The limbic-hypothalamic-pituitary-adrenal (LHPA) axis functions with a rapid response to stressful stimuli and rapid “shut down” of the stress response. The hypothalamus receives all signals which are coded as stressful by the brain. Secretagogues within the hypothalamus, corticotropin releasing hormone (CRH), regulate the secretion of adrenocorticotropic hormone(ACTH) from the anterior pituitary. Circulating ACTH interacts with receptors on the adrenal cortex, which produces an elevation of plasma cortisol. The rapid increase in cortisol results in feedback which inhibits the release of factors in the hypothalamus and in the pituitary. The LHPA is known to interact with the Growth Hormone (GH) Axis. The GH Axis modulation involves two hypothalamic peptides: Growth Hormone Releasing Hormone (GHRH) and somatostatin. The interactions between GHRH, which promotes GH release from the pituitary, and somatostatin, which inhibits GHRH within the hypothalamus, regulate the release of GH into the circulation. From human and animal studies we know that acute administration of CRH, causes an increase of somatostatin release and inhibition of GH secretion. Growth retardation linked to stressful environments is observed in Psychosocial Dwarfism (PSD), an entity characterized by low GH, induced exclusively by psychological stress. We have started to study the LHPA axis in PSD compared to normally growing short stature children. The subjects were matched for bone age and sex. Three aspects of the LHPA axis are reported here: 1) circadian cortisol secretion, 2) cortisol and ACTH response to insulin hypoglycemia (0.1 units/kg) and 3) ACTH feedback inhibition to a hydrocortisone infusion (Solucortef, 5μg/kg/min). We find that although circadian and basal cortisol hormone measurements do not distinguish the PSD population from normally growing children, the challenges (1 and 2) point to an impaired fast feedback mechanism. Specifically, compared to normal short stature children, PSD patients fail to effectively “shut down” the ACTH and cortisol response to insulin hypoglycemia. Failure to effectively inhibit ACTH secretion is also observed upon Solucortef infusion. These data suggest that the dynamics leading to adrenal stress steroid secretion and termination of the stress response are altered in children subjected to chronic stress during childhood development. The resulting alterations have negative repercussions for the growing child.
Sponsored by DA02265 and M01RR00042.
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Vázquez, D., Watson, S. & Lòpez, J. Hypothalamic-Pituitary-Adrenal Axis and the Termination of the Stress Response: Alterations in Children with Psychosocial Growth Failure† 495. Pediatr Res 43, 87 (1998). https://doi.org/10.1203/00006450-199804001-00516