is then used for steroidogenesis or stored in the cell. The initial part of conversion of cholesterol into steroid hormones involves a number of enzymes of the cytochrome P450 family that are located in the inner membrane of mitochondria. Transport of cholesterol from the outer to the inner membrane is facilitated by steroidogenic acute regulatory protein and is the rate-limiting step of steroid synthesis. The layers of the adrenal gland differ by function, with each layer having distinct enzymes that produce different hormones from a common precursor. The first enzymatic step in the production of all steroid hormones is cleavage of the cholesterol side chain, a reaction that forms pregnenolone as a product and is catalyzed by the enzyme P450scc, also known as cholesterol desmolase. After the production of pregnenolone, specific enzymes of each cortical layer further modify it. Enzymes involved in this process include both mitochondrial and microsomal P450s and hydroxysteroid dehydrogenases. Usually a number of intermediate steps in which pregnenolone is modified several times are required to form the functional hormones. Enzymes that catalyze reactions in these metabolic pathways are involved in a number of endocrine diseases. For example, the most common form of congenital adrenal hyperplasia develops as a result of deficiency of 21-hydroxylase, an enzyme involved in an intermediate step of cortisol production. Regulation Glucocorticoids are under the regulatory influence of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoid synthesis is stimulated by adrenocorticotropic hormone (ACTH), a hormone released into the bloodstream by the anterior pituitary. In turn, production of ACTH is stimulated by the presence of corticotropin-releasing hormone (CRH), which is released by neurons of the hypothalamus. ACTH acts on the adrenal cells first by increasing the levels of StAR within the cells, and then of all steroidogenic P450 enzymes. The HPA axis is an example of a negative feedback system, in which cortisol itself acts as a direct inhibitor of both CRH and ACTH synthesis. The HPA axis also interacts with the immune system through increased secretion of ACTH at the presence of certain molecules of the inflammatory response. Mineralocorticoid secretion is regulated mainly by the renin–angiotensin–aldosterone system (RAAS), the concentration of potassium, and to a lesser extent the concentration of ACTH. Sensors of blood pressure in the juxtaglomerular apparatus of the kidneys release the enzyme renin into the blood, which starts a cascade of reactions that lead to formation of angiotensin II. Angiotensin receptors in cells