Editorial [ HPA Axis Guest Editor: Brian Dyck ]

The pituitary is the preeminent gland of the body, synthesizing and releasing key hormones including growth hormone, thyroid-stimulating hormone, prolactin, luteinizing hormone, follicle-stimulating hormone and adrenocorticotropic hormone. The secretion of these hormones is regulated by the hypothalamus via the hypothalamus-hypophyseal portal veins. The target organ of adrenocorticotropic hormone is the adrenal gland, which regulates serum levels of cortisol. The trio of the hypothalamus, pituitary, and adrenal glands, termed the HPA axis, is responsible for coordinating an organism's response to exogenous stressors. A number of hormone-receptor systems within the HPA axis provide likely targets for pharmacological manipulation, three of which are reviewed in this issue. For some time, the importance of the hormone corticotropin releasing factor (CRF) as a regulator of stress states in mammals has been recognized. It is a key controller of the neuroendocrine system and is the dominant hormone responsible for governing stress response. However, despite the fact that peptide CRF receptor antagonists have been known for twenty years and small molecule antagonists have been known for more than a decade, no phase two, placebo-controlled proof of concept study showing efficacy has been disclosed. In their review, Tellew and Luo discuss recent advances in the field of CRF receptor antagonists and speculate on the characteristics of the ideal molecule. In contrast to CRF receptor antagonists, which have not been used medicinally, modulators of the glucocorticoid (GC) receptor have been used to treat inflammatory and immune conditions for more than half of a century. These drugs, however, come with significant side effects, which limit their use as first line therapies. One innovative solution to the unfavorable side effect profile of current glucocorticoids is to find organ (tissue) selective agonists. Takahashi, Razavi and Thomson discuss progress towards this goal and also speculate on the issues that may arise from the discovery and development of GC receptor antagonists for the treatment of diseases resulting from excess circulating cortisol. Calcitonin gene-related peptide (CGRP) and its receptor are best known for their role in vasodilation and their potential application to migraine. However, CGRP has wide expression throughout the central nervous system and has been shown to interact with the HPA. Rudolf, Arndt, Muller and Doods review recent reports in the field of CGRP receptor antagonists and speculate on the potential of a CNS-penetrating GCRP receptor antagonist. These reviews present an update on several drug targets related to the HPA axis. It is hoped they will not only provide the background and state-of-the-art for these molecular targets, but will also help to spur further research in this area.