Chapter 2 Steroid Biosynthesis and Regulation of Cortisol Production The adult adrenal cortex produces three classes of steroid hormones glucocorticoids mineralocorticoids and adrenal androgens The specialized fetal adrenal in conjunction with the fetal liver the placenta and some maternal organs produces the steroid hormones of pregnancy Cortisol the major glucocorticoid in humans is rapidly synthesized and secreted in response to ACTH this is part of a response to stress and increases circulating levels of energy providing compounds glucose free fatty acids and free amino acids Aldosterone the major human mineralocorticoid is synthesized and secreted in response to angiotensin II it helps prevent ECF depletion by promoting sodium reabsorption and fluid retention The physiological roles of adrenal androgens are poorly understood Because the actions of these steroid hormones result from effects on gene expression the effects generally have a slow onset and are long lived Many clinically significant examples of adrenocortical hypo hyper and dys function are known Adrenal Morphology As shown schematically in Figure 1 the adrenal is surrounded by the capsule a tough layer of connective tissue that protects the organ and helps to maintain its structure and shape Within the capsule are three layers or zones of cells that comprise the steroidogenic structures of the adrenal the zona glomerulosa the zona fasciculata and the zona reticularis Structure Direction of Blood Flow Steroids Produced Capsule Zona Glomerulosa Aldosterone Zona Fasciculata Cortisol DHEA DHEAS Zona Reticularis Cortisol DHEA DHEAS Medulla None Figure 1 Cartoon of Adrenal Morphology The zona glomerulosa the outermost zone is the site of aldosterone production The zona fasciculata is the largest zone and is the major site of cortisol synthesis the zona fasciculata also produces the adrenal androgens DHEA and DHEAS The innermost steroidogenic zone is the zona reticularis which also produces cortisol 19 Chapter 2 The Adrenal Cortex Part I Endocrine Dr Brandt DHEA and DHEAS The steroid profiles produced in the zon fasciculata and reticularis are similar It is not clear why there are two zon with the same products although it has been suggested that the zona reticularis is more involved in adrenal androgen production This is supported by the fact that the zona reticularis is poorly organized until adrenarche The cortex surrounds the adrenal medulla a non steroid producing modified neural tissue The blood flow in the adrenal is centripetal i e from the outside toward the center As a result each zone is exposed to increasing levels of adrenal steroids This is particularly important in the medulla which requires high cortisol concentration to induce one of the enzymes necessary for epinephrine biosynthesis The fetal adrenal consists of two zon the relatively thin definitive zone also called the neocortex and the fetal zone The definitive zone develops into the cortex after birth The fetal zone which is the site of DHEAS synthesis during fetal life regresses and differentiates into the fasciculata following birth The adrenal medulla is not present as a discrete structure during fetal life and only forms during and after regression of the fetal zone Note that the zona fasciculata is the middle zone of the adult the reticularis is not fully organized until adrenarche at age 8 12 when adrenal androgen production increases markedly Adrenarche is also characterized by the loss of the connective tissue barrier between the cortex and medulla The fetal adrenal is large compared to the size expected based on the size of the fetus At term it usually contains about 8 grams of tissue comparable in size to the adult organ shrinking to about 5 grams a month later The fetal adrenal has low levels of 3 hydroxysteroid dehydrogenase 5 4isomerase this results in DHEA and DHEAS being the major products The other steroidogenic enzymes appear to be present although probably largely in the definitive zone and the fetal adrenal does produce some cortisol and aldosterone either from cholesterol or from maternal progesterone Adrenal Cell Structure There are some differences in detail between cells of different zon but the general structure is similar to that of any cell specialized for steroid biosynthesis The cells contain a number of lipid droplets which are the storage site for cholesteryl esters the precursors for all steroid hormone synthesis The cells also contain large amounts of smooth endoplasmic reticulum and many mitochondria The steroid synthetic enzymes are associated with the membranes of these organelles Steroid Biosynthetic Pathways The major synthetic pathways for the adrenal steroid hormones are shown on the next page Figure 2 The chart begins with cholesterol and goes to the adrenal products aldosterone cortisol and DHEA S and to the non adrenal steroid hormones progesterone testosterone and estradiol The steroids within the grey box are not produced by the adrenal Note that while progesterone is synthesized in the adrenal it is generally not released in significant quantities instead it merely serves as a precursor for some of the adrenal hormones 20 Chapter 2 The Adrenal Cortex Part I Endocrine Dr Brandt O HO Cholesterol O SO 3 P450 scc O O DHEA Sulfate O OH HO HO 17 OH Pregnenolone Pregnenolone HO Dehydroepiandrosterone 3 Hydroxysteroid dehydrogenase 5 4 isomerase O O O O OH O O 17 OH Progesterone Progesterone O Androstenedione HO Estrone 17 Hydroxysteroid dehydrogenase P450 21 OH OH O O OH OH OH O O Deoxycorticosterone P450 18 or 11 P450 11 OH O HO O Corticosterone Estradiol OH O O Aldosterone aldehyde form Cortisol Name Cholesterol side chain cleavage enzyme 17 hydroxylase 17 20 lyase 21 hydroxylase 11 hydroxylase 18 hydroxylase aromatase Note that P450 17 catalyzes both reactions in the conversion of pregnenolone to DHEA and in the conversion of progesterone to androstenedione Non enzymatic OH HO O O O OH Designation P450scc P450 17 P450 21 P450 11 P450 18 P450 arom P450 18 HO HO O O Testosterone OH HO O O Deoxycortisol Denotes mitochondrial enzyme all others located in the smooth endoplasmic reticulum Aldosterone hemiacetal form Figure 2 The major steroid biosynthetic pathways of the adrenal The steroids within the grey box are not normally produced within the adrenal 21 Chapter 2 The Adrenal Cortex Part I Endocrine Dr Brandt The chart appears complex but is logically organized In each case the difference between one row and