The Male Hormone Connection:
Treating Diabetes and Heart Disease
The purpose of this paper is to examine the links between testosterone, obesity, type II diabetes, and cardiovascular disease. The anti-aging physician approaches and treats obesity, type II diabetes, and cardiovascular disease in a very different way than that of a conventional physician. Here we will focus on testosterone replacement therapy, and will discuss the reasons for recommending a patient for replacement therapy, its benefits and its side effects.
Is there a link between testosterone, obesity, diabetes, hypercholesterolemia, and cardiovascular disease? Why do men die? What are the leading causes of death in men? What is the relationship between men and women?
Cardiovascular disease (CVD) is the prime cause of death among the elderly in industrialized countries, and a major determinant of chronic disability. Cardiovascular disease, cancer, stroke, accidents, medication, Lyme disease, and murder are the leading causes of death in men.
If a patient gives you $10,000 to estimate his risk of dying from a myocardial infarction (MI) in the next five years, what would you measure? Most doctors would take the patient’s blood pressure; others may order an ECG as well. There is a world of difference between how a cardiologist and an anti-aging doctor would respond to such a question. A cardiologist would conduct an invasive exam with a heart catheter, arteriography etc. Anti-aging doctors would turn to the laboratory instead. So what can we do? Insulin is a strong predictor of MI within the next five years. Another is C-Reactive Protein (CRP), a marker of inflammation. CRP is produced in response to interleukin-6 (IL-6). Other predictors of myocardial infarction include DHEA-sulfate, homocysteine, plasminogen activator inhibitor type 1 (PAIl), IGF-I, and lipoprotein-a (Lp(a)).
The lifetime risk of CVD is much larger in men compared to women, suggesting that testosterone or the lack of estrogens play an important role. On the other hand, testosterone levels decrease with age, coincident with the age-related increase in atherosclerotic disease. Results obtained from cross-sectional studies suggest that men with CVD might have lower testosterone levels. While intervention studies with testosterone in older men with CVD suggest an improvement of ECG. In addition, testosterone exerts significant effects on several risk factors for CVD. Studies on intima-media thickness (IMT) of the carotid artery suggest an improvement by administering testosterone. There is a gap in lifespan and in onset of severity of CVD with a male disadvantage. The higher rate of CVD has been attributed to the decrease of testosterone in aging men. Of significant note is that CVD and unfavorable biochemical CVD risk profiles in men (low HDL-cholesterol, high LDL-cholesterol, high triglycerides, high fibrinogen, and high PAI-I levels) are associated with low rather than normal levels of testosterone.
The number of people in Germany who die from sudden death by Ml or non-stable plaque per year is 100,000. In the US this figure is 1.3 million. A German study of approximately one million people showed that obesity is increasing with age. This is a major public health problem, as we know that body mass index (BMI) is one of the major risk factors for heart disease. The average hip-waist ratio is also on the increase. We know that the mean increase of fat mass in men between the age of 25 and 70 is 15 kg; the mean loss of lean body mass over the same period is approximately 8 kg. The reason for this rise in BMI, hip-waist ratio, and obesity is simple: it is attributable to lifestyle.
PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1 (PAI-1)
The physiological role of PAl -1 is the inhibition of fibrinolysis. Therefore, the increase of PAI-I levels caused by PAI-I polymorphism is linked to increased blood clotting and decreased fibrinolysis. P AI-I polymorphism correlates with high risk of CHD, stroke, embolic disease, and myocardial infarction. Women who are affected by this polymorphism should be treated with estradiol replacement, as it reduces P AI-I levels. It is important to control aromatase activity by monitoring estradiol levels and SHBG (sex hormone binding globulin) during testosterone administration. The risk of acute MI increases with plasma levels of thrombogenetic factors (fibrinogen, PAI-I, factor VII). Those plasma levels are inversely correlated with endogenous testosterone in men.
Insulin is a potent stimulator of PAI-1
In the arterial wall smooth muscle cells (SMCs) form the extracellular matrix, and play an important role in determining arterial tone. Proliferation and migration of SMCs are important steps in the formation of neointima and stenoses. Apoptosis of SMCs contribute to plaque instability and rupture. Macrophages play a key role in atherosclerosis as they can internalize large amounts of exogenous lipids by phagocytosis. They also form foam cells, cytokines, and growth factors (EGF platelet derived factor, IL-I, TNF-alpha), and stimulate the migration and proliferation of SMCs.
Obesity reached epidemic proportions at the beginning of the new Millennium. The prevalence of obesity increases with age and reaches a maximum between the ages of 50 and 59 years. There is a tendency for the mean BMI to decrease in the oldest age group.
Aging is associated with visceral fat accumulation in both genders, with the highest prevalence being in the oldest age group (> 60 years). Energy intake, as well as fat intake, either drops or remains unchanged with age, and thus age-related weight gain is associated with a decrease in energy expenditure due to an increasingly sedentary lifestyle.
Recent figures suggest that Greece has the highest obesity rates in the world. The same figures placed Germany and the US in joint fourth place. However, when Americans are obese, they tend to be severely obese. The reason for that is the carbohydrate problem in the United States. You can say that it is an "American paradox": after removing cholesterol and fat from the diet something was needed to give people the feeling of fullness. As a result the American diet became packed-full of carbohydrate: bread, noodles, rice, potatoes, and so on. This is the reason why the weight and obesity problem in the US is still on the increase, despite the popularity of low-fat or no-fat diets. Of men in the US, 23% have the metabolic syndrome, in which insulin resistance plays a key role. Epidemiological studies indicate that insulin levels and testosterone are inversely correlated.
A study by Hwang examining the ·correlation between leptin, sex hormones, and fat distribution in middle-aged and aged men, showed that free testosterone, DHEA-S and SHBG levels were significantly different in middle-aged men and their older peers. However, leptin, testosterone, and estradiol levels were similar. The study also revealed that sex hormone levels change steeply during middle-age, but much more steadily in older-age. Testosterone and leptin levels were found to be strongly linked with BMI and waist-hip ratio.
Lipoprotein-a (Lp(a))levels are affected by levels of thyroxin, human growth hormone (hGH), estrogens, and progestins. Levels of 30 mgldL and above are considered an independent risk factor for coronary. cerebral vascular, and peripheral atherosclerotic vessel disease. But what about cholesterol? Cholesterol is not a predictive factor of MI. Unfortunately. cholesterol has been relegated to a convenient marketing tool for a lot of industries to sell product. Recent studies suggest that the cardiovascular risk factors we should be concerned about are Lp(a), insulin. homocysteine, fibrinogen. and PAl-I.
The Fat Cell, as we know, does not only store fat, it is a very active metabolic cell. Fat cells secrete a number of substances that have a direct effect upon insulin. They also manufacture estradiol. estriol. and estrone by aromatization of testosterone. thus obese people lose their testosterone to their fat cells. Fat cells also secrete angiotensin. which is known to increase blood pressure. Furthermore. there are three hormones that increase the number of fat cells and increase fat storage in these cells. thus making a bad situation worse. These are cortisol. insulin, and estradiol. Estradiol plays a role in pregnancy. and men and women who get high levels of estradiol get fatter and fatter. Estradiol is a fat hormone.
Leptin. which stimulates the hypothalamus, is secreted by adipocytes. Leptin by itself is a product of the OB gene, the obesity gene, and is an adipose cytokine. It is secreted by white fat cells, and its primary role is in adaptation to negative energy balance. In normal circumstances, leptin stimulates the hypothalamic satiety center and creates a feeling of fullness. However, obesity increases leptin levels and can cause leptin resistance. If a person has leptin resistance. the concentration of leptin is sufficient to stimulate the hypothalamic satiety center. however, due to the body's resistance to leptin. only some of the leptin stimulates the hypothalamus. This triggers hunger, and thus the person feels the need to eat more.
Leptin also plays a role in the regulation of insulin levels and insulin sensitivity. When we have higher body fat, we also have higher leptin levels and higher insulin levels. This is the correlation between leptin. BMI. and fat. Metformin is used to decrease insulin levels in people with type II diabetes. However. what is interesting is that metformin does not increase leptin levels. Metformin is the only drug that lowers insulin levels without raising leptin levels.
Another hormone of interest is Adiponectin. Adiponectin is interesting because it has a direct correlation with insulin. Adiponectin is an adipose-derived peptide and it acts as a systemic regulator of glucose and lipid metabolism. There is a strong relationship between adiponectin, BMl. and body composition. We also know that adiponectin is a mediator of insulin sensitivity. and an enhancer of fatty acid oxidization. Thus. suggesting that it encourages fat burning and weight loss. If adiponectin levels are low, insulin is not able to phosphorylate the insulin receptor, which normally happens at the tyrosine residuals of the insulin receptors. This phosphorylation stimulates the starting of the insulin effect. This is why we need adiponectin. Low levels of adiponectin have been linked with an increased risk of cardiovascular disease.
Atherosclerosis is a chronic inflammatory disease. In the early stages of all age-related diseases we find the same pathogenesis: inflammation. Inflammation provides us with a link between Alzheimer's disease, heart disease, and cancer. It takes a long time to build up plaques. A fundamental part of the pathology of atherosclerosis or coronary sclerosis is damage to the endothelial wall of the artery. This causes macrophage-stimulating cytokines to migrate to the damaged endothelium and trigger inflammation. Then we start to see the development of plaques. Atherosclerotic plaques begin to develop when oxidized cholesterol molecules accumulate inside the wall of an artery. However, the problem is not caused by cholesterol itself. The problem is the inflammation and the oxidation.
One of the central mediators for inflammation is cyclooxygenase-2 (COX-2). COX-2 expression is exacerbated by omega-6 fatty acids but inhibited by omega-3 fatty acids. Cytokines, such as interleukin-6 (IL-6), and proliferation factors (SMP) that are produced by macrophages all increase the supersensitive CRP. High CRP levels (2.0 or higher) are a predictor for atherosclerosis. Both COX-2 expression and cytokines are inhibited by testosterone.
Coronary atherosclerosis in most men is a chronic disease. Most men have plaques that are very stable. But plaques that are unstable can erupt tomorrow. This is why you cannot predict sudden death, for example, by bike ergometry. So we have to diagnose very early. What is very interesting is that the whole scientific community is now beginning to turn to preventive medicine after years of focusing on curative medicine.
Atherosclerosis is a multifactorial disease. According to the International Task Force for the Prevention of Cardiovascular Diseases, its pathogenesis is favored by non-modifiable risk factors, such as age, sex, and positive family history, as well as:
Insulin and Type /I Diabetes
Insulin levels are on the rise in obese people. Insulin levels can be elevated even when glucose levels are normal. It is possible for a person to have a glucose level of90 or 100, which is normal for people of around 50-years of age, and an insulin level of 16 or 20.
Insulin levels, serum glucose and lean body mass are very closely correlated. When insulin is increasing, what happens then? This is called insulin resistance. Insulin affects HDL, and fibrinolysis. It also increases the proliferation of smooth muscle cells, which can lead to the development of atherosclerotic plaques and hypertension.