Role of testosterone in older men: recent advances and future directions

Testosterone, ill-health & male aging

In cross-sectional and longitudinal studies of men spanning middle to older age, low testosterone has been associated with various measures of ill-health, including poorer memory and cognitive status, metabolic syndrome, Type 2 diabetes, sarcopenia and osteoporosis [1–5]. In addition, it is now evident that low testosterone levels predict increased overall mortality and mortality from cardiovascular disease in men [6,7]. However, reverse causation must be considered in these studies, as systemic illness is associated with lower testosterone levels [8]. Testosterone circulates bound to either sex hormone-binding globulin (SHBG) or albumin, with a small fraction of unbound (free) testosterone. Testosterone levels decrease as men progress from middle age to maturity, with a greater decrease in free testosterone compared with total testosterone [9,10]. This age-related decline in circulating testosterone places men at the upper extremes of age at the greatest risk of having low testosterone levels [11].

Changes in total & free testosterone levels in older men

The pattern of parallel declines in both total and free testosterone may be attenuated in older men. In the Osteoporotic Fractures in Men (MrOS) study of men older than 65 years, total testosterone concentration tended to fall only slightly with increasing age, whereas free testosterone showed a clearer decline in older-age groups [12]. In the Health in Men study of men aged 70 years and older, free testosterone declined with age while total testosterone was stable [13]. This highlights the role of SHBG, which increases with age [12–14], as a determinant of lower free testosterone in older men. These findings are relevant because free and total testosterone may possess distinct associations with specific health outcomes in older men. Lower free testosterone is associated with worse cognitive function and increased prevalence of depressive symptoms in older men after adjustment for various potential confounders, including poorer physical health [15,16]. By contrast, lower total testosterone and SHBG, particularly the latter, are associated with metabolic syndrome, a surrogate marker for risk of cardiovascular disease [17,18]. Lower SHBG may also carry some predictive weight for cardiovascular disease independently of testosterone as it is associated with the presence of smaller, denser low-density lipoprotein and, in one study, increased mortality from cardiovascular disease [19,20].

Role of SHBG in androgen action

The interaction between testosterone and SHBG is complex. Serum levels of total testosterone and SHBG are closely correlated [12,13]. SHBG acts as a carrier protein for circulating testosterone with high-affinity binding occurring between the steroid hormone and SHBG and weaker-affinity binding to albumin. In turn, the proportion of free testosterone can be calculated using mass-action equations taking serum total testosterone, SHBG and albumin concentrations into account [21]. However, it is important to acknowledge that calculation of free testosterone using these methods may not provide an exact estimate [22]. According to the ‘free-hormone hypothesis’, dissociation of testosterone from SHBG and from weaker-affinity binding to albumin provides the ‘free’ hormone capable of entering cells to activate the androgen receptor, a ligand-activated nuclear transcription factor. Recently, this concept has been challenged by the identification of a cell surface receptor for SHBG, megalin, which binds SHBG, facilitating its internalization [23,24]. This identifies a mechanism by which SHBG could directly modulate intracellular availability of testosterone. Adding further complexity to the interaction between androgens and SHBG is the observation that SHBG can also be synthesized locally in androgen-responsive target tissues, for instance in human prostate cancer cells [25]. It remains possible that both free (unbound) and SHBG-bound testosterone in the circulation contribute in varying degrees to the testosterone that will ultimately bind nuclear androgen receptors, with or without prior conversion by 5α-reductase to dihydrotestosterone in target cells. Thus, an analytical template for future studies of associations between androgens and ill-health in older men would include comparisons of the strength of associations between total and free testosterone with relevant health outcomes, and the analysis of potential relationships of SHBG with cardiovascular disease independent of total testosterone.

Testosterone therapy in men with reduced testosterone levels

A positive development over recent years has been the introduction of newer methods of replacing testosterone to treat hypogonadal men. Subcutaneous testosterone implants and long-acting intramuscular testosterone undecanoate offer consistent, stable levels of testosterone while avoiding the skin irritation seen with transdermal testosterone and both the repeated injections and the fluctuating trough-to-peak levels found with shorter-acting intramuscular preparations of testosterone [26]. However, balanced against this are the relatively limited data on the benefit of testosterone therapy in men with low-to-normal serum testosterone levels. Testosterone supplementation in these men provides a modest gain in lean mass and reduction in fat mass and improved bone mineral density, but only marginal or equivocal benefits on general and sexual health, cognitive function and well-being [8,27–29]. Exogenous testosterone supplementation will reduce SHBG levels [29], a potential consideration if higher SHBG levels are metabolically favorable. Additionally, testosterone therapy is associated with recognized side effects, including raised hematocrit and longer-term concerns over prostate cancer [30]. The use of selective androgen receptor modulators (SARMs), which could exert tissue-specific selective biological effects to maximize benefit and minimize adverse effects of androgen action, is a developing area of intense interest [31]. However, it is not clear when such novel agents might become available for wider clinical use. Thus, further studies, preferably of extended duration and randomized controlled clinical trials, are needed to establish definitively whether currently available testosterone supplementation in aging men with low-to-normal testosterone levels will preserve mental, physical and general well-being and reduce the incidence of cardiovascular disease. Until such data become available, only men who meet established criteria for androgen deficiency based on the presence of suggestive symptoms and at least two early-morning samples showing low total testosterone levels should be identified and offered treatment [32–34]. More information is needed before extending the use of free testosterone, particularly calculated free testosterone, in routine diagnostic criteria for hypogonadism. Finally, the biochemical confirmation of low total testosterone levels must take into account the inherent limitations of commonly used testosterone immunoassays, which require careful validation in diagnostic laboratories, preferably against the gold standard of a mass spectrometry-based methodology [35].

Can declining testosterone levels in men be prevented?

An added impetus to finding a wider solution for the issue of declining testosterone levels in aging men comes from reports of population-level falls in male total testosterone levels over the past 20 years, occurring independently of the age-related change [36,37]. If lower testosterone levels are confirmed as a causative risk factor for poorer health outcomes, a rigorous approach limiting testosterone supplementation to men with proven androgen deficiency will leave a substantial number of older men who have low-to-normal testosterone levels at risk of ill-health. Some of these men might obtain testosterone supplements outside of established guidelines for treatment and, of the remainder, only a minority are likely to be recruited into clinical trials of testosterone therapy, leaving a large number of older men whose optimal management remains to be determined. Thus, in addition to recognition and treatment of men with established androgen deficiency, more widely applicable strategies must be developed to address the age-related and population-level declines in male testosterone levels. In this respect, there are recognized risk factors for low testosterone levels that could provide an initial focus for interventional studies in aging men aimed at ameliorating the progressive decline in testosterone levels. Obesity and being overweight, manifesting with raised BMI or waist circumference, are strongly associated with low total and free testosterone levels, while smoking, lower alcohol intake and vigorous exercise have been associated with higher levels of both total testosterone and SHBG [38–43]. However, the adverse health impact of smoking prohibits this unhealthy behavior from consideration as a lifestyle intervention. Finally, insulin resistance, which is often associated with higher BMI or waist circumference, reduces SHBG [44,45]. Thus, prospective studies that focus on encouraging men to adopt healthy lifestyles, particularly to avoid or ameliorate being overweight and obesity, should be conducted with subsequent testosterone and SHBG levels included as end points.

Conclusion

In summary, low testosterone levels are associated with poorer health outcomes in aging men, but the optimal role for testosterone supplementation in older men who are not clearly hypogonadal requires clarification. The role of SHBG and its interaction with testosterone merits further attention. Currently available testosterone formulations can provide stable physiological levels of circulating testosterone, and further randomized controlled trials are required to determine whether testosterone supplementation in older men with low-to-normal testosterone levels will preserve long-term mental and physical health. Pending the outcome of such trials, men could reasonably be encouraged to adopt healthy lifestyle behaviors, particularly avoiding excessive weight gain.

Acknowledgements

BB Yeap thanks Osvaldo Almeida, WA Centre for Health and Ageing, University of Western Australia, for his helpful comments on the manuscript.

Financial & competing interests disclosure

BB Yeap is the recipient of a Clinical Investigator Award from the Sylvia and Charles Viertel Charitable Foundation, New South Wales, Australia. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.