Androgens: unlocking the key drivers of male health and wellbeing

Male health and wellbeing is testosterone dependent. Low circulating testosterone concentration is linked to an increased risk of developing chronic and age-related conditions, such as obesity, diabetes and heart disease. However, to date, the cause/consequence relationship has not been established, making it impossible to provide personalised therapy for these men. Testosterone replacement therapy is commonly used in men with low testosterone, and can improve symptoms in many cases, however, this is not without controversy, with several recent clinical trials suggesting treatment may increase risk of heart attacks and strokes, and increase the aggressiveness of prostate cancers. This places us the challenging position where both low testosterone and testosterone replacement therapy are associated with negative clinical outcomes. In adult men 95% of circulating testosterone is produced by specialised Leydig cells within the testes, as such the testis represents the body's 'testosterone factory'. The purpose of this research is to provide a fundamental understanding of the natural processes that support the development and maintenance of these Leydig cells, to support an optimal testosterone profile throughout life, as evidence suggests that this is the best protection for lifelong male health. We will also develop and test new therapies that can support or enhance testosterone production by the testis, as an alternative to testosterone replacement therapy. Establishing a healthy testosterone profile: Leydig cells form a stable population in adulthood, barely changing in number throughout life. Understanding how a population of fully functioning Leydig cell develops is essential if we are to develop strategies to support or increase testosterone production in men where it is suboptimal. We will investigate the origin of the Leydig cell population and determine how other cells and hormones within the testis interact to promote and support the development of the Leydig cell population. Through this process, we will not only generate understanding, but also identify factors that can be manipulated to improve Leydig cell development or function. Maintaining a healthy testosterone profile throughout life: Reduced testosterone production in adult life is unquestionably linked to pathologies. Understanding the cause/consequence relationships and identifying ways to retain and functionally support the Leydig cell population throughout adulthood is essential for promotion of lifelong male health. We will generate transgenic mouse models of premature ageing, to understand the impacts of ageing on the testosterone production machinery of the testis, and how a healthy testosterone profile can be maintained throughout life. We will also determine how obesity and diabetes suppress testicular testosterone production and identify approaches to overcome this. Repair, regenerate or replace the Leydig cell population: To develop new therapies that can support or enhance testosterone production by the testis, we will modify viruses to deliver new genetic material directly to cells of the testis. This approach will allow us to modify or ablate the function of a gene in order to understand its role under normal conditions. We will also use this system in a gene therapy approach, to deliver genes that will support or improve testosterone production by the testis. In a second approach, we will identify ways of specifically killing the Leydig cell population, as we know from rat studies that doing so leads to regeneration of a new, youthful Leydig cell population. Finally, in a third approach, we will inject new cells directly into the testis, which we believe will support or improve testosterone production. This Research will provide a detailed understanding of the mechanisms underpinning a healthy lifelong testosterone profile, and unlock the potential of the testicular 'testosterone factory' to support this in men throughout life.