Endocrine Abstracts

The stress system coordinates the adaptive responses of the organism to stressors of any kind. The main components of the stress system are the CRH and Locus Ceruleus-Norepinephrine (LC/NE)-Autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic β-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress while, via somatostatin, it also inhibits GH, TRH and TSH secretion thus suppressing the reproductive, growth, and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and β-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T4) to triiodothyronine (T3), contributing further to the suppression of reproductive, growth, and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (Metabolic syndrome X) and direct effects on the bone, causing 'low turnover' osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves stimulates local inflammation. Antalarmin, a novel CRH receptor type 1 antagonist, decreases the activity of the HPA axis, suppresses neurogenic inflammation and blocks CRH-induced skin mast cell degranulation, in addition to blocking the development and expression of conditioned fear and stress-induced colonic hyperfunction. Chronic administration of antalarmin is not associated with glucocorticoid deficiency. These data suggest that such antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, we will need potentiators of CRH secretion/action to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low hypothalamic-pituitary-adrenal axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.