Metabolism of Adrenal Steroids

metabolisme kelenjar adrenal
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  Metabolism of adrenal steroids Author: William J Kovacs, MD Section Editor: Lynnette K Nieman, MD Deputy Editor: Kathryn A Martin, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2017. | This topic last updated: Jun 20, 2017. INTRODUCTION —  The actions of glucocorticoids can be terminated by conversion of these steroids to biologically inactive forms. The processes by which these steroids are inactivated involve a number of enzymes and tissues. The importance of alterations in the metabolic degradation of adrenal steroids in human physiology and disease states is becoming increasingly clear and will be reviewed here. Adrenal steroid biosynthesis is reviewed separately. (See  Adrenal steroid biosynthesis .) GLUCOCORTICOID METABOLISM Hepatic —  The major site of cortisol metabolism is the liver. There, cortisol is reduced, oxidized, or hydroxylated, and the products of these reactions are made water soluble by conjugation with sulfate or glucuronic acid to facilitate their excretion in urine (figure 1). Gas chromatography with mass spectrometry (GC/MS) has provided quantitative data on the urinary excretion of each of these cortisol metabolites, allowing identification of a number of inherited and acquired disorders characterized by abnormal glucocorticoid dynamics [1]. Reduction —  Cortisol is inactivated mainly by reductive disruption of its 3-keto, delta-4 double bond structure. Reduction reactions can also result in regeneration of cortisol from its inactive metabolite, cortisone. ●Reduction of the keto group, with formation of a 3 -hydroxyl group, is carried out by 3-alpha-hydroxysteroid dehydrogenase. ●Reduction of the cortisol A ring double bond, which results in an asymmetric carbon atom at p osition 5, is carried out by 5-alpha-reductase (of which there are two isoforms expressed in liver) and 5-beta-reductase.  ●The 5 -alpha-reductase type 1 enzyme, encoded by a gene ( SRD5A1 ) on the distal short arm of chromosome 5 [2,3], is expressed in skin, adipose tissue, and liver in adult humans and exhibits maximal activity at alkaline pH [4,5]. The type 2 5-alpha-reductase is encoded by a gene ( SRD5A2 ) on the short arm of chromosome 2 and functions at an acidic pH optimum. SRD5A2  is expressed in tissues of the reproductive tract, where it amplifies the actions of testosterone, as well as in the liver, where its reduction of the cortisol A ring inactivates the hormone. ●The 5 -beta-reductase enzyme is encoded by a single gene (  AKR1D1 ) on the long arm of chromosome 7 [6]. This gene is a member of the aldo-keto reductase family, a group of related NADPH-dependent oxidoreductases [7]. The enzyme's substrate specificities suggest a primary role in bile acid synthesis rather than cortisol metabolism but no other gene encoding an enzyme with 5-beta-reductase activity has been identified [8] and detailed studies of a 13-year-old patient with a homozygous missense mutation in  AKR1D1  revealed nearly total absence of 5-beta reduced metabolites of cortisol and cortisone in urine [9]. In normal men and women, 5-beta-tetrahydrocortisol is slightly more abundant in urine than 5-alpha-tetrahydrocortisol. ●In healthy individuals, the majority of urinary glucocorticoid metabolites ha ve been reduced at both the 3-keto group (by 3-alpha-hydroxysteroid dehydrogenase) and at the 4-5 double bond in the A ring (by 5-alpha- or 5-beta-reductases). These tetrahydro- derivatives of cortisol and cortisone compromise more than 66 percent of urinary glucocorticoid metabolites in both women and men. ●The tetrahydrocortisols and tetrahydrocortisone produced by the actions of the 5 -alpha/5-beta reductases and 3-alpha-hydroxysteroid dehydrogenases can be further reduced at the 20-ketone (by 20-hydroxysteroid dehydrogenases) to yield the cortols and cortolones. These cortols and cortolones make up approximately 20 percent of total urine glucocorticoid metabolites. ●11 -beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD 1) is a key enzyme in cortisol metabolism, with both dehydrogenase and reductase activities. It is constitutively expressed in liver, adipose tissue, bone, and central nervous system [10-12] but is also inducible in a variety of other tissues [12]. While the enzyme has the capacity to inactivate cortisol by oxidation, the reverse (reductase) reaction (ie, conversion of cortisone to cortisol) normally predominates in the liver in vivo. The reductase directionality of 11-beta-HSD 1's catalysis is determined by the co-expression of an NADPH-generating system, hexose-6-phosphate dehydrogenase, which maintains a reducing environment within the endoplasmic reticulum where 11-beta-HSD 1 is localized [12,13]. In normal subjects, urinary 11-keto (cortisone) metabolites are slightly more abundant than 11-hydroxy (cortisol) metabolites. Oxidation —  Cortisol and its metabolites are also oxidized in the liver. Oxidative removal of the C20, C21 side chain yields a C19 steroid with a 17-ketone group [14]. Available evidence indicates that this side chain cleavage is not carried out by CYP17, the enzyme that catalyzes this reaction in androgen  biosynthesis [15]. The identity of the gene encoding this side chain cleavage enzyme activity is not known [13]. Hydroxylation —  6-beta hydroxylation of cortisol occurs in the liver by the CYP3A4 enzyme, but only to a minor extent, with 6-beta-hydroxycortisol accounting for less than 3 percent of total urinary glucocorticoid metabolites. When serum cortisol concentrations are high, as in patients with Cushing's syndrome, disproportionately large amounts of 6-beta-hydroxycortisol may be produced and excreted in the urine, possibly because of saturation of the reduction and oxidation pathways but also perhaps because of induction of CYP3A4 by hypercortisolism [16,17]. Conjugation —  The C19 and C21 metabolites of cortisol are more water soluble when conjugated to glucuronic acid or sulfate, primarily the former. Glucuronidation is catalyzed by one of the uridine diphosphoglucuronosyl transferases, enzymes that catalyze the glucuronidation of xenobiotics, bilirubin, and steroids in the endoplasmic reticulum of the liver [18]. Specific isoenzymes act on different substrates, even among the steroid hormones [19,20]. Glucuronide may be conjugated to any hydroxyl group, but the 3-alpha-hydroxyl is preferred. Most tetrahydrocortisol derivatives are excreted in the urine as glucuronides. Sulfation is catalyzed by cytosolic sulfotransferases. Only a small fraction of 3-alpha-hydroxysteroid metabolites, but most of the 3 beta-hydroxysteroids (both C19 and C21), are conjugated with sulfate [21]. While these conjugation reactions have generally been considered as Phase II metabolic processes that follow reduction reactions, evidence now suggests that conjugated steroids may, in fact, serve as substrates for some aldo-keto-reductase enzymes [22]. Alterations in hepatic metabolism of cortisol —  Several factors and conditions are associated with altered hepatic metabolism of cortisol, including hormones, age, disease, obesity, and drugs. Hormones ●Thyroid hormone alters cortisol metabolism. In patients with hyperthyroidism, cortisol clearance is accelerated, but serum cortisol concentrations are normal because of a compensatory increase in cortisol secretion [23]. Conversely, in patients with hypothyroidism, cortisol clearance is slowed and urinary excretion of cortisol metabolites is decreased, but serum cortisol concentrations still are normal. These changes in the rate of cortisol secretion occur because the hypothalamic-pituitary-adrenal axis is normal, and changes in serum cortisol concentrations elicit compensatory changes in the secretion of corticotropin (ACTH). The effect of thyroid hormone is due largely to an increase in hepatic 5-alpha- and 5-beta-reductase activity [24]. ●There are some differences in cortisol metabolis m between men and women. Women excrete relatively less 5-alpha- and 5 beta-tetrahydrocortisol than men but similar quantities of cortisol, cortisone, and tetrahydrocortisone [25]. Hormonal changes of the menstrual cycle do not appear to influence cortisol metabolism [25]. Hepatic conversion of cortisone to cortisol is not different between sexes.  ●In patients with Cushing's syndrome, 6 -beta-hydroxylation of steroids is increased [16], and proportionally smaller amounts of cortols, cortolones, tetrahydrocortisone, and 5-alpha-tetrahydrocortisol are excreted [26]. Glucocorticoids also stimulate hepatic 11-beta-hydroxysteroid dehydrogenase activity, while insulin and insulin-like growth factor-1 (IGF-1) inhibit it [27]. ●Hyperinsulinemia accompanying states of insulin resistance is associated with increases  in 5-alpha-reductase activity (presumably hepatic) as assessed by urinary excretion of 5-alpha reduced metabolites of cortisol. This relationship is observed in both men and women and is independent of body weight or fat mass [28]. Improvements in insulin sensitivity after weight loss result in reduction of 5-alpha- reductase activity [29]. Age and disease —  The effects of age and disease on the hepatic metabolism of cortisol include: ●The rate of metabolism of cortisol and urinary excretion of 17 -hydroxycorticosteroids (tetrahydrocortisols, tetrahydrocortisone) decrease with age [30], but serum cortisol concentrations do not. ●Enzymatic metabolism of cortisol usually is normal in patients with renal disease, but clearance of glucuronides is diminished so that these inactive compounds may accumulate in serum [26]. ●Women with polycystic ovary syndrome (PCOS) have increased 5 -alpha-reductase activity [31]. This increase in cortisol metabolism was observed in lean women with PCOS. Patients with cirrhosis have a reduction of both 5-alpha- and 5 beta-reductase activities, but 3 alpha-hydroxysteroid dehydrogenase and glucuronosyl transferase activities remain normal [32]. Men with fatty liver have been reported to have increased 5 beta-reductase activity [33] with a decrease in hepatic 11-beta-HSD 1 activity and an increase in total cortisol metabolites [34]. With progression to nonalcoholic steatohepatitis (NASH), 11-beta-HSD 1 activity was increased in comparison with both patients with steatosis and controls [34]. ●Cortisol metabolism is dramatically altered in critically ill patients with a wide variety of underlying diagnoses [35]. While cortisol levels are increased under the stress of such severe illness, ACTH is only transiently elevated in this setting, and the increase in cortisol levels has been attributed to adrenal stimulation by cytokines released during systemic inflammatory responses. In addition, however, diminished clearance of cortisol through enzymatic inactivation by 5-alpha- and 5-beta-reductases and by 11-beta-hydroxysteroid dehydrogenase type 2 appears to contribute to the increase in plasma cortisol. (See  Glucocorticoid therapy in septic shock , section on 'Activation of the HPA axis'.) Obesity and nutrition —  Obese subjects excrete significantly greater amounts of cortisol metabolites than do lean subjects. This difference persists even when the values are normalized for body surface area [36,37]. The cortisol production rate is increased in obese subjects, however, so that their serum cortisol concentrations are normal [32]. In obese men, a low-carbohydrate diet reverses this increase in hepatic clearance of cortisol [38]. Drugs —  Several drugs affect hepatic cortisol metabolism:
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