The use of testosterone in erectile function

Abdulmaged Traish, PhD & Ridwan Shabsigh, MD interviewed by Alvaro Morales, MD

Alvaro Morales, MD: Hello. My name is Al Morales. I am a Professor of Urology and Oncology at Queen’s University in Kingston, Ontario, Canada. We are here together with two very distinguished professors from the United States. I have the opportunity to attend the section presentation at the ISSAM meeting, this is the International Society for the Study of the Aging Male. It was an amazing presentation on the use of hormones in erectile dysfunction. I would like to ask my colleagues and friends to introduce themselves. Dr. Traish?

Abdulmaged Traish, PhD: I am Abdul Traish. I am from Boston University School of Medicine and my role is the Director of Research in the Institute of Sexual Medicine and as a scientist, it has been our long-term interest to understand the role of sex steroid hormones in male and female sexual function and dysfunction. In this meeting, I was very much interested to share some new data with the participants on the role of testosterone in modulating erectile function in the animal model and how this sex steroid hormone regulate tissue structure and function.

Alvaro Morales, MD: If I may add to what Dr. Traish is saying, it really gave the basics of how these hormones work at the level of the penis and this is becoming, obviously, a totally new field with normal clinical consequences. I am talking about clinicians. I would like to ask Dr. Shabsigh to introduce himself.

Ridwan Shabsigh, MD: Thank you. I am Ridwan Shabsigh. I am Associate Professor of Urology at Columbia University in New York and a Director of the New York Centre for Female Sexuality. I am happy to be here at the International Society for the Study of the Aging Male. I have had long-term interest in testosterone, hormones and erectile dysfunction.

Alvaro Morales, MD: So, Dr. Traish, one of the questions that came during the question period which was equally interesting, the audience was very, very interested and they asked a lot of smart questions. The question came up; what happened to the levels of testosterone? Do we know what androgen level in the serum can be considered the minimum for erectile function? Your animal model is exceedingly practical and good for answering these questions, and I wonder if you could comment on that.

Abdulmaged Traish, PhD: I would like to break this into two comments. One comment is that since the levels of testosterone in the human adult male range from somewhere around 200 nanograms per decilitre to 1,000 or more nanograms per decilitre, it tells us already that there is a huge range; however, within this huge range, I believe that within each individual there is a reference point at which below that there is what I would call androgen insufficiency and above that which I call adequate androgen sufficiency. This is a very, very difficult question because with this wide range, it is very difficult to draw a reference point in a small population study. You raise a very interesting point. This can be done in the animal model just to give us a handle on how to understand that in the human. In the animal model, we can go from a normal animal with a physiological level of testosterone to very, very low levels because we can do gonadectomy. We have the opportunity now to reconstitute the animal with small dosages over increasing doses and we can titrate and see at what point erectile function is regained. We can use that reference point in the animal study to design the study in the clinical sphere to find out how this wide range of testosterone levels in humans can now be narrowed down to really try to describe or fish out what is a good reference point. This study, hopefully as we go along, will be done in the animal model and when it becomes available, I think it will set the stage for future clinical studies.

Alvaro Morales, MD: Thank you very much. Now, Dr. Shabsigh, you obviously have taken the leadership on this very important issue of the combined use of testosterone and PDE-5. The consultation last year in Paris came with a recommendation that every patient with erectile dysfunction should have a serum testosterone level done. This is very controversial and many people argue that this should not be done. One of the presenters was Dr. Buvat, and he indicated that very few men with erectile dysfunction are really hypogonadal. I wonder if you can share with us your view of should we do serum testosterone levels on every man who presents with erectile dysfunction at the beginning or wait? What are your thoughts in this regard?

Ridwan Shabsigh, MD: The typical patients who present with erectile dysfunction for hypogonadism, I have screened them for hypogonadism with serum testosterone, is a controversial issue. I do believe that testing these men for testosterone is important at the beginning because this gives the opportunity to treat a type of erectile dysfunction that might be reversible and removes the need for planning with on-demand drugs, such as PDE-5 inhibitors. I would like to add to that, that it is especially important to test men for hypogonadism and to test serum testosterone in patients who fail oral therapy with PDE-5 inhibitors. We have learned that in a study that we performed at our centre as part of a multi-centre randomised double-blind placebo-controlled study on the use of testosterone gel versus placebo gel in men who failed prior sildenafil therapy at the maximum dose of sildenafil 100mg and who had low serum testosterone. Our study showed that testosterone improved response to sildenafil in those patients who had low testosterone and prior failure. I do believe that screening men with hypogonadism is especially important in those who fail oral therapy with PDE-5 inhibitors, such as sildenafil, tadalafil and vardenafil.

Alvaro Morales, MD: Thank you. I think there is one final very important issue and I would like to address this issue to both of my colleagues and friends. Both of you showed that hypogonadism results in structural and functional alterations at the level of the penis. There was a very interesting question that came from the audience and it referred to the use of the combination of androgen and PDE-5 inhibitors, and the question regarded cost. Could we continue the use of testosterone but decrease the amount of the PDE-5 inhibitor and, specifically, sildenafil? It seems to me it would not make sense to decrease the doses of testosterone, but perhaps the doses of sildenafil or tadalafil or vardenafil could be decreased once you have reached a steady state of the level of testosterone. I wondered if either one of you or both of you would like to comment on this issue from the purely clinical, practical point of view and economic point of view and also from the scientific point of view, does this make sense to you?

Abdulmaged Traish, PhD: If you do not mind, I can comment on the scientific point of view and let Ridwan comment on the clinical one. I think from the scientist’s point of view, it is very interesting. We see from this study that there is a reversible process, when I say reversible, it may be irreversible at some point in time, but there is a reversible process in tissue architecture so androgen insufficiency or androgen deficiency brings about dramatic structural and constant changes. Interestingly enough, we can restore these changes to normal levels and we can document in the animal’s body that normal physiology is obtained. To take this point, I think the androgen problem in patients may need to be continuously addressed because the fact that there is androgen insufficiency or deficiency, may mean that there may be other combining factors. However, the combination of PDE-5 plus testosterone, if the cost of PDE-5 is the issue, you may want to have studies which will test this by reducing the PDE-5 by changing the testosterone concentrations. That might be important. However, in my view, this would be require pre-clinical and clinical studies. There are no well-designed studies in the clinics to document that. This is not something that we can just start doing in patients, but we need pre-clinical and clinical data to support that.

Alvaro Morales, MD: Dr. Shabsigh, will you comment on that?

Ridwan Shabsigh, MD: Our clinical trials showed that testosterone does have an effect in converting patients who do not respond to PDE-5 inhibitor therapy to responders and we do not have long enough data to see whether this would have an effect in repairing the damaged erectile mechanism in the corpora cavernosa of the penis. We would need longer clinical trials to answer this question. However, from the practical viewpoint, there are a number of considerations. One important consideration is that the patient with erectile dysfunction usually has erectile dysfunction as a multi-factorial condition. This multi-factorial condition may be related to vascular risk factors, such as hypolipidemia, smoking, obesity, sedentary lifestyle, diabetes, depression, so the expectation in the large clinical sense that short-term reduction of the PDE-5 inhibitor dose would be achieved, those expectations are, in my opinion, low.

Alvaro Morales, MD: Thank you very much. I should say that there were probably twenty different questions at the end of the session, which reflected the interest of the audience on not only the topic, but the quality of the presentation. Unfortunately, we have time limitations. There is another session starting very soon, but I want to thank my colleagues and thank Schering for asking us to share with our colleagues all over the world what happened this morning. Thank you very much.

Abdulmaged Traish, PhD: I would like to take this opportunity to extend my thanks to Schering and to the organizers of this meeting. This is a very exciting symposium and if one thing emerges from this, it is that we need to have better understanding of the role of testosterone in the aging male, as well as in the erectile function field and we have just tapped the tip of this field. There are many more questions to be addressed in order for this field to forge ahead and I hope that a few years from now, we will be back in a meeting like this somewhere on this continent or another one, where we will have much more data and we will have answered some of these questions.

Alvaro Morales, MD: One last word Ridwan?

Ridwan Shabsigh, MD: I would like also to add my thanks to all of those who have been involved in this effort; to the participants, to the Society and to the pharmaceutical sponsors for the attention to men’s health. This is a wonderful opportunity to bring focus on a long-neglected issue of men’s health and overall aging men.

Alvaro Morales, MD: I couldn’t agree more, thank you very much.