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Audience Question: I have three questions one for Dr. Schubert, considering the nice effect on bone mineral density, how do you see the estradiol levels that you reach with testosterone undecanoate? Because of the gel, you are in the upper limit of estradiol levels after therapy. Are we the same with testosterone undecanoate in order to explain the good effect on bone?
Dr. Schubert: We measured estradiol levels and we spread the injection vial during the running trial, longer and longer, and in our follow-up phase there were some who were in the lower normal range. But concerning our data for bone mineral density, you have to keep in mind that the most of our operations were pre-treated, so we stopped testosterone therapy at a wash-out phase only of 3 months, so we didn’t expect any large changes if you treat a newly-diagnosed hypogonadal patient with testosterone, you get much higher increases in bone mineral density.
Dr Zitzmann: We observed and measured estradiol levels in our patients, as well, and we see that of course they behave like the testosterone levels and you do not have these high peaks that you observe, for example, with testosterone enanthate and we know that both hormones are important for bone health in men, testosterone and estradiol, so the effects cannot be ascribed to estradiol alone but both hormones are important and remain within the normal range.
Audience Question: One for Dr. Yassin about the first line therapy of androgens in erectile dysfunction. According to your data, you have marked hypogonadal patients below 2 ng/mL is slight hypogonadal men, our experience is that PDE-5 inhibitors alone can restore a good testosterone environment, so as for slight therapy in slight hypogonadal men I would remain on PDE-5 inhibitor. What is your comment on that?
Dr Zitzmann: We took the patient with the co-prevalence of hypogonadism and erectile dysfunction. Not each hypogonadal patient is going to respond in the same way or have the same “damage” at the outer structural level in the penis in the same way. It depends on level of testosterone, degree of hypogonadism or the duration, as well, which is very important and we do not know, we have no foggiest idea about that. So as a first line therapy in this cohort of patients and 18.3% is pretty reasonable because the data of other authors like (inaudible), for example, 18.7%, they have in other communities more, more than 30% or 37%, I guess I spoke to Dr. Eidecker last time and we enlightened that in different societies, it depends on the prevalence of hypogonadism regarding co-morbidities like diabetes mellitus and whatever. And in this case, I mean that first line therapy really in patients with ED and hypogonadism, as well.
Dr Morales: When I look at the papers by Aversa and Shabsigh, these patients were not profoundly hypogonadal. Actually, in Aversa, the patients were low normal testosterone, which I don’t know what normal means or low normal. But I don’t subscribe to the view that you have only have to be profoundly hypogonadal. What we know is that elderly people are very fragile in their response to lower levels of testosterone and younger men with relatively lower levels of testosterone can still function sexually quite well. So this issue has not been clarified.
Audience Question: Since Africans will not admit to sexual problems, we are not likely to get Nebido® there, but did I miss something? What is so special about castor oil that Nebido® has to be given intramuscularly with all its risks, when subcutaneous works so well for testosterone esters?
Dr Zitzmann: Basically, we do not really know what should happen to kinetics, for example, in these patients. We do not know what we could cause in terms of fat necrosis and you must remember that the volume is 4 ml and that is why a large muscle should be chosen. So we do not recommend that. You should take a longer needle and be careful that it is injected into the muscle because there is no experience and possible danger.
Audience Question: I am somewhat puzzled by the fact that you began by the full dose even in those performed hypogonadal patients. In my clinic where I have had sometimes some problem with no patient with hypo zero deficiency, very low testosterone, and you begin immediately by the full dose can have some neurological problems (inaudible) and so and so. So do you really mean you always begin by full dose?
Dr. Zitzmann: You know, the full dose means the dose that has been tested for kinetics. If you choose something else, you do not really know what happens and you have to remember that testosterone levels stay within the normal range and when you look at the studies conducted by Shalender Bhasin who gave up to 600 mg of testosterone enanthate for a week and all scores remained within the normal level, no changes in mania scores, for example, I am not aware of neurological symptoms.
Audience Question: It is a question for Dr. Zitzmann. He showed us that one of the contraindications, absolute contraindications of the testosterone treatment is the desire of paternity. But these patients are hypogonadal and in hypogonadal patients, substitutive treatment with testosterone is supposed to improve their quality of sperm and not to diminish the quality of sperm in hypogonadal men.
Dr. Zitzmann: Yes, of course, you have to substitute hypogonadal men, but you firstly you have to differentiate between primary and secondary hypogonadism and if you give external testosterone to a hypogonadal person, he will suppress as in a healthy person LH and FSH secretion. That means testosterone given externally is a contraceptive. That works and that is how we do male contraception.
Audience Question: In normal men, in normal men.
Dr. Zitzmann: Also in hypogonadal men. But even the hypogonadal men have to get gonadotropins to induce spermatogenesis and intratesticular testosterone production and that only works in secondary hypogonadism. In primary hypogonadism, we do not have a choice because they already have high LH and FSH levels and if you give them testosterone and they are azoospermic, nothing will happen unfortunately.
Audience Question: Because Dr. Schubert showed us that there was a diminishment in the levels of FSH and LH but only at the normal levels and not at the low levels in your diagram.
Dr. Nieschlag: But he had patients with primary hypogonadism.
Audience Question: Yes.
Dr Schubert: Exactly.
Audience Question: I think it is quite a concern.
Dr. Schubert: So the data showed and I hope I said that our mixed group. So our groups had primary and secondary hypogonadism. If you look at the standard deviation in our groups, they are pretty large for this reason, so if you, when most of our patients who suffer from secondary hypogonadism do have pituitary surgery behind them, so I would totally agree with Dr. Zitzmann’s statement about this.
Dr. Nieschlag: I think we should make perfectly clear that testosterone undecanoate and all other testosterone preparations are for all patients with hypogonadism but for nobody who wants fertility you would give testosterone. The patient, who requires fertility and is hypogonadal with secondary hypogonadism, gets gonadotropins. But in no ways is testosterone a pro-fertility drug. This is what we often see in our practice that patients come from urologists and have been treated for infertility with testosterone, which was absolutely wrong. So I think it is important that you brought up this question. Thank you.
Audience Question: And a question for Dr. Yassin. Sir, you have raised a very important point about testosterone and venous leak, but you based it on Cavernosometry, which to my mind is an obsolete procedure and does not help either in the diagnosis or in the management of venous leak. Now I do a lot of penile Doppler studies and I can tell you that testosterone is useful only in the sub-group of venous leak, where there is muscular dysfunction. It is not of any use in anatomical venous leaks or in arterial causes of venous leaks where there is a deficiency in the arterial part. Would you agree to this, sir?
Dr. Yassin: This is a little bit controversial, I agree with you. What we looked for or what we mean now in the comment is this venous leak could be, according to the animal data, a metabolic disorder rather than mechanical one, clarified by a lot of publications and our own experience telling us that after venous ligation, you have a recurrency within one or three years. They are coming back. It is good business for us and going to cut it a little bit out, but I am sorry for that. So it means and I did that in the imaging, I did not care about pressure decay, equilibrium pressure, so what I wanted to show here in this small cohort of patients, we need more studies, for sure. Not placebo controlled, we have the evidence here in animal studies, so we need more studies regarding Doppler and regarding duplex they use in that and regarding Cavernosometry, as well, and we need that, but I get that, the initial experience was 5 patients, very impression. If you look at the posters upstairs, we have one today of clinical experience with Nebido® and a part of that is the Cavernosography and you can look at the procedure. Another poster is coming tomorrow with more than one case, I think there are different cases. But we have 5 of them and we submitted them to a journal. I hope they are going to agree with that. We are waiting for the reviewers.
Audience Question: Yes, just a point that I would like to add is that if you use penile Doppler more regularly, maybe our results for venous leak surgery will improve because we will pick up the anatomical ones and not do it on the physiological ones where it is not likely to succeed.
Dr. Yassin: That is right. How often would like to re-surgery at one patient if you have recurrency.
Audience Question: If we do it for anatomical, the recurrence rate is practically zero because you are treating the problem of the venous leak; whereas if you do it for where there is a problem with inflow . . .
Dr. Yassin: I give you right with this axis that is a mechanical one, I didn’t say that every venous leakage depends on metabolic syndrome and alteration of the outer structure where you might run into it. I never said that. I admit a part of that could improve our results in this respect. I had only 5 successful cases within 8 months or now a little bit more than one year. Five cases, other cases, they could be yours, for example. Thank you very much.
Audience Question: Thank you, sir.
Audience Question: This is a rather general comment I would like to make to all those who treat men with hormones. Since Dr. Morales asked me to bring it up, I dare and I am pleased to bring it up. I am a bit disappointed here that what I hoped to get, I don’t find. Normally, those who treat men, they check testosterone, the free testosterone and sometimes LH, FSH and in Dr. Yassin’s list, I even saw dihydrotestosterone. Especially the dihydrotestosterone and progesterone because those two hormones among others, have a very important role in the balance of the hormone profile. I see sometimes in men with low testosterone, very high dihydrotestosterone levels with nearly no or very low progesterone and when one gives them progesterone, you reduce the dihydrotestosterone, the hyperplasia prostate may stop growing. With my very few male patients, I normally treat women, these are the husbands of some of my patients, I can’t get the answers I had hoped to hear from others who have more material, what this means, what one can do and I think it is high time that we really look at the whole hormone profile and not just on testosterone.
Dr Zitzmann: So yes, of course, all hormones are important in men. Also, for example, the thyroid hormones are important, you shouldn’t forget this and growth hormone. And if you give testosterone, the men will make their own estradiol. Concerning progesterone, I think this is a forgotten hormone in men and to date, the only evidence we have is that progesterone may have inflammatory effect in men, but we do not really know. But progesterone substitution for men seems to be very experimental. If you do that, you will suppress what is there and the endogenous production of testosterone because you influence the pituitary, so you cannot treat men like women. Don’t give them progesterone.
Dr. Nieschlag: I think it is very important that you remind us that there is a whole spectrum of steroids and you may know that we probably gather some further knowledge about the effects of gestogens in men and progesterone from male contraceptive trials. So from this, we may learn, but I think for the time being, it is most important that we take testosterone for androgen substitution because it can be converted into male metabolites, namely DHT and estradiol. And that is why we got away from the synthetic androgens which may not have this spectrum, so I think your point is well taken. Thank you for reminding us.
Audience Question: I also have a question for Dr. Yassin. Your slides on the Cavernosographies caught my attention and I was listening very carefully to what you were saying. So you stated that in that series of hypogonadal patients, they were not responding to penile injections using prostaglandin. You treated them with testosterone and you claimed in one of the following slides that testosterone is the way to go for every single patient with ED and that all cases would be resolved. This goes against tons of data which have been published in the recent years in the literature of veno occlusive dysfunction, including immunohistochemistry study, pathology studies, so it is extremely incredible result which of course I would like to congratulate you on. So do you think Nebido® is really a wonderful drug, a wonder drug, more than a wonderful drug, because it is evident from this brilliant symposium that the results that you can obtain are very good but I do not think that you can ask too much to a single drug? Would you comment on this?
Dr. Yassin: Okay, my comment is going from back to forth. Wonderful drug is wonderful drug, I am working with that and I have excellent results. Dr. Montorsi, I never said, I never said that in all cases testosterone worked very well in cavernosal venous leakage. I said with selected patients, they are non-responders to PDE-5 inhibitors and non-responders to intracavernosal injection and they have, according to AMS score from Dr. Heinemann, hypogonadal symptoms, as well. So because if you have a patient with severe hypogonadism, with 1.07 ng/mL he is hypogonadal and he has a lot of symptoms, not only this one. And if you catch now the fact that we had successful full remission in 4 patients and 1 is partially you can see that on my poster, so it means that we have almost only 40% of the 11 months, 40%, that is all. And I never said that for each problem you have testosterone to give, but you have to calculate that in very accurate way, very individually, for each patient. So I wouldn’t say as a scientist and, or clinical researcher, that in all cases, you have success. Never.
Audience Question: Would you please re-state again and I will be short, that those were patients were not responding to penile injections, they were treated with Nebido® only and they became potent?
Dr. Yassin: That is right.
Audience Question: Without any other compound?
Dr. Yassin: That is right. That is right. To be sure, the gentleman you saw, he is 58 years old and that initiated our thinking in this way and that as a following. I will tell you the story. I gave him the injection because also hypogonadal stuff because he is a diabetic one and he came back after 9 weeks and tells me, doctor, I got erection. I said what? He said, yes, I slept with my wife after 3-1/2 years of not enjoying a sexual life. He came without an appointment and I do not like always patients without appointment in this term, I tell you the truth. I ask him to come after 3 weeks and repeated that, according to our methods from, this is from university, and the Cavernosography and we found no venous leakage at all. The series of 5 patients, I would like to get them published, I hope they are going to be published, they are already submitted and we will see that, but I would like to ask you to share us in that experience, as well Dr. Montorsi. You are a very well-known man and you have a lot of patients a big cohort of patients with erectile dysfunction and will by yourself make sure this is true or not. Thank you very much.
Audience Question: Anyone from the podium: any azoospermic individuals from the database? That became azoospermic after using Nebido®? Yes? And is that so, is that it can be reversible?
Dr Zitzmann: You know that we are working on male contraception and male contraception involves always a testosterone preparation and you know that for about 70% to 80% of all Caucasians get azoospermic by testosterone alone. The others need an additional gestogene and multiple trials have been conducted and there was experience in over 1,500 men who received such regimens and became azoospermic, their sperm counts returned to normal after the treatment was given up.
Dr. Schubert: Yes, I would like just to state that we have a patient that is under 22 TE and became azoospermic and the literature is supporting that some of them are irreversible and not involve any other treatment. I have the literature because I reviewed this recently.
Audience Question: I am wondering if there is any age adult adjustment in selected patients with upper high level or upper normal level of liver function tests, and also any adult adjustments in patients with chronic renal failure.
Dr. Zitzmann: Concerning high liver parameters, you have to be careful but there is no indication that testosterone given in such normal doses will alter liver parameters and, as you may know, before erythropoietin was introduced to the market, patients with renal failure received very high doses of testosterone to induce hematopoesis. So that is a safe regimen.
Audience Question: My question to Dr. Yassin, the only slide you showed on the relationship between erectile function and testosterone replacement was about anti-apoptosis. Was it the only mechanism and would you comment on the effect of the testosterone replacement on the modulation of PDE-5 or (inaudible), etc.
Dr. Yassin: The issue is the compartments of the outer structure in the penis, they are not only one, they are five smooth muscle cells, you have vessels, you have nerves, you have extracellular matrix, ECM, and you have also the collagen fibres. Each of them is in some positive or negative way is testosterone dependent. You know that about the endothelial dysfunction is also testosterone dependent. We have a lot of studies of that and the issue is not only the fibrosis, the issue is the alteration in the tissues at the micro-anatomical levels in general. It is very important. These changes in the micro-anatomy on the infrastructure is going to initiate changes also in the biology, it means also in the function. That is the issue. So you can repair a lot of stuff under testosterone therapy.
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