Endocrine Abstracts

Purpose: Sepsis is hallmarked by high circulating glucocorticoids in face of low plasma adrenocorticotropic hormone (ACTH) (1). At the hypothalamic-pituitary level, ongoing stress-induced corticotropin-releasing hormone- (CRH) and arginine vasopressin- (AVP) driven expression of the ACTH-precursor POMC coincides with impaired proprotein convertase 1 (PC1/3)-mediated processing into ACTH, with ultimately leaching of unprocessed POMC into the circulation (2). Despite uncertainty of the effects on the hypothalamic-pituitary-adrenal axis, current guidelines continue to recommend glucocorticoid treatment in all patients with vasopressor-refractory septic shock. We hypothesized that further augmenting systemic glucocorticoid availability through exogenous administration of hydrocortisone would aggravate the sepsis-induced impairment in pituitary POMC processing, while infusion with CRH would restore it.

Methods: Male C57BL/6J mice (n48) were randomized to 4 groups: a healthy control group, a sepsis group treated with hydrocortisone (HC, continuous rate of 1.2 mg/day), with CRH (CRH, continuous rate of 1 µg/day) or with placebo (P, Plasmalyte). Sepsis was brought about by standardized cecal- ligation and puncture and mice were fluid-resuscitated, parenterally fed, opioid-analgesics and broad- spectrum antibiotics-treated. On day 7 of illness, mice were sacrificed and plasma concentrations of ACTH and POMC were quantified, as well as pituitary expression of POMC and ACTH, mediators of hypothalamic signaling (CRH-receptor, CRHR and AVP-receptor, AVPR), mediators of POMC processing into ACTH (PC1/3) and inflammatory markers (TNFα and IL1β).

Results: Sepsis-induced reduction of plasma ACTH was substantially further suppressed in HC-treated mice (P ≤ 0.0001 in comparison with P-treated sepsis and healthy controls), coinciding with suppressed pituitary ACTH content (P ≤ 0.001 vs. P-treated sepsis and vs. healthy). Plasma ACTH was normalized in CRH-treated sepsis (P = 0.23 vs. healthy). Pituitary gene expression and plasma POMC was always increased during sepsis, irrespective of treatment (all P ≤ 0.05 vs. healthy). Pituitary gene expression of CRHR and AVPR was lower in HC-treated as compared with P-treated sepsis (P ≤ 0.01). Pituitary protein expression of PC1/3 was suppressed in HC- and P-treated sepsis (both P ≤ 0.05 vs. healthy), but not in CRH-treated sepsis (P = 0.55 vs. healthy). Pituitary gene expression of TNFα and IL1β was increased in, respectively, CRH-treated sepsis (P ≤ 0.05 vs. healthy) and in HC- and CRH-treated sepsis (both P ≤ 0.05 vs. healthy), but not in P-treated sepsis (P > 0.05 vs. healthy).

Conclusion: Increasing the systemic glucocorticoid availability in sepsis by continuous infusion of hydrocortisone further suppressed pituitary and plasma ACTH, suppressed pituitary CRHR and AVPR gene expression, but did not further suppress PC1/3 protein expression. In contrast, CRH infusion resulted in a normalization of plasma ACTH through restoration of PC1/3 protein expression. However, both therapies coincided with increased expression of inflammatory markers within the pituitary gland. The effects of the treatment-induced changes in plasma ACTH on adrenocortical steroidogenesis remain to be studied.

References: 1. Teblick A et al. Adrenal function and dysfunction in critically ill patients. Nat Rev Endocrinol. 2019;15(7):417-27.

2. Teblick A et al. The role of pro-opiomelanocortin in the ACTH- cortisol dissociation of sepsis. Crit Care. 2021;25(1):65.