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It is my belief that not in this group but that many physicians are uncomfortable with the idea of identifying men with hypogonadism and treating them because of three concerns. The first is about diagnosis; the second is uncertainty about the benefits; and the third is concern about the risks, especially giving older men prostate cancer. So I would like to address these with you.
Hypogonadism. I do not know about you but I find the diagnosis very confusing if you listen to people. We have so many tests, we have so many thresholds, there is very little agreement and consensus, but I think it is simpler.
If you look here, this is a male and his testosterone is normal.
If you look here, there is a problem. Many of you have patients, as I do, that look like this. We can measure his testosterone and probably it will be low, not necessarily.
But there is a syndrome of signs and symptoms and I agree with Dr. Morales who in a previous presentation said if the clinical presentation does not match the biochemistry, listen to the patient and deal with the symptomatology. In general, we will find that it is associated with reduced testosterone levels, but if there is a conflict, think about the patient. You all are better clinicians than you are biochemists.
What are the sexual symptoms of low testosterone? If you listen to your patients, it includes several things and Professor Maggi just went over this very nicely and they include diminished libido, erectile dysfunction, changes in the orgasm experience, some of the men will say, doctor, when I used to have an orgasm, it was like wow! And now I say to myself, is it over? Some men will have reduced ejaculate volume because testosterone is involved in the prostate and the seminal vesicles which makes up most of the semen.
There are non-sexual symptoms of low testosterone and these have all been covered here in multiple presentations, including depressed mood, impaired cognition, changes in muscle mass and strength and then this sense that a lot of men appreciate when we treat them, which is they have lost their energy, their drive. Some of you who are getting tired now, it is the late afternoon, maybe you should have your testosterone checked.
There also are some signs of low testosterone. Remember the distinction is between symptoms, which is what the patients says, and signs are something that you can measure and these include decreased bone density as Professor Behre nicely showed, body composition and anaemia.
You know, it is hard to be one of the last speakers in a day of testosterone, I think you have seen all my slides and you have seen these before, but basically a three-year study by Wang and others using testosterone gel showed that there was an increase in sexual desire early that was maintained all the way through for 3 years. The same with erection, it improved early and was maintained for 3 years.
Some of you may have seen this which is we know that women get fractures as they get older in their post-menopausal years. Many people are unaware that the curve for men is similar, parallel, but happens about 10 years later and may well be related to hormonal changes in men, too.
If we look at micro MRIs of the tibia in a normal man and a hypogonadal man, we see that there is a different kind of less dense bone.
You have seen this slide, as well. This is the study that Dr. Bremner presented yesterday. A placebo group of hypogonadal men and then a 3-year study of men getting either testosterone or testosterone and finasteride showing significant and substantial increases in bone density.
Bone mineral density seems to be better in the spine than the hip, but it does happen and it can take several years.
We have increases in lean body mass, which is muscle, we have decreases in fat so we are looking at many different systems, aren’t we?
Moods, positive moods go up. There is some evidence that depression is improved with treatment and negative moods, everybody thinks men are so irritable and they want to fight because of testosterone. It is not true. We fight for other reasons, but when men have testosterone levels go down, it is associated with irritability when it is low, not when it is high.
Hopefully you believe a little bit that there are some benefits in many systems, but we worry about the risks. The first two, prostate and cardiac issues, I am going to spend a few slides on, but while I am here, I just want to mention quickly some of these others. It is true that when you treat men with testosterone, the hematocrit will increase on average about 3%. In some men it will go too high and so all men on testosterone treatment must be monitored for their hemoglobin or hematocrit forever. Most of those changes happen early as Dr. Morales pointed out, also.
Sleep apnea has been reported to occur de novo for it to get worse. In my practice, I have to say, this has not been a clinical issue at all, but you should be aware of it. Gynecomastia can be a sign of hypogonadism or it can be an adverse effect from testosterone from its conversion to estradiol and edema has been reported but again, in my practice and experience, this has not been a problem at all.
Other effects to be aware of: some men get oilier skin and they may see pimples for the first time in 30 years. Something that was brought up in the last discussions about the testicles: exogenous testosterone will make the sperm count go to zero or almost zero, so before you start testosterone, you must ask the man if he has any interest in starting a family soon because if he does, you cannot give him testosterone replacement therapy.
Liver issues show up over and over and over again and it is nonsense. The only agents with which we see liver toxicity are the methylated agents that are still available in the United States, but injections, gels, patches, buccal treatments are not associated with liver abnormalities and you do not need to get liver function tests for those men.
So what about heart disease? People think men have more heart disease than women, maybe its testosterone. If you look at men who are getting coronary catheterization and they get grouped into either having coronary disease or not, the men who do not have this, have higher testosterone. Men who do have heart disease have lower testosterone.
If you take men with known heart disease and low testosterone and you give half testosterone and half placebo and you put them on exercise, the men who got TRT had longer angina-free episodes of exercise than men on placebo.
If you look at atherosclerosis, this is the Rotterdam Study, they used ultrasound to look at a large number of men for atherosclerosis of the aorta, this, they broke their group into thirds by testosterone. This is the lowest, the medium, the high. I am sorry, this is the DHEAs, but it is all the same: low, medium, high. The people with the lowest risk of having atherosclerosis progress are men with the highest testosterone. The men at risk are men with low testosterone.
What about lipids? Lipids are a precursor or predictor of disease. In a meta-analysis of 19 studies, Whitsel showed that the majority of these studies show no changes in lipids at all; in others, there was a minor and neutral effect.
What about prostate cancer? I think this is the number one worry and there has already been a lot of talk about it this morning, but what I would like to show you is this is what we are worried about. But, in fact, is it true?
When we look at what is the rate of prostate cancer in clinical trials, the number is 1%. If we look at prostate cancer screening, what is the number of cancers that we find? One percent.
If you do longitudinal studies where you take blood from people today and follow them for 5 or 10 or 20 years, and then 20 years later maybe you see a group with cancer and a group without, you go back and you say what did testosterone levels back 10 years ago or 20 years ago show. Out of 16 published reports, 15 show no relationship between testosterone and prostate cancer. Recently was a report in a small journal but it was presented at the AUA and it made a big fuss where they showed that there was a relationship only with calculated free T, not with total, but what’s funny is that actually the men with prostate cancer had lower calculated free T, so I do not understand how they did it. Others have shown the same data with no support for that conclusion.
Finally, we have to deal with the most important epidemicalogic fact about prostate cancer that people seem to forget. When men are young, we have almost no prostate cancer, even though testosterone levels are high. It is only as we age and testosterone levels decline that we see prostate cancer rates go up.
What are the benefits of testosterone replacement therapy? All of these and we have been through them multiple times. Many systems. Not only do men come in with sexual symptoms we see and we treat them, they come back, they say how is your libido, I say? They say, it is great, but even better, doctor, I feel normal again.
So TRT beneficial effects, multiple systems, I believe it is safe as long as we have appropriate medical monitoring.
Sometimes it takes a while for the truth to come out, but eventually it does and what we really want is our patients to leave us looking like this.
Thank you very much.
Dr. Morales: For Dr. Morgentaler and for the audience, this is a 58-year-old man with a marked decrease in sexual desire, there is no evidence of depression, he is healthy and he is taking no medication. Most of you are familiar with the ADAM questionnaires that John Morley developed. This patient answered yes to questions 1, 2, 3, 7 and 9. He essentially is, according to the questionnaire, very hypogonadal. On rectal examination, the prostate was found to be moderately enlarged, is smooth, no nodules no suspicion of anything, clinically benign and here we have the initial biochemistry. A total testosterone of 250 ng/dl so he will be considered hypogonadal, biochemically. The PSA was 7.1 in a 50-year-old man.
The biochemistry has confirmed the initial diagnosis of hypogonadism. A PSA was repeated and it was reported at 6.9, not a big change. The ratio of 19 very close, very close to a normal ratio and this patient underwent a transurethral biopsy, I am sorry, a transrectal ultrasound-guided biopsy of the prostate, 16 samples were taken and your report came back as high prostatic intraepithelial neoplasia (HG-PIN), but no evidence of carcinoma.
Here comes the question. What will you do? The first possibility will be forget about testosterone therapy. This man appears to need testosterone therapy, but you saw the problems, so you forget about it. You will consider testosterone therapy. The third possibility you will consider testosterone therapy plus a 5a reductase inhibitor of the type of finasteride. Finally, you will consider treatment with DHEA, not with testosterone, but with DHEA.
Dr. Morgentaler: So, you know, really the story about that case is there are two parts of it I think that people are worried about. One is there is a high PS, I think everyone wants to treat the man with testosterone if they thought his prostate would be normal. I don’t think that’s a problem. There are two issues: one is that his PSA is high, that makes people very nervous, and the second is his biopsy did not come back perfect, it came back with high grade PIN and people worry about this as a precursor for development of prostate cancer. So here is what I can tell you. We actually and again in the next session, there is going to be a little bit more focus on the prostate cancer and I am going to show some of the data, but just to preview: we have actually treated these men with PIN and we published a few years ago, together with Dr. Roden from Brazil who is here with me, what happens in these men who get PIN and they are treated with testosterone replacement therapy for a year and the answer is not much. So there were 20 men, one of them did develop prostate cancer over the course of the year, so it is 1 out of 20, but the natural history in many studies is that over 3 years, about 25% get cancer. So this is a very high risk group and I think it’s safe to say even with small numbers that giving these men testosterone does not create an explosion of prostate cancer. No explosions.
Dr. Morales: But Abe, could I interject here?
Dr. Morgentaler: Yeah.
Dr. Morales: It seems to me that 28% of your people, of the audience, read your paper. What about the people who felt no, certainly testosterone therapy is absolutely out of the question?
Dr. Morgentaler: Right. So I mean the other question is, here is a guy with, a lot of people don’t want to give testosterone just if the PSA is 4.1. If the PSA is abnormal, I don’t want to give testosterone, the guy probably has cancer. This case is what, 6.9? Oh my god, for sure he has cancer. Well, guess what? You did the biopsy, 16 cores that’s more than I do, there was no cancer. Could you have missed it? Yes. We could have missed it in everybody, every man sitting here could have prostate cancer and most of you have normal testosterones right now. So why doesn’t your normal testosterone right now make that hidden prostate cancer grow? Maybe we should castrate every man in this audience.
Dr. Morales: Not me!
Dr. Morgentaler: Okay. Not me, either! I like my testosterone. Now what is the 5 reductase? Aha. This is from Ian Thompson’s paper. Yes, the prostate cancer prevention trial. You know, the idea is that if you give finasteride that we reduce the risk of cancer, but I am not sure that the data are clear that if you have an existing, identified cancer that treating with finasteride has any effect. We don’t know that. But I can understand why somebody would want to do it. But personally, I would go ahead and treat that man. I think that we have, the biopsy was absolutely right to do and once the biopsy is negative, I go ahead and treat. Now some people would do a second biopsy if PIN comes back. There is some recent data that shows you probably don’t need to do that with 12 cores, but that is up for discussion.
Thank you very much.
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