The recent study, “Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels” published Nov. 5 in the Journal of the American Medical Association (JAMA), is flawed and will discourage aging men from properly restoring their testosterone levels, according to a review by Life Extension scientific and medical staff affiliated with the Fort Lauderdale, Fla.-based longevity organization.
The study suggested testosterone therapy may increase the risk of cardiovascular events like heart attack. However, according to Life Extension’s scientific review, there were several significant shortcomings in the study's design and methodology, and the results conflict with an existing body of research.
In studies designed to assess the impact of testosterone replacement therapy, one of the most important considerations is to measure subjects' blood levels of testosterone regularly throughout the study period. This allows the physicians and researchers conducting the study to make sure subjects are taking their testosterone as directed and that their blood levels are rising as expected.
In the retrospective study published in JAMA, only 60 percent of study subjects receiving testosterone had a follow-up blood test to assess their testosterone levels. Among them, average testosterone levels rose from a very low level of 175.5 ng/dL at baseline to a still far-from-optimal level of 332.2 ng/dL during testosterone therapy.
Raising testosterone levels from a very low 175.5 ng/dL to a still low 332.2 ng/dL is unlikely to deliver robust health benefits. In fact, research has shown that restoring testosterone levels to at least 500 ng/dL is associated with pronounced health benefits, whereas benefits may be less evident at lower levels.
“Over the years, several studies have shown that testosterone replacement therapy to appropriate levels in aging men with low testosterone levels at baseline improve several markers of male vitality, such as bone density, sexual desire, psychological health, and cardiovascular benefit, in contrast to this flawed study,” says Steven V. Joyal, M.D., chief medical officer with Life Extension.
For example, in a revealing study, researchers identified 2,416 men (aged 69 to 81 years) who were not on any kind of testosterone-affecting treatment. These men were subjected to a battery of blood tests that included total testosterone and estradiol. The first observation was that men with increasing levels of testosterone had a decreased prevalence of diabetes, hypertension, and body fat mass. Compared to men with the highest testosterone levels, those with low testosterone were twice as likely to have a history of cardiovascular disease. Specifically, men in the highest quartile of total testosterone (above 550 ng/dL) had a 30 percent lower risk of cardiovascular events. Any level of total testosterone below 550 ng/dL resulted in significantly increased risk, thus helping establish a minimal baseline as to where total testosterone should be to guard against heart attack or stroke.
“Furthermore, additional data suggests that low testosterone is linked with an increased risk of type 2 diabetes and abdominal obesity in aging men,” continued Dr. Joyal.
Based on a review of research by Life Extension, the study also fails to account for the impact of estrogen. One of the biggest perils facing aging men is the conversion of their testosterone into estrogen by aromatase. Aromatase is an enzyme that converts testosterone and other androgens into estrogen, primarily estradiol. Although some conversion of testosterone to estradiol is essential for health, too much conversion can have devastating consequences for men.
In the retrospective study recently published in JAMA, there was no report of the subjects' estradiol levels. If estradiol was not monitored during testosterone administration, this oversight means that the men receiving testosterone could have experienced a concurrent rise in estradiol levels. This reaction may have compromised their cardiovascular health and could partially account for the increased risk observed in the testosterone-treated group.
Based upon an analysis of this study and the existing research, Life Extension continues to recommend that aging men restore testosterone levels to youthful ranges for optimal health.
“The goal of testosterone restoration in most cases is to restore youthful blood levels of the hormone. Typically, Life Extension suggests men target a blood level of testosterone between 700-900 ng/dL for optimal health,” says Luke Huber, N.D., M.B.A. and vice president of product innovation and scientific development for Life Extension. “In this study, average testosterone levels rose from a very low level of 175.5 ng/dL at baseline, to a still far-from-optimal level of 332.2 ng/dL during testosterone therapy. Also, the testosterone treated group had significantly lower baseline testosterone levels than controls. The effects of years of potentially lower testosterone levels was not accounted for in the study and may have skewed the results,” says Dr. Huber.
Life Extension doctors note that the decline of men's testosterone levels over the years is inevitable. Unless aging men replace their diminishing testosterone, they could succumb to any of the numerous health problems linked to low testosterone levels including frailty, muscle loss, weight gain, impaired cognition, fatigue, loss of self-confidence, depression, declining bone health, increased risk of type 2 diabetes, stroke, and cardiovascular disease.