Sponsored by an educational grant from Solvay
So my talk is TRT and sexual dysfunction.
I have divided the talk into different parts. One is the prevalence of hypogonadism patient with sexual dysfunction and the other one is effect of hypogonadism treatment and sexual dysfunction.
According to the previous talk and based on biochemical evidence, if the measured testosterone is above 12nom/dl or 350ng/dl, we are invited to not do testosterone substitution. If the testosterone level is below 8nom/dl or 230ng/dl, we invite you to do testosterone substitution, but if the testosterone blood level is between 8 and 12nom/dl for testosterone substitution, we have to consider the clinical picture of LOH.
Which is the clinical picture of LOH? We have already learned that there are several symptoms but the easiest symptoms that seem to be recognized are those some way linked to sexual dysfunction, which are sexual desire, erectile quality and frequency and particularly nocturnal erection.
So I would like to present some of our data that has been obtained in the public outpatient clinic for sexual dysfunction on the Association of Hypogonadism and Clinical Symptoms.
The instrument we employed is the structured interview called S.E.I.D.Y., which is a multi-dimension instrument for quantification of pathogenetic issue on erectile dysfunction. Based on this instrument, we can obtain scores on the organic domain of erectile dysfunction on the marital or relational domain and on the intrapsychic domain and I would like to show the association with all hormonal parameters.
In a population with a clinical picture of hypogonadism having sexual dysfunction, you can see in this slide the well-known relationship between total testosterone and age. If you consider a patient with testosterone blood level below 8nM or 230ng, one over 20 of your patients has overt LOH. If you consider patients with testosterone blood level below 12nM or 350ng, one over four of your patients will have hypogonadism. So in patients with sexual dysfunction, the diagnoses of LOH is quite often performed.
Let me show which are the clinical association of LOH in patient with sexual dysfunction. I will show these as relative risk to develop hypogonadism in a log scale. Higher the risk will be more distance will be the point from the one that is no statistically significant risk. In other words, I will show you in few minutes the likelihood to have testosterone below 12nM. At general anamnesis, it was statistically significant: advanced age, delay of puberty, the history of cryptorchidism and the history of pituitary diseases, as obvious. At sexual anamnesis, it was statistically significant: severe loss of erection, a decrease in nocturnal erection, a decrease in the volume of ejaculate, guiltiness with masturbation, decreased sex frequency and decreased libido. At physical examination, it was statistically significant: a decreased testis volume and an increase in waist more than 102 cm and please note that weight triplicates the risk to develop hypogonadism.
Now move to the relationship between various degrees of loss of sexual desire that is hypoactive sexual desire, and circulating total testosterone, in this large series of patients, i.e. almost 2,000 patients. As you can see, there is a statistically significant correlation with a low hypoactive sexual desire.
But testosterone is not the only determinant of sexual desire in humans and these are the items that are statistically significant in this larger series of patients. You can see testosterone inside the red circle. You can see that the relational factor as loss of partner libido, partner’s diseases, a longer relationship, conflicted couple relationship, conflict at home are as significant as testosterone. In addition, you have to consider the use of medication as serotoninergic drug and anti-dopaminergic drug for loss of sexual desire and in case of prolactin, that is more important than testosterone and depression and, in addition, the sex frequency, that is invariably related to sexual desire.
Coming to the relationship between testosterone and penile erection, we didn’t find any statistical significant association between a history of partial erection of any degree and total testosterone and we found just a mild statistical significant association between testosterone and the severe absence of erection.
The picture is totally different when we consider nocturnal erection. Now we can find a very high statistically significant relationship with testosterone and also with free testosterone.
So coming to the second part of my talk is the fact of hypogonadism treatment and sexual dysfunction.
So this one is one of the more important papers that have been produced during the last year and been published in JCEM from Christina Wang. In this paper it was considered 123 hypogonadal subjects that have been testosterone below 10.4nM, that is 300 ng/dl. All these patients had been treated for three years with a variable dose of AndroGel® and the sexual parameters have been considered using self-reported questionnaires and changes in this result were more evident in the youngest population. Which are the changes? An increase in sexual desire with testosterone replacement, increase in sexual activity, satisfaction with erection and other areas.
This concept is still more strengthened by the result recently published by the Andrea Fabbri - Andrea Lenzit group in Clinical Endocrinology with meta-analysis of 17 intervention studies collected during the last 30 years. These are randomised, placebo-controlled trials in patient with hypogonadism, testosterone below 10nM, they found that there was a statistical significant improvement in several domains of erection and libido.
But considering the libido and erection there are different results. If you look at patients with overt hypogonadism and testosterone below 7nM, the advantage for libido and erection is quite clear.
In patient with mild hypogonadism, testosterone between 7 and 12nM, still the gain to treat the patient is evident.
But in patients with no hypogonadism, that means testosterone higher than 12nM, there is no evidence at all for any statistically significant improvement from this meta-analysis to treat patients with sexual dysfunction.
Another important result from the Fabbri group have been provided in Clinical Endocrinology three years ago show that in 20 patients who were resistant to sildenafil and mild hypogonadism, the average testosterone was around 13nM treated with testosterone by patches, they can increase the IIEF score and also they can increase the systolic velocity at PDU. So that message from this paper was that treating hypogonadism restores responsiveness to sildenafil.
This message was further strengthened by another study published two years ago in Journal of Urology; this was a multi-centre, placebo-controlled randomised study on 70 patients, again who were resistant to sildenafil with blood testosterone below 14nM with normal low testosterone. In this group of patients, Dr. Shabsigh showed that at some point of the study but not at all, there was statistically significant increase in total IIEF score and other erection parameters, but more important they show that all the signs point to the orgasmic function was improved by testosterone replacement. So again, the message is treating hypogonadism, restore responsiveness to PDE-5 inhibitors orgasm function.
There are two more papers recently appeared in the literature one on Journal of Sexual Medicine, the other Journal of Impotence Research, saying more or less the same message. Treating hypogonadism restores responsiveness to PDE-5 inhibitors.
So which patients with sexual dysfunction are treatable for testosterone replacement therapy? The answer is easy. The hypogonadal patient. That is it. And in hypogonadism, so a patient with testosterone below 12nM, testosterone has positive effect on erection and libido. Testosterone associates more with spontaneous than sex-related erections, that is more with nocturnal erection than to sex-related erection. Testosterone is associated with libido but weakly and you have should consider also other factors and finally testosterone restores PDE-5 inhibitor responsiveness but more studies are needed.
Finally I have to acknowledge my collaborators, in particular Giovanni Corona who is in the audience. Thank you.
Eberhardt Nieschlag: But there is a case, an educational case and I would like to ask Dr. Morales to present it.
Dr. Morales: The case here is a 54-year-old man who presents with a progressive problem with erectile dysfunction. He reports a decrease in sexual desire, he feels tired most of the time and his wife reports that he is very irritable. This has been going on for about two years. The environment at home and at work they are quite stable. The physical examination was really not very contributory; the BMI was 23 kg/m2, the rectal examination was negative. He has an initial investigation with the biochemistry demonstrated a PSA of 0.5, which is pretty good for his age. The testosterone was borderline within the normal limits but borderline. His gonadotropins were slightly elevated and the depression, the presence of depression, were ruled out.
The next step is, please choose one. Number one is further hormonal assessment for instance repeat the serum testosterone, bio-available T or calculated free, prolactin, TSH, we have not heard anything about TSH. What about testosterone supplementation, would that be your next step? Will you consider giving him activity PDE-5 inhibitor or you will say, no, I will give him both? A PDE-5 inhibitor, as well as testosterone supplementation.
Well, the vast majority of people feel there should be an additional investigation. Testosterone supplementation got a very low rank and Dr. Maggi, could you just make a quick comment. How do you feel about these answers? What would be your approach?
Dr. Maggi: I think that is quite reasonable because as we have
learned before, just with total testosterone, we cannot make the diagnosis of
this gray-zone of hypogonadism that is between 8 and 12nM and this will be something
like around 300 ng/dl and you should consider also other factors, so you should
confirm with the bio-available testosterone and you should consider the possibility
that there are other factors as I showed before, prolactin levels, which are
very important although hyperprolactinaemia is quite an unusual finding in our
clinic. It is less than 1%, but this is very important determinant to sexual
desire and as you mentioned before, TSH is also important but the association
of hypothyroidism with loss of sexual desire is very mild but is statistically
significant.
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