SAT-358 Corticosterone Treatment during Sepsis Results in a Primary Adrenal Defect in Male Survivors

Abstract

Abnormalities of adrenal gland function have been described in survivors of prolonged critical illness, but whether an acute inflammatory illness such as sepsis causes lasting changes in adrenal function is unknown. Critically ill patients with sepsis are often treated with high doses of corticosteroids for their vasoactive properties, which may also affect adrenal function. To examine the effect of sepsis and corticosteroid treatment on adrenal function, we used a naturalistic mouse model of sepsis, cecal ligation and puncture (CLP). Male and female C57Bl/6 mice (N = 20 per group, 10 male/10 female) underwent CLP or sham surgery and were treated with daily injections of either corticosterone (13 mg/kg) or vehicle for five days. Mice were maintained on a 14:10 light-dark cycle with lights on at 6 AM. Three weeks after surgery, mice were sacrificed at baseline (between 9:00 and 12:00) or after stress (6-minute swim) and blood collected for hormone measurements. Adrenal weights, adrenal gland histology, and gene expression analysis were performed on a subset of mice. The results showed that female mice had higher adrenal weights and higher plasma corticosterone, but lower plasma ACTH, when compared to males. Corticosterone and CLP had sex-dependent effects on adrenal function. Specifically, corticosterone-treated male sepsis survivors had higher morning ACTH/corticosterone ratios than the other groups without any difference in stress ACTH/corticosterone, and this group had heavier adrenal weights. These findings were not explained by adrenal histology. Gene expression analysis of male adrenals showed that corticosterone treatment increased adrenal expression of Sonic Hedgehog, Disabled-2, and COUP-TF in the sham mice, but this effect was absent in sepsis survivors. We conclude that corticosterone treatment during sepsis causes a defect in adrenal function after recovery only in males. The increased ACTH/corticosterone ratio suggests a compensatory increase in pituitary activity, while the gene expression analysis shows an absence of the normal recovery process from corticosterone treatment in the sepsis survivors. These novel findings could have clinical implications for the maintenance of appropriate adrenal function after corticosteroid treatment during acute illness. This work was supported by grants from the NIMH, NIDDK, Office of Naval Research, Hope for Depression Research Foundation, and the Brain and Behavior Research Foundation.

Glucocorticoids and the Brain after Critical Illness

“…In patients with prolonged critical illness, the adrenal glands showed loss of the typical zonation, decreased lipid content, and reduced steroidogenic enzyme expression, suggesting decreased adrenal reserve ( 37 ). Furthermore, in mice, we have seen normal corticosterone with high ACTH levels 3 weeks after sepsis induced by cecal ligation and puncture compared with a sham condition ( 38 ), suggesting appropriate central compensation for decreased adrenal corticosterone production. The clinical significance of these findings remains to be seen.…”