Melatonin modulation of the chronic dexamethasone-induced adrenal insufficiency.

Abstract

Purpose: Chronic exposure to synthetic glucocorticoids/GCs, widely in use to treat many diseases, may compromise the hypothalamic-pituitary-adrenal/HPA axis leading to a condition of adrenal insufficiency/AI. This study demonstrates the efficacy of the melatonin/MEL in amelioration of chronic dexamethasone (DEX)-induced AI.

Methods: Mice (Parkes Strain/Male/8 weeks old/30-33 g) were maintained in four groups (10 mice/group) for 30 days: Group 1/Control received intraperitoneal (i.p) vehicle (alcoholic 0.9% normal saline); Group II/DEX (400 µg/kg BW/day/i.p), Group III/(DEX + MEL 750 µg/kg BW/day/subcutaneous), and Group IV received only MEL. Adrenal, pituitary, and blood samples were collected from six mice/groups. Four mice/groups were subjected to the Lipopolysaccharide (LPS) challenge. Adrenal histology, ACTH immunohistochemistry, and plasma ACTH and corticosterone/CORT levels were measured.

Results: DEX exposure suppressed the pituitary ACTH expression significantly from control as revealed by morphometry and circulating hormones (Density, p < 0.01; size, immunointensity, plasma ACTH, and CORT; p < 0.001). Increased adrenal histopathology indicated probable AI. MEL co-supplementation significantly increased the corticotropes' density (p < 0.05), size (p < 0.001), immunointensity (<0.01), and plasma level of ACTH (p < 0.01) compared to the DEX group. The adreno-cortical width, zona fasciculata cell density and size, and the plasma CORT level (p < 0.001) were also significantly increased. The enhanced CORT response of the HPA axis in the DEX + MEL group compared to the DEX group on the LPS challenge provides support for the MEL restoration of the HPA axis functioning.

Conclusion: Further research on the MEL modulation of the HPA axis may support its role in preventing AI.