Testosterone Myths Part 2: Major Adverse Cardiovascular Event (MACE) 

Introduction

First and foremost, 

MEN, be grateful and thankful for Abraham Morgentaler, MD, a well published Harvard based Urologist, who did many of the studies on TRT (testosterone replacement therapy) showing it to be of benefit and not harmful to men.

TRT Has More Benefits than Risks for Most Middle Aged Men:

Because of Dr. Morgentaler’s research, men can replete their testosterone levels without fear: 

• of developing prostate cancer, (link to prostate and first T blog)
• or adverse cardiovascular events such as stroke, heart attacks or death. 
• In fact, just the opposite can occur.  

“Morgentaler’s research has shown TRT for men with low T can improve libido, sexual function, muscle mass, mood, and cognitive function”.  A side benefit is better relationships. 

Men often state, ‘I feel more like myself again’ referencing:

• increased energy, 
• increased cognitive function, 
• increased motivation and ability to exercise, 
• increased recovery,
• better sleep 
• decreased erectile dysfunction, 
• decreased joint pain
• and overall, feel healthier in all aspects of physical health, mental health and quality of life when on TRT.

What Your Doctor Might NOT tell you about TRT:

This series of blogs is about negative things you may hear, or your doctor may tell you about TRT.  If your doctor tells you repleting testosterone is harmful to your health, ask them to review the last 20 years of research and then give you, their opinion. Every patient can be different!!  

This blog discusses in chronological order how the belief TRT was thought to cause major adverse cardiac events (MACE) was started, and summarizes events leading to the reversal of this belief in 2025.  It is a story of a faulty article being accepted by a well-renown journal, a false outcome exaggerated by the media, and the subsequent effects ultimately affecting patient care adversely. And the cause of thousands of medical lawsuits against TRT drug makers. 

Why Your Doctor May tell you TRT is Bad for your Heart?

TRT therapy used for 86 years suddenly became controversial November 6, 2013:

• After a Flawed study:
  • was published in JAMA, Immediately After Which Retraction Efforts Began.

• • The Untrue Title:  
    • ‘Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with Low Testosterone Levels’  

• This title means TRT causes major adverse cardiac events (MACE). 

• The article was repudiated by many doctors around the world who proved the opposite to be true based on raw data from the study; 

• Testosterone does not cause adverse cardiac events.  

• However, the stone had been cast, and the media caused a frenzy as reported by CBC, CBS, NBC nightly news, and Bloomberg. In addition, television advertising started immediately exaggerating “ the risk of medical treatments, (referencing testosterone) to the detriment of public health and health care.” 

• The media spread hysteria and lie of the title.  

• Churchill once said paraphrased, “a lie gets halfway around the world before the truth has a chance to get its pants on”.  

• “The power of narrative is once a story is established , it is difficult to change it, no matter the strength of contradictory evidence.

• Prior to 2013 and after 2013 only a handful of mostly retrospective studies alluded to TRT causing MACE.

 

• • Doctors Still Refer to This Article as Truth: 
    • There are a significant number of doctors still referring to this article when citing reasons not to do TRT.  
    • They should not be citing this article as the article is flawed and conclusions were not accurate.  

• Corrections were made to the article, but the article and title itself were never retracted.

 

• 2013, The Study Data: 
  • Claimed a 29.8% absolute event rate of adverse cardiovascular events in treated men, which was later corrected to 10.1%.  
  • Many more flaws pointed out by Morgentaler and others, included 9% inclusion of women in a male-only dataset, criticized as “medical literature malpractice”.  
  • In fact the actual, “ post-prescription MI rate of 4.75 events per 1,000 person-years was very low, approximately one-third the expected rate based on the National Heart, Lung, and Blood Institute’s “CVD Risk Calculator”.

• The Controversy: 
  • Following the identification of severe, “gross data mismanagement,” 25-29 medical societies, including the Androgen Study Group, called for the study’s retraction. 
  • Dr. Morgentaler highlighted the study’s conclusions were directly opposite to the raw data.
  • JAMA failed to retract the flawed study.
  • A 2015 Mayo Clinic Proceedings article by Morgentaler et al. concluded the original JAMA study was a “weak source of evidence” highlighting Testosterone Therapy (TRT) does not increase cardiovascular risks. 

 

• 2015 FDA adds black box warning:  
  • To complicate the controversy, the FDA reacted to the study by putting a black box warning on Testosterone for MACE, 
    • despite backlash of MD’s around the world, 
    • and despite the FDA warning stating “To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non‐fatal myocardial infarction, non‐fatal stroke, and cardiovascular death, with the use of testosterone compared to non‐use”. 
  • This FDA warning encouraged doctors to believe the 2013 article was the truth.
  • FDA mandated a study be done to clear the controversy.

 

• 2023 FDA Mandated TRAVERSE Study Results were Released: 

• This study mandated by the FDA to clarify testosterone’s effect on MACE included 316 clinical-trial sites in the US and enrolled 5246 men 45-80 years old with preexisting or high risk of cardiovascular disease and symptoms of Low T (hypogonadism). Testosterone used for TRT was 1.62 % testicular gel every day. 
• Data: Major Adverse Cardiac Events occurred in:                                                        
• TRT Group:      182 patients (7.0%)   (182/2601) 
• Placebo Group: 190 patients (7.3%)   (190/2596)

• Conclusions: TRT is generally safe for the heart, 
  • TRT does not increase risk of major adverse cardiac events (MACE) in hypogonadal men. 
  • Low T is linked to poorer outcomes in congestive heart failure (CHF), coronary artery disease (CAD), metabolic syndrome, Type II Diabetes
  • The study incidentally noted a higher incidence of non-major events, atrial fibrillation and acute kidney injury. These will be addressed in another blog as there is mixed evidence.
  • Positive findings incidentally noted were:
  • correction of anemia linked to increased red blood cell production and a decrease in Type II Diabetes

 

• 2024 Androgen Society Position Paper:  

• “Androgen Society. an international, multidisciplinary medical organization committed to advancing research and education in the field of testosterone deficiency and testosterone therapy”.  

• • • Position Paper Response to the 2023 TRAVERSE study: “Results revealed no greater risk of MACE (myocardial infarction, stroke, or CV death) or Veno- thrombotic events in men who received TRT compared with placebo. 

• Review of prior literature reveals near uniformity of studies reporting no increased MACE with TRT. 

• This includes 2 additional large randomized controlled trials, multiple smaller randomized controlled trials, several large observational studies, and 19 meta-analyses. 

• In view of these findings, it is the position of the Androgen Society it has now been conclusively determined TRT is not associated with increased risks of heart attack, stroke, or CV death.”

 

• • April 4, 2025. FDA issued Testosterone labeling changes:  
    • Removal of black box warnings regarding MACE
    • FDA stated there is no increase in risk of major adverse cardiovascular events (MACE). 
    • FDA issued new warnings regarding increased blood pressure. This has also found not to be true and will be addressed in another blog.

• The only media coverage was by NBC. 

 

SUMMARY

• In 2013, a highly flawed study was allowed to be published in JAMA, a highly respected medical journal, the title stating TRT causes major adverse cardiac events (MACE).
  • This caused a frenzy of media exaggeration who supported the results of the flawed article. 
• The data when corrected showed the opposite outcome; men receiving testosterone had lower adverse cardiac events. 
  • In addition, patients with low T had poorer outcomes of congestive heart failure, CAD, metabolic syndrome and Type II Diabetes. 
• In 2015, despite corrected data, and FDA stating ‘data was inconclusive for determining the risk of MACE’,  
  • the FDA put a black box warning on testosterone for MACE 
  • this resulted in an immediate decrease number of testosterone scripts being written, impacting men’s health in need of TRT.
• In 2023, ten years after the original article, the 2023 TRAVERSE study proved what was already known:
  • TESTOSTERONE DOES NOT CAUSE ADVERSE CARDIAC EVENTS 
• In 2025, FDA takes off the black box warning but adds a warning of high blood pressure which will be presented in another blog showing TRT over time decreases high blood pressure. 

The testosterone controversy created by a flawed but unretracted article is a major reason why doctors may tell you testosterone is bad for your heart.  Although proven to be incorrect, the original article title remains in the literature creating confusion for all. 

Results of the 2023 TRAVERSE study never made it to multiple news media outlets as did the original flawed article. Therefore, the general public and some doctors were not aware of this reversal, and not aware TESTOSTERONE DOES NOT CAUSE MAJOR ADVERSE CARDIAC EVENTS. 

Have an exceptional day, Dr D