Though the first question is, what is there more to say? There have been a number of excellent presentations digging deeply into the issue of the metabolic syndrome. I will at least try to add something, and at least add to your confusion, as that seems to be a sign of education and not of aging.
This is actually a very old phenomena and this year it is the 83 year anniversary of the first observation of the study linking morbidity to increased, or changes in body composition, and in fat distribution, was a Swedish doctor, Kylin, in a small town in southern Sweden who reported this in 1923. The next significant, and very cited paper, focusing on the lipid distribution or the fat distribution was by Vague in a paper published in 1947, this came the (inaudible) type of adipose deposition.
So far there are observations of things that eventually carries an increased risk for cardiovascular disease. And the name of the metabolic syndrome, which we all carry around, may lead us to think that it is a true syndrome, but we really don’t know that. We can only conclude that there is a cluster or variety of risk factors that seem to co-occur, though is there a common denominator or not? In what way will testosterone be involved in the aetiology, and also offers option for therapy? This is already rehearsed a number of times and I will focus a lot on this central obesity.
This is a normal patient, which we all have seen. He has a low testosterone level. In this case it was due to orchitis, about 36 years of age. At this picture, he was 56 years of age. The clinical picture of this male resembles quite a bit someone with hypercortisolism, but in this case it was a pure hypoandrogenic state. The accretion of abdominal fat, a little bit of gynaecomastia, poor muscle development, and his symptomatic complaints, except for the metabolic derangements, were mostly associated with joint and muscle pain. There is a little bit of an overlap between the catabolic state of hypercortisolism and hypogonadism.
As we have heard and we all know that increase in abdominal fat causes a lot of perturbances, primarily in the function of the liver as the free fatty acids enters the liver and the increased turnover of fat from a higher fat mass is one significant factor that then causes a series of events and from that perspective the omental fat may be one of the stronger common driving forces for all the metabolic derangements that we see in the metabolic syndrome, or in type II diabetes. We also have a lot of peripheral effects and other mechanics that may or may not be directly related to this, or indirectly related to secondary phenomena. We can explain a lot of the changes in insulin resistance in the glucose intolerance and changes in lipoprotein metabolites just by the fact that we have an increased abdominal fat mass.
So the dynamics of the visceral fat pool is accumulation and turnover and delivery of free fatty acids to the liver. One of the conspicuous side effects of high cholesterol therapy is accumulation of fat in the abdomen. Cortisol is certainly a driver when it comes to increasing both the amount of lipids available in the abdomen and also the contribution of inflow fat to the liver, which then causes changes in the glucose metabolism, lipoprotein metabolism of the liver. For instance, we have a few (inaudible), which is changed so we have an increased output of glucose, also the common phenomena we see in type II diabetes. We have an impact that causes them an increase in circulating glucose levels and an increase in insulin levels for a variety of reasons.
So we have different types of body composition and body shapes, and obviously there is a difference in between these normal persons, with the generally obese and then this person with a more predominant abdominal obesity. I think that taking from the epidemiological studies, I think the first study that really, clearly identified the low BMI, high waist circumference person as the one carrying the highest morbidity in cardiovascular disease was the Gothenburg, 1913, year-old, mediolongitudinal study published by Tibblin, Svardsudd and collaborators. It showed that this was the really significant risk factor. While general obesity up to a certain level is not. And in fact, if you look at general obesity you may even have a risk reduction to a certain point. Taking these two things together the more of general fat accumulated at a certain point you will step over a threshold where the abdominal fat mass becomes too much and you will get all the metabolic derangements.
There are several studies that have been cited. This one has not been cited because this is the one we have done ourselves a few years ago, and it is about to be published.
We picked out a group of men with type II diabetes over the age of 40 with an increased abdominal fat mass and we took the waist-hip ratio of over 0.95, which is a little bit over the risk increasing threshold you see in epidemiological studies, and a sagittal diameter which measures more purely the intra abdominal fat level over 22 cm. Testosterone cut off levels were set to 15, just a little bit higher into the normal range generally referred to. The reason for that was some other studies that had been performed in populations with definitions of the metabolic syndrome, and who had even higher testosterone levels, and where it was demonstrated in small groups that it had a significant impact on glucose tolerance and insulin insensitivity. So they had type II diabetes, verified by increase in C- peptide levels. They were not too obese and they were in relatively good glycaemic control.
Age about 60, height around 177 (cm), weight around 90 kg. BMI 28.9 to 28.4, and the average waist-hip ratio was 1.01 in the treatment group and 0.99 in the placebo group. The duration of diabetes was fairly similar.
We enrolled 226 subjects, screening failure due to high levels of testosterone mainly, ended up in 79 subjects that were randomised, 40 in the treatment group and 39 in the placebo group. Twelve subjects discontinued the trial due to a variety of reasons, some due to adverse events, some due to requirement for insulin therapy. In total 30 subjects were treated with testosterone for one year and 37 were treated with a placebo. This was a relatively low dose of testosterone, 5.0 mg per 24 hours, which is different from the previous and other intervention studies which have used injectable testosterone, producing higher testosterone levels.
We had a difference in the randomisation process between the placebo and the testosterone treated group. So the group that received testosterone therapy were at baseline in the worst metabolic state than the placebo group. That the things that happen in randomisation procedures.
The system produced a significant increase in morning testosterone levels, about 40% in numbers from an average of about 10 to 14 nmols/L, so a slight increase up to the lower part of the normal reference range.
Free testosterone also increased, somewhat more, but still a very mild, so to say, increase in circulating testosterone levels. Oestrodial levels did not change significantly.
While DHT levels differed or increased actually due to relative decrease in the placebo group.
At end follow up after one year of testosterone or placebo therapy we looked at lipid profiles and there were no significant changes during this period, which add to the database for non-interfering with the cholesterol metabolites in any significant way by testosterone therapy.
We looked at the other variables that we measured. We have no change in HbA1c levels significantly, we had an increase in hematocrit, slight but significant, which is predictable. We had a suppression of LH in the treatment group. There was no change in PSA levels through this 12-month period.
However, looking at the body composition, this would be computerized tomography; we could demonstrate an increase in muscle mass or fat free mass or lean body mass, which was significant, due to only this slight increase in testosterone levels. You also had a significant increase in muscle surface area and we had a significant decrease in subcutaneous adipose tissue around the circumference. There was a change in subcutaneous as well as in intra-abdominal fat mass, which is only distinguishable if you do a CT or MRI assessment. This is maybe of importance as we can have a different, or we can be misled, by a decrease in waist circumference due to a decrease in subcutaneous fat, which is not of metabolic significance.
We had all these subjects undergoing glucose clamp to study glucose disposal rate, and we did not see any significant change between, these are the baseline levels, from the baseline levels between the active and the placebo group. So this increment in testosterone level in this cohort of people did not manage to change the insulin sensitivity.
On the safety side we also looked at the prostate with ultrasound and there was no significant difference between the active treatment and the placebo group.
However, if we looked at relative changes in testosterone levels and we divided the group, treat them with testosterone who had the larger or less increase of testosterone; there was a significant difference in metabolic change. This was an increment in glucose disposal rate in those that had less than 50 percent increment in testosterone, and this was the increase in the glucose disposal rate in those who had the higher increase in testosterone level. The level of testosterone and the delta change in testosterone is probably of significance, and as pointed out by the previous speaker, the level to reach significant changes in the metabolic parameters may require a higher threshold than for other things. One of the important observations I think that we did was that we looked at the liver attenuation and one of the phenomenon that occurs when you have a higher intra abdominal fat mass is that you get liver steatosis. You see slightly elevated liver enzymes. This liver steatosis is just a phenomenon overload of fat into the liver. During testosterone therapy in the group that had the largest increase in testosterone this therapy was able to reduce the liver fat mass. So we could have a reversal of the liver steatosis, which is one significant change reflecting a beneficial effect, and a normalisation, that could go along with the normalisation seen in other studies.
So why didn’t we achieve the expected increase in testosterone? We know that 5.0 mg of testosterone in men weighing less than 110 kg usually produces average testosterone levels of about 20 nmols/L. In this group we reached 40 nmols/L. One observation that partially could explain this is that if you look at testosterone levels at baseline and at follow-up, the Xs are the placebo group and the filled dots are the testosterone treated groups. You can see that we have an LH suppression, which occurs very early. And this will hypothetically lead to the idea that this group of men with type II diabetes and metabolic syndrome actually have a different sub-point for testosterone. Their internal secretion is shut off at an earlier point, which then could contribute to the achievement of lower testosterone levels than we expected. So, it is not just a testicular failure, a testicular impact, but it is seems also to be a central impact.
These are data from Márin’s earlier studies, where he used injectable testosterone and looked at glucose disposal rates. As you can see, the lower the testosterone levels in the beginning, the greater increment in glucose disposal rate. Again, iterating the idea that you need to change the testosterone levels quite significantly to achieve a metabolic effect.
Another thing that is of importance is; is it testosterone, is it testosterone metabolism that contributes to this? This is from another study where it was compared, testosterone therapy, with DHT therapy. And obviously the change in glucose disposal rate that is changed in insulin sensitivity did not occur with DHT, as it did with testosterone. So something that is linked to testosterone being able to be metabolised seems to be of importance and the obvious question is that an oestrodial effect or not? That is a part of the normal physiology of testosterone.
Unpublished but in press data from a colleague of mine at the Karolinska Institute, Effendic, and his group, who is working with a knock out model for the oestrogen-alpha and beta-receptor. What is conspicuous in these models is that the knock out of the alpha-receptor develops an incredible insulin resistance. So the oestrogen-alpha receptor seems to be a major regulator of insulin sensitivity. I think that is something we need to take into account when we consider androgen therapy with different modalities; that oestrogen is an important part of the effects that we study in the end point.
This is an old cartoon from the late Per Björntorp who prematurely died a few years ago and he is one of the important figures in theorising around the endocrine background to the metabolic syndrome. What came out of a series of studies was that we have this in a bit of a simplified thinking, but we have these two hormones that drive accumulation of intra-abdominal fat. We have testosterone and growth hormone, which both counteract this, through different methods. In a normal state we have balance in between this. If we have a Cushing Syndrome or we treat people with high doses of corticosteroids, we tip this balance. The same thing happens if we have a decrease in testosterone and growth hormone as maybe a part of the aging process, and concurrent diseases. We have a shift in the balance. As we know the cortisol levels remain fairly stable throughout life, while androgen and growth hormone levels decrease on average. We have this catabolic/anabolic imbalance, which facilitates the accretion of intra-abdominal fat. But we also have a number of other factors that have impact on this. We have a lot of psychosocial factors. There are studies that demonstrate that the risk for developing the metabolic syndrome or type II diabetes one of the strong risk factors is psychosocial burden, significant psychosocial events. Chronic stress which in the terms of endocrinology is conveyed by changes in corticosteroid metabolites and that facilitates, as well as depression, which is also a strong risk factor.
Taking this altogether, trying to get some sort of a background where the catabolic-anabolic balance is one of the entry portals to the metabolic syndrome is that we have all these factors here that increase the tone or CRH ACTH and cortisol. What does this axis do to the anabolic axis? Well, it has a central suppressing effect on the growth hormone axis and on the gonadotropin gonadal axis. Furthermore, increases in cortisols have a local effect on the testes’ ability to respond to gonadotropins. This part here may be of significant importance for triggering all this mechanism that we somehow are able to counteract by adding testosterone later on.
A couple of observations and this is old medicine and it has been practised for many, many years, to use testosterone to counteract catabolic effects of corticosteroids. It goes in and out of fashion, but I think it is on its way back because there are more data coming out, and I think the guideline for androgen therapy will also include use of testosterone therapy concomitant with high dose corticosteroids. The reason for that is there are a number of studies that demonstrate they are small studies but that show significant effect, that testosterone therapy concomitant to glycocortocoids can completely abolish the change in body composition. The other study with the same question that demonstrated the counteraction between corticosteroids and testosterone is that you can preserve or eliminate or prevent the loss of bone during corticosteroid therapy while giving testosterone simultaneously. So despite high corticosteroid levels, you can still act to prevent some of the catabolic effects and I think that’s where we are in a lot of the intervention we are doing in men with metabolic syndrome – that we are counteracting corticosteroids.
This was already shown and this is a very significant thing demonstrating that pluripotent stem cells mean different things to different things and testosterone seems to be a passageway to the master switch to drive the differentiation from adipocytes to muscles or other tissues. And if you add androgens to these pluripotent stem cells you lower the proportion of cells that develop into adipocytes. So, low testosterone facilitates formation of adipocytes.
We do change quite a bit with androgen therapy as seen on the outside and I think that today we are at the point where we treat androgen deficiency by androgens and we treat diabetes with the means of diabetes treatment. But all the ongoing studies may actually change our treatment paradigm and if things turn out the way we hypothesise may open the road for an anabolic therapy in conjunction and in prevention of with the risk factors of the metabolic syndrome.
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