Johan Svartberg, MD, PhD, T. Hugh Jones, MD, MB, ChB, BSc, MRCP, FRCP, Andrea Fabbri, MD, PhD and Stefan Arver, MD, PhD
view presentationAudience question: I have a question for Dr. Arver, when you were starting your study were you expecting a decrease to change the cholesterol levels?
Dr. Arver: In the intervention study, if we expected a decrease in cholesterol; well, this has been shown in a number of studies that in healthy men, men without the metabolic syndrome, with (inaudible) and in men with the metabolic syndrome, who are treated with, or who are achieving normalisation of testosterone, in general have small changes in their lipoprotein profile, with lowering of total cholesterol levels and lowering of LDL level as well as to some part HDL levels. There is a very well documented positive correlation between circulating testosterone levels and HDL levels. Whether you look at random samples, of men in the public, or you look at men who are under treatment with testosterone you still have positive correlations, so the more testosterone, the higher HDL levels.
Audience question: But my question is if you were to start over this study again, do you think that you are going to start with higher dosage?
Dr. Arver: Yes, I think one of the reasons why our study did not show any significance in that terms, is probably in the light of what other studies have suggested that we did not reach the threshold. So the planned studies for the future will aim at higher testosterone levels, yes.
Audience question: Traditionally we are told that steroids in general and testosterone in particular would have adverse affect on liver functions and may be hepatotoxic. It was a nice observation to know that hepatic steatosis actually reduces. The transaminase changes would look at favourably in certain patients as the study has recently shown. Now is there a method of, normally whenever we are trying to prescribe testosterone we are getting a liver function test, and if there are deranged liver enzymes we withhold, and do not prescribe testosterone. You have shown a study where even with deranged transaminases, you have given testosterone, and it does help. Is there a proper guideline as to how much the range should be the serum enzymes where you can expect a reversal of steatosis? Or would it be converse? Is there a way to predict?
Dr. Arver: There are two different sets of studies that have demonstrated in terms of endocrine addresses to the liver steatosis. One of the approaches has been to decrease corticosteroid production, and that has been done in a fairly crude way with ketoconazole. Ketoconazole is known to have liver toxic effect in a small proportion of patients. However, in giving the ketoconazole therapy to men and women with type II diabetes has shown a significant decrease in liver enzyme levels. In one small study performed in Gothenburg a few years ago, they also demonstrated an increased liver attenuation with CT verified. I don’t think the data are there to set out any guidelines, these are observations pointing to a mechanism of significance, but it is not at all demonstrated or verified in large numbers of subjects to get any sort of suggestions.
But, on the other hand, testosterone therapy as viewed as a liver toxicant and I think that we can conclude that it has no side effects on the liver; it has been verified in large number of well-controlled, longitudinal studies.
Audience question: I have two questions, one for Dr. Jones and one for Dr. Fabbri. The first question, your group shows two different studies about the effect of testosterone TNF Alpha. The first study is one by Malkin, and by one month it showed a significant reduction, a decrease of TNF Alpha for testosterone treatment for one month. There was another study published in 2005 in which testosterone demonstration for three months didn’t show any effect of testosterone TNF Alpha.
Audience question: The second question is for Dr. Fabbri, what do you think about the role of TS sex hormone, binding globally now, in metabolic syndrome? Many studies both cross-sectional and longitudinal study show that the SHBG has more effect on the metabolic syndrome, just more strongly associated with metabolic syndrome than testosterone. And also, our studies and Chianti’s study we found the same relationship between sex hormone bonding globally and metabolic syndrome according to ATP3 criteria, but their lower effect of total testosterone on metabolic syndrome, while bio-available testosterone and free testosterone were not associated with metabolic syndrome. This is just the two questions, thank you.
Dr. Jones: I think the answer to the first question is that the study that we did on hypogonadal men, a large proportion of them had coronary heart disease, and they probably had higher inflammatory levels. So you are going from a higher level to reduce them with testosterone, as opposed to the other studies. I think it is the clinical state that may have led to the differences, I do not know. That is all I can suppose.
Dr. Fabbri: That is a good question about the association between low SHBG and risk of metabolic syndrome. From the slides that I presented it was also clear that there was a close, very strong association between low SHBG and risk of metabolic syndrome. And this is possibly due to the fact that in these subjects there is an increase in insulin resistance, higher insulin levels, and insulin is an inhibitor of SHBG production. So the association between low SHBG and risk of metabolic syndrome is SHBG is just a phenomenon of increased insulin.
One slide that I wanted to stress is what we found regarding leptin inhibition of testosterone, or a cessation between higher depositing and lower testosterone. Also when we corrected for SHBG the effect was present. So, this is another fact.
Audience statement: Yes, thank you. I just asked this one because most of these studies, after adjusting for insulin levels, the fact of SHBG stays. This is one possible answer but the link between SHBG and metabolic syndrome is not particularly clear, which is why I asked this particular question, thank you.
Audience question: Question for Dr. Allan, androgens increase are anabolic, and oestrogen is perhaps just a fat anabolic and lean catabolic. But methodological question is, to what extent is the apparent increase in muscle simply water retention, because the only true measure of anabolism is whole body potassium, whole body nitrogen and strength. The messages we use in clinical practice largely depend on total body increase or change, which is water and body water, for example by BIA or DEXA scan.
Dr. Allan: We have in fact looked at that data in the study that we did in our aging men. We have done very detailed body compositions studies, including in-vivo neutron analysis studies, and we are still looking at that data. So, I am afraid I don’t have the answer to your question right now. But we have addressed that question to see if we can look at whether or not it is an increase in total body nitrogen or protein. I can tell you the preliminary look at the data suggests that it isn’t an increase in total body nitrogen, but I can’t at this point give you any clearer answer to that, but we do have the data in and we are analysing it.
Audience question: Hello? Yes, my question is for Dr. Fabbri too. You told us that the leptin receptor in Leydig cells. In the women there is insulin receptor described in the ovary, which behaves sensitively to insulin instead of resistance in the other parts of the body. Do you have any data about insulin receptor in the testes and how they behave?
Dr. Fabbri: There are receptors for IGF-1 that is present in Leydig cells. IGF-1 (inaudible) insulin could act through this kind of receptor. But the leptin effect is more prominent than that of insulin because we have a reduction of testosterone even if in the presence of insulin resistance.
Regarding the female part, this is completely opposite because their androgens are doing the opposite way. So it is a model that is not comparable to what is going on in males.
Audience question: When you teach at the medical school how do you define in one phrase, what is hypogonadic man?
Dr. Allan: I can answer that quite easily. Being in Australia we actually have a set definition…I hear with interest that in fact some countries also have guidelines. To the best of my knowledge we are the only country that actually have guidelines that define our prescribing, and these were proposed by the Endocrine Society of Australia in 2000 and have been adopted by our pharmaceutical benefits scheme, which subsidizes prescribing of medication. So if you have a known testicular or pituitary pathology, you are eligible for treatment, irrespective of your baseline testosterone. Because of course, bear in mind that some men with Klinefelter’s Syndrome will still maintain serum testosterone levels of 8 and even in our case, sometimes 10 to 12 nanomolar. However, if you are a male over the age of 40, you need to have two morning total testosterone samples, two, separate days, of less than 8 nanomolar, or a testosterone level of between 8 and 15 nanomolar and an increase in your LH level of 1.5 times the normal range. The data of course remained relative to Australia having just been published showing the problem with assay platforms. It would very much depend of course on where you sent your serum testosterone level. A level that read 8 in lab may read 12 in another, and we have yet to come to terms with that. And indeed the people that participated in the andrology Australia study were also those people who proposed the guidelines and I think they are about to come under review.
Audience statement: Oh, thank you very much.
L. J. G. Gooren: No more questions? Then I thank the speakers for their contributions.
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