How does pituitary androgen signalling support lifelong health and wellbeing? An integrated transgenic and systems biology approach

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The pituitary gland holds such influence over the body it is commonly dubbed the 'master gland'. Located at the base of the brain, it responds to local and circulating factors by secreting circulating hormones that influence the function of many organs and tissues to support the body's health and wellbeing. Each hormone made by the pituitary is produced by a unique cell-type, which link together to form their own networks inside the gland. Currently we don't completely understand how the pituitary's cells respond to signals from the rest of the body to control the production of these hormones. Testosterone is produced by the testes and is required for healthy development and function of men's bodies, but is also made in small amounts by women too. Receptors for testosterone (called androgen receptors) are found inside all of the cell types in the pituitary gland. It was previously thought that testosterone was required for the production of a pituitary hormone called luteinising hormone (that itself controls the production of testosterone by the testes in a negative feedback loop), however in a recent ground-breaking study using transgenic mice we have shown that blocking of the testosterone signal in the pituitary by knocking out androgen receptors, changes production of two of the pituitary hormones: prolactin and growth hormone, but not luteinising hormone. Taken together, these exciting findings demonstrate that our understanding of the role of androgens in the pituitary is far from complete and that an urgent re-evaluation of this system is required. Therefore in this project, we aim to unequivocally establish the fundamental role(s) for androgen signalling in the pituitary, and how this supports lifelong health and wellbeing. We will first produce a computer simulation of pituitary hormone production using software established in our previous BBSRC-funded projects. This will coalesce all of the published information on pituitary function into a single location and will be used throughout the project to support experimental design, with results fed back into the model to refine our understanding. In our laboratory experiments, we will use mice as a model as their pituitaries contain androgen receptor and produce the same hormones as humans. We can also manipulate the genetics of the mouse by the deletion of genes (known as knockouts or by using mouse genes to control the production of fluorescent reporter genes that label specific cell types.Firstly, we will knockout testosterone signalling just within the prolactin-producing cells (lactotrophs) of the male pituitary to determine whether circulating prolactin concentration is controlled by testosterone in the lactotroph or in another pituitary cell-type. We will determine how testosterone normally suppresses prolactin production, and whether the organisation of the network of lactotroph cells within the pituitary is shaped by testosterone. We will define the role of testosterone in controlling the growth hormone-producing cells of the pituitary (the somatotrophs). We will determine whether testosterone controls the frequency of growth hormone secretion, and whether the organisation of somatotroph cells within the pituitary is shaped by testosterone.We will also define the role of testosterone in the luteinising hormone producing cells of the pituitary (the gonadotrophs). We will dissect the interplay between testosterone, prolactin and luteinising hormone, establishing how these hormones work together in the pituitary.Finally we will determine the localisation of androgen receptor in the female pituitary, and whether blocking the testosterone signal in females impact the estrous cycle or pregnancy. Completion of this project will result in a comprehensive redefinition of our understanding of the roles for pituitary testosterone signalling; significantly improving our understanding of the maintenance of lifelong health and wellbeing.