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 position 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 have 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 metabolism 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-HSD 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-HSD type 2 appears to contribute to the increase in plasma cortisol. (See "Glucocorticoid therapy in septic shock in adults".)
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:
●The adrenocorticolytic drug mitotane increases 6-beta hydroxylation but does not increase the overall metabolism of cortisol. Mitotane does accelerate the metabolism of halogenated synthetic steroids, including dexamethasone, betamethasone, and 9-alpha-fluorohydrocortisone. Phenytoin, carbamazepine, and phenobarbital have a similar effect [39,40].
●The antituberculous drug rifampin accelerates the metabolism of both synthetic steroids (including 9-alpha-fluorohydrocortisone) and cortisol [41-43], and urinary 6-beta-hydroxycortisol excretion is increased in rifampin-treated patients [44].
●Cimetidine inhibits hepatic CYP (cytochrome P450) enzymes, but it has no effect on prednisolone or dexamethasone metabolism [45,46].
●Troglitazone, a thiazolidinedione that is no longer marketed for therapeutic use, is a potent inducer of CYP3A4 (6-beta-hydroxylase) and accelerates dexamethasone metabolism sufficiently to alter dexamethasone suppression test results. Rosiglitazone and pioglitazone do not appear to have such CYP3A4 induction activity [47].
Extrahepatic — The kidney is a major site of extrahepatic cortisol metabolism in humans [48]. There, cortisol is converted to cortisone by the high-affinity, NAD-dependent form (type 2) of 11-beta-HSD that is encoded by a gene on chromosome 16q22 [49,50]. This conversion reduces cortisol access to the mineralocorticoid receptor (MR) [51,52], which otherwise binds cortisol and aldosterone with equal affinity [53]. Restricting cortisol access to MR therefore allows aldosterone to exert its physiologic effects. Genetic or pharmacologic impairment of 11-beta-HSD type 2 results in cortisol-mediated mineralocorticoid effects. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)
The enzyme 11-beta-HSD 1 is not restricted to hepatic expression but is found in many, perhaps all, glucocorticoid target tissues, including pituitary corticotrophs [54]. It plays a major role in regulating the concentration of cortisol to which target cells are exposed. Mice with global "knockout" of 11-beta-HSD 1 are protected from the development of adiposity, insulin resistance, hepatic steatosis, hypertension, myopathy, and dermal atrophy associated with chronic glucocorticoid excess, suggesting an important role for the enzyme in the development of many features of the Cushingoid phenotype [55].
Transgenic mice overexpressing this enzyme in adipose tissue developed obesity and the metabolic syndrome [56], suggesting that local conversion of cortisone to cortisol in visceral fat might contribute to these conditions. Adipose-specific knockout of the 11-beta-HSD gene results in protection from the hepatic steatosis resulting from exogenous glucocorticoid excess [55] and brown adipose cells from mice lacking 11-beta-HSD 1 are resistant to the adverse metabolic effects of glucocorticoids [57]. Alterations in gut microbiota of animals lacking 11-beta-HSD 1 have also been postulated to contribute to the metabolic phenotype [58]. In human subjects, the production of cortisol by 11-beta-HSD 1 in adipose tissue has been found to be quantitatively negligible compared with hepatic production of cortisol by this enzyme [59-61].
While increased adipose tissue expression of 11-beta-HSD 1 is observed in subjects with insulin resistance and impaired glucose tolerance [28], it has also been found that weight loss after gastric bypass surgery in obese, insulin-resistant women results in significant reduction in expression of 11-beta-HSD in adipose tissue [62]. These data have raised the question of whether increases in adipose tissue 11-beta-HSD activity are a consequence, rather than a cause of obesity and insulin resistance. Nevertheless, inherited alleles of 11-beta-HSD 1 associated with lower hepatic expression have been reported to confer increased risk for the development of nonalcoholic fatty liver disease [63].
In human skin, the level of 11-beta-hydroxysteroid dehydrogenase expression rises with age, ultraviolet light exposure, or chronic glucocorticoid excess [64]. The dermal atrophy resulting from altered collagen synthesis and degradation as well as reductions in keratinocyte and fibroblast proliferation under these conditions is reversed by inhibition of 11-beta-hydroxysteroid dehydrogenase, suggesting a role for locally generated glucocorticoids in the development of the phenotype [65].
11-beta-HSD 1 is expressed in the cells of the adaptive and innate arms of the immune system, including developing thymocytes [66-69]. The enzyme is further induced in T cells by receptor-mediated activation. Some evidence suggests that neutrophil 11-beta-HSD 1 might function to attenuate local inflammatory responses [69], a physiologic role for paracrine or autocrine actions of glucocorticoids generated in T cells is yet to be defined.
11-beta-HSD 1 is expressed in both cardiac muscle cells and fibroblastic elements of the heart, and experimental inhibition of enzyme expression or function results in attenuation of adverse cardiac remodeling events after myocardial infarction, and prevention of heart failure in that context [70,71].
In the brain, 11-beta-HSD 1 is involved in the age-related decline in learning and memory tasks in mice; rodents lacking the enzyme appear protected from the decline in the brain function observed with aging [72] and chemical inhibition of 11-beta-HSD 1 results in improved cognitive performance in mouse models of Alzheimer's disease [73,74]. The enzyme is also expressed in human brain; whether modulation of its function could impact human brain function is not known. Newer central nervous system-penetrating inhibitors of the enzyme are under study as potential treatments for Alzheimer's disease [75].
Additional mechanisms may exist for terminating the actions of steroid hormones within target tissue cells. Glucuronidase activity is found in many human and monkey tissues [76]. The uridine diphosphoglucuronosyl transferase enzymes in these tissues metabolize primarily androgens and estrogens, but these and other enzymes that metabolize glucocorticoids and mineralocorticoids presumably are found in their target tissue cells and may play an important role in terminating steroid hormone action.
ALDOSTERONE METABOLISM
Reduction — Aldosterone, like cortisol, is reduced predominantly by a hepatic delta-4,3-ketosteroid-reductase, and a 3-alpha-hydroxysteroid dehydrogenase (figure 1). The cytosolic delta-4-reductase also has 5-beta-hydroxysteroid reductase activity, so that the major metabolic product is 3-alpha, 5-beta-tetrahydroaldosterone. This metabolite, in the form of tetrahydroaldosterone glucuronide, accounts for 35 to 40 percent of the aldosterone metabolites in urine [77]. A 21-deoxy form of tetrahydroaldosterone is further reduced to the 20-alpha-hydroxy form [78]. The 20-alpha-hydroxyl group can condense with the hydroxyl of the C18 hemiacetal to form an aldosterone metabolite with hemiacetal rings [79].
Conjugation — Tetrahydroaldosterone is conjugated to glucuronic acid in the liver at the 3-keto position, and tetrahydroaldosterone glucuronide is the major urinary metabolite of aldosterone [80]. Another conjugate, aldosterone-18-glucuronide, is produced by direct conjugation of unreduced aldosterone and accounts for approximately 10 percent of the aldosterone metabolites excreted in the urine [81].
Alterations in aldosterone metabolism — In patients with cirrhosis and ascites, the production rate and serum concentration of aldosterone are often high as a result of increased plasma renin activity [32]. The ability of the liver to metabolize aldosterone is impaired, so a greater fraction is metabolized extrahepatically [82,83]. Patients with severe congestive heart failure and impaired perfusion of the liver also have impaired aldosterone metabolism [84]. Treatment with spironolactone results in inhibition of the enzyme responsible for 18-glucuronidation of aldosterone. The elevated aldosterone levels observed in spironolactone-treated subjects may reflect, at least in part, this inhibition [85].
ADRENAL ANDROGEN METABOLISM — The steroid produced in greatest quantity by the adrenal cortex and its major C19 androgenic product is dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA sulfate [DHEAS]). Most of the DHEA is converted to androstenedione by oxidation of the 3-beta-hydroxyl group and isomerization of the delta-5 double bond to the delta-4 position. Androstenedione is reduced by 5-alpha-reductase to androsterone and by 5-beta-reductase to etiocholanolone, which are then reduced by 17-beta-hydroxysteroid dehydrogenase to yield the respective -diol derivatives, followed by conjugation and excretion in the urine [26].
DHEAS can be directly excreted in the urine; the sulfate group can be hydrolyzed to yield free DHEA, which is metabolized as just described, or DHEAS can be metabolized by 16- or 17-hydroxylation or by reversible 17-beta-reduction to yield androstenediol sulfate [86]. DHEAS and its metabolites are cleared more slowly from serum by the kidney than their nonsulfated analogues [86]. Fecal excretion of DHEA and its metabolites is quantitatively more important than for other steroids; 30 to 45 percent of the metabolites of DHEAS may be excreted via the biliary tract and appear in the feces [26]. (See "Adrenal hyperandrogenism".)
SUMMARY — The actions of glucocorticoids can be terminated by conversion of these steroids to biologically inactive forms.
●The major site of cortisol metabolism is the liver. There, cortisol is reduced or oxidized and 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). (See 'Glucocorticoid metabolism' above.)
●Several factors and conditions are associated with altered hepatic metabolism of cortisol, including thyroid hormone, age, liver or kidney disease, obesity, and drugs. (See 'Alterations in hepatic metabolism of cortisol' above.)
●The liver is also the major site of aldosterone metabolism. (See 'Aldosterone metabolism' above.)
●The steroid produced in greatest quantity by the adrenal cortex and its major C19 androgenic product is dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA sulfate [DHEAS]). Most of the DHEA is converted to androstenedione. (See 'Adrenal androgen metabolism' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
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4 : Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression.
5 : Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity.
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42 : Update on rifampin drug interactions.
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44 : Letter: Induction of hepatic cortisol-6-hydroxylase by rifampicin.
45 : Effects of cimetidine and ranitidine on the conversion of prednisone to prednisolone.
46 : Cortisol and dexamethasone elimination during treatment with cimetidine.
47 : Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test.
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49 : Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme.
50 : Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11 beta-hydroxysteroid dehydrogenase.
51 : Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor.
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54 : Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action.
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56 : A transgenic model of visceral obesity and the metabolic syndrome.
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86 : AN ADRENAL-SECRETED "ANDROGEN": DEHYDROISOANDROSTERONE SULFATE. ITS METABOLISM AND A TENTATIVE GENERALIZATION ON THE METABOLISM OF OTHER STEROID CONJUGATES IN MAN.
