Endocrinology of the metabolic syndrome

Stefan Arver, MD, PhD interviewed by Hugo Verhoeven, MD

Hugo Verhoeven, MD: Good afternoon, my name is Hugo Verhoeven from the Centre for Reproductive Medicine and Endocrinology in Dusseldorf, Germany. I am reporting from the 4th World Congress on the Aging Male here in Prague.

It is my exceptional pleasure to sit together with Professor Stefan Arver from the University Hospital Karolinska in Sweden. He is the Director of the Andrology Centre at Karolinska. The topic we are going to discuss today together is the metabolic syndrome in men.

Professor Arver, thank you very much for giving me this pleasure. If we are talking about metabolic syndrome, the first question is of course, what is the metabolic syndrome? What is that?

Stefan Arver, MD, PhD: Thank you for inviting me. The metabolic syndrome is a group of symptoms that stick together and is an expression or a change in our metabolism, and it ends up as we lose control over our blood sugar regulation, our blood lipid regulation, and also shows an expression in hypertension. There’s a series of different changes ending up in a clinical situation where you have several symptoms. Each of them are threats to health, and all together they form a very strong factor giving rise to increased morbidity, and also mortality, being untreated.

Hugo Verhoeven, MD: So, if we are talking about a syndrome, we mean we have a conglomerate of different symptoms that are not clinical symptoms, but also endocrinological and morphological symptoms.

Stefan Arver, MD, PhD: Yes, it has a clinical expression and if you want to define it, it’s the combination of insulin resistance, what we see as typically type 2 diabetes, increased blood lipid levels, and hypertension. This also goes together with changes in our fat metabolism, and in our accumulation of fat, especially accumulation of fat in the intraabdominal cavity.

Hugo Verhoeven, MD: What is the aetiology of this syndrome?

Stefan Arver, MD, PhD: There are a number of different hypotheses. One hypothesis builds on endocrine changes. The series of events that seems to happen is that we may have, long term, a little increase stress status of the body, resulting in slightly increased levels of corticosteroids, cortisone in the blood. That impacts directly on the process of accumulating fat in the abdomen.

Another aspect of increased stress is the suppression of both the growth hormone secretion capacity, and on the gonadal axis. The deleterious thing here is that decreasing the circulating levels of testosterone and the growth hormone, its active peptide IGF1, decreases our ability to maintain a good lean body mass. It also decreases the resistors towards accumulating fat in the abdomen.

Hugo Verhoeven, MD: Before I forget, I think lean body mass is not an expression that everybody understands. Maybe you should talk just 30 seconds on the lean body mass.

Stefan Arver, MD, PhD: We can translate that into muscle mass. If we look at our bodies, it’s composed of fat, and it’s composed of muscles and then we have bone and other tissue. The main components we are talking about here are the fat mass, and the muscle mass, and the muscle mass is usually expressed as lean body mass.

Hugo Verhoeven, MD: Okay – is this syndrome typical for men, and typical for the aging man, or not?

Stefan Arver, MD, PhD: The syndrome exists in both men and women and has the same type of expression, the same components, and the same symptoms. It is something that occurs and becomes more prevalent in middle age men. It starts earlier, but the development into full clinical syndrome, identifiable at a doctor’s visit, is usually appearing around the age of 45 plus. The peak of incidence, or the prevalence, really starts to peak in men between 45 to 55 years of age.

Hugo Verhoeven, MD: What typical picture does this man between 45 and 55 present to the doctor who sees him for the first time?

Stefan Arver, MD, PhD: The first thing that is noticeable is that there is an increase in abdominal fat, so the belly starts to increase. That seems to be a very critical happening in the development of this syndrome. Coming to the doctor, he makes an examination; he can measure the circumference around the waist and the hip. In the metabolic syndrome, typically the ratio, what we can the waist-hip ratio, just finding the circumference of the waist and the circumference of the hip, is over a ratio 0.93, or if you just take a ruler and measure your belly circumference, if it’s over approximately 100 cm, you are at risk.

Combine that with measuring blood sugar levels, or doing what we call a challenge test, when you drink a measured amount of sugar solution and then measure how the body can handle this glucose amount. This give us a sensitivity to sugar intake, or inability to appropriately take care of this amount of sugar. So, the blood sugar level increases.

The other thing is that the blood lipids usually are elevated, cholesterol, triglycerides. Then we have the blood pressure, which is commonly increased in this syndrome.

Hugo Verhoeven, MD: Are there any other clinical findings that are typical in those patients? I’m just thinking that the GPs seeing those men will probably not think about severe pathology, if a man has a little bit more obese abdomen. So, are there other typical signs that every doctor should be able to remark in those patients?

Stefan Arver, MD, PhD: Not in general. These are the key factors actually, and if you look at the rest of the body you can see a normal hair pattern. You can see a normal male appearance in terms of what we see as androgenic activity. Maybe in the later stage of the development there is a shift, so you also have a decrease in muscle mass, a decline in muscle formation in the body.

Hugo Verhoeven, MD:Maybe you should also talk a little bit about the endocrinology behind this syndrome. What about the oestradiol production, the aromatase production, the SHBG production, and the testosterone production in those men. Is there also, well, probably there is, a shift? I would be interested to know what’s happening exactly in the fat tissue in the abdomen.

Stefan Arver, MD, PhD: One thing that differs in men with metabolic syndrome from those who have not developed this, is a drop in testosterone levels a drop in circulating testosterone levels, which can be assessed with a blood test. There is usually also a change in SHBG levels, which also drop. But the drop in testosterone is sharper, so there is actually a drop in what we call the free testosterone levels, or the ratio of testosterone available to the tissues.

Hugo Verhoeven, MD: And also because of an elevation of the aromatase activity you also have an elevation of the oestradiol or not?

Stefan Arver, MD, PhD: That is dependent on how much fat you have in the rest of the body. This may be a person who looks lean except for the belly. Or it can be a person who is generally obese, generally overweight, and the generally obese person also develops the metabolic syndrome, or is at risk for developing the metabolic syndrome, mainly because the proportion, or the amount of fat accumulated in the abdomen, reaches a critical level.

The worse risk scenario is actually the person who looks very lean, and has a disproportionate accumulation of fat in their belly. That is the real risk factor presenting at the doctor’s office. That is the person who should be taken seriously in terms of measures to counteract these metabolic changes.

Hugo Verhoeven, MD: That would be of course my next question, that person presents not just a clinical image but he has probably, for the rest of his life, a lot of risks. He is going to develop different pathology that could end in death. What are his risks?

Stefan Arver, MD, PhD: The main risks are threats to the cardiovascular system, increased development in arterial sclerosis, and an increased risk of the processes that are caused by arterial sclerosis, like cardiac infarction; or a cerebral vascular disorder, like a haemorrhage or a thrombosis in the cerebral circulation. Also, peripheral vascular disease, which manifests itself in poor circulation, in the legs and in the foot, and also in erectile dysfunction. That is also part of the vascular system that is affected by these changes in lipid and glucose metabolism.

Hugo Verhoeven, MD: Before we talk about potential treatments, what about prophylactic treatment, how can you avoid that?

Stefan Arver, MD, PhD: It is well known that negative stress and people who have experienced situations in life with great stress, like unemployment, maybe financial problems, divorce, these life events accumulate the risk.

Another thing that impact on this is physical activity. Daily physical activity, not in the athletic range, but maybe to the extent of about a one hour brisk walk a day. That is the level of physical activity that actually has a direct preventative effect on this syndrome.

In general, be cautious about weight gain and also excessive intake of alcohol. Alcohol has its own way to support development of the metabolic syndrome. There are dosing levels here, and we know that a little bit of alcohol, like one to two glasses of wine per day, has a preventative effect. It’s not to refrain from alcohol totally, but to stay away from the excessive drinking.

Hugo Verhoeven, MD: Is it true that beer drinkers are at higher risk of the metabolic syndrome?

Stefan Arver, MD, PhD: I think beer drinking carries a lot of calorie intake, and beer is very good, so it’s easy to drink too much, and get too much fuel, too much energy. But otherwise there are no specifics about beer drinking in terms of risk for development of the metabolic syndrome.

Hugo Verhoeven, MD: As soon as the metabolic syndrome develops, what can we do for those patients?

Stefan Arver, MD, PhD: A change of lifestyle with dietary regimens and physical activity are the main fundament to counteract and treat this problem. It sounds easy, but we all know that changing habits is very difficult. It takes a lot of motivation, and it takes a lot of understanding that this is really something that will do great good in the long term.

We also have medication that might be necessary. If we have an elevation of cholesterol levels and blood lipids, it is very well documented that lowering of blood lipid has a preventive effect on the development of cardiovascular disease.

Then we have specifics around diabetes and increased blood glucose levels. We need to cope with increased blood sugar levels with diet, and maybe medication to control the blood sugar.

Hugo Verhoeven, MD: And for the reduction of the amount of fat in the body, would for instance, liposuction be a good way to lower the aromatase activity, and maybe also to lower the oestradiol component? Or do you think that plastic surgery interventions have no place in this treatment of the fat belly?

Stefan Arver, MD, PhD: I don’t think it will be something that could be used in general, but from an experimental point of view, it is actually the amount of fat in the abdomen that is the risk. So, even if you remove that surgically you will improve in your metabolase. We can say that the fat in the abdomen is a poison to your metabolase. It poisons the liver, and the liver is the central coordinator for blood sugar and lipids. Removal of that by any means has a beneficial effect.

Hugo Verhoeven, MD: Just to make it clear. If you take a cross-section of the abdomen with an MRI scan where would that fat tissue be?

Stefan Arver, MD, PhD: It would be inside the abdomen. It’s not the subcutaneous layer, the thing you can feel between your fingers, your spare tires. It’s not the tires; it’s what’s inside the belly. That is the fat mass that impacts on the liver, and that’s where the metabolic syndrome actually develops.

Hugo Verhoeven, MD: So, in the treatment of the syndrome we are going to treat the different symptoms. But there is no aetiological treatment?

Stefan Arver, MD, PhD: There are approaches to finding an aetiological treatment. Beside the lifestyle changes and the dietary changes, as we have fairly good evidence that we have this increased stress level, there are actually two pharmaceutical programs addressing that. Trying to break this negative spiral by mainly blocking cortisone production. That is one approach.

The other approach is to go the atabolic pathway, that is to compensate for the loss of testosterone. This is still at the clinical study level; it’s nothing that is out as a treatment program. There’s a lot of documentation understanding that needs to be in place before we can see this as a symptom therapy thinking. But it’s very interesting that if we normalise testosterone in this group of men, there seems to be a reversal of the metabolic syndrome.

Hugo Verhoeven, MD: If you say normalising, that means elevation of the testosterone?

Stefan Arver, MD, PhD: Yes. So, in general these men have lower testosterone than normal men, and by replacing testosterone up to a normal level you see this reversal effect.

What we still do not fully understand is what dose levels do we need to reach. What are the ideal levels of testosterone to counteract these metabolic changes? We know that we can change it, but the fine tuning of this is what is a matter of scrutiny right now.

Hugo Verhoeven, MD: Two final questions, what is the incidence of the metabolic syndrome, and what would be the implication of that for the costs of health care of the aging population in the future?

Stefan Arver, MD, PhD: The trouble here is that the incidence is increasing, and in Western Europe incidence numbers are like 15% to 20%. In the US it’s about 25% of the population. Then we have sub-groups of people, especially Indian Americans. The prevalence is about 60%. In Afro-American women living in the US, it’s about 80%. This is a very prevalent, and to some extent, devastating condition that puts a lot of burden on the health system.

The best thing would be prevention, not entering into this syndrome. The nice thing is to treat the symptoms and keep them under control, which limits the long term complications that we see from increased blood sugar levels in diabetes, and increased blood lipid levels.

Hugo Verhoeven, MD: So, prevention, early diagnosing and counseling of the patient will be most important.

Stefan Arver, MD, PhD: This starts very early so don’t wait until this has developed. It is starting already I would say in your teenage period, in your 20s, to create a life pattern where you are physically active, where you are concerned about what and how you eat. Also, take care of your social situation avoiding stress, or coping with stress.

So, it’s early prevention of the type of lifestyle you later develop, because once we’ve developed our lifestyle, we are kind of caught, and it’s very difficult to change the way of living.

Hugo Verhoeven, MD: Is there also a genetic basis or familial basis? If your parents have a metabolic syndrome, can you be sure that whatever you do, you will get it also?

Stefan Arver, MD, PhD: There’s definitely a genetic burden here. There is a genetic risk that also I think impacts on the difference, of the susceptibility of different ethnic groups, causing for instance, Indo-Americans to be much more susceptible to what the lifestyle, what’s the eating habits than perhaps Caucasians are.

Hugo Verhoeven, MD: Well, I think we learned quite a lot. Thank you very much for this interesting interview and I wish you a nice meeting.

Stefan Arver, MD, PhD: Thank you.