New Study Linking Low Testosterone to Premature Death in Males
Jeff Morris
A new study by Bu B. Yeap, MBBS, Ph.D., et al, published in the Annals of Internal Medicine on May 14, 2024, questions the long-held belief that testosterone shortens men’s lives. This meta-analysis of 11 studies conducted from July 2019 to March 2024 found that participants with the lowest testosterone levels were more likely to die.
The study’s conclusion states that men with low testosterone, high luteinizing hormone, or very low estradiol concentrations had increased all-cause mortality. It says sex hormone-binding globulin concentration was positively associated and dihydrotestosterone concentration was nonlinearly associated with all-cause and CVD mortality.
A summary of the study written by Daniel Kelly, a senior lecturer in biochemistry at Sheffield Hallam University and published May 17 in “The Conversation” says in the study, led by a team at the University of Western Australia, the researchers combined the results of 11 high-quality studies (known as a meta-analysis) investigating the effect of testosterone levels on lifespan. The studies followed men for at least five years and found that participants with the lowest testosterone levels were more likely to die.
Kelly notes that death in this study was from any cause, but digging deeper into the analysis reveals that this is mostly due to heart disease – still the leading cause of death in men globally.
Kelly says it is interesting that the same process underlying heart disease might also contribute to erectile dysfunction. Erectile dysfunction often occurs much earlier than symptoms of heart disease and can act as an early warning sign of existing or future heart problems. Testosterone is known to have a large effect on erectile function, again linking levels of this hormone to heart disease.Â
In his summation, Kelly says testosterone levels typically decline as men age, dropping by about 1% per year from the age of 30. This is sometimes referred to as the male menopause or andropause. This decrease over time is at least partly due to a slow waning of the ability of the testicles to produce testosterone and a reduction in the signals that tell them to. However, other factors can accelerate this decline, including chronic disease.
Edwin Lee, M.D., Assistant Professor of Internal Medicine at the University of Central Florida College of Medicine and a member of the AMMG Conference Planning Committee, told the AMMG E-Journal, “The findings from Yeap et al.’s meta-analysis shed light on the complex relationship between testosterone levels and mortality risks, particularly regarding cardiovascular health. The results showed that healthy men with low serum testosterone of less than 213 ng/dl increase all cause of mortality and men with very low serum testosterone of less than 153 ng/dl increase the cardiovascular disease.”
Dr. Lee continued, “The methodological strength of the meta-analysis lies in the precision of testosterone measurement, facilitated by the use of mass spectrometry versus the previous studies using immunoassays to measure testosterone.”Â
One limitation of the study, noted Dr. Lee, is its predominantly white sample population. “Including diverse ethnic groups in future research could provide a more comprehensive understanding of how testosterone levels influence health outcomes across populations,” he said. But overall, he concluded, “low testosterone levels increases all cause of mortality including cardiovascular disease.”
Mark L. Gordon, M.D., Medical Director of Millennium-TBI & The Millennium Health Centers in Encino, CA, as well as Medical Director of Education, Access Medical Laboratories, Jupiter, FL, and also a member of the AMMG Conference Planning Committee, commented on the study as well. He told the E-Journal, “This recent article noting that low levels of testosterone are associated with an increase of dying at a young age, is pathognomonic of the importance of healthy levels of testosterone, throughout life for both males and females.” He said that once we “move away from the superficial perceptions of Ttestosterone as a gender or reproductive hormone, we will be able to see that it is truly a pleiotropic hormone that influences many biological systems from the brain to skin.”
Dr. Gordon delved deeper into the underlying conditions referenced by the study. “The first question,” he said, “is why do we even see an age related drop off in testosterone? The assumption is that it may represent our genetics or is part of biology of aging, but I contend that it represents a cumulative response by our hypothalamic-pituitary axis due to subconcussive and concussive brain traumas(1). We are aware that head trauma (neurotrauma) causes inflammation which shuts down the hypothalamic production of gonadotrophin releasing hormone (GnRH) thereby leading to the failure of the anterior pituitary to release luteinizing hormone (LH). If there is no LH, there is no stimulation of the Leydig cells to produce testosterone(2,3).
Other causes for primary hypogonadism, said Dr. Gordon, can be in association with genetic abnormalities, testicular trauma, autoimmune disorders affecting the testes, infections like mumps orchitis, or exposure to toxins or radiation (4).
“Neurotrauma and the direct damage to the gonads are the most common causes for low testosterone or hypogonadism which creates the low testosterone level,” said Dr. Gordon.
In their conclusion, Yeap et al state, “We found that the testosterone concentration below which men had higher risk for all-cause mortality was 7.4 nmol/L (213 ng/dL). This adds information on reference ranges based on distributions of testosterone in selected samples of healthy men. Higher SHBG concentrations were associated with higher all-cause mortality, which may be related to its role as the major binding protein for sex steroids in the circulation. We found a U-shaped association of DHT with all-cause and CVD-related mortality risks, which were higher at lower and very high DHT concentrations. Men with very low DHT concentrations also had increased risk for incident CVD events. Further investigation into potential underlying mechanisms for these associations in warranted.”
Original study: Annals of Internal Medicine, 14 May 2024. doi:10.7326/M23-2781