Real world experience with Tadalafil in aging patients with erectile dysfunction (ED)

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Jacques Buvat, MD with G. Bou-Jadoué¹, M-H. Colson², A. Lemaire¹; ¹Cetparp, Lille, France; ²Marseille, Marseille, France

I have a presentation that will be much more clinical than the previous one. In a field which is very difficult to describe because nothing is clear, we have very few substitutes, very few well-designed studies. As an introduction I would like to remind you of some basic knowledge that we have accumulated concerning the effects, of the physiological effects, of testosterone and sexual function in men. Following several double-blind, placebo-controlled studies in hypogonadal men, which were performed 10 or 15 years ago, sexual desire and arousal, are clearly testosterone dependent, that is, the main effect of testosterone on sexual activity in men. Spontaneous erections, I mean nocturnal and morning erections, are also clearly testosterone dependent. So psychic erections have been thought for some time to be testosterone independent, but in fact, they are also partly testosterone dependent and orgasm and ejaculation are only partly testosterone dependent.

An interesting issue is how much testosterone is needed for a normal sexual function? 

And you know that this has been much debated and I would like to remind you of a very old study by Salminies that you see here, which seems to indicate that the minimal level for a complete effect of testosterone upon sexual function, varies according to individual sensitivity. You will see that in these studies they treated 15 patients with hypogonadism with different dosages of testosterone, or placebo, according to the double-blind design and seven patients have the testosterone level of below 2 ng/ml, and all seven patients had impaired sexual function, and all responded to treatment in the dose related manner, with an increase in sexual desire, increase in the number of erections and increase in the number of ejaculations. And the eight other patients with testosterone between 2 and 4.5 ng/ml, half of these patients followed an impaired sexual function quite similar to that of the preceding patients, and responded to treatment in a dose related manner. But those four other patients with the same testosterone level had an amazingly high frequency of erections and ejaculations. They didn’t note any change occurring after treatment. That could be interpreted like there is a threshold under which sexual function is always routine only to be about 2 ng/ml for sexual activity. More studies are supporting this idea. 

There would be a threshold above which sexual function would be always optimal and non, or little, stimulated by increasing the level of testosterone. It would be the lower limit of the normal range of the young male, that is to say about 4 ng/ml. Between them there would be a range within which sexual function may be, or may not be, optimal according to the patient, according to the individual sensitivity of the hypothalamic centre to testosterone. In this model I could explain a lot of conflicting observation which have been met in the hypogonadal men.

Is there a role of testosterone in the maintenance of sexual function at all ages in humans? 

So, in fact, we have very little objectives that are in this field. You see here also studies are being reported of correlations of the testosterone with sexual function in all ages. You see that no one study has reported significant correlation with total testosterone. But an old study by Davidson has reported correlation relationship, with significant relationship between free testosterone and sexual sorts, morning erections, and sexual activity in aging males, and three more recent studies have reported significant relationships of free testosterone or bioavailable testosterone with the front parameters for the international index of erectile function and especially the erectile function of the orgasmic function domain.

But I would also like to remind you of this old study by Schiavi which is in my opinion one of the best studies ever done on the relationship between testosterone and sexual function at old age. You will see that 77 healthy men were recorded for four nights for response of their nocturnal erections, and for one night recording their serum hormones every 20 minutes. They found there is no original or significant inverse correlation between age and desire, arousal, sexual activity and the nocturnal erections. On the other hand bioavailable testosterone, but again, not total testosterone, they also found it was more interesting the significant correlation between bioavailable testosterone and desire, arousal and nocturnal erection, which could suggest there was a role of bioavailable testosterone on this function. But, in fact, most of the correlation with bioavailable testosterone disappeared after adjustment for age. I have never seen another study for adjustment of the data for age, and I am almost sure that in those three preceding studies with correlation within the international index of erectile function, the significance would have disappeared by adjusting the data for age.

So now, what is the place of hypogonadism in erectile dysfunction? 

In fact you have here the prevalence of low serum testosterone values in the men with erectile dysfunction. You will see a literature review I have done with the ten most important series and you will see that the lower limit of the normal range was, according to the studies, 2 or 3 ng/ml. The sad thing, in more than 4,000 patients you have an overall prevalence of 7.8%. You can see in the personal studies in more than 1,000 patients that in fact this prevalence is clearly different in the younger patients, less than 50 years old, it is only 4% if you take the limit of 3 ng/ml. In the elder patients you have here, the patients that are more than 50 years old and this time it is almost 20%, it is 19%.

What are the effects of testosterone in those patients who are referred for erectile dysfunction, and who are subsequently found hypogonadic? These patients are quite different from the patients who have been studied in previous studies of young hypogonadal males diagnosed at the time of puberty. You can, in fact, see further that there are no control studies in the literature, and I have been obliged to compare this eight observational studies but you can see that with a total number of more than 250 patients, the results are extremely disappointing. Even if you have some studies where you see a success rate of 61%, but it is rather unusual. You can see that in fact, if you consider only the patient definitely impose, that is to say the patients who are telling you, “Oh doctor, it’s good. I don’t need anything else in addition to the testosterone therapy”, it is only 36% of the patients who are such fully satisfied with testosterone therapy. 

You have here in an illustration in a very recent study by Mulhall in the last issue of Urology. You see here in 32 hypogonadal men referred for erectile dysfunction, you have the erectile function domain, and you can see that following different types of testosterone therapy, there was after one month a significant increase in the score of the erectile function domain. But subsequently following that, there was a decline the therapy effect, and that from month three and also at month six, there was no more such significant difference with respect to baseline. But you may also see in this panel another effect of testosterone therapy, very important and very often neglected, and especially in our patients it is as a beneficial effect on libido. You see that this time there was a significant improvement in the sexual desire of men at one month, there was again some decline at three months and six months, but finally, the effect was still significant at three and six months on the libido. 

Here you have some personal data showing you that we have with a higher number of patients, who again were referred for erectile dysfunction, and were subsequently found with low testosterone level, total testosterone of less than 3 ng/ml, of 18 patients, all year low bioavailable testosterone levels were less than .75, ng/ml. Here you are at baseline, and here you have on testosterone therapy, it is not a control study. You see that there is some increase, and that at three months it is still significant in our experience but you have to realise that the significant increase in the erectile function domain doesn’t mean clinical significance. I have some patients who are fully satisfied with testosterone therapy. But many of them tell you, “Oh, there is some improvement in my erection but clearly I am not satisfied, it hasn’t been sufficient.” You see that it is in many ways that the effect of testosterone in these types of patients is clearly lower than the effects that you can have in those patients this time with no more testosterone level with PDE-5 inhibitors. You see here for example, the effect of Tadalafil and you see clearly the effect is closer to the normal range.

And so finally, when testosterone therapy fails, we are led to prescribe to our patients, PDE-5 inhibitors and very often it is working. You have as demonstrated in this study the reason by Chen you’ll see 48 patients referred for erectile dysfunction subsequently found with hypogonadism. They were treated with AndroGel therapy alone, and this was normalising their erectile function domain score in 64%, which is a rather high success rate, and rather unusual in this field. But in the other 16, 17 or so patients, having failed on AndroGel alone, they combined tadalafil and this time the erectile function domain score was normalised in every case.

All this data, and all this evidence, of rather disappointing, rather poor efficacy of testosterone alone, may lead you to suggest that, in fact, in many cases a low serum testosterone levels that you find in an ED patient may not be the real cause, or at least the only cause, of this erectile dysfunction. First you have to think of the lability of the serum testosterone, and if you find a low level you have to repeat the test. Because, in my experience, in 40% of the cases, the second test will be normal. Obviously in many cases low testosterone levels is only one of the many consequences of aging in a multi-factor ED. Especially it is very often associated with abnormalities of the penile research, and in all studies we have found in 40% of our impotent males with hypogonadism, or at least with endothelial dysfunction.

Finally, it could also be a consequence of erectile dysfunction rather than its cause. And you have here a perfect illustration in this study by Jannini in Italy, and you see that they have determined to total testosterone, and free testosterone, in normal controls and in ED patients there were age matching of the two groups. You see that they found significantly the mean level of the total and free testosterone was significantly decreased in those patients with erectile dysfunction. Following that they treated their patients with non-hormonal therapies, that is to say psycho or sex therapy, and trichromosine injections, and they have classified their patients in three categories according to their spontaneous erection, partial or full recovery. You can see that when there was recovery of erections and satisfaction of the patient, there was a significant increase in testosterone. They regained the testosterone following treatment. And that even in the group of patients with full recovery of the erection, you have in fact, normalisation of the testosterone levels, you have exactly the same level as in the normal control men. Clearly in this series, the low testosterone level was not the cause of erectile dysfunction, it was more the consequence.

What could be the mechanisms? The mechanisms could first be a reduced sexual activity because it has been shown that sexual activity stimulates testosterone secretion. It could also be stressful depression, which inhibits gonadotropic centres at the level of the hypothalamus, and that is also illustrated by another study of the group of Jannini in Italy.

You see here that they have replicated their initial study, and this time they have determined not only testosterone but also LH. And not only the immunoactive LH that you are regularly determining, but the bio-active LH. Here you see the ED patients and here  you have the normal control study, which were matched for LH. You see that the immunoactive LH was significantly in place in the ED patients, the bioactive LH significantly reduced, and so the ratio of the bioactive to immunoactive LH was reduced.

The facts in the individuals of non-hormonal treatment, so for erectile dysfunctions psycho-therapy and trichromosine injections, vacuum therapy. And again, here you are the patients with the normalisation of their erections, full satisfaction with their erectile function following treatment. Again you have an increase, a significant increase in this sub-group of the ratio of the bioactive to immunoactive ratio and I have not time enough to discuss all these things, but the hypothesis is that the mechanism would be the same as in hypothalamic amenorrhoea in women. That is to say, that stress could be able to reduce the GnRH pulse frequency. You know that the GnRH pulse frequency is modulating the bioactivity of LH, and in that case if you relieve the stress because of improvement of sexual function, you can improve the activity of the GnRH progenitor. You could improve the bioactivity of LH, and of course you could improve the testosterone secretion.

So now we’ve solved these conflicting results and all these poor results. You may wonder why it is the Endocrine Committee in the very recent Second International Consultation on Erectile Dysfunction last July in Paris concluded that testosterone determination is requested in most patients referring for erectile dysfunction? Is it not really useful to screen for testosterone deficiency? Why not prescribe directly a PDE-5 inhibitor? In fact, there are four reasons to still prescribe the serum determination; first the testosterone deficiency in your patient would be one of the very last chances to restore spontaneous erection, that is to say to save him from planning sexual activity, which is the case with all the PDE-5 inhibitors. I agree with tadalafil it is less demanding, it is more convenient, but you have also to plan your sexual activity even if it is two days before. Again, it is the only chance testosterone therapy of restoring sexual desire. What would be the interest of restoring the erection in a patient not interested in using them? It may also help improving other aspects of Androgen Deficiency of the Aging Male. And also probably in some thin patients you are prescribing testosterone therapy,  they come back  tell you, “Oh doctor, the erections are the same, you have not improved them, but I would like to continue your treatment, your testosterone serum therapy because I feel so well! I am more dynamic, less tired, I am less anxious.” And finally, because as you are going to see, minimal testosterone levels might be required for a full efficacy of PDE-5 inhibitors. 

This hypothesis has been suggested for a long time but there was a paucity of objective data, and the hypogonadal patients that have been excluded from most clinical trials, and it is only in this last year that we have some more data available in humans. I am not speaking even if we have very few well designed studies. There are three recent and controlled studies supporting more or less the beneficial effect of testosterone supplementation in non-responders to PDE-5 inhibition with low testosterone levels. 

This study presented at the last University of Michigan meeting in Chicago by Rosenthal. Eighty ED patients, non-responders to 100 mg Sildenafil. Twenty-four, that is to say 30% at the testosterone level of less than 4 ng/ml. That is to say low, or low-normal. They were treated with a combination of testosterone shell with Sildenafil and this combination improved potency in 92% of these patients. This study by Kalinchenko in the recent issue of The Aging Male, 120 diabetic ED patients were resistant, non-responders to 100 mg Sildenafil. Their mean testosterone level was significantly lower than that of a population of diabetic patients, this time responders to Sildenafil. They were this time supplemented with testosterone and Andriol. They also reported a marked improvement in erections in the sensitivity to Sildenafil in 70% of the patients. The last one has been presented in Istanbul recently and also in this meeting by Yassin 69 men, this type non-responders to taladafil, and you see that they reported that 52% were improved by the combination with different types of testosterone therapies. What was original and interesting in their study was that they separated their patients into two sub-populations. One was treated for four weeks with testosterone before starting again taladafil, and you see that the success rate was 40% who have regained sensitivity to taladafil, and the other support population did the same for 10 weeks before reintroducing taladafil. This time the success rate was 65% and that would suggest that the longer period of impregnation with the embochin could result in a better result. But in fact, all these three studies are uncontrolled. They are interesting but they have to be confirmed. There are only two controlled studies recently, one I am going to present, the first one by Aversa and one will be presented by Dr. Ridwan Shabsigh in his talk and clearly is the best study presently in literature.

Previously Aversa reported that in ED patients he found a significant relationship of free-testosterone levels with resistance as assessed with arteriogenisis in the penile arteries, and you will see that in the 20 patients with arterial genital erectile dysfunction, the total testosterone, and free testosterone level in the lower quartiles normal range, they were non-responders to six trials of sildenafil, dosage of 100 mg and they were randomised to either transdermal testosterone with patches, or placebo patches, according to a double-blind design for one month plus sildenafil and they underwent colour duplex ultrasound of the penile arteries.

You see here the emonadate data. You see here, in fact, the endocrine data, you see a total testosterone and free testosterone, which was increased only in the group receiving the testosterone patches. You see that it is in this same group that you have a significant increase in peak systolic velocity measured with Doppler ultrasound. Following dosing with sildenafil, and also a significant difference in the resistance index. They concluded that there was thus an increase in the arterial inflow to the cavernosa bodies following the use of sildenafil in those patients supplemented with testosterone. 

You have here the IIEF data you can see that it is only in the group sildenafil plus supplementation with testosterone, that there was a significant increase in erectile function domain score, the intercourse satisfaction score, and the overall satisfaction of the patient. Also there was a global assessment question, and the response was positive that is to say “my erections have been improved with this treatment” in only one of ten patients on placebo, and in eight of ten patients on testosterone and the difference was significant. What you see clearly that the impact of this study is limited by the fact of the number of patients which was very small, only 20 patients and only 10 patients on testosterone.

And here are my conclusions about the responsibility of hypogonadism in men referred for erectile dysfunction. Hypogonadism concerns less than 10% of them but, in fact, more after the age of 50 years, about 20%, and more if you are determining the bioavailable functions of testosterone. Hypogonadism is rarely the main cause of erectile dysfunction, with which it is associated. In some cases, or many cases, it could even be a consequence of erectile dysfunction. Erections are definitely improved by testosterone replacement in less than 50% of the patients with hypogonadism, in cases of testosterone therapy alone, due probably to the frequent association of predominant vascular or endothelial factor. But significant other benefits may be expected on the libido and on other symptoms of testosterone deficiency. And lastly, if you are thin as you will see again with the talk of Dr. Shabsigh, testosterone therapy might salvage failures of PDE-5 inhibitors, suggesting the possibility that there is also peripheral action of testosterone in men as it has just been reported by Dr. Traish.

Thank you for your attention.