At the Endocrine Society’s recent ENDO 2015 meeting in San Diego, I managed to score a seat in a packed-to-overflowing symposium discussing some of the controversies surrounding testosterone therapy in men.

At the heart of the discussion ws the fact that testosterone prescribing in men has dramatically increased over the last several years, primarily due to an increase in prescribing of this hormone to
men who do not have a medical reason for failure of testosterone production (ie a testicular or pituitary problem), but rather, are men who have a low-ish testosterone due to aging or obesity, in hopes that they may feel better with testosterone therapy. The prescribing of testosterone in men without a true failure of testosterone production has raised a number of safety concerns – in particular, whether testosterone may increase the risk of heart attacks or stroke.
The first point that was made in the symposium by Dr Alvin Matsumoto is that men may be labelled as having low testosterone, when, in fact, they don’t. The problem here lies with a number of concerns with the accuracy of measurement of testosterone levels in men:

  • First of all, testosterone needs to be measured in the morning, as levels are highest in the morning and fall later in the day; ‘normal’ ranges have been developed based on the early morning measurements.
  • Second, there are a lot of problems with the accuracy of testosterone measurement – one study looked at over 1000 different labs and found that testosterone levels on the same sample varied by 6 fold (ranging from very low to well within the normal range).
  • Third, testosterone levels are not the same from day to day in one particular man – in fact, in men who have a low testosterone measured initially, about a third will have a normal level on repeat testing.  
Dr Shehzad Basaria then took us through an excellent review of the conflicting data around the effect of testosterone on cardiovascular (CV) risk.  Population studies suggest that testosterone
treatment decreases the risk of CV events, but it is possible that it is men more concerned about/interested in their health that were taking the testosterone, so these results may just reflect that healthier men were tending to take testosterone in the populations studied.  Other retrospective studies, on the other hand, have suggested that testosterone treatment increases the risk of CV events – these studies suggested that it is older men, and those with pre-existing heart disease, who had the highest risk.  This is highly relevant to the discussion of whether it is safe to prescribe testosterone to men with age- or obesity-related decline in testosterone, as this is a group of men who are older and more likely to have pre existing heart disease.
We always look to randomized, controlled clinical trials for the answers to these questions if at all possible – and in fact, a recent study called the TOM study was stopped early because they saw a higher risk of CV events in the group of men receiving testosterone treatment. The TOM study results have been criticized because they were studying muscle strength as their primary endpoint of interest and not CV events per se – but the results are what they are.
As far as how exactly testosterone treatment could increase the risk of heart attacks, we don’t know, but several possibilities have been suggested, including increase in clotting tendency/inflammation, driving testosterone levels too high with treatment, and fluid retention.
Because of the concerns that testosterone treatment may increased the risk of cardiovascular events, the FDA has now stated that testosterone treatment is only approved for men with true failure of testosterone production caused by certain medical conditions (these would include a primary problem with the testicles such as previous injury, mumps, or chromosomal issues; or the pituitary gland such as a pituitary tumor or radiation damage). They go on to state that the benefit and safety of testosterone has not been established for the treatment of low testosterone due to aging, even if a man’s symptoms seem related to low testosterone.  The FDA also now mandates that the labeling for testosterone treatments includes a warning that it may increase the risk of heart attack or stroke.
Clearly, much more research is needed to answer our questions in this controversial area.

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