narrowing of the blood vessels which is really an ominous finding, never been reported with any drug before. Although they didn't look at what are called hard endpoints…

Norman Swan: So they didn't look at heart attacks and strokes.

David Handelsman: It was only a 12-month study, it wasn't able to look at the really long-term cardiovascular effects. But this must be one of the most convincing things for coronary artery disease, actually measuring the plaque itself.

Norman Swan: So we're dealing with men who don't have what's called pathologically low testosterone levels in these trials, ordinary men but they might be unhealthy for various reasons, but there is this group of men who have got what's called hypogonadism, with pathologically low levels of testosterone. Are these heart plaque findings from this study a worry for them?

David Handelsman: I wouldn't use the term hypogonadism or pathologically low to refer to them, these are men who don't have disorders of the reproductive system. In that setting I think it is a concern. It's quite ominous in a way to show that there is increased coronary plaque.

Norman Swan: And what about men with reproductive disorders and that's the reason they've got low testosterone?

David Handelsman: The likelihood is that they are protected from cardiovascular disease over the years when they have low testosterone, replacing it should really bring them back to normal. Just take someone who's had both their testes removed, it's a replacement, you are simply restoring back to physiology what nature or disease has removed. It's very different when someone has a functional disorder due to obesity, smoking or cardiovascular disease that causes a low testosterone, in those situations testosterone is a concern, but the right thing to do is to remove the cause of the low testosterone because it's reversible.

Norman Swan: So it comes back up.

David Handelsman: Yes, it does. The best examples of that are in obesity where clearly testosterone recovery occurs proportional to how much reduction in weight.

Norman Swan: I'm going on a diet tomorrow. And we've just recruited the 1,000th patient to the largest ever trial of testosterone in Australia.

David Handelsman: It's one of the great coincidences that on the day that these studies came out in JAMA the T4DM, testosterone for diabetes mellitus study, which was an Australian study under Gary Wittert's guidance in Adelaide, recruited its 1,000th participant. This study is already substantially larger than the testosterone trials which have just been the subject of what we've been talking about where they had less than 800 men, studied for a year. The testosterone trials are 1,000 men for two years. So when they come out in about two years' time, they will be the biggest study ever done.

Norman Swan: Looking at diabetes prevention.

David Handelsman: Looking at prevention of diabetes, quite remarkable because it is done in the Australian efficient clinical research terms, on a 10th of the US budget.

Norman Swan: So is this the end of testosterone supplements for men?

David Handelsman: Well, for men with pathological disorders, by no means is it the end, in fact that just continues because it's a natural and reasonable form of replacement therapy if something is missing. Whether testosterone could be used for pharmacological purposes is a question that can always be addressed, like it is in the T4DM study with a proper placebo-controlled study. It just shouldn't be used on a wide scale without prior information safety and efficacy. And at this point I should say that the context is important here because in the last 30 years there has been a 100-fold increase in testosterone sales without any proven new indications for it. And in the US and in Canada over one decade from 2000 to 2011 there was a 40-fold increase in Canada and a 10-fold increase in the US, all without any justification medically. So it's not the end of testosterone, it's probably the end of frivolous uses of testosterone, but proper uses as a powerful drug still has quite a future, but it should be based on proper trials.

Norman Swan: David Handelsman, thanks for joining us.

David Handelsman: Pleasure.

Norman Swan: Professor David Handelsman, who is director of the Anzac Research Institute at the University of Sydney.

And you're listening to the Health Report here on RN, ABC news radio and CBC radio across Canada.