Brian R. Walker

Minireview: 11β-Hydroxysteroid Dehydrogenase Type 1— A Tissue-Specific Amplifier of Glucocorticoid Action1

11β-hydroxysteroid dehydrogenases (11β-HSDs) catalyze the interconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone). 11β-HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivates glucocorticoids, thus allowing aldosterone selective access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast, the function of 11β-HSD type 1 has, until recently, been little understood. 11β-HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucocorticoid target tissues. However, increasing data suggest that 11β-HSD1 acts as a predominant 11β-reductase in many intact cells, whole organs, and in vivo. This reaction direction locally regenerates active glucocorticoids within expressing cells, exploiting the substantial circulating levels of inert 11-keto steroids. While the biochemical determinants of the reactio...

Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease

Context Patients who take glucocorticoids appear to have an increased risk for cardiovascular disease. However, data about the magnitude of this increased risk are lacking Contribution In this large, population-based study, the use of glucocorticoids was associated with an increased risk for cardiovascular events, with a clear dose-response relationship. Patients who received high-dose glucocorticoids were more than 2.5 times as likely as patients who did not use glucocorticoids to experience a cardiovascular event. Implications These data will help clinicians estimate cardiovascular risk among patients who require glucocorticoids. The Editors Glucocorticoids are commonly used as anti-inflammatory and immunosuppressive therapy in diseases such as asthma, inflammatory bowel disease, and inflammatory arthritis. Well-known adverse effects of glucocorticoids include hypertension, diabetes mellitus, and obesity (1-3), all of which are independent risk factors for cardiovascular disease. The principal physiologic glucocorticoid is cortisol. Increased cortisol secretion and action, even within the physiologic range, is associated with several risk factors for cardiovascular disease (4, 5). Indeed, studies have proposed that subclinical Cushing syndrome may be an important cardiovascular risk factor (6, 7). However, whether, and to what extent, the adverse effects of exogenous glucocorticoids on these risk factors for cardiovascular disease cause cardiovascular morbidity and death has not been established (8, 9). This is not predictable, especially since glucocorticoids may also have cardioprotective effects mediated by their anti-inflammatory and antiproliferative actions in the vessel wall (10, 11). We tested the hypothesis that users of exogenous glucocorticoids have an increased risk for cardiovascular disease. In particular, we hypothesized that high doses will be associated with cardiovascular disease, while doses equivalent to or below the physiologic range of endogenous glucocorticoid secretion may be compensated for by decreased cortisol levels and will not incur excessive risk. We have tested this by using the MEdicines MOnitoring unit (MEMO) record linkage database to compare people who were exposed and not exposed to glucocorticoid therapy. Methods We performed this study in the Tayside region in Scotland by using the MEMO record linkage database. The MEMO database covers a geographically compact population and serves about 400000 patients in the National Health Service (NHS) in Scotland, 97% of whom are white. The NHS in Scotland is tax-funded and free at the point of consumption and covers the entire population. In Tayside, almost no health care is delivered without the NHS. The data collection methods for this database have previously been described (12). In brief, this database contains several data sets, including all dispensed community prescriptions, hospital discharge data, mortality data, biochemistry data, and other data, that are linked by a unique patient identifier, the community health index number. These data are made anonymous for the purposes of research, as approved by the Tayside Caldicott Guardians (a group appointed by the government to protect the confidentiality of medical records). The Tayside committee on research medical ethics also approved the project. We cleaned and validated all data before analysis. We included all patients who resided in Tayside and registered with a general practitioner in January 1993, who were 40 years of age or older, and who remained a resident in Tayside until December 1997 or who died during the study period. Definitions of Exposure to Glucocorticoids Exposed and Comparator Cohorts All patients who received 1 or more dispensed prescriptions for glucocorticoids (including inhaled steroids, topical steroids, oral and parenteral steroids, rectal application steroids, and nasal steroids) between July 1993 and December 1996 formed the exposed cohort. They entered the study at their date of first prescription. The rest of the study sample made up the comparator cohort. We excluded patients who were hospitalized for inflammatory bowel disease and chronic obstructive airways disease during the follow-up period because they may have been given glucocorticoids as hospital inpatients without the prescriptions being identified by MEMO. We generated a random date of entry to the study for each member of the comparator cohort by using a frequency-matched calendar year generated from the dates of entry to the study in the exposed cohort. We excluded patients from both cohorts if they were hospitalized for cardiovascular disease before study entry. Dose of Glucocorticoids For about two thirds of dispensed oral or systemic glucocorticoid prescriptions, we recorded the date of prescription, dose of tablets, amount dispensed, and instructions on how medication should be taken. For these prescriptions, we could determine daily exposure during prescribed courses. For the remainder, we knew the total dose dispensed but, because prescriptions were marked take as directed, could not accurately determine the daily dose and duration. We therefore calculated the average daily dose by dividing the total amount of glucocorticoid dispensed by the total number of days of observation. For multiple simultaneous formulations (oral and inhaled) of glucocorticoids, we used only the oral glucocorticoids to calculate the daily dose. We categorized glucocorticoid exposure according to average daily doses throughout the follow-up period for each patient as high (oral, parenteral, and rectal steroids with daily dosage 7.5 mg [that is, supraphysiologic doses]); medium (oral, parenteral, and rectal steroids with daily dosage <7.5 mg [that is, approximately equivalent to the physiologic range of endogenous glucocorticoid secretion]); or low (inhaled, topical, and nasal steroids with daily dosage less than the equivalent physiologic range). As a result of this calculation, we included patients who took large dosages for a short period in the medium-dose group. We calculated dose equivalents of prednisolone as follows: 1 mg of prednisolone = 5 mg of cortisone = 4 mg of hydrocortisone = 1 mg of prednisone = 0.8 mg of triamcinolone = 0.8 mg of methylprednisolone = 0.15 mg of dexamethasone = 0.15 mg of betamethasone (13). The MEMO database does not collect information for prescriptions dispensed in hospitals. We considered participants hospitalized for asthma, inflammatory bowel disease, or chronic obstructive pulmonary disease (disorders usually treated with high-dose glucocorticoids in the hospital) as being exposed to a typical dosage of glucocorticoids (30 mg/d, prednisolone) during that period. Analysis of Events during Glucocorticoid Exposure (On Treatment vs. Off Treatment) We did a subgroup analysis of those patients for whom we had data on daily dose of glucocorticoid exposure. For each patient, we divided exposure to glucocorticoid into the time that the patient was exposed (on treatment) and the time that the patient was not exposed (off treatment). We then temporally related these periods to the occurrence of cardiovascular events. Incident versus Prevalent Use For each patient in the cohort exposed to glucocorticoids, we used the 6 months before entry to the study as a screening period. We classified patients who did not receive glucocorticoids during this period as incident users of glucocorticoids and patients who received glucocorticoids during this period as prevalent users. Continuous versus Intermittent Use We did an analysis comparing cardiovascular risk in continuous use (180 days between prescriptions) versus intermittent use (>180 days between prescriptions). Exposure by Disease Indication We identified patients with chronic obstructive pulmonary disease if they were hospitalized for asthma or chronic obstructive pulmonary disease or were prescribed an inhaled steroid or bronchodilator drug before study entry. We identified patients with inflammatory bowel disease if they were hospitalized for colitis or were prescribed a rectal steroid preparation before study entry. We identified patients with inflammatory arthritis if they were hospitalized for inflammatory arthritis or were prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs before study entry. Outcome Variables We collected the outcome data on each patient until 31 December 1997. The outcome of the study was a cardiovascular event defined as the composite end point of hospitalization with a primary diagnosis of myocardial infarction, angina, angioplasty or coronary revascularization, stroke, transient ischemic attack, congestive cardiac failure, or cardiovascular death during follow-up. We censored patients at their first event if they had several events. We ascertained diagnoses of myocardial infarction, angina, angioplasty and coronary revascularization, stroke, transient ischemic attack, and congestive cardiac failure from the hospital discharge diagnosis data, which were validated (14) in the Scottish Morbidity Record 1 by primary International Classification of Diseases, Ninth or Tenth Revisions, codes. We also ascertained diagnoses of angioplasty and coronary revascularization by the code of classification of surgical operations and procedures. We also obtained the death certification data for all Tayside residents who died. Statistical Analysis We counted events that occurred during the study period and compared rates of events between cohorts. We used the Poisson regression model to investigate the association between glucocorticoid exposure and cardiovascular outcome. We included the following covariates: age at study entry; sex; social deprivation; use of angiotensin-converting enzyme inhibitors, anticoagulants, antiplatelet agents, -blockers, -blockers, calcium-channel blockers, cardiac glycosides, diuretics, nitrates, lipid-lowering drugs, hormone replacement the

Adrenocortical, Autonomic, and Inflammatory Causes of the Metabolic Syndrome Nested Case-Control Study

Background—The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. Methods and Results—This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both −0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r =−0.19;P =0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. Conclusions—Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required.

Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats

The role of glucocorticoids in obesity is poorly understood. Observations in obese men suggest enhanced inactivation of cortisol by 5alpha-reductase and altered reactivation of cortisone to cortisol by 11betahydroxysteroid dehydrogenase type 1 (11betaHSD1). These changes in glucocorticoid metabolism may influence corticosteroid receptor activation and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA). We have compared corticosterone metabolism in vivo and in vitro in male obese and lean Zucker rats, aged 9 weeks (n = 8/group). Steroids were measured in 72-h urine and 0900 h trunk blood samples. 5alpha-Reductase type 1 and 11betaHSD activities were assessed in dissected tissues. Obese animals were hypercorticosteronemic and excreted more total corticosterone metabolites (2264+/-623 vs. 388+/-144 ng/72 h; P = 0.003), with a greater proportion being 5alpha-reduced or 11-oxidized. 11-Dehydrocorticosterone was also elevated in plasma (73+/-9 vs. 18+/-2 nM; P = 0.001) and urine (408+/-111 vs. <28 ng/72 h; P = 0.01). In liver of obese rats, 5alpha-reductase type 1 activity was greater (20.6+/-2.7% vs. 14.1+/-1.5%; P<0.04), but 11betaHSD1 activity (maximum velocity, 3.43+/-0.56 vs. 6.57+/-1.13 nmol/min/mg protein; P = 0.01) and messenger RNA levels (0.56+/-0.08 vs. 1.03+/-0.15; P = 0.02) were lower. In contrast, in obese rats, 11betaHSD1 activity was not different in skeletal muscle and sc fat and was higher in omental fat(36.4+/-6.2 vs. 19.2+/-6.6; P = 0.01), whereas 11betaHSD2 activity was higher in kidney (16.7+/-0.6% vs. 11.3+/-1.5%; p = 0.01). We conclude that greater inactivation of glucocorticoids by 5alpha-reductase in liver and 11betaHSD2 in kidney combined with impaired reactivation of glucocorticoids by 11betaHSD1 in liver may increase the MCR of glucocorticoids and decrease local glucocorticoid concentrations at these sites. By contrast, enhanced 11betaHSD1 in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity.

Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study

Objective: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. Design and setting: Nested case–control study within a cohort of patients (⩾ 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. Patients: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430–436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. Main outcome measure: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. Results: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose–response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). Conclusions: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes.

Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure.

Increased vascular resistance in essential hypertension occurs mainly in microvessels with luminal diameters < 100 microm. It is not known whether abnormalities in these vessels are a cause or consequence of high blood pressure (BP). We studied 105 men (aged 23-33 yr) in whom predisposition to high blood pressure has been characterized by both their own BP and those of their parents. Factors that are secondary to high BP correlate with offspring BP irrespective of parental BP, but factors that are components of the familial predisposition to high BP are more closely associated with higher BP in offspring whose parents also have high BP. Offspring with high BP whose parents also have high BP had impaired dermal vasodilatation in the forearm following ischemia and heating (289+/-27 [n = 25] versus 529+/-40 [n = 26], 476+/-38 [n = 30], and 539+/-41 flux units [n = 24] in other groups; P < 0.0001) and fewer capillaries on the dorsum of the finger (23+/-0.8 capillaries/0.25 mm2 versus 26+/-0.8 in all other groups; P < 0.003). Except for BP, other hemodynamic indices (including cardiac output and forearm vascular resistance) were not different. The dermal vessels of men who express a familial predisposition to high BP exhibit increased minimum resistance and capillary rarefaction. Defective angiogenesis may be an etiological component in the inheritance of high BP.

Inhibition of nitric oxide synthesis increases blood pressure in healthy humans.

Objective: To examine whether endogenous production of the endotheliumderived vasodilator nitric oxide influences blood pressure in healthy humans Methods: After preliminary pilot dose-ranging studies, 3mg/kg NG-monomethyl-l-arginine (l-NMMA), an inhibitor of nitric oxide synthase, and saline placebo were infused intravenously over 5 min to eight healthy subjects in a two-phase, randomized, single-blind crossover study. Blood pressure and cardiac and renal function were measured Results: Compared with placebo, L-NMMA increased mean arterial pressure by 10%, decreased heart rate by 19%, decreased cardiac index by 25% and increased calculated total peripheral resistance by 46%. Effects were maximal 10-15 min after starting l-NMMA infusion. Urinary sodium and fractional sodium excretions were increased by l-NMMA, but creatinine clearance was unchanged Conclusions: Basal generation of nitric oxide influences total peripheral resistance and blood pressure in healthy humans. The natriuresis induced by L-NMMA may be related to the increase in blood pressure, or arise from inhibition of the intrarenal actions of nitric oxide. Any decrease in nitric oxide generation, as has been postulated to occur in essential hypertension, could have substantial effects on blood pressure and tissue blood flow

Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome

Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of glucocorticoid excess (Cushings syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of glucocorticoids is not manifest in long-term weight loss in humans. The effects of glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in glucocorticoid concentrations in the plasma and/or in tissue sensitivity to glucocorticoids are important in metabolic syndrome. The effects of glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome.

Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients.

Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. Objective: Our objective was to establish the health status of adults with CAH. Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years. Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.

Reduced Cortisol Metabolism during Critical Illness

BACKGROUND Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism. METHODS In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes. RESULTS Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons). CONCLUSIONS During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).