Total Glucocorticoid Research Articles

Antecedent Hyperglycemia Is Associated With an Increased Risk of Neutropenic Infections During Bone Marrow Transplantation

OBJECTIVE—To use bone marrow transplantation (BMT) as a model for testing the association between hyperglycemia and infection.RESEARCH DESIGN AND METHODS—This cohort study included 382 adults (6.5% with diabetes) who had no evidence of infection before neutropenia during BMT. Mean glucose was calculated from central laboratory and bedside measurements taken before neutropenia; the primary outcome was neutropenic infections.RESULTS—Eighty-four patients (22%) developed at least one neutropenic infection, including 51 patients (13%) with bloodstream infections. In patients who did not receive glucocorticoids during neutropenia, each 10 mg/dl increase in mean preneutropenia glucose was associated with an odds ratio of 1.08 (95% CI 0.98–1.19) (P = 0.14) for any infection and 1.15 (1.03–1.28) (P = 0.01) for bloodstream infections, after adjusting for age, sex, race, year, cancer diagnosis, transplant type, and total glucocorticoid dose before neutropenia. In those who received glucocorticoids during neutropenia (n = 71), the adjusted odds ratio associated with a 10 mg/dl increase in mean glucose was 1.21 (1.09–1.34) (P < 0.0001) for any infection and 1.24 (1.11–1.38) (P < 0.0001) for bloodstream infections. There was no association between mean glycemia and long length of hospital stay, critical status designation, or mortality.CONCLUSIONS—In a BMT population highly susceptible to infection, there was a continuous positive association between mean antecedent glycemia and later infection risk, particularly in patients who received glucocorticoids while neutropenic. Tight glycemic control during BMT and glucocorticoid treatment may reduce infections.

Impaired glucose tolerance and insulin resistance are associated with increased adipose 11beta-hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5alpha-reductase activity.

OBJECTIVE—The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active cortisol from cortisone, and 5α-reductase (5αR), which inactivates cortisol, has been implicated.RESEARCH DESIGN AND METHODS—A total of 101 obese patients (mean age 48 ± 7 years, BMI 34.4 ± 4.3 kg/m2, 66 women, 35 men) underwent 75-g oral glucose tolerance testing (OGTT), body composition analysis (dual-energy X-ray absorptiometry), assessment of glucocorticoid metabolism (24-h urine steroid metabolite analysis by gas chromatography/mass spectrometry), and subcutaneous abdominal adipose tissue biopsies.RESULTS—A total of 22.7% of women had IGT compared with 34.2% of men. Two women and five men were diagnosed with type 2 diabetes. In women, adipose 11β-HSD1 expression was increased in patients with IGT and correlated with glucose levels across the OGTT (R = 0.44, P < 0.001) but was independent of fat mass. Total glucocorticoid secretion was higher in men with and without IGT (normal 13,743 ± 863 vs. 7,453 ± 469 μg/24 h, P < 0.001; IGT 16,871 ± 2,113 vs. 10,133 ± 1,488 μg/24 h, P < 0.05), and in women, it was higher in those with IGT (7,453 ± 469 vs. 10,133 ± 1,488 μg/24 h, P < 0.001). In both sexes, 5αR activity correlated with fasting insulin (men R = 0.53, P = 0.003; women R = 0.33, P = 0.02), insulin secretion across an OGTT (men R = 0.46, P = 0.01; women R = 0.40, P = 0.004), and homeostasis model assessment of insulin resistance (men R = 0.52, P = 0.004; women R = 0.33, P = 0.02).CONCLUSIONS—Increased adipose 11β-HSD1 expression in women may contribute to glucose intolerance. Enhanced 5αR activity in both sexes is associated with insulin resistance but not body composition. Augmented glucocorticoid inactivation may serve as a compensatory, protective mechanism to preserve insulin sensitivity.

Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency.

It remains controversial whether long-term glucocorticoids are charged of bone demineralization in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The aim of this study was to know whether cumulative glucocorticoid dose from the diagnosis in childhood to adulthood in patients with CAH had a negative impact on bone mineral density (BMD). This was a retrospective study. Thirty-eight adult patients with classical and non-classical CAH were included. BMD was measured in the lumbar spine and femoral neck. Total cumulative glucocorticoid (TCG) and total average glucocorticoid (TAG) doses were calculated from pediatric and adult files. We showed a difference between final and target heights (-0.82+/-0.92 s.d. for women and -1.31+/-0.84 s.d. for men; P<0.001). Seventeen patients (44.7%) had bone demineralization (35.7% of women and 70% of men). The 28 women had higher BMD than the 10 men for lumbar (-0.26+/-1.20 vs -1.25+/-1.33 s.d.; P=0.02) and femoral T-scores (0.21+/-1.30 s.d. versus -1.08+/-1.10 s.d.; P=0.007). In the salt-wasting group, women were almost significantly endowed with a better BMD than men (P=0.053). We found negative effects of TCG, TAG on lumbar (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), predominantly during puberty. BMI was protective on BMD (P=0.006). The TCG is an important factor especially during puberty for a bone demineralization in patients with 21-hydroxylase deficiency. The glucocorticoid treatment should be adapted particularly at this life period and preventive measures should be discussed in order to limit this effect.

Renal Net Acid Excretion and Plasma Leptin Are Associated with Potentially Bioactive Free Glucocorticoids in Healthy Lean Women1, ,

Primarily experimental evidence suggests that endogenous glucocorticoids may be suppressed by adipocyte-derived leptin and elevated by dietary acidity. Therefore, we examined whether these factors may also be relevant in healthy adults on unrestricted diets. For this we used a new methodological approach in which potentially bioactive free glucocorticoids were determined as the sum of urinary free cortisol and urinary free cortisone and that also takes into account total adrenal glucocorticoid secretion assessed by the sum of the 3 major urinary glucocorticoid metabolites tetrahydrocortisone, tetrahydrocortisol, and 5α-tetrahydrocortisol. Body composition, plasma cortisol, plasma leptin, and 24-h urinary excretion rates of net acid and glucocorticoid metabolites were examined cross-sectionally in 30 healthy adults (15 women; 22–44 y old; BMI 20–25 kg/m2). Plasma leptin, percentage body fat, and body surface area-corrected adrenal glucocorticoid secretion showed the usual sex dimorphism (male vs. female, P < 0.05 in each case: 2.8 ± 1.6 μg/L vs. 7.6 ± 4.9 μg/L, 16.8 ± 4.2% vs. 26.9 ± 4.9%, and 5.1 ± 1.6 mg · m−2 · d−1 vs. 4.0 ± 1.3 mg · m−2 · d−1, respectively), whereas net acid excretion, plasma cortisol, and potentially bioactive free glucocorticoids did not differ between the sexes. Potentially bioactive free glucocorticoids correlated positively with body fat and leptin in men (P < 0.05) but not in women. After adjustment for total adrenal glucocorticoid secretion, net acid excretion was a positive and leptin a negative predictor (P < 0.05) of potentially bioactive free glucocorticoids in women only (total explained variability R2 = 0.71). Our findings indicate that, at least in women, variability of potentially bioactive free glucocorticoids is not only explained by adrenal glucocorticoid secretion but is also metabolically affected by circulating leptin and diet-dependent net acid excretion.

Alveolar bone loss in liver transplantation patients: relationship with prolonged steroid treatment and parathyroid hormone levels

To evaluate the relationship among alveolar bone loss (ABL), bone status and calcium-regulating hormones in liver transplantees. Twenty-one liver transplantees underwent a full oral examination. The correlations among bone densitometry, bone metabolic status and drug treatment were examined. Twelve patients had osteopenia, and six were osteoporotic. ABL was 4.33+/-2.32 mm (range 0.67-9.92). Parathyroid hormone (PTH) levels ranged from 14 to 106 (mean 55.2+/-26.4). The mean 25(OH)D(3) was 11.68+/-4.7, range 3.5-21.1 ng/ml. Nine patients were vitamin D deficient (<10 ng/ml); none of the patients had 25(OH)D(3) levels > or =30 ng/ml. No correlation was found between ABL and current or total glucocorticoids dose, although there was an inverse relation with the duration of treatment (r =-0.474, p=0.03). A positive correlation was found between ABL, PTH (r =0.419, p=0.059) and hip bone mineral density (BMD) (r=0.482, p=0.027). ABL correlated closely with age, PTH, glucocorticoid treatment (duration) and hip BMD (r =0.810, p=0.004). The majority of liver transplant patients had insufficient 25(OH)D(3) serum levels. Changes in calcium-regulating hormones and hip BMD were correlated with ABL. Therefore, therapeutic intervention aimed at treating vitamin D deficiency and secondary hyperparathyroidism should be considered in these patients. The benefits of vitamin D treatment in the management of secondary hyperparathyroidism and possible decrease in ABL deserve further evaluation in controlled trials.

Effects of electromagnetic irradiation on glucocorticoid in serum and its receptor expression in rat hippocampus

To explore the role and mechanism of glucocorticoid (GC) in the harmful bio-effects of electromagnetic irradiation. Rats were exposed to 65 mW/cm(2) electromagnetic wave for 20 min. At 10 min, 30 min, 3 h, 12 h after irradiation, their learning and memory abilities were tested by Morris water maze. The levels of corticosterone (CORT) in serum were measured by radioimmunoprecipitation assay and the changes of total glucocorticoid receptor (GR) expression and GR nuclear translocation in rat hippocampus were measured by reverse transcription-polymerase chain reaction and Western blot. The rats had learning and memory deficits at 10 min, 30 min and 3 h after irradiation, but at 12 h had no difference from the normal control. The levels of corticosterone in serum increased significantly at 10 min, 30 min, decreased at 3 h and increased significantly compared with 12 h after irradiation. GR mRNA and total GR protein expression in rat hippocampus had no significant changes at 10 min, 30 min after irradiation. At 3 h, 12 h GR mRNA expression significantly decreased by 69%, 76% respectively and GR total protein decreased by 58%, 67% respectively. There were significant differences between the two groups and the corresponding controls (P<0.05). And compared with the control, the GR nuclear translocation increased significantly at 3 h and 12 h (P<0.05). GC may take part in the injury to learning and memory abilities after electromagnetic irradiation, and the non-genomic and genomic effects of GC may play a major role in the early and late stage, respectively.

The role of corticosterone in human hypothalamic– pituitary–adrenal axis feedback

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. 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, single-blind, 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). Outpatients undergoing diagnostic lumbar puncture who were subsequently deemed to be free of disease. Feedback was tested in healthy male volunteers. Plasma and CSF corticosterone to cortisol ratio was calculated and the ACTH response over time after the bolus glucocorticoid measured. 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. 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.

Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements

Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements. Cross-sectional study in the outpatient department of a university teaching hospital. Forty-six patients (19 men, 27 women, age range 16-76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37.5 mg cortisone acetate (range 25-50 mg) since 10 +/- 7 years (range 1-31 years). Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long-standing glucocorticoid replacement. Thirty-seven patients were considered well replaced, whereas clinical scores suggested over- or under-replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight-adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under- and over-replaced patients (P < 0.05) but neither group differed significantly from well-replaced patients. Bone mineral density was normal in all patients studied. Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow-up.

Posttransplant Diabetes Mellitus in Kidney Transplant Recipients Receiving Calcineurin or mTOR Inhibitor Drugs

The aim of this study was to evaluate the incidence and risk factors for posttransplant diabetes mellitus (PTDM; defined as new insulin use and/or new hyperglycemia) in 528 kidney recipients using different immunosuppressive agents. Maintenance therapy included mycophenolate mofetil or azathioprine plus glucocorticoids in combination with Group I cyclosporine (263); Group II tacrolimus (60); or Group III sirolimus (205). The mean follow-up was 39.2 (range 9.0-103.8) months. Overall, the number of patients needing insulin was 7.4% (39/528). The incidences for Groups I, II, and III of 7.6%, 11.7%, and 5.9%, respectively, were not statistically different. Characteristics of patients with PTDM included older age (P=0.007); greater body weight (kg) at transplant, 6 months, and 12 months, respectively (P<0.001); greater BMI (kg/m2) at transplant, 6 months, and 12 months, respectively (P<0.001); more acute rejection episodes 28.2% vs. 13.5% (P=0.012); and increased incidence in African Americans (P=0.03). Multivariable analysis demonstrated increased risk for PTDM (defined as new insulin use) for tacrolimus, (hazard ratio [HR] 3.794, P=0.007); treated rejections (HR 2.491, P=0.0115); age (HR 1.407, P=0.0116); and BMI (HR 1.153, P<0.0001). New insulin use occurred sooner and with less total glucocorticoid dose for tacrolimus patients. If PTDM is defined as all cases of new hyperglycemia, then no immunosuppressive drug group demonstrated an increased risk. CONCLUSION.: The risk for developing PTDM is greatest among older recipients, and those obese at the time of transplant; those given steroid pulse therapy were at exceptionally high-risk. PTDM risk reduction should focus on weight loss in the obese end-stage renal disease population prior to transplant.

The hormonal and behavioral response to group formation, seasonal changes, and restraint stress in the highly social Malayan Flying Fox ( Pteropus vampyrus) and the less social Little Golden-mantled Flying Fox ( Pteropus pumilus) (Chiroptera: Pteropodidae)

This study examined behavioral and physiological responses (changes in inter-animal spacing, total glucocorticoids, testosterone, and body mass) to the formation of breeding and same-sex groups in two bat species, the socially gregarious Malayan Flying Fox ( Pteropus vampyrus) and the less social Little Golden-mantled Flying Fox ( Pteropus pumilus). We hypothesized that social instability, especially in the breeding groups and especially in P. vampyrus, would result in elevated glucocorticoids and that social facilitation of breeding and/or male–male competition would result in persistently higher levels of testosterone in breeding males. Seasonal rhythms in all measures were also predicted, and the glucocorticoid stress response was expected to vary by sex, season, and group type. Nearly all animals responded to group formation with elevated glucocorticoids, but, for breeding animals (especially aggressive male P. vampyrus), these responses persisted over time. In both species, breeding group formation resulted in elevated testosterone in males. Glucocorticoids, testosterone, testes volume, and body mass generally peaked in the breeding season in males (late summer and early autumn), but the seasonal glucocorticoid peak in females occurred in late winter and early spring. All animals responded to restraint stress with elevations in glucocorticoids that largely did not differ by sex, time of year, reproductive condition, group type, or, in lactating females, the presence of her pup. Changes in both behavior and physiology were more evident in P. vampyrus than in P. pumilus, and we believe that their underlying social differences influenced their responses to group formation and to the changing seasonal environment.

Estrogen Protects Cardiac Myogenic (H9c2) Rat Cells Against Lethal Heat Shock-Induced Cell Injury

In the present study we have established that exposure of rat cardiac myoblasts (H9c2 cells) to 46 degrees C for 1 hour (lethal heat shock) resulted in optimal cell injury as determined by lactate dehydrogenase release. Pretreatment of H9c2 cells for 24 hours with 17beta-estradiol significantly protects myoblasts against subsequent lethal heat shock exposure in a concentration-dependent manner with maximum protection obtained at 1 microM of 17beta-estradiol. With Western blotting, it was observed that 17beta-estradiol-protected cells had significantly higher levels of the estrogen receptor alpha and inducible heat shock protein 70 (hsp70) as well as inducible nitric oxide synthase (iNOS) levels compared with lethal heat shock-exposed cells. In contrast, lethal heat shock-exposed cells had significantly higher levels of total cellular glucocorticoid receptors (GR), both cytoplasmic and nuclear, compared with 17beta-estradiol-protected cells. Immunofluorescence technique using confocal microscopy revealed nuclear localization of the glucocorticoid receptors (GR) in lethal heat shock-exposed H9c2 cells while 17beta-estradiol-protected cells had primarily extranuclear localization of GR. We conclude that (1) 17beta-estradiol protects H9c2 cells against lethal heat shock insult by a receptor-independent mechanism, and (2) the protective effects are likely mediated by modulation of GR, hsp 70, and iNOS expression.

Evaluation of the influence of S-adenosylmethionine on systemic and hepatic effects of prednisolone in dogs

To evaluate the influence of a 1,4-butanedisulfonate stable salt of S-adenosylmethionine (SAMe) administered orally on clinicopathologic and hepatic effects induced by long-term administration of prednisolone in dogs. 12 healthy dogs. Following a pilot study (4 dogs), 2 groups of 4 dogs received prednisolone (2.2 mg/kg) orally once daily (84-day trial). One group received SAMe (20 mg/kg/d divided in 2 doses) for 42 days and then a placebo for 42 days; the other group received treatments in the reverse order. Before and during the trial, numerous variables were monitored, including serum total alkaline phosphatase (ALP) and glucocorticoid-induced ALP (G-ALP) activities, serum haptoglobin concentration, and total and oxidized glutathione (TGSH and GSSG) and thiobarbiturate-reacting substances (TBARS) concentrations in erythrocytes and liver tissue (days 0, 42, and 84). Hepatic specimens also were examined microscopically. The stable salt of SAMe was biologically available; plasma concentrations of SAMe or prednisolone were not affected by coadministration. Compared with baseline values, serum ALP and G-ALP activities and haptoglobin concentrations increased and erythrocyte GSSG and TBARS concentrations decreased with both treatments. Erythrocyte TGSH concentration decreased with the prednisolone-placebo treatment. Administration of SAMe appeared to conserve erythrocyte TGSH values and did not inhibit hepatocyte glycogen vacuolation but increased hepatic TGSH concentration and improved the hepatic tissue GSSG:TGSH ratio. In dogs, administration of 20 mg of SAMe/kg/d may mitigate the apparent pro-oxidant influences of prednisolone but did not block development of classic clinicopathologic or histologic features of vacuolar hepatopathy.

Diagnosis and Treatment of Early Postoperative Inflammatory Intestinal Obstruction in Young Children

目的 探讨小儿急性阑尾炎术后早期炎性肠梗阻的临床特点、诊断、治疗和预防措施.方法对我院1999年1月～2004年1月13例小儿急性阑尾炎术后早期炎性肠梗阻的诊治经过进行回顾性分析.治疗包括禁食、胃肠减压、全肠外营养、糖皮质激素及中药的应用.结果本组13例均治愈,平均治愈时间为17.2天.结论小儿急性阑尾炎术后早期炎性肠梗阻多发生在术后1周左右,应首选非手术治疗。

Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine

Adult rats were given antidepressant drugs orally. Fluoxetine, but not moclobemide, venlafaxine, tianeptine or desipramine, increased total glucocorticoid receptor (GR) mRNA in the hippocampus after 4 weeks. Further examination revealed that GR mRNA containing the brain-specific exon 1 7 was increased across all hippocampal subregions. In contrast, expression of the major exon 1 10 and another brain-specific exon 1 5-containing GR mRNAs were unchanged. Tissue-specific first exon usage may contribute to the differential regulation of GR by fluoxetine in brain subregions.

Choice and dose of corticosteroid for antenatal treatments

Although antenatal glucocorticoids are standard of care for women at risk of preterm delivery before 32 to 34 weeks' gestation, the choice and dosing of the corticosteroid has not been standardized. An analysis of the trial data demonstrates that the risk of neonatal death is decreased with betamethasone, but not dexamethasone. Other clinical data also indicate that betamethasone is the drug of choice for antenatal treatment. The pharmacology of the corticosteroids suggests that a lower total glucocorticoid dose per treatment may be as effective as the current treatment recommendations. However, a change from current practice will require further randomized controlled trials.

Changes in baseline and stress-induced glucocorticoid levels during the active period in free-ranging male and female little brown myotis, Myotis lucifugus (Chiroptera: Vespertilionidae)

Baseline and stress-responsive glucocorticoid (GC) levels were characterized during the active period in free-ranging male and reproductive female little brown myotis ( Myotis lucifugus). Bats were trapped and blood was sampled within 3 min of capture at two maternity sites during the summer and at one swarming site prior to hibernation in New England. Both GC hormones, cortisol and corticosterone, were detected, with cortisol accounting for an average of ∼95% of total circulating GCs. Samples collected at the dusk emergence and after the first return from feeding showed significant seasonal differences across the active period (early pregnancy, mid-to-late pregnancy, lactation [and comparable mid-summer times for males], and pre-hibernation) within and between each sex. Elevated baseline values were found in mid-to-late pregnancy females at emergence, and in both males and females at the swarming site compared to other groups. Female GC values during mid-to-late pregnancy and during the pre-hibernation period were greater than those for males. Significantly higher GC levels following 15 min of restraint were exhibited by all animals in the summer and prior to hibernation. There was little variation between groups or sexes in the total GC levels reached following restraint. Taken together, these results suggest that: (1) GCs may be involved in the increased feeding and/or fat deposition characteristic of pregnancy and the pre-hibernation period, (2) GCs may be related to mating and to the generally increased levels of activity that occur during the pre-hibernation period, and (3) regardless of sex or reproductive condition, all animals maximally respond to restraint stress.

Glucocorticoid receptor expression in fetal non-human primate lung

The purpose of this study was to use a unique set of phosphorylation state–specific antibodies to examine the activation of glucocorticoid receptors in steroid-treated and untreated fetal baboon lung. Pregnant baboons were randomized to receive either betamethasone at a dosing regimen of 175 μg/kg/day or saline for 48 hours. Cesarean deliveries were performed 12 hours after the last dose of either treatment or placebo, corresponding to a gestational age of 136 days (comparable to 28-29 weeks' gestation in humans). Immunohistochemistry was performed on serial sections of paraffin-embedded blocks of fetal lung biopsies and stained with antibodies for total glucocorticoid receptor (GR) and for phosphorylated GR at serine-226. GR expression was quantified by sampling three parenchymal fields (mediastinal, middle, peripheral) using 100× magnification with oil immersion. Cell counts were performed and positively staining cells were recorded as a percentage of total cells per field. The examiner was blinded to treatment conditions. Subjectively, fetal lung tissue from steroid-treated animals exhibited increased total GR expression. There was a notable gradient of GR expression (higher in the periphery, lower in the mediastinal area). Mean GR expression in the fetal lungs from steroid-treated animals was 63% of cells versus 55.8% in saline-treated (t-test, P = 0.04). Recycling GR (phosphorylated GR at serine-226) activity was not statistically significant between the two groups. Antenatal glucocorticoid treatment is associated with increased total GR expression in the fetal baboon lung model. This contrasts greatly with low levels of GR expression in human adult lung and suggests that GR expression may be downregulated during the transition from fetal to postnatal development.

Adrenal Enucleation in MSG-Damaged Hyperleptinemic Male Rats Transiently Restores Adrenal Sensitivity to Leptin

It is known that the neonatal treatment of rats with monosodium L-glutamate (MSG) induces several metabolic abnormalities, resulting in enhanced adiposity and hyperleptinemia. Our study was designed to explore the consequences of MSG-induced chronic hyperleptinemia on adrenal sensitivity to the inhibitory effect of exogenous leptin. Neonatal male rats treated with MSG or vehicle (controls, CTR) were followed during 150 days in order to study changes observed over development in body weight, food consumption as well as in vivo hypothalamo-pituitary-adrenal (HPA) axis and adipocyte functions. During adulthood, adrenal response to adrenocorticotropin (ACTH) was evaluated both in vitro and in vivo in order to determine the adrenal sensitivity to the inhibitory effect of leptin. For this purpose, sham-operated as well as CTR and MSG rats with bilateral adrenal enucleation (AE) were used. Our results indicate that: (1) between 30 and 150 days of age, MSG animals developed hypophagia, accompanied by arrest in body weight gain, and concomitant enhanced basal levels of all HPA axis components and of leptin; (2) adrenals from of 150-day- old MSG rats displayed an in vitro adrenocortical hyperresponse to ACTH stimulation as well as an adrenal refractoriness to the physiological inhibitory effect of leptin on ACTH-stimulated glucocorticoid output, and (3) bilateral AE in adult MSG-treated rats transiently reversed the MSG-induced hyperleptinemia, restoring normal leptin levels as well as a normal adrenal sensitivity to the inhibitory effect of leptin. Our data indicate that adrenal exposure to the chronically high plasma leptin levels observed in MSG rats is involved in the loss of the inhibitory regulatory effect of leptin at the adrenal level, being therefore, at least in part, responsible for the increased total and free glucocorticoid production measured in MSG adult rats. Furthermore, this study strongly suggests that the adrenal overfunction, frequently associated with different phenotypes of obesity, could be due to an adrenal resistance to the leptin-negative regulation.

Secondary Osteoporosis in Liver Transplant Recipients: a Longitudinal Study in Patients With and Without Cholestatic Liver Disease

Background: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation. Methods: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A—chronic cholestatic liver disease (n = 28), and group B—chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-l-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals. Results: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving'cyclosporin A. Conclusion: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort.

The phenotype of the Metabolic Syndrome (hypertension, insulin resistance and hyperlipidaemia) bears similarities to Cushing's Syndrome, in which the cause of these features is elevated cortisol production. We have investigated relationships between glucocorticoid production and features of the Metabolic Syndrome in a cohort of elderly subjects. A cross-sectional analysis was carried out of a subset of a birthweight cohort from Sheffield. 92 men and 40 women (aged 69-75 y) representative of the original cohort were investigated. Features of the Metabolic Syndrome (blood pressure, BMI, waist hip ratio, fasting glucose, insulin and triglycerides) were recorded and urinary glucocorticoid metabolites were measured by gas chromatography mass spectrometry. Total glucocorticoid metabolites were correlated with the overall phenotype of the Metabolic Syndrome (P = 0.002), whereas specific pathways of metabolism (activity of 11 beta-hydroxysteroid dehydrogenases and A-ring reductases) did not show significant associations. Specifically total glucocorticoid production increased with increasing systolic blood pressure (r = 0.21, P = 0.013), fasting glucose (r = 0.19, P = 0.02) and insulin (r = 0.23, P = 0.025). Glucocorticoid production was greater with increasing abdominal girth (r = 0.19, P = 0.033), but there was no association with enhanced metabolism via a specific pathway. Within this cohort, birthweight was not associated with total glucocorticoid metabolites. However, decreasing birthweight (P = 0.022), increasing obesity (P = 0.026) and increasing total glucocorticoid production (P = 0.009) were all independent predictors of fasting glucose. These data support the concept that cortisol production is enhanced in the Metabolic Syndrome, although they did not confirm the recent evidence that increased cortisol secretion is predicted by low birthweight.