Testosterone Replacement Therapy

Transcript

And made the cover of Time magazine a few years ago. The writer was careful to say the main potential danger of testosterone replacement therapy is the effect on the prostate gland, and it is this potential danger that this study was designed to address. Despite many years of concern. Testosterone. Replacement therapy may not carry the risks to the prostate, commonly believed. With synthetic testosterone and now readily available, many doctors quickly embraced the use of the hormone to treat the male climacteric as it was referred to in this early paper. We now call this late onset hypogonadism, one of the early publications on this topic is shown right here, and it happens to be from JMA in 1944. For these authors observed that satisfactory results were obtained by intramuscular injections of testosterone. This condition, which may be he may see referred to as andropause male climacteric, male menopause, viral pause, or atom androgen decline of the ageing. Deal maybe to find this way. It's the clinical reflection. Of an age-related decline in testosterone seeding up to 50% of men in the last third of life, it may be considered a physiologic extreme of the male ageing process. The onset is insidious, gradually progressive and most often recognised in the 5th or 6th. Decade of life. Its manifestations are a decline in bodily function normally maintained by testosterone, that is, libido, potency, mood, intellect and also bone, muscle and lean body mass. The treatment is testosterone replacement. Testosterone replacement therapy has many potential benefits. Including its effects on libido, erectile function, energy, well-being muscle mass and the rest. But there are also potential concerns with testosterone replacement therapy. And the number one concern is the potential effect on the prostate, which could be the most serious of all of these at about the same time that testosterone was being introduced as a therapy for andropause. Charles Huggins, shown here at the University of Chicago, showed that men with advanced prostate cancer. Could actually have their disease put into remission by eliminating testosterone for this work, another Nobel Prize was awarded. But what about the flip side of this? What happens to the prostate when men are given replacement therapy or exogenous testosterone? Actually, in men with advanced prostate cancer, a little bit of information is available and clearly giving testosterone to men with advanced prostate cancer is detrimental. There, this kind of work was done in various clinical trials here in New York at Memorial Sloan Kettering in gents like this with bone metastatic bone disease. The results are generally unfavourable. Of 52 men gathered over several decades years ago, when these men received testosterone, pain increased nausea and vomiting, increased metastases increased. There were even deaths. So clearly it's contraindicated in advanced prostate cancer. In fact, the director of the National Cancer Institute. Andrew, Vanishing Back America's number one cancer doctor, told the New York Times recently recognising the dependency of prostate cancer on testosterone. I am not convinced there's enough evidence on its safety to justify widespread use to help determine just what testosterone does to the prostate. We designed our clinical. Trial our hypothesis was simply. That exogenous testosterone enters the prostate is converted there to dihydrotestosterone, the active metabolite within the the gland and affects biological change there. We thought it remarkable that even in the early years of the 21st century, basic information like this was not available, our study participants. Immune with low testosterone levels, symptoms referable to low testosterone levels and no prostate cancer on a screening biopsy. With PSA's less than 10, we didn't want to risk giving this to anyone with cancer at this early stage. The trial was a randomised trial of six months duration and all men in this trial underwent biopsy. Baseline this was the unique aspects of this study was that we studied prostate tissues directly, while others before us had studied gross measures of the prostate, like changes in size or indirect measures such as serum PSA level. Thus, all men had biopsy at baseline and then were randomised to receive either testosterone replacement therapy or placebo for six months, and then underwent rebelliously at the end of the study. The first thing we found in these 41 men who completed the trial was that cancer was not increased at the microscopic level. Two cancers were found on biopsy in this group at conclusion that the testosterone treated men and four in the placebo group. So actually 4 even more men from placebo were found to have cancer than in the prostatic than in the test. Mushroom group. So clearly this medicine that testosterone replacement therapy was not stimulating the development of new cancers. And these cancers were approximately equal in severity in. The two groups. It's also interesting to realise very likely these six cancers were there from the beginning. We also wanted. To look at the. Fundamental biology of the prostate, and that's really what this was developed. The study was designed for, so the prostate biopsies taken here and these are what these little cores actually look like. They were then harvested first for chemical study of the hormones testosterone and dihydrotestosterone. They were harvested for detailed microscopic evaluation and also for changes in gene expression. Gene is the fundamental unit of biology and our theory was that if no change in gene expression was present, then certainly we must not be affecting the tissues. Placebo men are in. The white boxes and the active testosterone treated men in the grey box. This first baseline and then the six month level testosterone shown here and dihydrotestosterone shown here. The first thing noted is that in serum these are all serum. Now there was an expected increase to the mid normal range for serum testosterone levels and dihydrotestosterone. Also increases statistically significant fashion. However, in tissue, in prostate tissue, the testosterone and the dihydrotestosterone levels don't change. They remain essentially the same as at baseline. So just to reemphasize this point. The expected increase in serum levels of these hormones from the replacement therapy we were administering, but no change in tissue hormone levels supporting the chemical data with these tissue measures all done by experts in a blinded fashion. There was no treatment related change in atrophy that is cell. Shrinkage or growth or inflammation or cancers, as we've shown before, and nor was there any change in cellular composition. We also looked at detailed studies of the tissue biomarkers. For cell proliferation, that is how rapidly the cells are turning over. We looked at the androgen receptor, which tells how the hormones bind to the to the tissue. And we looked at angiogenesis markers that has to do with small vessel in growth, important in malignancy, no change. Any of these parameters study very importantly, there were also no significant changes in gene expression a microarray, a gene microarray was created from prostate glandular cells and there was no treatment related change in gene expression. Seen we looked at particularly at genes known to be androgen regulated, and four of them are shown here no treatment effect on androgen regulated genes and the same was noted for these two cancer related genes. Thus the genetic studies from this project support. The tissue studies and the hormone changes no effect in these in these patients. Normalisation of serum testosterone for six months resulted in no change in prosthetic levels of and. Begins Histology biomarkers, gene expression or cancer frequency. Or severity, we conclude that the prostate risks from testosterone replacement therapy of six months duration may not be as great as once feared. However, caution here, these data do not assure prostate safety for populations of older men. And harbouring highly prevalent subclinical disease, we know that if you do thorough studies of the prostate glands of ageing men, microscopic foci of cancer are present in many of them that do not seem to be clinically significant. This doesn't guarantee that some effect won't be. Seen when entire populations of men are studied for safety, but this would require a much bigger, much longer study in the individual patient, especially with the negative biopsy at baseline. The risk appears to be quite small. A degree of prostate safety for men undergoing testosterone replacement therapy is established. Hopefully this finding won't lead to abusive widespread application of this finding from a laboratory standpoint. Again, the fallibility of the PSA test for prostate cancer is shown. This supports an emerging body. Have thought to show that PSA levels are not great markers for prostate cancer. Best we've got. At the moment. But they are fallible because of the. Men in this. Study who were found to have cancer on biopsy. Only one had a PSA level greater than 4. Which is the. Usual usual trigger point for prostate biopsy. With regard to the basic Physiology of the prostate gland. It's interesting that the tissue levels within the prostate of the male hormones don't change, despite a wide range of circulating levels in the serum. In the bath surrounding the prostate bathing the prostate, there seems to be a buffering mechanism in effect protecting the gland from a very wide. Range of circulating hormones. Now how this buffering mechanism is established and how it breaks down in extremes such as in castration or in supranormal dosages of testosterone, that information is not. Is not yet available. I want to. Conclude by acknowledging the great contributions of this project from these fine medical scientists. And finally, thanks very much once again to Doctor Deangelis and Dr Ponderosa and their fine staff and JAMA, who helped make this article coherent. Thank you. Yeah, you're pointing out a major limitation of this study. It was only at six months duration, this is a. I I think what you've got to. Realise about this. Particular study is that it was a biopsy study and the 44 men in this study gave 2 biopsies for science. We were glad to have that six months to follow up. I think you're right. I think we need to know the long, the long haul. I think you're right. I think IGF one is one of the most interesting of the genes currently being looked at. These six genes were the ones that we did quantitative RT PCR. On to to. Determine their quantitative they they fell out of the. They were selected out of a gene microarray of for hundreds of prostate genes and prostate relevant genes that we're all looked at. So yes, yes, a microarray, a complete gene microarray was created. Hundreds and hundreds of jeans were looked at. Yeah. Thank you for bringing that up, that is. A concern of mine. It is estimated that about 5,000,000 American men would be candidates for testosterone replacement therapy. The NIH actually hired the Institute of Medicine to look into this for them a few years ago, and a blue ribbon panel of the Institute of Medicine was convened and recommended. This was published last year. That focused efficacy trials should be done first. Small focused efficacy trials should be done first to be sure that the benefits were were conclusive before spending $100 million of the taxpayers money to fund a the 6000. And trial. So that's the, that's where we. Are right now. I do agree there is a a concern that that some physicians may may misinterpret these data and start using. Testosterone, Willy nilly and my hope is that it won't be used that way. There are some limitations on how much you can generalise from this project.

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