Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice

Abstract

Purpose It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition. Methods Metabolic and HPA-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal day, PND) and after 70 days of a peaceful (unstressed) period (90PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC). Results At 21PND, SM presented an increased exhibition of hypothalamic CRH and pituitary POMC -derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs CTR. At 90PND, SM showed hyperglycemia, with also suppression of hypothalamic CRH , while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant versus CTR at 90PND. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90PND. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationConclusion These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene. Response to Reviewers:Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice Endocrine Dear Dr. Loizzo, Your paper has now been carefully evaluated by an Associate Editor and ad hoc external Reviewers. We are sorry to say that it is not acceptable for publication in Endocrine in its present form. However, we would be ready to reconsider it if appropriately and extensively revised according to the enclosed comments. If you are prepared to undertake the work required we encourage you to resubmit your revised manuscript although at this stage no commitment can be made on our final decision.Dear Editor,We thank the Reviewer for their interest in our work. We did our best to respond to the point raised. As reported below, we have checked to the comment provided by the Reviewer and have made changes according to his indications. COMMENTS FOR THE AUTHOR:Reviewer #1: The authors have demonstrated that the early-life stress can induce ACTH-dependent hypercortisolism after a 70 days unstressed period. This observation is a very interesting, and may be a clue for the elucidation of the etiology of Cushing's disease. I am very curious about the histology of mice pituitary histology. Can you show us the data of pituitary histology of PND and 90PND mice, since I wonder if the hypertro...

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

“…On the other hand, other data support the idea that aberrant expression of one or more GPCRs and their ligands in adrenal tissues is a secondary rather than a primary event (71). Interestingly, very recent evidence from animal studies suggests that chronic stress in early life can induce persistent up-regulation of the HPA axis that generates endocrine, metabolic, and somatic alterations similar to those found in ACTH-dependent human ACTHdependent hypercortisolism (72).…”

Pregestational Prediabetes Induces Maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and Results in Adverse Fetal Outcomes: Influences on HPA Axis and Development

“…However, research has been shown that exposure to glucocorticoids in utero is associated with increased adrenocortical function in juvenile period with increased fasting cortisol concentrations in adults [139,140]. The upregulation of postnatal HPA function in other species may reflect changes in the HPA axis at the level of the hypothalamus, pituitary or adrenal gland itself [141,142]. Previous studies that have shown maternal and fetal/newborn cortisol levels are correlated and maternal cortisol levels are associated with reactivity of the newborn HPA axis [22,143].…”

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

“…After being stressed in early life, the mice developed an autonomous pituitary ACTH secretion with GC excess persisting even after the resolution of the stressful period. This was confirmed by high ACTH and corticosterone levels and, clinically, by a significant increase in body weight and fasting plasma glucose levels [ 33 ].…”