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.

Male health and wellbeing is androgen dependent. This Programme Grant will address the multifaceted challenges relating to the fundamental understanding of the development and maintenance of an optimal androgen profile throughout life, as the best protection for lifelong health, and seek to develop therapeutic strategies to support endogenous/restorative health for men. We will use a combination of mouse models, and primary human cell culture systems.

1. We will establish the origin of two recently identified adult Leydig cell populations and determine their roles.
2. We will determine how Sertoli cells control adult Leydig cell development and function, and pursue key factors as potential therapeutic targets.
3. We will determine the mechanisms by which androgens, and other paracrine factors drive Leydig cell maturation and manipulate these to support healthy androgen profiles.
4. We will generate models of cell-specific premature ageing, to determine the impacts of ageing on the androgen production machinery of the testis, and how this can be abrogated.
5. We will elucidate how obesity and diabetes impact Leydig cell function, characterizing the mechanisms by which metabolic hormones suppress testicular androgen production and identify approaches to overcome this.
6. We will develop a novel lentiviral gene therapy system to establish gene function in promotion of Leydig cell function, and validate this as a gene therapy vector to support/improve Leydig cells.
7. We will generate novel cell-specific ablation models to identify endogenous pathways that can be activated to induce Leydig cell apoptosis and regeneration of a new, youthful Leydig cell population.
8. We will validate cell transplantation as a mechanism to induce new Leydig cell development.

This will provide a detailed understanding of the mechanisms underpinning a healthy lifelong androgen profile, and unlock the potential of the testicular 'androgen factory' to support lifelong male health

In our increasingly ageing and obese society, where the prevalence of androgen-associated co-morbidities such as cardiovascular disease, obesity and diabetes is increasing in prevalence, our programme of research will ultimately benefit men, by supporting their lifelong health and wellbeing, and thus a sustained quality of life.

Specifically, our research is likely to benefit men in the long-term by (1) providing a platform of fundamental understanding of the processes underpinning the development and support of a healthy androgen profile, (2) identifying biomarkers predisposing to poor androgenic profiles, or reflecting perturbed Leydig cell development, (3) identifying potential pathways and targets for therapeutic development, (4) validating several preclinical therapies relevant to improving androgen profiles in men, and (5) through our results and communication plan, raising public awareness of men's health as a significant societal issue.

Long-term, healthcare providers and policy makers will also benefit from our research, as understanding how we can ensure healthy androgen profiles develop and are maintained throughout life is likely to reduce the prevalence of co-morbidities associated with low androgens (which may require hospital admission and long-term treatment), and also reduce the requirement for expensive androgen replacement therapy (£11.7M per annum cost to NHS in UK; >$3Bn, in USA).

More immediately, our development of new understanding and new technologies with significant potential for wider applications will benefit the larger research community, as this information will be widely disseminated, with data-sets and resources made freely available to others for non-commercial use (please see Academic Beneficiaries Section).

Economic benefits, likely arising through IP protection and spin-out company development surrounding our lentiviral technologies, will be facilitated by the University of Edinburgh's strong commitment to translation and commercialization, and their investments in this area.

Finally, MRC strategic investment in this Programme will significantly enhance the research capacity in the under-resourced field of men's health research. Supporting this nucleation of resources and expertise will permit the training of highly skilled researchers in this field, and provide a solid platform of understanding to support downstream fundamental and translational research in this area both by ourselves, our collaborators, and the wider scientific community throughout the world.