Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans?

A robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness. The pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABA(A) receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans. Implications of this research to the development of human stress-related illness are discussed in the context of two human stress-related psychiatric disorders - major depressive disorder and premenstrual dysphoric disorder. Neurosteroid-mediated HPA axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified.