The existence of the principle of hypothalamic hypophysiotropic factors, predicted so prophetically by G W Harris in the 1940s, has been confirmed by irrefutable evidence. This principle is central to the survival of complex organisms as both individuals and species. Life exists through maintenance of a complex dynamic equilibrium, or homeostasis, that is constantly challenged by intrinsic or extrinsic adverse forces, or stressors. Thus, stress is defined as a state of threatened homeostasis that is re-established by a complex repertoire of physiologic and behavioral adaptive responses of the organism. Neuroendocrine hormones play crucial roles in the coordination of both basal and threatened homeostasis and mediate the pathogenesis of dyshomeostatic disease states. The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal central effectors of the stress system, which are highly interlinked, include the hypothalamic corticotropin-releasing hormone (CRH), arginine vasopressin, and proopiomelanocortin-derived peptides (alpha-melanocyte-stimulating hormone and beta-endorphin), and the brainstem locus caeruleus (arousal) and central autonomic norepinephrine. The principal peripheral effectors are the glucocorticoids, the catecholamines norepinephrine and epinephrine and, interestingly, peripheral (immune) CRH and interleukin-6. The targets of these effectors are in the brain, including the reward, fear and executive systems and the wake/sleep centers, the growth, thyroid and reproductive axes, as well as the gastrointestinal, cardiorespiratory, metabolic, and immune systems. Appropriate basal activity and responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate basal activity and responsiveness of the stress system may impair growth, development and body composition, and may account for many endocrine, metabolic, autoimmune, allergic and behavioral disorders. The development and severity of these conditions primarily depend on the genetic and constitutional vulnerability of the individual, the exposure to critical period or concurrent adverse or protective environmental factors, and the timing, size and duration of the stressor(s). Prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors.
Overproduction of CRH and stress system abnormalities are observed in behavioral/psychiatric disorders, such as hypothalamic oligo-amenorrhea, obligate athletisism, depression, anxiety, post-traumatic stress disorder, eating disorders and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists, such as the prototype Antalarmin, suggest therapeutic potential for treatment of these and other neuropsychiatric entities. Overproduction of CRH in the brain and the periphery and disruption of the hypothalamicpituitaryadrenal (HPA) axis and the arousal and sympathetic systems, on the other hand, are also found in somatic disorders, suggesting that CRHR1 antagonists may also be efficacious in treating common stress-related diseases, such as obesity/metabolic syndrome and essential hypertension, that are often associated with subtle but chronic hyperactivity of the stress system, representing central dysregulation of CRH and norepinephrine, and leading to cardiovascular disease. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. As CRH modulates bowel and gastric activity both directly and through the autonomic nervous system and influences centrally the processing of viscerosensory and visceromotor neural signals, it is not surprising that preclinical and clinical evidence suggests a central role of CRH in the pathophysiology of these stress-related gastrointestinal disorders as well. Neuroendocrine, autonomic and immune aberrations are also present in chronic inflammatory/autoimmune and allergic diseases, as well as in the chronic fatigue and fibromyalgia syndromes, with considerable evidence linking low CRH activity to the observed abnormalities. Similar low CRH activity has been implicated in atypical, seasonal depression, postpartum blues/depression and the late luteal dysphoric disorder and climacteric depression.
03 - 07 May 2008
European Society of Endocrinology