Sponsored by an educational grant from Ipsen
Professor Schulman: Dr. Guay, from the US from Boston, will discuss some of the different important aspects of testosterone related to erectile function and also give some further information regarding different preparations of testosterone that are not all similar as you’ll guess.
Dr. Guay: We have heard a little bit about low libido, but now we are going to key in on the sexual activity and the erectile activity. We do know, actually, from our clinical history, those of us that see patients, men who come in with a low testosterone actually do complain of decreased seminal volume, they do complain of decrease in orgasmic power during ejaculation and we hear this quite often.
The treatment of these patients will restore not only libido but will help to restore sexual function and, as I mentioned this morning, barring other causes for sexual dysfunction, especially if you have a high percentage of hypogonadal men in diabetes and other chronic illnesses. Don’t forget that they have other chronic illnesses that cause the erectile dysfunction, as well.
We know that erectile dysfunction increases with age and these studies here show that testosterone deficiency increases with age and this has been shown with the total testosterone blood assay, this has been shown with the bio-available testosterone that measures both free and loosely bound to albumen testosterone and also with equilibrium dialysis free testosterone or, as we see here, the calculated free testosterone as done by the Sodergard equation. This has been verified to correlate with equilibrium dialysis by Dr. Vermeulen in a study in the late ‘90s.
There is, therefore, a link between testosterone deficiency and erectile dysfunction because they both increase with age. It was felt that these are independently distributed disorders, basically from a study by Dr. Korenman in 1990, but Dr. Korenman eliminated many patients with chronic illnesses, so I believe that we should have a larger shaded area here showing the link between these two conditions.
Now, if you look at an ED clinic, some studies have shown about an 18% prevalence of hypogonadism and as I am firmly convinced that men with chronic illness have a low testosterone and it is mostly secondary hypogonadism from stress of the illness suppressing the hypothalamic pituitary function, we have seen this in diabetes and this has been presented before, it was presented this morning, as well. Men with positive HIV have a 30% prevalence of hypogonadism and when they develop full-blown AIDS, this increases to 50% and greater as they become more catabolic.
We looked at what makes up the character of an ED clinic when you have it run by an endocrinologist. This was in the days when urologists ran most of the clinics and when you have an endocrinologist, you are going to have a 36% prevalence of hypogonadism. There are many andrologists here in Europe who probably have mirrored this higher prevalence. Also, we look at the chronic illnesses we see – hypertension, diabetes, atherosclerotic cardiac disease, tobacco abuse – and you can see the inter-relationship between testosterone deficiency and these chronic illnesses.
Of interest, and I want to highlight this, when we look at this 30% prevalence of hypogonadism, the majority of men, 30%, had secondary hypogonadism, low testosterone and low to low-normal LH, and only 6% were primary testicular failure. Secondary hypogonadism is much more common in the world and, as an aside; this shows us here that when we treated the testosterone deficiency, we only cured about 38% in this study. In another study I performed, it was 36%, so there are an awful lot of people who still have erectile dysfunction after replacing the testosterone. This is due to their chronic illnesses. In fact, when we looked at the percentage of the incidence of hypogonadism in our diabetic population, it was a little over 30% as we see here, but that was the same as the population on a whole, so I think that any chronic illness, and not only diabetes and HIV, can cause this problem.
The role of testosterone is both central and peripheral. By central, I mean not only decrease in libido as has been shown today and other times, but also there are essential signals that come down the spinal cord to help erectile physiology and this, too, is affected by lack of testosterone and I will show that testosterone does affect the nitric oxide system, it can affect the endothelial and endothelial-independent functions, as well.
Those of you who attended the symposium this morning and that brilliant lecture by Dr. Traish, I don’t know anyone who could leave here and say that testosterone is not effected or does not effect erectile physiology. I don’t want to go through this in detail because I believe most of you were here, this is just the basic model to show this - is to take a rabbit and measure the intracorporeal pressure after pelvic nerve stimulation and you see an increase in pressure and erection. If you castrate that rabbit, you no longer can stimulate an erection by stimulating the pelvic nerves and if you castrate the rabbit and replace the testosterone, you again have the response. The argument is, is it due to testosterone or its aromatisation to estradiol, so if you give estradiol you do not get as good a response.
This model is used in many studies on basic science. Dr. Traish showed this also, if you have this control group and the hypogonadal group and if you add vardenafil, a PDE-5 inhibitor, to hypogonadal men, you do not have an increase in erection and whether these are hypogonadal from castration or from Lupron suppression of the GnRH axis. This shows us in clinical practice that when testosterone levels are low, there is an impact on the effect of PDE-5 inhibitors which is important because that is what the males come in for.
The important basic science study to look at this is done by Dr. Rafer’s group and they looked at whether testosterone affects endothelial function. They didn’t measure corporeal pressure, they measured nitric oxide synthase activity itself in the penis and they found the intact rat in this case was normal, the castrated rat had much less nitric oxide activity, therefore less endothelial activity. When you replace the testosterone, it comes back to normal. If you add a 5a reductase inhibitor, finasteride, you lose the activity again, suggesting that the dihydrotestosterone is the active agent and when you give dihydrotestosterone, you get the activity again. So this is good evidence and this is only one of a number of papers that have shown endothelial activity.
Well, how about endothelial-independent activity? This was done by Dr. Reilly at Georgia and what they did here they again measured the pressure in the penis and this was the castrated animal and then when the testosterone is replaced, it comes back, this theme comes back over and over again. If you gave these animals L-NAME, which is L-nitro L-arginine methyl ester, this is an endothelial blocker, so if you block the endothelial function, you lose the activity and if you keep the patients on this L-NAME blockage and give testosterone, you get a partial response indicating that there is also a non-endothelial stimulation to sexual function. Again, this is not the only study like this. There are a number of animal studies that have done this.
How about clinical correlation? Dr. Aversa in Italy took men with arteriogenic ED, that is men with corpus duplex ultrasound and stimulation at less than 30 cm per second cavernosal artery flow and these men all failed sildenafil, 100 mg, six tries.
They separated the group of failures and they took the testosterone in the lowest quarter and that gave you a mean testosterone of 368 and free testosterone at 75, so you had men who were hypogonadal by our definition and low-normal, and then if you gave half of them testosterone and half placebo, you saw this response in testosterone.
What happened once you re-challenge these men with sildenafil, you see the placebo group was not different from the basal group but the testosterone group did increase their cavernosal blood flow. So this is a human correlation to the basic studies.
I am not going to go into this study by Foresta in any great detail, but these men actually failed sildenafil and failed apomorphine. As you know, apomorphine stimulates the central mechanisms of the brain to send signals down the spinal cord and, again, they separated their groups in hypogonadal and those who had treatment. For those who replaced the testosterone, they re-challenged with both sildenafil and apomorphine and they had a response to both of these agents after testosterone. Here was measuring the number of erections and here, which is just as important, the maximal rigidity of these erections improved. So this is indirect evidence that testosterone acts both centrally and peripherally to manage erectile physiology.
We did a study when sildenafil came out. We gave it to 521 men and we wanted to look at the response in different categories. How many diabetics responded, how many hypertensives? We had men with a low testosterone, the lower range of normal in our lab at that time in the mid 50 to 70 (years of age) was a 11 pg/ml, we were using analog-free testosterone at that time which we do not anymore, but if the level is just a little below normal, Viagra worked like it did in the other categories, but when the level of testosterone dropped from 10.6 to 8.1, we had less than 50% response; when it dropped to 7.4, we no longer had a response. So this is looking at it a little bit backward, that if the testosterone level drops, men may lose their response and we are seeing men come back to the office after they have been successfully treated, they come back a year or two later and say these drugs no longer work. Well, they either have developed another medical risk factor or their testosterone is low and this is a clue, certainly for me and others, to look at what is going on and what the testosterone level is.
Now as far as the products in the United States, we see that the gels have taken a large share of the market, about two-thirds now. We still have a large percentage of men who are using injections and these are by and large men in our Medicare population who do not have good insurance coverage and they have to come in to the office to get an injection and if they do that, Medicare will pay for the entire visit versus the patient paying for the gels or patches, whatever they use. This is a large part why we have 17% of men still on injections.
It has been shown from the two gels that the gels are not alike. There is AndroGel® and there is Testim®, and we do see a higher blood level with Testim®. This is with a single dose, although it was a cross-over study, but this single dose does correlate with some of our clinical data we found and we showed some good levels in a poster even today.
We find that clinically we have three times as many patients on AndroGel® who required two packets a day than we have on Testim® requiring two tubes and this is verified by a Verispan analysis, this is a marketing analysis, and prescribing practices are available for people to look at and when they look at these practices, we are able to see how many men titrate up from one to two packets or tubes of the various products and you can see that it does not matter who prescribes it, whether it is endocrinologists, urologists, primary care physicians and all others, there are higher percentages of people who are getting two packets of AndroGel® versus two tubes of Testim® and it correlates with our clinical impression.
In summary, I think we showed that testosterone stimulates central mechanisms, not only of libido but signals that go down the spinal cord and stimulates the peripheral mechanisms, endothelial-dependent and endothelial-independent. It also stimulates other areas. Dr. Traish this morning showed the effect on the alpha receptors and we know that dihydrotestosterone is the active hormone and we know that testosterone is important for proper function of the PDE-5 inhibitors.
Audience question: Congratulations for this nice presentation. I am however somewhat surprised you did not mention thyroid disease found at your consultation. As far as we are concerned, we find around 2% to 5% of hypothyroidism, very rarely hyperthyroidism. What is important, of course is those patients have normal low testosterone and you do not have to treat them because if you treat their hypothyroidism then the testosterone improves and often their sexual problems improves.
Dr. Guay: There is very little data on the effect of thyroid. I reviewed a paper, which I am not even sure has been published yet, on thyroid disease on hypo- and hyperthyroidisms showing that there is a percentage. In our clinical experience, we find that as you say, we can treat the thyroid disease and get rid of the fatigue and a lot of the symptoms, as a crossover on symptomatology and as far as hyperthyroidism, you have to have flagrant Graves Disease to have weakness in energy, but again there is such a crossover in those two diseases that we have not mentioned it. We eliminate it from our patient study population because there is such a crossover.
Audience Question: You know it is a problem of subclinical hypothyroidism because, of course, formerly one thought hypothyroidism needed a very high TSH and a very low T4, and now we know a slightly high TSH may be the first type of hypothyroidism and maybe it has to be treated, so one has to be very careful about that.
Dr. Guay: I think you and I are old enough to have seen this come around full cycle. I remember the data on subclinical hypothyroidism that one out of four would respond to symptoms if you treated them. Then this was discounted and now we are seeing data come back again saying that maybe we can change the QT interval or affect the EKG or do other things. We have to have 30 years or so of experience to have seen this repeat itself. But thank you for that.
Audience Question: Hello, it was stated a few days ago in this audience, that each erection is a small miracle, which means that successful erection is a success of many factors. My question is; what is the impact of social and cultural factors on testosterone treatment and does it matter if the patient during treatment keeps on activity or retires? Does it matter if he loses his wife or changes sexual partner; any cross-cultural norms?
Dr. Guay: Do we have another hour to go through this?
Professor Schulman: You have some time to go into change of partners or for medicine, yes.
Dr. Guay: I think you are absolutely correct. We do not live in a vacuum. Life is not a placebo-controlled event, which I like to say in my lectures and of course if someone is in the middle of a divorce, we have to take the history of people who do not respond. This is where I obtain my data on saying, well, only 36% to 38% of the men who replace testosterone correct their sexual problem. The others have, and I mentioned only chronic illness but I failed to mention the diagnosis of depression, bipolar disease, relationship issues, stress of work or any other of the psychosocial issues we have to take into account when we are looking for non-response. Absolutely very important, especially if you are dealing with symptoms like libido, which are multifactorial. Thank you for that.
Audience Question: If a patient fails to respond to one pack of the gel, there is what I call the American solution which is to apply two packs. But there is also Scottish solution, slightly more economical, that if you get them to apply the same amount to the armpits, then as it’s been known for about 40 years, you get two to three times the absorption and can keep the cost of the treatment down. Can you foresee any adverse aspects to the Scottish solution for this problem?
Dr. Guay: The only problem I see with some of these things is the same things we see in patients using antiperspirants, that you can affect the glands and irritate the glands with the alcohol content. But I failed to mention that when I use either AndroGel® or Testim®, I have the patients split the amount and put it on a wider surface area so A) you get a better absorption and the alcohol blows off quicker. We presented some application data, patient data, today in a poster showing that we can get absorption of Testim® in more than one site: we did the calves and we did the lateral chest and abdomen, where we do get good absorption.
Audience Question: One question that I would say is asked frequently about testosterone, erection and PDE-5 failures, you showed that it is well-known that you can rescue the failures, but then what happens once you have rescued them? Do they need to continue to get both drugs, the combination or can some get rid of the PDE-5, Viagra and others and just be satisfied with testosterone as we have seen in practice – they do not need it sometimes anymore.
Dr. Guay: It depends on what you are dealing with. If you are dealing with primary testicular failure, of course they are going to need both. If you are dealing with one of the more under-diagnosed conditions like sleep apnea which causes hypoxia which suppresses the hypothalamic function so you get a secondary hypogonadism picture, if you treat the patients with testosterone for six months while they are getting diagnosed, treated with CPAP, starting to lose weight, then you may be able to withdraw the testosterone and their own production rate will then take over. I think it is an individual decision, if it is an acute pneumonia that causes the low testosterone, these things will resolve themselves. If it is chronic illness or multiple chronic illnesses in older men, most will require, and we have done this when withdrawing the testosterone, the levels go back down again because the chronic illnesses don’t disappear.
Audience Question: My question for Andy, what I would love for you to speculate on, is 1) why do you think people do not use testosterone more to treat erectile dysfunction and 2) what needs to happen so that they do consider it?
Dr. Guay: I think this idea that testosterone is involved in erectile physiology is a rather new one and has only evolved over several years. Dr. Traish is a lead author on the first comprehensive review of this subject which won’t be published until May, looking at a couple of hundred references which is evidence-based. The other issue that is hovering especially in the United States, is the liability issue because there is a perception that testosterone will cause prostate cancer and we are all trying to dispel this by lectures and talks we are doing but this takes time. I think there are multiple issues here as to why people haven’t thought about it or haven’t put the two together. We’re preaching to the choir here, hopefully, if the choir goes home and teaches their physicians and their local groups about this, we will disseminate this, but this will take another decade, I think.
Copyright © 2006 ISSAM