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I am not an expert on Nebido®, but I am going to give you what I have learned about this. I have looked at the results that have been presented previously and I compare to what has happened with my experience with other testosterone preparations. So let us start.
You have seen this many, many times. You know that the action sites of testosterone in the body are everywhere. We have here what happened in lipids, what happened in erectile function, what happened in bone, what happened in muscle, but don’t remember that there is also changes in the skin, the adipose tissue, blood vessels, the kidney, everywhere. So you know that and I know that, so I won’t spend any more time on this.
The other one that is worthwhile to remember at this point, what are the late onset hypogonadism manifestations? And essentially, as you can see there, all the arrows go down with the exception of obesity and depressed mood. These are the things that increase with the testosterone goes down.
We all know that prior to treatment, ideally, and I want to emphasise ideally, we should have a biochemical confirmation. We have stick our neck with a publication in the British Journal of Urology indicating that when the clinic and the biochemistry don’t match, listen to your patient rather to the biochemist. Some people have accepted that and I am very grateful for it. That could be an area for very interesting discussion.
For the first year and you heard for Dr. Zitzmann and Dr. Schubert telling us in the first year is when most of the changes are going to occur, particularly the possible potential adverse effects of testosterone, so the first year is crucial and that is the reason we recommend the assessment should be done quarterly. For those patients who are going to receive Nebido®, the first assessment will be at 6 weeks because you remember; they have to require the first injection and then the second injection at 6 weeks, not at 12 for the first 2 injections. After that, if the patient is stable, if they have no adverse effects, yearly assessment, yearly monitoring is mandatory for the duration of treatment. You may find that there is a slight elevation of the PSA, maybe that the haemoglobin is going up a little faster than you wanted. You may want to see this patient in 2 months; you may want to see them in 3 months. So this is probably the most important thing that I can tell you is that nothing substitutes for good clinical judgment and the basic knowledge of testosterone replacement therapy.
Now what could happen after you start administering testosterone with Nebido® or any one of the other compounds? The effects can be subjective and objective and in the first controlled visit at 6 weeks for Nebido®, but week 12 for the other compounds, you are going to look at sexual function. Every single publication I have seen in my own experience is the patient with sexual dysfunction be desire, be erectile dysfunction, are going to respond, they will respond within the first 3 months. If they do not respond in 3 months, I doubt very much they would respond later on. Patients will tell you, I feel better, but they may say I do not feel any difference. The mood has changed and do not forget that there is a placebo effect and I quote here my friend, John Morley: “the placebo effect for testosterone or for placebo may last up to a year in about 10% to 15% of patients.” So sometimes they feel better, they are doing great and it turns out they are taking a placebo, okay, that happens with almost any medications.
Objective manifestations following the administration of testosterone for Nebido® at week 6 and for other compounds of week 12, haemoglobin and hematocrit, you already saw the graphs that have been presented that there may be already changes, significant changes in the haematology. The total cholesterol, do not forget you have done the baseline studies, but for total cholesterol, LDL and HDL, and as an urologist, of course, I have to put here the PSA which is probably the biggest concern for everybody using testosterone.
You have seen this graph and there is not much difference between the Nebido® and the testosterone undecanoate in urethral paresis. Here we have the haemoglobin and here we have the hematocrit and there is an increase in those, but nothing that was out of the ordinary, but please keep an eye on this patient. This may be very important, particularly in the elderly man who may have a touch of heart failure, may have a touch of renal failure, oedema, etc.
What happens in the longer term when you have administered testosterone? Let us look at the efficacy. The strength, there may be an increase in the strength, in muscle strength. Total body mass, there are big significant changes in total body mass. We saw from the illustration, there is a decrease in the fat body mass, there is an increase in bone mineral density, not in the lumbar spine but in the hip, and we expect that there is going to be an increase in prostate size. This increase will go up to the expected for individuals of the same age who is eugonadal. We do not expect that it will go into a gigantic prostate because you are just giving testosterone.
You saw some of the illustrations of what happened with Nebido® in muscle strength and here you can see in the grip strength in yellow is for the patients who received the testosterone undecanoate, Nebido® and in green for those who received the enanthate of testosterone (inaudible) for muscular injection and you can see there is a significant improvement within the first 30 weeks of treatment for both of them, the enanthate and the undecanoate.
The same thing happened with the lean body mass. As you can see, the change in kilograms for both compounds, the enanthate and the undecanoate.
The same thing is happening for the bone mineral density. You measure it by DEXA. The changes are not as marked, certainly not at this point. Please look at this week 30. When we talk of long-term, week 30 is not very much, we have to look at least at to a year or two to see the most significant changes. But you may notice for the first time even at week 30 that there is already an improvement in the bone mineral density and it happens to most of these preparations as you can see here.
Perhaps the most important and my duty today is re-emphasise the question of monitoring for safety, quarterly for the first year and yearly thereafter, that is what we recommended and that is what we stand for. What do you look for? Prostate health most important, the biggest concern that everybody expressed, this involved the wives, the girlfriends, the patient himself, the family doctors, the urologist, the endocrinologist, the psychiatrist not so much, but prostate health seems to be the great concern and is very simple. Rectal examination and PSA. The haematology is again, very simple: lipid levels with a simple blood test. Liver function test, this is kind of a story. I do not know if it is a joke or what, but every single company that produces testosterone in the insert, they talk about liver toxicity. Liver toxicity was common when the methyl-testosterone was being used. Methyl-testosterone is available only in the US and very few people use it. In most of the countries, it is illegal; in my own country you cannot find the methyl-testosterone. That was liver toxic, but these new modern preparations are not. However, for legal reasons, perhaps you should do liver function test as a baseline and then maybe once a year. Mood and behaviour, the patient will tell you, and particularly his partner will tell you, this guy is impossible to live with, his behaviour has changed completely, but this is extremely rare. However, you should ask abut it. The possibility of sleep disorders is greatly debated. Some people say that it exacerbates sleep disorders, most people say actually administration of testosterone improves sleep. It is something you have to ask your patient what is going in his particular situation.
I continue talking about the monitoring and prostate health. One of the things that we say, well, how do we monitor? The rectal examination is very simple. If there is a nodule there, there is no question; you have to do a biopsy. But what about if there is no nodule there but some changes in the PSA? As I mentioned before and it has been mentioned by my colleagues, initially there is always going to be a moderate increase in the PSA. So here we have these relatively simple recommendations. Many of these patients have been followed for a very short time. Other people have been followed for a longer time. If the follow-up is less than 3 years, less than 3 years that they are receiving testosterone, an increase of above half a nanograms per year, the PSA goes up half a nanograms per year, be very, very worried. This may represent a significant change in the prostate. I am not saying it means cancer, I am saying be concerned there is a red flag. Perhaps you should assess this patient and follow him even closer.
If the follow-up is more than 3 years, so now this patient has been on, is eugonadal because he is receiving testosterone, an increase of more than .2 to .3 nanograms per year should raise a red flag and say keep a very close eye on him, maybe consider a biopsy, I leave it up to your good judgment. There are other parameters for prostate health, like measuring the post-void residual, the urine flow, the I-IPSS, these are all very optional. The patient will tell you, doc, before I start treatment, I was peeing very well, now I have enormous difficulty. So you have to assess him or refer him to your friendly neighbourhood urologist. The ultrasound of the prostate is very optional. I do not think it provides you with much information except a very objective assessment of prostate size.
The haematology, the hematocrit increases by more than 52%, what are you going to do? Well, first one, perhaps you consider switching the preparation. If you are giving an injectable, go to a transdermal. If you are giving a transdermal, go to the injectable, use your judgment. Consider a dose reduction. We saw that this is an effective way to reduce adverse effects. Instead of giving it every 12 weeks, give it every 14 weeks or 15 weeks. You will reach a point that nothing, nothing solves the issue of the haematological problems, you may consider phlebotomies, regular phlebotomies. Some patients come for phlebotomies every month. They give a unit of blood and that keeps the haematology in manageable levels. If everything fails, you may have to discontinue treatment, but it is usually a decision for the patient and his family.
So allow me to conclude that I am very glad to hear that most of you have the same experience with Nebido® that I do, which is zero. But we can see that this is a product that hopefully will come to our countries in the near future. I do not believe that the monitoring for Nebido® is any different than the monitoring for any of the other testosterone preparations. Nebido® offers parameters of safety and efficacy which are similar to other delivery forms of testosterone. The consensus recommendations that Dr. Yassin referred to from Paris in 2003 apply equally to Nebido®. They were published in the Journal of Sexual Medicine in volume one. Nebido® offers unique potential advantages over other testosterone preparations. There are men who really like the idea of seeing the physician only every 12 weeks, they don’t mind the injections, but do not forget that every patient has his own idiosyncrasies. There are men who hate needles, they just get horrified at needles and I recently read in one of the North American newspapers that with the epidemic of obesity that you are having or that we are having, because I’m in North America, too, many of these patients not just for intramuscular testosterone but other preparations, if they are very fat, unless you use an appropriate needle, you are not giving an intramuscular injection, you are giving a subcutaneous injection. This simple, silly little thing is important for us to remember.
I appreciate very much your attention and I hope that we have a very fruitful discussion.
Thank you, Mr. Chairman.
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