Discussion

Veldhuis: This brings us well into the androgen discussion in ageing at the level of the target tissue. John Morley, I thought it would be good to give you the chance to comment.

Morley: What always amazes me is that David Handelsman and I agree on the conclusions, but for totally different reasons. Of the available data, I don't believe Snyder's study (Snyder et al 1999) was very rigorous for a variety of reasons. One was the addition of Ca2+ and vitamin D willy-nilly in a group who were chosen to be osteoporotic. This can affect muscle strength among other things. That alone questions that study. The other problem is that many of the men were not hypogonadal: as David Handelsman says (and I agree), the data suggest that you should treat hypogonadal males, not non-hypogonadal males who have drifted down into the normal range. I think that the strong data that we are about to see come from the unpublished study by Tenover. This study shows an improvement in strength as well as improvement in bone mineral density. Similar unpublished data are coming from the Baltimore group for upper limb strength. I think that the improvement of upper limb strength with testosterone may well be real in hypogonadal males. Bebb's data look very similar, but he is also going to take a while to publish. The Kenny paper is in press, and shows clear bone effects without Ca2+ and vitamin D addition in patients who were more hypogonadal than Snyder's. In a very small group, she found lower and upper limb strength increased, but not quite to a significant level. If you put these unpublished studies together with the other published data, you can conclude that testosterone most probably has beneficial effects, but it is in people who are hypogonadal. This does not mean that every single man should get testosterone supplementation. The other unanswered question — which I think is the big one — is whether high, almost pharmacological doses are needed to produce effects, or whether lower doses, such as those delivered by patch techniques, are sufficient. We have a long way to go; we clearly need long, well-controlled trials. We also need to know who we are entering into these trials. I know some of these are in development, but so far I'm not aware of any funding agency that has been prepared to study the 3000— 4000 men needed, equivalent to the women's health studies, to really answer these questions. Until we have these, we should treat men who are clearly hypogonadal, no matter what their age, and there will be a good outcome. There are three controlled trials that David didn't mention. Two of these are from Portland (Janowsky et al 1994, 2000) and there is another one from Matsumoto and Bremner's group (Cherrier et al 2001), all showing very positive effects on cognition. In fact, if you were to choose one thing that testosterone really seems to help for the majority of middle-aged to elderly men, it is cognitive function.

Handelsman: Both of our studies have a variety of cognitive measures. We also had gait, mobility and cognitive tests and quality of life measures: none were significantly improved. In particular, in the human chorionic gonadotropin (hCG) study we also had actigraphy measures for spontaneous physical activity as well as insulin clamps in 40 men before and after treatment. There was no significant change.

Veldhuis: And do you agree that the data are sparse on the route and dose-dependency of androgen repletion?

Handelsman: The data are sparse altogether. There is just one other comment I'd like to add putting the Snyder study in perspective, he got less than 100 patients out of screening 1000. You have to keep this high degree of selectivity in mind. This is with a testosterone level of <16nM. If you insist on subjects being really hypogonadal (i.e. < 10 nM), you will have 1 in 1000. This would be a very small subpopulation.

Morley: That is not necessarily true. He also acquired people who were osteopaenic to some extent. They had to have a lower bone mineral density. He had a number of other exclusion criteria. If you take the Massachusetts male ageing study, this does not fit at all with what the population numbers are. It is not what we found in California, and it is not what has been found by other people in other areas.

Handelsman: In our study we also recruited about 10%. The main reason for rejection was baseline testosterone concentrations.

Veldhuis: This permeates the area until we get a broad prospective open study. It makes the final results very subgroup dependent.

Burger: How does one define hypogonadism in the male who is said to be in the andropause? What are the criteria, and what range of testosterone concentrations are we to use? Is the young normal range the appropriate one or should we be working from a different one? These are crucial issues in this debate.

Veldhuis: Let me try to simplify this, does anyone have the nerve to give a number?

Handelsman: The Endocrine Society of Australia was bold enough to make a stab at this, and came up with a figure of 8 nM, independent of age (Conway et al 2000). Above this testosterone concentration, the diagnosis in absence of underlying pituitary or testis pathology was regarded as unequivocal.

Morley: The bioavailable testosterone or free testosterone index may be better. We use the bioavailable level of 70 ng/dl, which is about 3 nM. This is one of the choices.

Veldhuis: Is that independent of age? We would consider that level profoundly low in a young man.

Morley: In our lab, that is two standard deviations below the mean. We see no young men below 3 nM.

Wang: We have lots of debate in the USA about the cut-off level of testosterone to define the andropause. If serum testosterone levels are below 250 ng/dl, the men are hypogonadal and should be treated. The problem is when the levels are between 250 and 300. Unless we have large studies that can show that the benefit is outweighing the risk, we are hesitant to proceed.

Shalet: Is it possible to build a gonadotropin component into these definitions? What about raised LH?

Veldhuis: In the allostatic state that we learned about this morning, if the LH is elevated, you could argue that this is a physiological marker as an elevated thyroid stimulating hormone (TSH) is in early thyroid failure.

Laron: I think that is a wrong terminology. We measure male hypogonadism by millilitre volume of the testes. This shouldn't be confused with the quantitative secretion of androgens. They involve different cells.

Veldhuis: We heard that these volumes are pretty stable.

Morley: You could use andropause to get around this.

Veldhuis: I would argue that this is an age-dependent population-sensitive measure. It is assay dependent; you can't come up with a single number. I am with Henry Burger: we have to develop norms that are pertinent for the patient in question who is being compared. If the patient is a 78 year old individual, that clearly represents a potential population base that is readily distinguishable under usual health definitions for all body systems. Their glomerular filtration rate, lung diffusion capacity and bone mineral density are all reduced. If you are going to say whether a person has a disease, beyond the fact that they have survived to age 78, you have to show me other 78 year olds who are not complaining. He is entitled to complain, but I may not attribute the complaint to that level solely if I find it matches those of all other men of similar age and disposition who are not complaining.

Riggs: Just to take the position of devil's advocate, we have struggled in the bone field about whether t scores or z scores are more important. In other words, should the normal range be that of young adults, or should it be age adjusted? We have come down strongly on the side of the former, because there is a critical value for bone density below which there is a marked increase in fracture risk, regardless of age.

Veldhuis: We don't have the targeted end point to tell us. I haven't heard this acknowledged. We need the dose-dependent target for different end points. They are not necessarily the same for osteopaenia as for muscle weakness and for decreased cognition.

Handelsman: If you are thinking about growth hormone studies in ageing, the advantage is that dose can be titrated with insulin-like growth factor (IGF)1 as an independent end-point. We don't have any equivalent form of titration with testosterone, which is a serious limitation. It is quite likely that the thresholds and/or sensitivity are different for different tissues. The sensitivity may not be the same for different age groups and populations.

Veldhuis: Absolutely. We have heard innuendos that the cognitive end-points might be more responsive, but this remains to be proven. It's an exciting issue. We picked muscle gene expression because Randy Urban in Texas showed increased IGF1 mRNA by two- to threefold in three weeks by titrated androgen replacement in six men.

Ruiz-Torres: We are interested in the question of why prostrate volume is so closely related to age, despite the fact that testosterone secretion declines. We thought that this could be due to an increased number of androgen receptors of the epithelium cells. However, we have found that the cytosolic receptors are increased, but the nuclear receptors do not show any change. One possible explanation is that the transfer from the nucleus to the cytoplasm is altered by ageing. In any case, it seems that androgens are not the cause of hypertrophic prostrate. Nevertheless, the benign prostatic hyperplasia (BPH) is mainly due to an increase in smooth muscle cells where testosterone could play a role as an anabolic effector. But normally in ageing the testosterone levels are low, so that this possibility concerns the treatment with androgens only.

Handelsman: It takes quite a bit of looking into what BPH and prostate growth with age means. BPH is actually nodular growth: I have always thought of this disease process as very much like fibroids. It doesn't necessarily occur smoothly, even though there is that famous study which suggests that there is a small rise (Berry et al 1984). In fact, it probably occurs in punctated bursts of growth, just like fibroids. The changes in the central zone are much more marked than those that occur in the total prostate volume: we can see changes earlier and more prominently in the central zones. The fact is that with dihydrotestosterone (DHT) treatment, we didn't see any prostrate growth. My explanation for this is that using DHT you don't get any intraprostrate amplification ofandrogen action. Thus androgens which are not 5a reducible or activated would be expected to have less effect on the prostate. In balance, however, I have to add this may not actually be an advantage. There are reasons why having a prostate that doesn't have 5a reduction or full growth is a disadvantage. The disadvantage is that ejaculate volume is dependent on prostate fluids. If you don't have this, it could be that ejaculation may be experienced like in retrograde ejaculation, which may be symptomatically unacceptable.

Veldhuis: Are there any data on androgen receptor localization or activity in ageing? I recall diverse reports, one showing a change in the brain that was opposite to that in the prostate, and one showing no change. Per Bjorntorp, you alluded to an androgen receptor polymorphism. Do you know of any data on the effect of ageing on androgen receptor expression?

Bjorntorp: Yes, there are some microsatellites in the first exon which codes for the transduction domain. When this is too short, there is an increased risk for prostate cancer.

Veldhuis: That's a polymorphism without a known change in receptor function. Bjorntorp: I think these recent microsatellite developments are very interesting. In the androgen receptor gene, for example, these microsatellites have been altered in transgenic mice. The shorter the microsatellite, the stronger the effect of the produced protein.

Ruiz-Torres: The number of androgen receptors in the prostatic epithelium depends on the location. We have found that the content of nuclear receptors of cells from the posterior zone — where cancer usually appears — is higher than in the case of the central zone, which is mostly affected by BPH.

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