Glucocorticoids are essential for life and, before the synthesis of cortisone, a diagnosis of adrenal failure was a death sentence. Replacement and therapeutic use of glucocorticoids accelerated rapidly, driven by the massive impact their use had on patients. In many instances, the effects were so dramatic that no clinical trials were done, beyond gazing in wonder at the transformation in the recipient.
Following the enthusiastic roll out of glucocorticoid treatment, mainly for people with inflammatory diseases, it became clear that the glucocorticoids were a double-edged sword, with a spectrum of severe and irreversible side effects. Even then, no trials were performed to formally assess the adverse effects and therapeutic benefits, in the sense that we would now require trial evidence before drug approval by regulatory authorities.
In order to retain the therapeutic benefits of glucocorticoids for management of inflammatory diseases, and to replace missing glucocorticoid synthesis in adrenal insufficiency or congenital adrenal hyperplasia, efforts have focused on new, synthetic molecules with selective modes of action. These act either to limit activation of the mineralocorticoid receptor, such as prednisolone or dexamethasone, or in a way analogous to the partial oestrogen receptor agonists used to treat breast cancer. In addition, attention has switched to formulation of the compounds for local use, such as inhaled glucocorticoid, or topical application to the eye, skin etc. Finally, the role of timing of administration has been explored.
MECHANISM OF ACTION
In order to come up with better glucocorticoid therapeutics, it would help to understand how these compounds work. Although the glucocorticoid receptor (GR) was cloned in 1987, and much is known about how ligand activation of the receptor drives phenotypic change, there are gaps in our knowledge. It is possibly because of these gaps that the field has fallen behind the progress seen with other, related receptors, such as oestrogen and androgen receptors and peroxisome proliferator-activated receptors.
Briefly, activated GR binds to target sequences in DNA, to switch on gene transcription and thereby change the proteome of the cells, and so its function, and that of the whole person. As the GR is expressed ubiquitously, this explains why topical application of the drugs is a good approach, to limit target effects.
The focus on therapeutic glucocorticoids has meant that rather little attention has been paid to replacement glucocorticoids, which are the realm of the clinical endocrinologist. These are rare conditions, there is little big pharma interest, and trials can be hard to recruit to.
What do we know about physiological glucocorticoids? Strikingly, endogenous production of glucocorticoids lies under control of multiple systems, resulting in wide variations in measured plasma concentrations during the course of a day. This is why dynamic or stress tests are used in the clinic to assess adrenal production of glucocorticoids. Glucocorticoids are secreted in discrete pulses into the circulation, with the frequency of pulses varying through the day to result in a marked diurnal change in plasma concentrations, with the peak levels achieved before waking. Glucocorticoid production is also stress responsive and starvation responsive, driving mobilisation of energy substrates.
It turns out that time of day also affects how tissues respond to glucocorticoids. So we can see a coincident model with time-dependent changes in glucocorticoid production, and also variation in the amplitude and spectrum of responding genes through time. This is more complex than the conventional models acknowledge.
THERAPEUTIC APPLICATIONS
This variation also opens up the possibility of using timing to dial up greater disease sensitivity, target the spectrum of glucocorticoid effects, and limit off-target actions. For example, replicating the pulsatile secretion of endogenous glucocorticoids, with changes in pulse frequency through the day, will mimic the natural pattern and may improve well-being in people reliant on replacement steroid (see Richard Ross’s account of the development of Chronocort). In addition, targeting administration of therapeutic glucocorticoid to the time window when the disease is most likely to respond may allow greater efficacy or dose-sparing to be achieved.
The explanation of why the time of day matters is now becoming clear. The operation of a circadian clock within all cells of the body is fundamental to health, driving 15–20% of metabolic circuits. Core circadian clock component proteins are capable of direct interaction with the GR to change its function. In this way, the cell can interpret the incoming glucocorticoid signal in the context of the time of day. This is achieved both by modifying how the GR can activate gene transcription, and also by specifying which site in the genome the GR can bind to.
As components of the circadian clock can be affected by light, behaviour and feeding in terms of physiological change, and now can be directly targeted by new classes of drug-like molecules, this interface between the clock and glucocorticoid action is very exciting therapeutically. Further complexity is suggested by observations that obesity, and fat-loading of the liver, may introduce further control of how the GR works, potentially pointing to new mechanisms explaining the altered physiology seen in obesity.
Although therapeutic glucocorticoids have been around for more than 70 years, there is potential from the new biology of circadian endocrinology to drive greater benefits from this drug class and drug target. The combination of new molecules, new formulations and new administration paradigms offers new hope for patients. As more than 1% of the population have a regular, repeat prescription for a glucocorticoid, this is a huge target group of people, who stand to benefit. Exciting times for an old drug target.
DAVID W RAY
Professor of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford
