Three hormones serve as the principal regulators of calcium and phosphate homeostasis: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and vitamin D via its active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D) (Figure 42–2). The role of calcitonin (CT) is less critical during adult life but may play a greater role during pregnancy and lactation. The term vitamin D, when used without a subscript, refers to both vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). This applies also to the metabolites of vitamin D2 and D3. Vitamin D2 and its metabolites differ from vitamin D3 and its metabolites only in the side chain where they contain a double bond between C-22–23 and a methyl group at C-24 (Figure 42–3). Vitamin D is considered a prohormone because it must be further metabolized to gain biologic activity (Figure 42–3). Vitamin D3 is produced in the skin under ultraviolet B (UVB) radiation (eg, in sunlight) from its precursor, 7-dehydrocholesterol. The initial product, pre-vitamin D3, undergoes a temperature-sensitive isomerization to vitamin D3. The precursor of vitamin D2 is ergosterol, found in plants and fungi (mushrooms). It undergoes a similar transformation to vitamin D2 with UVB radiation. Vitamin D2 thus comes only from the diet, whereas vitamin D3 comes from the skin or the diet, or both. The subsequent metabolism of these two forms of vitamin D is essentially the same and follows the illustration for vitamin D3 metabolism in Figure 42–3. The first step is the 25-hydroxylation of vitamin D to 25-hydroxyvitamin D (25[OH]D). A number of enzymes in the liver and other tissues perform this function, of which CYP2R1 is the most important. 25(OH)D is then metabolized to the active hormone 1,25-dihydroxyvitamin D (1,25[OH]2D) in the kidney and elsewhere. PTH stimulates the production of 1,25(OH)2D in the kidney, whereas FGF23 is inhibitory. Elevated levels of blood phosphate and calcium also inhibit 1,25(OH)2D production in part by their effects on FGF23 (high phosphate stimulates FGF23 production) and PTH (high calcium inhibits PTH production). 1,25(OH)2D regulates its own levels by stimulating the enzyme 24-hydroxyase (CYP24A1), which begins the catabolism of 1,25(OH)2D, suppressing PTH production, and stimulating FGF23 production, all of which combine to reduce 1,25(OH)2D levels. Other tissues also produce 1,25(OH)2D; the control of this production differs from that in the kidney, as will be discussed subsequently. The complex interplay among PTH, FGF23, and 1,25(OH)2D is discussed in detail later.