Testosterone – Safety

A recent Veteran’s Administration study published in JAMA, the Journal of the American Medical Association, has received much media attention, raising fears regarding the use of testosterone replacement in aging men. The study had multiple flaws that limit its usefulness. Some of these flaws include:

• This was an observational study. These types of studies do not show cause and effect.
• Subjects in this study were relatively sick with advanced coronary disease.
• Only 60% of study patients received one follow up blood study to see if their blood levels had improved.
• Of those that had follow up testosterone levels, the average level was only 332 with the “normal range” being 250-1100. This could hardly be considered a therapeutic level.

The results of this study are contrary to the vast majority of studies supporting the benefits of testosterone replacement. Other studies using better methodology have concluded that:

• “In men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment.”  (Journal of Clinical Endocrinology and Metabolism, 2012)
• “…testosterone concentrations are inversely related to mortality due to cardiovascular (heart) disease and all causes.” (Circulation, the Journal of the American Heart Association, 2007)
• “In older men, lower total testosterone levels predict increased incidence of stroke or TIA (mini stroke) after adjusting for conventional risk factors for cardiovascular disease. Men with low-normal testosterone levels had increased risk.” (Journal of Clinical Endocrinology and Metabolism, 2009)

Testosterone’s effects are body wide. Because about 30% of testosterone is bound to sex hormone binding globulin (SHBG), it is not biologically available. It is the 1% to 2% of free testosterone (free T) that is physiologically active. Its presence is (or lack thereof) manifest in multiple organ systems, with testosterone associated with retention of desirable values of actuarial disease risk and with well-maintained body composition. The impact of falling testosterone levels upon many of these parameters is examined as part of this presentation.

Aging

The decline in testosterone levels associated with normal aging is multi-factorial, with no one event being the most common finding in a given patient population. These events can be measured as the levels of serum testosterone begin to change. Studies suggest that about 20% of men in their 60s, and half of men in the 80s have low serum testosterone levels. Concommintently, metabolic syndrome (MetS), and its conditions of obesity, type 2 diabetes mellitus, and hypertention increase the risk of hypergonadism. Not only MetS impacts men’s health, but adverse environmental factors are attributed to testosterone deficiency.5 6

Anatomy and physiology

Anatomy and physiology change. There is a decline in the absolute number of Leydig cells in the testes; each remaining cell shows a decline in testosterone production. There is an associated decline in testosterone synthesis proteins and enzymes, evidenced in aging Leydig cells. The net result is the presence of fewer cells, lower production per cell, and loss of previous response to stimulatory signals.

pituitary gland

Additionally, the pituitary gland loses the ability to coordinate pulsatile LH secretion patterns and becomes more random. The loss of coordinated LH pulses—rather than a decline in over-all amount of LH production—is associated with diminished testosterone production.

SHBG

Another factor affecting the functional availability of testosterone is the age-related increase in SHBG. SHBG levels increase with age, regardless of intervention, and lower the amount of unbound (free) testosterone. These proteins “cling” to testosterone. Even though testosterone may be present, it is not “free” or biologically available to do its work. Increasing SHBG levels, therefore, reduces free testosterone to an even greater extent than the reduction seen in total testosterone. These factors, act additively to lead to less total testosterone production, and an increase in binding protein levels, further depressing free/functional testosterone levels.

OBESITY

Obesity, however, is associated with decreased SHBG productions, then increases total T, but decreases free T. Although this might seem contradictory, other factors exist. Obesity is associated with increased inflammatory cytokine production and increased aromatization to estradiol in peripheral fat tissues. Consequently the pituitary production of gonadotropins is decreased which then decreases testicular production of T.