From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health

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Abstract
New knowledge of the biological and clinical importance of the steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] and its receptor, the vitamin D receptor (VDR), has resulted in significant contributions to good bone health. However, worldwide reports have highlighted a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a disturbing realization is growing that the newer scientific and clinical knowledge is not being translated into better human health. Over the past several decades, the biological sphere of influence of vitamin D3, as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis (intestine, bone, kidney, and parathyroid). Now, research has shown that the pluripotent steroid hormone 1α,25(OH)2D3 initiates the physiologic responses of ≥36 cell types that possess the VDR. In addition to the kidney's endocrine production of circulating 1α,25(OH)2D3, researchers have found a paracrine production of this steroid hormone in ≥10 extrarenal organs. This article identifies the fundamentals of the vitamin D endocrine system, including its potential for contributions to good health in 5 physiologic arenas in which investigators have clearly documented new biological actions of 1α,25(OH)2D3 through the VDR. As a consequence, the nutritional guidelines for vitamin D3 intake (defined by serum hydroxyvitamin D3 concentrations) should be reevaluated, taking into account the contributions to good health that all 36 VDR target organs can provide.