Testosterone Replacement Therapy (TRT) - does it really increase risk of heart attack? Commentaries from medical organizations

We previously posted a commentary on the recently published and notoriously flawed study which concluded that TRT increases risk for heart attack.

Does Testosterone Therapy Really Increase the Risk of Heart Attack?

http://www.agelessforever.net/anti-aging-news-articles/entry/does-testosterone-therapy-really-increase-the-risk-of-heart-attack

This is the study which caused the media debates:

January 29th issue, the Scientific Journal PLOS (Public Library of Science) ONE published the article: 

"Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men."

Here we have gathered commentaries from other medical professionals, all in one place:

AMMG

Opinion: Comment on a Recent Testosterone Article

Edwin Lee, M.D., Jeffry Life, M.D., Ph.D., Ron Shane, Ph.D. and Karan Pandar

The authors present their reaction to the article's conclusions. 

The William Finkel et. al. retrospective study on the relationship between testosterone therapy in non-fatal myocardial infarction is certainly misleading, especially when reading the abstract. However, after reviewing this study, the cases of non-fatal myocardial infarctions (MI) were less in the testosterone group as shown on Table 3. The number of cases of non-fatal MI (695) were less under all the all ages when compared to after testosterone therapy, where there were 152 cases of non-fatal MI. Similarly, there were less cases of non-fatal MI for the groups less than 65 years old and over 65 years old. However, the outcome of the study was based on rates per 1000 persons per year, rather than the actual cases of non-fatal MI, which was less when testosterone was used. If the statistics were preformed with the actual numbers of subjects having non-fatal MI, then the outcome most likely would be favorable. 

Dr. Abraham Morgentaler, Associate Clinical Professor in the Department of Urology at Harvard University, wrote the following regarding the statistical results of the study:  “It is possible that the men’s heart attacks in this study were caused by their underlying medical problems not testosterone… most heart attacks occurred in the first 90 days after a prescription was written. It is unlikely that heart attacks could develop in such a short period of time.” (Featured interview: USA Today, January 29, 2014)

An important recent study about the benefits of the use of testosterone was not mentioned in this study. Dr. Shores and her colleagues published "Testosterone treatment and mortality in men with low testosterone" in 2012 in the Journal of Endocrinology and Metabolism 2012 Jun;97(6):2050-8. The results showed that the group that received testosterone had less mortality compared to the untreated group. In regards to William Finkel’s retrospective study, the type of testosterone replacement was not standardized, blood levels were not evaluated, therapy goals were not set and the use of rates of myocardial infarction per 1000 persons per year was used instead of evaluating the actual number of subjects having MI lead to a misleading conclusion. I do agree that a larger non-pharmaceutical-sponsored prospective study is needed to settle this recent debate.

 

http://worldhealth.net/news/a4m-testosterone-therapy 

In response to William Finkle, et al. in PLOS One (29 Jan. 2014) the A4M finds the statistical study fails to represent an actual causal relationship between Testosterone therapy (TT) and myocardial infarction (MI). 

Dr. Abraham Morgentaler, Associate Clinical Professor in the Department of Urology at Harvard University, writes the following regarding the statistical results of the study:  “It is possible that the men’s heart attacks in this study were caused by their underlying medical problems not testosterone…most heart attacks occurred in the first 90 days after a prescription was written.  It is unlikely that heart attacks could develop in such a short period of time." (Featured interview:  USA Today Jan 29, 2014). 

This statistical study is a manipulation of data, and does not represent an actual causal relationship between testosterone therapy and myocardial infarctions. These researchers’ statistical findings are extremely flawed as they don’t accurately account for any phenotypical variability or the fact that multi-factorial variables were not examined in their research project.  There was not any form of analysis of various serum parameters, EKG, exercise tolerance, muscle to fat ratio, the particular nature of testosterone therapy as well as dosing and administration of other drug interactions.  It is possible for any researcher to a manipulate a particular database and exhibit a correlational relationship between testosterone therapy and non-fatal myocardial infarctions.  It is also likely that the succinct population used in this study may have a greater disposition to cardiovascular events as compared to another cohort population of males over 65.  

William Finkle et.  al. writes in their discussion that there are difficulties with this study.  The homogeneous database employed in this study is definitely not representative of other global heterogeneous databases, and most likely in terms of the correlational outcome of this study cannot be generalized to a larger population configuration.  This study should not have ever been published due to its methodological limitations, and Finkle et. al., did not review any of the other variables which needed to be analyzed in order to make an accurate assessment in terms of the relationship between exogenous testosterone normalization and cardiovascular morbidities.  The comparison that was employed in this study using the PDE5I group clearly makes this study invalid.  PDE5I induces vasodilation and therefore is not a valid control group.   What this study does point out is that actual research investigations should be conducted, in the rodent model as well as humans, about how higher levels of testosterone in the older phenotype impacts transcriptional and translation activities which eventuates in modifications in the cardiovascular system.  Furthermore, William Finkle et. al. did not consider any kind of epigenetic factors in his insufficient data analysis.  He is raising certain issues as to criteria which needs to be considered prior to a clinician prescribing testosterone for older males, such as certain phenotypes that should be excluded, based on their pathophysiology from receiving exogenous testosterone replacement. 

Finkle et. al. states the following regarding the shortcomings of his study:  “Further study is needed to examine the risk of a variety of specific serious adverse cardiovascular events in relation to TT dose and duration, and to assess if the risks of TT vary by level of serum testosterone and presence or absence of hypogonadal disease”.  Paradoxically, these researchers discuss elsewhere “low endogenous testosterone levels may also be positively associated with cardiovascular events.”  This article makes salient many issues regarding this therapeutic protocol for the treatment of andropause in men.  Finkle  et.  al. does state that this therapy is pathophysiological, however, his correlational analysis as mentioned is flawed.  Clinicians should consider when prescribing testosterone to the older phenotype whether his overall health status or way of living should warrant this therapeutic protocol. 

Finkle et. al.  did discuss some of the recognized side effects of testosterone therapy “increase of blood pressure, polycythemia, reduction in HDL cholesterol and hyper viscosity of blood and platelet aggregation.”  These pathophysiological parameters can be readily alleviated by a competent clinician with the employment of medicinal protocols.  It is not likely that polycythemia if regulated by a physician could engender cardiovascular events in the older phenotypes who have been placed on testosterone therapy. There have been a plethora of studies which have demonstrated that exogenous testosterone replacement to physiological levels does, in fact, mitigate the risk of cardiovascular morbidities. 

Should a lethargic, obese, and hypertensive patient who is a borderline type 2 diabetic over 70 be prescribed exogenous testosterone therapy?  The physiological parameters of a male patient that is highly educated and involved in cardiovascular exercise programs, and who has an optimal fat to muscle ratio with an exquisite BMI is very different from an obese, hypertensive, pathogenic 65 year old male phenotype.  There is certainly more risk associated with the prophylaxis of a pathophysiological male compared to those optimally conditioned older cohorts.  In the hands of a highly qualified Anti-Aging physician, practicing preventative endocrinological therapies aka Anti-Aging Medicine (see www.worldheath.net),  testosterone replacement therapy can be used in conjunction with exercise, dietary manipulation and other cardiovascular risk factor reductions including the routine monitoring of hematocrit, blood viscosity, platelet counts and other indicators of polycythemia. It is also common practice to remove 100-200cc of whole blood in individuals who are on long-term testosterone therapy to maintain optimal indices. 

This article has caused unwarranted and exaggerated fears in the media and in the non-medically trained public. It has already induced unwanted trepidation regarding this medicinal therapy which has for the preceding 50 years improved the quality of life in millions of males and females.  The popular media will interpret the results of this skewed correlational study, which is unrepresentative of the overall older male population, as causing myocardial infarctions in patients being titrated with this therapeutic strategy.  However, physicians have the responsibility to judiciously manage patients in older phenotypes with multiple co morbidities.  

At the most recent ENDO 2013 Annual Meeting (sponsored by The Endocrine Society), many of the speakers from the international endocrinology community lauded Testosterone therapy as an extremely viable prophylaxis for the mitigation of the symptomology associated with aging-related declines in male hormones.  There was no discussion of increased risk of cardiovascular morbidity with properly administered and monitored Testosterone therapy.  The speakers at the Winter 2013 Session of the 22nd Annual Congress on Anti-Aging Medicine, sponsored by the American Academy of Anti-Aging Medicine (A4M; www.worldhealth.net & www.a4m.com), held December 2013, also lectured on this topic.  These speakers cited overwhelming evidence of benefits of Testosterone therapy; and this protocol for the treatment of Testosterone decline reduced the risk of myocardial infarction. 

Submitted by:

Ron Shane, PhD., O.M.D.

Tina Miranda, M.D., M.B.A., Diplomate ABIM

Karan Pandar

Ronald Klatz, M.D., D.O., President, A4M

Sharon McQuillan, M.D.

Jeffry S. Life, M.D. Ph.D.

 

Commentary by Dr Trutt on the study and on a media presentation of the study: 

http://truttmd.com/brief-comment-yesterdays-ny-times-testosterone-article

Last modified on Thursday, 17 April 2014 19:18
Monica Mollica

Medical Writer & Nutritionist

MSc in Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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