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Summary Objective In humans, the glucocorticoid corticosterone circulates in blood at 10‐20-fold lower levels than cortisol, but is found in higher relative amounts in postmortem brain samples. Access of cortisol and corticosterone to the central nervous system may not be equal. Additionally, the relative affinities for the glucocorticoid and mineralocorticoid receptors differ, such that corticosterone may play a significant role in human brain function. Design We measured cortisol and corticosterone levels in paired plasma and cerebrospinal fluid (CSF) samples. To test the relative potency of cortisol vs. corticosterone on hypothalamic‐pituitary‐ adrenal (HPA) feedback, subjects underwent a three-phase, singleblind, randomized study assessing the postmetyrapone ACTH response over 3 h to an intravenous bolus of vehicle, cortisol or corticosterone (0·15 mg / kg and 0·04 mg / kg). Participants Outpatients undergoing diagnostic lumbar puncture who were subsequently deemed to be free of disease. Feedback was tested in healthy male volunteers. Measurements Plasma and CSF corticosterone to cortisol ratio was calculated and the ACTH response over time after the bolus glucocorticoid measured. Results Plasma corticosterone : cortisol was 0·069 ± 0·007; CSF corticosterone : cortisol was 0·387 ± 0·050 ( P < 0·001). Cortisol and corticosterone (0·15 mg / kg) suppressed ACTH vs. vehicle ( P = 0·002); there was no difference between corticosterone and cortisol. The 0·04 mg / kg dose had no effect on ACTH despite supraphysiological plasma corticosterone levels. Conclusions Corticosterone contributes almost 40% of total active glucocorticoids (cortisol and corticosterone) in the CSF. Significant effects on HPA axis suppression were only seen with supraphysiological levels of corticosterone, suggesting that corticosterone is not important in this model of nonstress-induced ACTH hypersecretion, in which the effect of cortisol predominates.

Summary objective Among babies born at term, intrauterine growth retardation (IUGR) predicts adult hypertension and hyperglycaemia. This might be due to elevated circulating glucocorticoids in adulthood, as described in animal models and in several cohorts of men who were low birthweight at term. Recently, we found that premature low birthweight babies also have adult cardiovascular risk factors, irrespective of IUGR. We have now investigated cortisol secretion in this group. design patients and measurements We studied 29 women and 23 men aged 22–25 years who had been recruited at birth as either normal term (mean birthweight 3·1 kg, gestation 39 weeks), premature appropriate for gestational age (AGA; 1·7 kg, 32 weeks), or premature IUGR (1·7 kg, 35 weeks) babies. Body composition was measured by dual-energy X-ray absorptiometry (DEXA); plasma was obtained at 0900 h after overnight fast; and cortisol metabolites were measured in a 24-h urine sample by gas chromatography/mass spectrometry (GCMS). results Cortisol metabolites were different in men and women, so results were analysed separately. Among women, adult body composition did not differ between groups. Plasma cortisol was not different, but total urinary cortisol metabolite excretion was lower in AGA (3·29 ± 1·91 mg/day, n = 7, P

OBJECTIVES The commonest side-effects of GH replacement therapy relate to sodium retention but its mechanism is unclear. In rats, GH inhibits renal and hepatic 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activities. In man, this action might impair inactivation of cortisol to cortisone in the distal nephron thereby allowing cortisol to activate mineralocorticoid receptors. In this study, we examined the effects of GH replacement on cortisol metabolism. DESIGN A randomized double-blind study comparing 6 months GH replacement with placebo in adults with GH deficiency due to pituitary or hypothalamic disease. PATIENTS 6 men and 8 women received placebo and 8 men and 9 women received GH. MEASUREMENTS Cortisol and its metabolites were measured in overnight urine samples and in a fasting morning plasma sample at baseline and at 6 months. RESULTS Five patients withdrew from the study, 4 because of adverse effects of GH. Amongst those who completed the study, the effects of GH on cortisol metabolism differed between patients with and without ACTH deficiency. Amongst those receiving hydrocortisone replacement (n = 18), GH had no effect on plasma cortisol/cortisone ratio, or urine tetrahydrocortisols/tetrahydrocortisone ratio, but produced a substantial reduction in total urinary cortisol metabolites (from 1326 +/- 191 to 777 +/- 229 micrograms/mmol creatinine; P < 0.01) and an increase in urinary free cortisol/cortisone ratio (from 0.88 +/- 0.10 to 2.57 +/- 0.74; P < 0.02). By contrast, GH had none of these effects in patients with normal ACTH secretion. There were no changes in blood pressure or plasma electrolytes, aldosterone, or renin activity with GH, and no changes in any variables with placebo. CONCLUSIONS The increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11 beta-HSD2 and the conversion of cortisone to cortisol by hepatic 11 beta-HSD1. It is unclear why this action of GH only affects patients with ACTH deficiency. The reduction in total cortisol metabolite excretion suggests that GH also affects bioavailability of hydrocortisone tablets. These observations suggest that glucocorticoid replacement therapy may need to be adjusted in hypopituitary patients who are commenced on GH replacement.

Causes of visceral fat accumulation include glucocorticoid excess or decreased oestrogen/androgen ratio either in plasma or within adipose tissue. In obese subjects, the intra-adipose cortisol-generating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is increased, but information on sex steroid signalling is sparse. We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue.A cross-sectional study.Forty-five healthy men and women with body mass index (BMI) 21-36 kg/m(2).In subcutaneous adipose biopsies we measured mRNAs for enzymes metabolizing local oestrogens (aromatase) and androgens [5alpha-reductase type 1; AKR1C2 (3alpha-HSD3); AKR1C3 (17beta-HSD5, 3alpha-HSD2)] and for sex steroid receptors [oestrogen receptor (ER)-alpha and androgen receptor (AR)]. We related these to body fat mass and distribution.Generalized obesity (BMI) was associated with increased aromatase mRNA (r = 0.35, P0.05). Central obesity (waist : hip ratio) was associated with mRNA for AKR1C2 (r = 0.28, P0.05) and AKR1C3 (r = 0.38, P0.01) but not aromatase (r = 0.06). 5alpha-Reductase type 1, ER and AR mRNA levels did not predict fat amount or its distribution.These data on transcript levels suggest that, in idiopathic obesity, increased intra-adipose oestrogen generation by aromatase predicts peripheral fat distribution, while androgen metabolism by AKR1C isoforms predicts central fat distribution, supporting the hypothesis that intra-adipose sex steroid metabolism is a determinant of gynoid vs. android patterns of body fat.

Summary Objective Glucocorticoid hyperactivity in adipose tissue, due to up-regulation of local glucocorticoid reactivation by 11β-hydroxysteroid dehydrogenase-1 (11HSD1) or of glucocorticoid receptors (GR), may underpin susceptibility to the metabolic syndrome. This hypothesis has been tested extensively in subcutaneous adipose tissue (SAT) but inadequately in visceral adipose tissue (VAT). The aim of the study was therefore to examine expression of 11HSD1, GRα and hexose-6-phosphate dehydrogenase (H6PDH), which supplies cofactor for 11HSD1, in abdominal adipose tissue compartments and to characterize their relation to metabolic syndrome parameters. Design and subjects A cross-sectional study including 26 premenopausal South African women. Measurements Biopsies were taken for measurement of mRNA levels by real-time polymerase chain reaction (RT-PCR) and 11HSD1 activity from VAT, and deep and superficial SAT compartments during elective surgery. Prior to surgery, blood pressure, blood lipid profile, body composition [by dual X-ray absorptiometry (DEXA) scan], body fat distribution [by computed tomography (CT) scan], and glucose tolerance were determined. Results 11HSD1 activity (P

Among babies born at term, intrauterine growth retardation (IUGR) predicts adult hypertension and hyperglycaemia. This might be due to elevated circulating glucocorticoids in adulthood, as described in animal models and in several cohorts of men who were low birthweight at term. Recently, we found that premature low birthweight babies also have adult cardiovascular risk factors, irrespective of IUGR. We have now investigated cortisol secretion in this group. DESIGN PATIENTS AND MEASUREMENTS: We studied 29 women and 23 men aged 22-25 years who had been recruited at birth as either normal term (mean birthweight 3.1 kg, gestation 39 weeks), premature appropriate for gestational age (AGA; 1.7 kg, 32 weeks), or premature IUGR (1.7 kg, 35 weeks) babies. Body composition was measured by dual-energy X-ray absorptiometry (DEXA); plasma was obtained at 0900 h after overnight fast; and cortisol metabolites were measured in a 24-h urine sample by gas chromatography/mass spectrometry (GCMS).Cortisol metabolites were different in men and women, so results were analysed separately. Among women, adult body composition did not differ between groups. Plasma cortisol was not different, but total urinary cortisol metabolite excretion was lower in AGA (3.29 +/- 1.91 mg/day, n = 7, P0.02) than in either normals (6.77 +/- 4.10, n = 14) or IUGR (9.47 +/- 8.84, n = 8). Relative excretion of cortisol and cortisone metabolites was not different. Statistically significant differences in cortisol parameters between groups were not seen in men.Premature AGA baby girls have lower cortisol secretion in adulthood but normal plasma cortisol, suggesting impaired metabolic clearance of cortisol. By contrast, premature IUGR babies maintain normal cortisol secretion as adults, suggesting that IUGR, rather than premature delivery, is responsible for programmed activation of the hypothalamic-pituitary-adrenal (HPA) axis. The ability to detect such dramatic differences in a small study suggests that programming has a potent influence on adult cortisol secretion.