Clinical Geriatrics

Introduction
For younger males with profound hypogonadism, such as those with hypogonadotropic hypogonadism due to Kallmann’s syndrome, testosterone is routinely prescribed to induce and maintain secondary sex characteristics, to allow for normal sexual function, to promote a male body composition, and to provide estrogen for bone health. The situation is more complex when it comes to older men with borderline low testosterone levels and nonspecific symptoms of hypogonadism. The Endocrine Society recently published a Clinical Practice Guideline entitled “Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes.”¹ The punchline of the guideline is to consider testosterone therapy in older men who have both signs and symptoms of androgen deficiency plus multiple documented levels of low testosterone. Although this guideline is very useful in providing 25 specific recommendations, questions and controversies persist due to the quality of evidence used to formulate the guideline. Using an evidence-based medicine grading approach, all recommendations were based upon low- or very low-quality evidence. In particular, there is no consensus as to what constitutes a low testosterone, nor is there consensus as to how many signs and symptoms of androgen deficiency are needed to establish the diagnosis. Hence the controversies in this field. This article seeks to help clinicians decide which hypogonadal men may benefit from testosterone therapy. Exogenous testosterone is not recommended to men with normal testosterone levels for “anti-aging” purposes.

Testosterone and Aging
In men, most testosterone is produced in the testes from cholesterol precursors. Not all testosterone remains testosterone. Some testosterone is aromatized to estradiol, and some is converted via the enzyme 5-alpha reductase to the more potent androgen dihydrotestosterone. The signal for testicular testosterone production comes from pulses of luteinizing hormone released from the pituitary gland. These pulses are responsible for the variable serum levels of testosterone within an individual on a given day. This interindividual variability highlights the need for multiple measurements of testosterone, especially in the morning when levels tend to be higher.²

It is well known that levels of testosterone and other hormones (eg, dehydroepiandrosterone, growth hormone) decline during aging. Data from men age 39-70 from the Massachusetts Male Aging Study show a yearly decline of 1.2% in free testosterone and 0.4% in total testosterone.³ Would any of these men benefit from replenishing their low testosterone?

What is a “Low Testosterone”?
Members of the Task Force that compiled the Endocrine Society’s Clinical Practice Guideline disagreed on the level of total testosterone below which testosterone therapy should be offered.1 Some panelists favored 300 ng/dL, and others favored 200 ng/dL. Because testosterone levels decline with normal aging, Mohr et al⁴ have proposed using the 2.5 percentile to define the normal lower limit of total testosterone by decade in healthy men age 39-70 from the Massachusetts Male Aging Study. According to their calculations, the lower limit of testosterone would drop from 251 ng/dL for men in the fifth decade to 156 ng/dL for men in the eighth decade.

Given our rapidly growing geriatric population, the “normal” level of testosterone will determine the burden of male hypogonadism in terms of millions of men. Using a cut-point of total testosterone less than 325 ng/dL, Harman et al⁵ calculated the prevalence of low testosterone at 30% for men in their seventies.