This is Tromsø at a sunny day, which is not always the truth.
Disclosure first here, I’ve had some consultant and so on. Thank you.
There was a lecture yesterday about different definitions of the metabolic syndrome, and of course, there is not only one definition, there are several. That always makes it a little more difficult, wish we only had one, so I will not go into detail but this is the NCEP.
And we have the WHO, and of course, there is also one International Diabetes Federation, but this will not be an issue on my talk.
The Tromsø study has been an ongoing population-based health survey. They started in 1974, mainly focusing on cardiovascular disease. But in the fourth study, 1994 – 1995, we also had hormone data. In phase one of the study 27,159 subjects participated, that was all subjects about 55 were invited to the study and as I said, seeing here 80% attended. There were also some minor cohorts from younger men and women. At the second phase where they performed a lot of different investigation we also measured hormone analyses and we had hormone analyses on 1,565 men.
First I will start with association between the different components of the metabolic syndrome.
Lipids have been studied, as I said, many different epidemiological studies, most of them are cross-sectional and they have found most, but not all, have found association with low levels of testosterone with lower levels of HDL, low levels of LDL and low triglycerides. Longitudinal analysis in MRFIT have confirmed a relationship that actually the high levels of testosterone has been the preferred status in this male.
We had the same in Tromsø study. We made a score that we would say that a good lipid level would be about HDL of 0.9 and triglyceride below 0.818. When you look at these scores you can see of course that there is a significant difference of the one having the more nice lipid scores. As waist circumference or BMI is always important in this, we also looked at the different BMI levels. For each BMI level here as you see, there is still a difference between the one with the more favourable lipid profile, compared to the ones that have less favourable lipid levels.
We have disadvantages in our study and one of these disadvantages is that the testosterone levels are not always measured in the morning. As this was a large study of 27,000 people they had to come between 8:00 and 4:00, and the whole study was performed in one year. So we always had to deal with issue of the circadian rhythm of testosterone. But you can always try to make an advantage of that. When we looked at triglycerides of course we found that high testosterone levels were associated with lower triglyceride levels. But then we wanted to see what happened during the day. So we looked at time quartiles when the men had their testosterone measured. Then we could see that if we split the men in two above and below the 50th percentile, actually the men with low levels of testosterone, they increased their triglycerides over the day. While the men who had high levels of testosterone above the 50th percentile, actually did not increase. That was, I think, a little unexpected because these are not fasting levels, so you would expect everybody to be eating over the day and the triglycerides should then probably increase for most people. But the men with the higher testosterone levels did not increase. You would suspect that they had a better fat metabolism. Of course this is cross-sectional data and we will have to show that in studies we are doing at the moment.
As I said, there are different studies. We have been looking at HDL and triglycerides before and some have been negative and some have been positive. There is, as in our study, a positive relation with high testosterone levels and higher HDL levels, but as I said, does not all show this. With triglycerides it has been more – most studies have shown inverse relationship.
Now, abdominal obesity: this has also been shown before that there is a relationship with high testosterone and lower anthropometrical measurements in these studies.
In the Tromsø study we also looked at waist circumference in this study. This study here in this first analysis we adjusted also for body mass index as would be a more measure of total obesity and focusing on the central obesity. These are the health scores by Lean and the group below 94, between 94 to 102 and 102 and above. As you see for each of these increase in waist circumference testosterone decreased. This has also been shown before but not in such a large population with waist circumference.
We also wanted to know how much impact BMI had on this so we made this graph. Here we have tertiles of this group, men with the lowest waist circumference and the highest, and men with the lowest BMI and the highest. Let’s focus on these two here. The men with the highest waist circumference but still the lowest BMI, and this would be the man I think you can always picture with the biggest belly, but actually skinny otherwise. He had the lowest testosterone level and also definitely the lowest free testosterone levels. I think again, this is cross-sectional data but you could expect men with the biggest bellies to be definitely in risk of having the lowest testosterone levels.
Tromsø is way above the polar circle so we have two months of no sun in the winter and we have two months of midnight sun. Of course we had to look at the possibility of seasonal variation of testosterone levels, and we found it. And unexpectedly we found lowest level of testosterone in the summer; we would expect it was different. Different study looking at the sperm count for young men could show that in Oslø, the capital of Norway, which is way below the polar circle, the situation was a little opposite. So, at least we found the seasonal variation.
We wanted to show also that actually there was a relationship with anthropometrical measurements. We found that at the same time in the summer we found the highest waist-hip ratio.
If we just flip the curves, you would see that actually they fit quite nicely to each other. So there is even during the season we found some association between waistline and testosterone level.
You could say that in the summer, when it is the most light, you have the lowest testosterone, the largest waistline, and the highest temperature.
Blood pressure: In earlier studies from 1982, ’84 and ’88 been looking at blood pressure and some studies have found no association, while Khaw and Per Conner found a negative association but between systolic and diastolic blood pressure.
We also found an association with systolic but not with diastolic blood pressure. Here we looked at categorical hypertension and as you see we used cut offs, systolic blood pressure below 140 and diastolic below 90 and in the group with hypertension was also added all that used drugs for hypertension. As you can see both age and BMI adjusted there was a difference between these two categorical groups. But also, it doesn’t matter actually what age group you are in because you will find the same difference in all of our age groups.
We did not measure glucose in the Tromsø study but before there have been different studies looking at insulin resistance and impaired glucose intolerance, and they have all found negative association with insulin resistance and testosterone.
However, we measured glycosylated HbA1c. We can just look here, this is the man with the lowest testosterone compared to the highest, and we of course find a difference. This would be a better measurement of long-term high levels of glucose. As you can see these are not pathological levels of HbA1c. You can see the same in other studies that the trend for increase in HbA1c is not cut point or anywhere, it is constantly increased risk for cardiovascular disease. It is important to keep low in this level.
We also show that we have lower levels of testosterone in men with diabetes. This has also been confirmed by other groups.
These were the different components of metabolic syndrome but there are actually a few studies, a few epidemiological studies also looking at testosterone and the metabolic syndrome.
This is the Rotterdam study and there was a cross-sectional study of 400 men between 40 and 80. They could show that for adding one or two or three or more of the metabolic risk factors you had a trend in lowering your testosterone levels.
Adjusted odds ratio also showed a decreased risk for each increase in standard deviation increase in testosterone. The risk was reduced of having metabolic syndrome. It was marginally, it was close to statistical significance also for bio-available testosterone. These alterations were adjusted for age, smoking, alcohol consumption, physical activity, BMI and waist circumference.
But the Kuopio Ischemic Heart Disease Risk Factor study and they have also published a paper on this and they have looked in longitudinal study and compared men for 11 years follow-up. This is the odds-ratio for developing metabolic syndrome for men in the lowest testosterone quartile.
There was a 2.28 odds-ratio increased, double increased if you were in the lower testosterone levels, 11 years before this study. They found also for free testosterone a marginal effect. Of course, again, this is cross-sectional study. Here you cannot say the direction of the action and I hope we will hear more about this later in this symposium.
But they also made it the opposite way. They looked at the odds-ratio for developing hypogonadism. I mean just changing the reason. They found actually having metabolic syndrome also definitely increased the risk of having no testosterone, of being in 11 years later by 2.8, depending on what kind of definition you use for the metabolic syndrome. I think that is also very interesting because that means that lifestyle intervention can also increase the risk of having hypogonadism later in life. So here is a large possibility to actually do something.
In summary, there is a strong association between low levels of testosterone and the different components of metabolic syndrome. There is also an association with the metabolic syndrome in both cross-sectional and prospective studies. Again, men with metabolic syndrome have an increased risk of developing hypogonadism. Still, this is cross-sectional data, they should generate hypothesis and we are conducting a study in Tromsø now that we hope will answer some of these questions.
My co-workers in Tromsø and at UCSD in La Jolla.
Thank you for the attention.
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