Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations

Abstract

The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effective in ameliorating distinct symptoms of late-onset hypogonadism (LOH), its safety remains to be demonstrated. Besides humans, multiple other species exhibit age-related reductions in circulating testosterone levels, raising the question whether such changes are an inherent, pathological feature of growing organismal age or rather reflect an adaptive response. In this manuscript, we apply key principles of evolutionary medicine to testosterone biology and LOH to provide a novel perspective on these two fields. Additionally, we discuss insightful data derived from the animal kingdom to illustrate the plasticity of individual testosterone trajectories across the lifespan, outline cost-benefit-considerations of TRT in LOH and highlight potential caveats of such therapies.

Keywords: Endocrinology; Evolution; Hormones; Late-onset hypogonadism; TRT; Testosterone.

Figure 1:. Symptoms of hypogonadism.

Low circulating testosterone levels are associated with several detrimental health effects including diminished libido, erectile dysfunction, loss of muscle and bone mass, increased visceral adiposity (potentially yielding impaired glucose tolerance), melancholia (eventually culminating in depression) and anemia. Whether hypogonadism actually confers enhanced risk for cardiovascular disease is still a matter of controversy.

Figure 2:. Aging as a trade-off between reproduction and repair.

According to Darwin’s theory of evolution, natural selection favors traits conferring enhanced fitness. The term “fitness” is often loosely defined but essentially refers to reproductive success, i.e. higher fitness (better adaptation to a given environment) equals enhanced reproductive success. However, selection of traits conferring higher reproductive fitness will inevitably result in lower resource allocation into repair programs (maintenance) because organismal resources are finite. Consequently, prioritization of reproductive success limits lifespan (trade-off). Neither too much, nor too little investment into repair is favorable because both will result in reduced fitness: the former because of “overinvestment” of resources into repair programs, the latter due to premature death. Yet, indefinite survival would only be achieved if resources were placed sub-optimally. Since this strategy would culminate in impaired (reproductive) fitness, such traits will not be selected for. Hence, organisms do not exhibit these extensive repair programs, which may explain their finite lifespan (after Kirkwood & Cremer, 1982).

Figure 3:. Testosterone trajectories in baleen whales.

In baleen whales, hormones are embedded into the baleen matrix in a continuous fashion, thus providing a unique opportunity to study individual testosterone trajectories over the lifespan. The left panel shows annual testosterone cycles in a baleen bowhead whale. Material close to the base reflects new baleen corresponding to a more recent endocrine status. Note that the magnitude of the annual testosterone peak progressively declines with growing age of the animal, reminiscent of decreasing circulating testosterone levels in aging humans. The right panel illustrates similar dynamics in a male North Atlantic Right Whale (NARW). After being challenged by an insult in one year (entanglement, sickness), the animal exhibited a strongly decreased testosterone peak in the consecutive year perhaps reflecting a prioritization of resource allocation into maintenance and repair programs rather than growth/reproduction. Comparable adaptations occur in humans, where almost any persistent evolutionary relevant stressor (e.g. infection, starvation, cold) evokes suppression of testosterone levels (after Hunt et al., 2018).