Melatonin modulation of the chronic dexamethasone-induced adrenal insufficiency

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.

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.

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.

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