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Testosterone's beneficial impact on cardiovascular health.

It was not so long ago that cardiologists were warning us to avoid testosterone as they believed that it increased the risk of heart disease. Those original studies have been dismantled and shown to be inaccurate as they were poorly constructed and poorly interpreted. Newer literature has at every turn shown us that testosterone is a tremendous key to advancing cardiovascular health. Hypogonadism that results in suboptimal testosterone levels is very dangerous as it contributes to higher risk of diabetes, hyperlipidemia, hypertension, vascular plaque, metabolic syndrome, and myocardial infarction. This article presents and explores some of the notable research that needs to be instilled into our cardiovascular decision making.

Of significant interest is the observation that testosterone levels are dropping in our general civilization. From the 1980s through the 1990s and into the 2000s, we have seen serial drops in testosterone levels over time for all men of all ages. The Travison study exposed this 10 years ago, and we need to explore why this is occurring as it contributes to our general cardiovascular risk. (1)

The study by Travison measured testosterone levels in three different groups of healthy males age 45 to 80 from 1987 through 2004. They demonstrated an alarming trend in testosterone reduction that was age-independent. This represents a population-based decline, not just the typical testosterone decline that we see with aging. They measured an approximate 22% decline in overall testosterone production across all age groups. So, the question become why are we seeing this drop in testosterone?

There are a host of reasons that may explain why testosterone levels are dropping:

* BPA, Toxins and Pesticides (2-11)

** Arrest hypothalmic and pituitary function and interfere with receptors;

** BPA is correlated with every sexual dysfunction imaginable.

* Polypharmacy

** Increased drug use results in "poisoned" physiology.

** US is 5% of the world population, yet we ingest 50% of all pharmaceuticals made.

* Stress--HPA-G Axis

** Cortisol is adversarial to testosterone

* sleep (12,13)

** Testosterone is victimized by short sleep cycles,

** Testosterone and REM sleep are restorative and directly correlate.

** Obstructive sleep apnea damages testosterone production.

* Weight Gain and Sugar (14-20)

** Obesity and a high fat diet poisons the Leydig cells, reducing testosterone levels,

** High glycemic diet reduces testosterone 25%.

As more men trend towards this problematic fate we need to ask if this drop in testosterone is really a problem or just a simple observation? The amount of literature exploring this is rather robust and shows a clear picture that hypogonadism is not only correlated with inflammatory vascular disease but is causative in the progression to coronary disease. Consider this simple paradigm:

* C-reactive protein (CRP) is predictive of diabetes and cardiovascular events; (21)

* CRP is consistent with obesity and inflammation;

* Elevated CRP is predictive of low testosterone, and testosterone replacement will reduce CRP and reduce obesity; (22)

* Testosterone lowers blood sugar and improves vascular health;

* Testosterone lowers risk for metabolic syndrome and cardiovascular events.

The simple paradigm becomes "inflammation drives coronary disease." Anything that increases inflammatory cytokines will work to reduce testosterone levels. The corollary is that the application of testosteroane in a low androgen state will suppress and reverse the inflammatory state. (23)

In 2013, Zhang looked at CRP-hs and testosterone levels in 1989 healthy men between the ages of 20 and 69. (22) These men did not have coronary disease, stroke history, cancer, rheumatoid illness, thyroid or renal disease. Divided into quintiles for testosterone and SHBG, he demonstrated a linear inverse relationship between CRP and testosterone levels. As testosterone goes up, CRP goes down.

Administration of IL-6 to healthy men suppressed testosterone levels. Inflammatory cytokines have an inhibitory effect on Leydig cell steroidogenesis, altering 3(3-hydroxysteroid dehydrogenase. In the study by Malkin, he demonstrated that testosterone replacement resulted in a significant reduction in inflammatory cytokines. TNFa dropped 50% and IL-1b dropped 37% while anti-inflammatory cytokine IL-10 rose 17%. (24) Kalinchenko's study confirmed this finding and showed that testosterone replacement significantly decreased CRP, and the inflammatory cytokines IL-i[beta], and TNF-[alpha] in hypogonadal men with metabolic syndrome. (25)

We know from other studies that CRP is a much more reliable predictor of coronary risk than simple LDL levels. (21) So, the simple construct is that inflammatory lifestyle drives a rising CRP and this in turn increases coronary risk, while this same lifestyle directly contributes to hypogonadism. Heart disease is the product of inflammation:

* Atherosclerosis is a disease of chronic inflammation.

* TNFa and IL-1b are mediators of atheromatous plaque.

* IL-10 is anti-inflammatory and inhibits atherosclerosis. (26-28)

* IL-10 improves prognosis following an acute coronary event.

These factors all improve under the influence of testosterone. The replacement of testosterone consistently reduces CRP and reverses coronary risk. In fact, in patients with coronary artery disease, testosterone deficiency is associated with poor outcomes associated with heart failure and has a significant negative impact on survival. (29)

Diabetes, Hypertension, and Lipids

Hypertension, diabetes, and hyperlipidemia are used to predict those at risk for coronary events and occupies the majority of the traditional efforts to halt the occurrence of coronary disease. So, what does the literature tell us about these three issues as they relate to testosterone?

Diabetes Mellitus and Testosterone

There is ample literature proving testosterone reduces the risk of developing type 2 diabetes as well as help reverse this condition. The study by Pitteloud looked at 60 men and assessed their mitochondrial function and expression of oxidative phosphorylation genes in skeletal muscle. (30) Those with low testosterone had a reduction in ATP production, thus, altering glucose control. There is a subset of 34 genes responsible for oxidative phosphorylation, and the rate-limiting gene UQCRB (ubiquinol-cytochrome-c reductase binding protein) is testosterone dependent. Consequently, as testosterone levels drop, the cell loses ability to generate ATP. A relationship between low testosterone and risk for abnormal insulin sensitivity was demonstrated.

Testosterone has a positive correlation with UQCRB expression, and testosterone is required for proper expression of genes that drive ATP that, in turn, drive the ATP-pump and affect glucose regulation. Other studies have shown this relationship play out in different ways:

* Among men with diabetes mellitus, the frequency of low testosterone is 20-64%. (31)

* Of men with type 2 diabetes, 54% had low testosterone. The men with lowest testosterone levels demonstrated highest fasting glucose levels compared to men with normal testosterone. (32)

* Men with higher testosterone levels had a 42% lower risk of type 2 diabetes. (33)

* Total testosterone is inversely related to BMI, body fat ratio, and insulin resistance. (33)

* Men with type 2 diabetes have lower testosterone levels than weight-matched non-diabetic control subjects (34,35)

Hypertension and Testosterone

There is older literature showing that testosterone has an inverse relationship with blood pressure. (36) Last year, Vlachopoulos compared non-diabetic, hypertensive middle-aged men to controls and accounted for variables such as age, BMI, smoking, and cholesterol. They found that total testosterone is independently and inversely associated with central pulse pressure, wave reflections, and left ventricular mass. (37)

We have the opportunity to see how blood vessels respond to sudden withdrawal of testosterone by following prostate cancer patients who engaged in androgen deprivation therapy. The study by Smith followed 22 prostate cancer patients as they received androgen deprivation therapy. As testosterone production was blocked (LHRH analog therapy using leuprorelin acetate), the central arterial stiffness was monitored using pulse wave analysis and showed an increase of 21% after just three months. (38) Of equal interest was that a return to normal was seen in those who discontinued the androgen deprivation therapy. Other findings included a loss of lean body mass while fat mass increased. Shocking changes in insulin levels were seen as insulin rose 28% (11.8 mil/liter up to 15.1mU/liter) in just the first month of therapy and further increase in insulin to 19.3 mU/liter was documented after three months of therapy. That's a 63.6% rise in insulin production reflecting a stark rise in insulin resistance, which directly drives oxidation of LDL and atherosclerotic process.

Lipids and Testosterone

Zhang looked at over 4000 subjects in a retrospective study and saw a clearly evident inverse relationship between testosterone level and LDL. (22) They separated 41-14 middle-aged men by quintiles according to testosterone level. This revealed a clear pattern that as testosterone levels rose, HDL level increased accordingly while LDL and triglyceride levels dropped.

The study by Johnston shows us that the ratio of oxidized LDL/HDL is one of the best predictors of vascular disease. (39) In fact this ratio was seven times more predictive than LDL level alone. Given that testosterone supports HDL elevation and is also an immune modulator that inversely correlates with oxidized LDL antibodies, it would make testosterone a valuable marker for heart disease in men as well as a therapeutic strategy.

Coronary Artery Disease and Testosterone

The oxidation of LDL is a critical step in atherosclerosis. Macrophages consume oxidized LDL driving foam cell formation. Autoantibodies to oxidized LDL predict carotid atherosclerosis, impaired coronary vasodilation, and myocardial infarction. Antibodies to oxidized LDL are the most predictive parameter for extent of coronary involvement. The study by Barud looked at a group of men, 65% of whom had a history of stable coronary artery disease, and looked at many variables in search of a correlation to antibodies of oxidized LDL. (40) Alteration in serum anti-oxidized-LDL antibody levels showed no correlation to classical cardiovascular risk factors such as body mass index, waist/hip ratio, smoking, total cholesterol, triglycerides, HDL-cholesterol, or LDL-cholesterol. In multiple regression analysis, only testosterone level was independently associated with anti-oxidized-LDL antibody levels. This suggests that testosterone is acting as an immune modulator, favorably impacting antibodies that drive atherosclerotic process.

Some of the most compelling evidence that testosterone is key to cardiovascular health is held within the studies showing testosterone's impact on cellular energy and GLUT-4 function within the myocyte. Myocardial infarction normally leads to loss of cellular energy within the myocyte. Post infarction is followed by a state of increased insulin resistance, reduced fatty acid oxidation, and impaired mitochondrial biogenesis. (41-43)

A remarkable study in 2016 by Yang showed that a low testosterone state would predict worse outcomes following myocardial infarction. (44) Castration of mice was followed by ligation of a coronary artery to induce cardiac ischemia. The low testosterone state resulted in reduced PPARa activity, increased cardiomyocyte apoptosis, and cardiac fibrosis, along with a decrease in ATP. Mice that received testosterone replacement experienced greater cellular energy and cell viability via GLUT-4 protein function, and greater fatty acid metabolism. Testosterone proved to be supportive of mitochondrial biogenesis and cell recovery.

This is confirmation of a prior study in 2013 by Wilson that demonstrated testosterone increases GLUT-4-dependent glucose uptake in cultured cardiomyocytes. (45) Testosterone increases the cardiomyocytes' ability to utilize glucose as a fuel source via the GLUT-4 glucose transporter, which becomes critical following ischemic events where the cell has severe energetic needs.

Final comments on testosterone's relationship with coronary health include the following:

* Low T is inversely linked to CAD even after adjusting for age and body fat. (46)

* Men with (+) angiography for CAD had lower T than controls, and the degree of coronary involvement correlated inversely with degree of testosterone deficiency. (47)

* Administration of T led to coronary dilatation. (48,49)

* Intima media thickness is increased in men with low T. (50)

* Rotterdam study showed low testosterone levels correlated with increased risk for atherosclerotic disease. (51)

Conclusion

The research of the past 20 years is pointing towards the conclusion that androgens are a key piece of the cardiovascular repair and recovery cycle. Low testosterone levels open the door for inflammation and vascular compromise. When this deficiency is corrected, there is a pattern of decreased inflammation, reduced atherosclerosis, and resultant drop in CAD. This is not to suggest that healthy testosterone levels are the only key needed for good cardiovascular heath, but it certainly plays an integral part in the process. The literature also dispels the myth that testosterone increases the risk for cardiovascular events. In conclusion, if we are not measuring and treating hypogonadism then we are not offering our patients every available avenue for cardiovascular recovery and good health.

References

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(33.) Ding EL, et al. Sex differences in endogenous sex hormones and risk of type 2 diabetes. JAMA. 2006; 295(11): 1288-1299.

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(35.) Andersson B, et al: Testosterone concentrations in women and men with NIDDM. Diabetes Care. 1994; 17(5):405-411.

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(41.) Amorim P, et al., Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression. Journal of Thoracic and Cardiovascular Surgery. 2010; 140 (5):1160-1167.

(42.) Heather LC, et al. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovascular Research. 2006; 72(3):430-437, 2006.

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(44.) Yang J, et al. Testosterone replacement modulates cardiac metabolic remodeling after myocardial infarction by upregulating PPARalpha. PPAR Research. 2016.

(45.) Wilson C, et al. Testosterone increases GLUT4-dependent glucose uptake in cardiomyocytes. Cellular Physiology. 2013; 228(12):2399-2407.

(46.) Phillips GB, et al. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb. 1994 May; 14(5):701-6.

(47.) Rosano GM, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. IntJImpot Res. 2007 Mar-Apr; 19(2):176-82. Epub 2006 Aug 31.

(48.) Webb CM, et al. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation. 1999; 100:1690-1696.

(49.) Chou TM, et al. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation. 1996; 94: 2614-2619.

(50.) Muller M, et al. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation. 2004; 109:2074-2079.

(51.) Hak AE, et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab. 2002; 87: 3632-3639.

Dr. Gary Huber is president of the LaValle Metabolic Institute. He spent 20 years as an emergency medicine physician before joining Jim LaValle in the practice of integrative medicine at LMI. Dr. Huber is an adjunct professor teaching integrative medicine practice at the University of Cincinnati College of Pharmacy as well as a clinical preceptor for pharmacy students. Dr. Huber also lectures on hormone replacement therapies and integrative care for the American Academy of Anti-Aging Medicine for the University of South Florida. He has developed the Metabolic Code Professional Weight Loss Program that has proved very beneficial in reversing metabolic syndrome issues. Dr. Huber has a long-held interest in nutrition and human physiology as they relate to wellness and longevity. He has served as medical director for the Flying Pig Marathon and is presently on the board of directors for Loveland's Amazing Race, a local charity event.

Caption: Graph from Travison article demonstrating testosterone trends in three groups of men from 3 different decades. (1)
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