Indications that the direct effects of supplemented vitamin D3 on the adrenal cortex are of secondary importance for glucocorticoid output.

Vitamin D3 supplementation is beneficial for various symptoms of aging and may stabilize hypothalamic-pituitary-adrenal (HPA) axis function. Systemic and local metabolic activation of vitamin D3 are essential for its acquisition of physiological activity and subsequent direct action. We reasonably believe that the direct effect of the active metabolite of vitamin D3 on the adrenal cortex is of secondary importance for glucocorticoid output, compared to the indirect, pituitary-mediated mechanism of its action. The initially decreased blood level of adrenocorticotropic hormone (ACTH), after the experimental application of vitamin D3, physiologically dominantly acts as a feed-forward mechanism that allows for subsequent increased secretion of stored corticosterone, from the lipid-droplets of adrenocortical zona fasciculata (ZF) cells. The observed absence of changes in mitochondrial dimensions and immunoexpression of 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme in ZF adrenocortical cells, indicating that glucocorticoid production is not intensified, devalues an alternative direct effect of the physiologically active form of vitamin D3 on the adrenal cortex. To verify our concept, specific (structural and expression) in vivo studies are needed, which investigate the effects of vitamin D3 application on the upper parts of the HPA axis. If it is confirmed that the dominant mechanism of action of supplemented vitamin D3 on glucocorticoid output is indirect (pituitary-mediated), and bearing in mind the pulsatile nature of ACTH-glucocorticoid secretion, the hourly and daily schedule of some therapeutic vitamin D3 administration could be more precisely adjusted.