by Jeffrey Dach MD
A Man with Progressive Coronary Artery Disease Unresponsive to Statins
62 year old Jim came just had his third cardiac stent. A year ago, Jim noticed a “tight feeling” in his chest radiating to his throat, was rushed to the ER, and doctors found he was having a heart attack. A coronary angiogram showed extensive coronary artery disease with irregular plaque formation.
Progressive Coronary Artery Plaque in Spite of Low Cholesterol
For 12 years now, Jim’s cholesterol level had been driven down into the 140 area by the “top cardiologist in the area”, who prescribed a hefty dose of a statin anti-cholesterol drug. In spite of the lowest cholesterol level on the planet, Jim’s heart disease progressed relentlessly with worsening calcium scores, worsening angiograms, and worsening symptoms of chest pain. His disease progression was obviously not caused by an elevated cholesterol level. For a discussion of how elevated cholesterol is NOT the Cause of Heart Disease, see my article on patients with familial hypercholesterolemia who have very high cholesterol, yet have no heart disease, proving the hypothesis that cholesterol levels are not necessarily a risk factor for heart disease, and reducing cholesterol levels with drugs may be a fruitless endeavor.
Doctors advise Jim to Stop Testosterone
Jim had been taking topical testosterone for the past 5 years, and recently stopped it because of advice from his cardiologist who pointed a finger and said, “You should stop the testosterone….The testosterone is bad for your heart and probably caused your heart attack“. Jim came to see me for a second opinion.
Jim’s Doctor is Right About That
Jim’s doctor is right in that a number of recent studies have shown a small increase in heart attack rate in men starting testosterone. This is caused by increased hematocrit (red blood cell count) and increased iron stores which thicken the blood and make it more susceptible to blood clot formation, all risk factors for heart attack. See my article on this. The simple solution is to monitor blood count and iron levels, and donate blood at the blood bank every 4 to 6 weeks to reduce iron and red cells.
Our Approach to Preventing Heart Disease
I must preface these remarks with our approach to prevention and reversal of heart disease which is outlined in Part One and Part Two of this series. We credit and rely heavily on the “Track Your Plaque Program ” by William Davis MD. We also use the Linus Pauling Protocol.
Bioidentical Hormones For Prevention and Reversal of Heart Disease
In this article we will revisit the role of the testosterone and estradiol in prevention and reversal of heart disease, looking at the latest research. Firstly, let’s try to answer the question:
” Is low testosterone a risk factor for heart diease, and is normal testosterone level protective of heart disease?”
Here we assume red cell count and iron levels are kept under control with monthly trips to the blood bank, so there is no short term increase in heart attack rate from hypercoagulability, as noted in a few recent studies of men started on testosterone.
Low Testosterone is Predictive for Increased Mortality from Heart Disease
If testosterone was causative of heart disease, one would expect men with high testosterone to have more heart disease, and men with low testosterone to have less heart disease. This is exactly opposite of four major studies showing men with low testosterone have both increased all-cause mortality and increased heart disease mortality.(1-4)
Testosterone Levels in Men With Heart Disease
A recent study by Malkin looked at Testosterone levels in men with known underlying heart disease. He showed that low Testosterone is common in men with underlying heart disease, and this is associated with almost double the mortality rate.(5) Again these findings suggest that higher Testosterone is protective and prevents progression of heart disease. The assumption that Testosterone causes progression of atherosclerosis plaque has been shown false.(6-9).
Above image: Cross section of arteries (left to right) showing development of fatty streak which enlarges into the atherosclerotic plaque.Animal Studies on Mechanism of Protection A number of elegant animal studies have been done to elucidate the mechanism by which testosterone is protective of heart disease. A 1999 study by Alex Andersen in rabbits showed that testosterone reduced aortic atheroscleosis.(10) Castrated rabbits had low testosterone levels and doubled the aortic atherosclerosis plaque formation, suggesting that testosterone has a strong preventive effect on male atherosclerosis. In the groups receiving testosterone or DHEA they found marked inhibition of atherosclerosis compared with placebo. The mechanism was not clearly defined. They speculated on a non-lipid mediated mechanism, possibly related to aromatase conversion of testosterone to estrogen.(10 )
Mouse Model- It’s Really the Estrogen That’s Protective
In an elegant 2001 study published in PNAS, Nathan et al used a mouse model of accelerated atherosclerosis to show that testosterone inhibits atherosclerosis by its conversion to estradiol by the aromatase enzyme. Similar protection from atherosclerosis was obtained by administering estradiol. In addition, blocking conversion of testosterone to estradiol with the aromatase inhibitor, anastrazole, eliminated the protective effect, and these animals had progressive atherosclerosis.(11) Dr Nathan says:
“Testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall”.(11)
This information suggests that men with heart disease should NOT take arimidex (anastrazole) along with their testosterone replacement therapy.
Genetically Altered Mouse Model Provides Answers
These findings were confirmed by Nettleship in a 2007 study published in Circulation using the Tfm genetically modifired mouse. This is a mouse genetically altered to have a defective androgen receptor. In these mice, testosterone cannot work through its normal pathway, since there is no receptor. In spite of the lack of androgen receptor, Nettleship found that testosterone replacement in these mice attenuated atherosclerotic changes (fatty streak formation), suggesting the protective effect of testosterone was independent of the testosterone receptor. The authors concluded that the protective benefits of testosterone were through aromatase conversion to estradiol, and then via the estrogen receptor pathways.(12)
Dr Nettleship’s findings were confirmed by Bourghardt in a Nov 2010 study published in Endocrinology which using “ARKO” mice, genetically modified to “knock out” the Androgen Receptor, modified to be Apo-E deficient (to accelerate atherosclerosis). The authors showed that testosterone therapy administered to the ARKO mice inhibited atherosclerosis. However inhibition of atherosclerosis was more profound in the wild type mice that still had intact androgen receptors. The authors concluded the mechanism of protection of testosterone was due to both mechanisms, through the Androgen Receptor as well as through aromatase conversion to estradiol.(13 )
These genetically modified mouse studies suggest that testosterone’s cardio-protective benefits are due to conversion to estrogen, and that estrogen is the cardioprotective agent. Both estrogen and testosterone are bioidentical hormones. Clearly the message here is Testosterone Replacement Therapy should be an important part of any heart disease prevention program, in those patients who have low Testosterone levels.
Why Do Men Have More Heart Disease Than Women ?
Men and women are quite different when it comes to heart disease. Men have more than twice the risk of dying from coronary disease than women. (14) In women, coronary artery disease (CAD) develops on average 10 years later than in men.(15) Could higher levels of estrogen (estradiol) in women explain the protection enjoyed by women?
Estrogen is Protective
Dr Xing from the University of Alabama would say, yes of course. In a 2009 article, Dr Xing names a number of mechanisms by which estradiol protects both men and women from heart disease. He says:
“Estrogens have antiinflammatory and vasoprotective effects. Natural endogenous estrogen 17β-estradiol (bioidentical) has been shown to cause rapid endothelium-independent dilation of coronary arteries of men and women, to augment endothelium-dependent relaxation of human coronary arteries, and improve endothelial function…Observational studies have shown substantial benefit (50% reduction in heart disease) of hormone therapy in women who choose to use menopausal hormones.”(15 )
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