Incorrect testosterone supplementation can increase cardiovascular risk

An important paper just published in The New England Journal of Medicine is a reminder that supplementing any hormone to levels above the normal physiological range can backfire. The authors intent was to investigate the safety and efficacy of testosterone treatment in older men with mobility limitations.

"Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter or a free serum testosterone level of less than 50 pg per milliliter were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months."

Things turned out so poorly that...

"The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group."

As the data came in a worrisome picture clearly emerged:

"...the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group...The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period."

There is an extremely important practical message here buried in the data for anyone interested in hormone replacement/supplementation and the practitioners caring for them. The authors made a supplementary appendix available with more detailed data. It showed what we always see when hormones are applied transdermally (through the skin by gel, cream or patch): in time they accumulate to levels of elevated beyond the range of what is physiologically normal (when we properly measure the bioactive free-fraction hormones). Higher than normal hormone levels cause problems, including symptoms similar to hormone deficiency due to receptor desensitization. This applies to any hormone. Deep in the supplemental appendix we find that the free testosterone went as high as 82 pg/mL during gel supplementation. The functional (physiological) range we use for males age 51-60 is 36-65 pg/mL, for males over 70 years it's 15-45 pg/mL.Another important point: the protocol for this study did not even include how much testosterone was being converted into estrogen by aromatase activity. Elevated estrogen is a serious risk factor for men. For hormone supplementation to be effective and safe we must properly assess all aspects of production, accumulation, receptor function, metabolism and elimination.