The pituitary corticotroph: an organizing centre for oscillatory activity of the HPA axis?

Rhythms are everywhere in nature, and nearly all hormonal systems in our bodies follow a daily cycle. A good example of this is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the secretion of the vital hormone cortisol, and is the major hormonal system in mammals that provides a rapid response and defence against stress. Cortisol levels are low during periods of resting (sleep) and rise early in the morning to prepare an individual for daily activity.

However, we now know that this hormone is actually secreted in pulses, or short bursts, every hour or so throughout the day, with larger pulses during the morning, making up the general circadian trend. There is now significant evidence that in order for tissues in the body to function 'optimally', oscillating levels of cortisol are essential.

Despite this, patients undergoing both hormone replacement and steroid therapy for inflammatory or malignant disease are typically exposed to constant levels of long-acting synthetic steroids. This pattern of delivery was developed before we understood the importance of cortisol pulsatility, and may well limit efficacy of treatment as well as contribute to the very high levels of side effects associated with the long-term use of synthetic steroids. Moreover, we also now know that the cortisol rhythm becomes disrupted in different physiological and pathological conditions. Good examples of this are the disruptions to the rhythm that are associated with ageing and prolonged stress.

Given that stress-related illness is a rapidly increasing feature of our society, and that aging is a major risk factor for cognitive decline, decreased immune response and frailty, it is very important that we understand the biological mechanisms that govern the body's endogenous production of cortisol; and also how these cycling levels of hormone help to optimise the body's response to environmental influences and to maintain normal internal regulatory processes. Given the complexity of the HPA axis, mathematical models provide a powerful tool with which to appropriately identify these biological mechanisms. By using this approach, we have recently identified a potential network in the body that regulates the pulsatile secretion of cortisol. This is particularly exciting because, now that we understand where this rhythm originates from, we can begin to systematically probe the key mechanisms that are important for maintaining a 'normal' rhythm. This, in turn, will help us to understand how and why the rhythm changes in ageing and disease, and how these changes cause, or protect us from pathological consequences.

The hypothalamic-pituitary-adrenal (HPA) axis, which regulates the secretion of vital glucocorticoid hormones, is the major neuroendocrine system that provides a rapid response and defence against stress. The HPA axis is characterized by an ultradian rhythm of glucocorticoid secretion that changes in different physiological and pathological states. If we can understand the precise biological mechanisms that regulate this rhythm, then we will be in a better position to understand how and why this rhythm becomes disrupted in conditions such as ageing and chronic stress.

There has been considerable dispute as to whether ultradian glucocorticoid oscillations originate from a neural pulse generator within the hypothalamus. I have used a combination of experimental and mathematical modelling to show that the ultradian rhythm of glucocorticoid secretion can originate from a pituitary-adrenal peripheral network, thus independently from any pulsatile hypothalamic activity. This in turn implies that corticotroph cells within the anterior pituitary play a crucial role by acting as an organizing centre that regulates the oscillatory activity of the HPA axis. To investigate this, I will use both theoretical and experimental approaches to understand how the balance at the pituitary between positive inputs from the hypothalamus, and negative inhibition from circulating glucocorticoids, determines the oscillatory activity of the pituitary-adrenal system.

There is now clear evidence that oscillating levels of glucocorticoids are essential for optimal gene transcription in target tissues, including the liver and the brain. Identifying where this rhythm originates from is particularly exciting because, for the first time, it provides a platform from which we can now begin to systematically investigate the mechanisms underlying the ultradian rhythm, and how these may change or malfunction leading to disrupted rhythms that we see in various physiological and pathological states.

This Impact Summary contains details of beneficiaries and the mechanisms by which my fellowship would achieve impact.

In the very short term, I and my direct collaborators will benefit. In particular, the fellowship will provide me with the opportunity to develop my own research career, and crucially to learn cutting-edge in vitro techniques that will enable me to address the challenging questions of the origin of dynamic glucocorticoid rhythmicity that I pose in the proposal. More generally, my direct collaborators will benefit from my fellowship which will act as a bridge between these world-leading research groups.

In the medium term (1-3 years), Patient Forums, Biomedical Researchers and the MRC will benefit. With regards to Patient Forums I will organize an outreach event that will involve representative groups for patients with HPA-related disorders. The MRC presently has a cross-board highlight notice: "Systems Biology for Medicine", the remit of which is satisfied by my fellowship proposal. As such, findings from my fellowship can be used to highlight the success of this notice by the MRC. Biomedical researchers will benefit, both from publication of my research findings, as well as the workshop that I will organize in year 3, which will enable direct interactions between researchers from different disciplines.

Longer term (4-8 years), there is the opportunity for impact within the clinical domain. For example, clinicians managing HPA disorders may be able to utilise the findings of my work through a methodological framework, which will analyse patient data and suggest patient specific treatments. Furthermore, an understanding of the mechanisms giving rise to dynamic rhythmicity, and the consequences of such rhythmicity, presents opportunities to commercial-sector pharmaceutical companies, for whom it may be possible to design and trial drugs whose pattern of release more naturally mimics the body's own secretion of glucocorticoids.

In the long-term (>10 years), these studies will ultimately impact on patients with HPA-related disorders through new treatments or novel application of existing treatments based on the findings of the research. By improving treatments and reducing the severity of side-effects, this will result in lower treatment costs, which will impact on health-sector managers and policy makers.