the basics of men's hormone replacement therapy

Since the 1940s data has shown that men with low testosterone have a higher incidence of coronary artery disease, stroke, and death.  Men with low testosterone have 88% increased mortality compared to men with a normal testosterone (1).  Men with coronary artery disease have significantly lower testosterone levels than men without coronary artery disease (2).  Animals surgically castrated show accelerated atherosclerosis that is reversed by testosterone replacement therapy (3,4).  Men treated with testosterone suppression therapy show a 16% increased risk of cardiovascular disease death from myocardial infarction (5).  Castrated men show similar results with a two fold increase in cardiovascular mortality (6).  Meta-analysis of 19 prospective studies showed a significant inverse relationship between testosterone and coronary disease in men older than 70 years (7).  These studies clearly show that men with low testosterone die of heart disease, and if you lower the testosterone of normal men they die of heart disease.  The current standard of care is to treat men with testosterone assuming that correcting testosterone levels will reverse this cardiovascular and stroke mortality effect.The recent controversy started in 2010 when a study showed that frail elderly men would improve their activity level when given testosterone, however the study was stopped early because of increased coronary artery disease in the men treated with testosterone (8).  This was a small study, and the reason for the increased heart attacks in the treated men may have simply been from their increased activity level.  Every winter frail elderly men have heart attacks while shoveling snow.  A more recent data analysis of the VA computer records showed that men given a prescription for testosterone after their angiogram had a higher incidence of heart attacks and strokes (9). Unfortunately the study did not document that the men actually took the testosterone, or why one group of men was given testosterone while the others were not.  This type of data analysis is very unreliable.  Prior scientifically performed studies have documented decreased coronary artery symptoms in men treated with testosterone.  Neither of these new studies has given us the proof that physicians need to advise our patients regarding testosterone therapy. They do however point out the need for a real scientific study to look into the possible risks.The frail male and VA prescription after angiography publications directly contradict the numerous studies that came before them.  A 2004 randomized placebo controlled trial (the gold standard for medical trials), found testosterone replacement therapy improved symptoms and exercise capacity in men with heart failure (10). Another study of testosterone replacement in men with angiographically proven coronary artery disease showed decreased angina with exercise persisting for the study period of 1 year (11).  There are numerous other studies showing improvement in diabetes, cardiac arrhythmias, cardiac risk factors, etc. while on testosterone. The most recent FDA statement regarding this controversy: “It has not been firmly concluded that approved testosterone treatment increases the risk of stroke, heart attack, or death.  Patients are advised to not discontinue their testosterone therapy without discussing with their healthcare provider.”Low serum testosterone and mortality in male veterans.  Arch Intern Med.  2006 166:1660-52    Anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999 99:1666-703    Natural androgens inhibit male atherosclerosis. Circ Res. 1999 84:813-194   Physiologic testosterone replacement therapy attenuates fatty streak formation and improves HDL cholesterol in the Tfm mouse: an effect that is independent of classic androgen receptor.  Circulation. 2007 116:2427-345    Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.  J Clin Oncol. 2006 24:4448-566    Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality.  J Natl Cancer Inst.  2007 99:1516-247    Endogenous testosterone and cardiovascular disease in healthy older men: a meta-analysis.  Heart 2011 7:870-58   Adverse events associated with testosterone administration.  N Engl J Med. 2010 Jul 8;363(2):109-229   Testosterone therapy associated with higher risk of death, heart attack, or stroke.  JAMA 2013, Nov 6.10   Testosterone treatment for men with chronic heart failure. Heart 2004 90:446-711    Long term benefits of testosterone replacement therapy on angina threshold and atheroma in men.  Eur J Endocrinology 2009 161:443-9