Discrepancies in the Recommended Management of Adrenal Incidentalomas by Various Guidelines.

PURPOSE: Adrenal incidentalomas are being discovered with increasing frequency, and their discovery poses a challenge to clinicians. Despite the 2002 National Institutes of Health consensus statement, there are still discrepancies in the most recent guidelines from organizations representing endocrinology, endocrine surgery, urology and radiology. We review recent guidelines across the specialties involved in diagnosing and treating adrenal incidentalomas, and discuss points of agreement as well as controversy among guidelines. MATERIALS AND METHODS: PubMed®, Scopus®, Embase™ and Web of Science™ databases were searched systematically in November 2019 in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement to identify the most recently updated committee produced clinical guidelines in each of the 4 specialties. Five articles met the inclusion criteria. RESULTS: There is little debate among the reviewed guidelines as to the initial evaluation of an adrenal incidentaloma. All patients with a newly discovered adrenal incidentaloma should receive an unenhanced computerized tomogram and hormone screen. The most significant points of divergence among the guidelines regard reimaging an initially benign appearing mass, repeat hormone testing and management of an adrenal incidentaloma that is not easily characterized as benign or malignant on computerized tomography. The guidelines range from actively recommending against any repeat imaging and hormone screening to recommending a repeat scan as early as in 3 to 6 months and annual hormonal screening for several years. CONCLUSIONS: After reviewing the guidelines and the evidence used to support them we posit that best practices lie at their convergence and have presented our management recommendations on how to navigate the guidelines when they are discrepant.

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Glucocorticoids Regulate Bone Marrow B Lymphopoiesis After Stroke.

RATIONALE: After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow. OBJECTIVE: To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke. METHODS AND RESULTS: We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88-/- and TLR4-/- mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers. CONCLUSIONS: Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.

Hormonal determinants of mammographic density and density change.

BACKGROUND: Mammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm2) and annual MD change (cm2/year). METHODS: This study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time. RESULTS: Greater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm2 per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm2), oesterone sulphate (+ 1.42 cm2), prolactin (+ 2.11 cm2) and SHBG (+ 4.18 cm2), and inversely associated with 11-deoxycortisol (- 1.33 cm2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was - 0.8 cm2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was - 0.96 cm2 and - 1.16 cm2 lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations. CONCLUSIONS: Our results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.

SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma.

BACKGROUND: Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study. METHODS: SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes. CONCLUSIONS: SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose. TRIAL REGISTRATION: NCT03406078 ( ClinicalTrials.gov ). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078.

Acute responses of comprehensive gonadosteroids and corticosteroids to resistance exercise before and after 10 weeks of supervised strength training.

NEW FINDINGS: What is the central question of this study? Although acute responses of the principal gonadosteroid and corticosteroid hormones to resistance exercise are well documented, there is no information regarding how the key lower-concentration intermediary hormones respond and potentially influence these hormonal pathways. What is the main finding and its importance? This study provides evidence for cascading conversions of some gonadosteroids, and the data suggest that the testosterone concentration increases independently of these hormones. These findings challenge future studies to determine the exact physiological roles of the lower-concentration gonadosteroids and corticosteroids during and immediately after resistance exercise. ABSTRACT: Resistance training is a potent stimulus for muscle growth, and steroid hormones are known to play a role in this adaptation. However, very little is known about the acute exercise-induced gonadosteroid and corticosteroid hormone responses, including those of key lower-concentration intermediate hormones. The present study determined the acute responses of these steroid hormone families using quantitative ultra-high performance liquid chromatography tandem mass spectrometry after resistance exercise in strength-trained men. Venous and fingertip blood samples were obtained pre-, mid-, 5 min post- and 15 min post-resistance exercise, both before and after 10 weeks of supervised resistance training. The experimental resistance exercise sessions consisted of three sets of 10 repetitions of bilateral leg-press exercise and three sets of 10 repetitions of unilateral knee-extension exercise, with 2 and 1 min recovery between sets, respectively. Statistically significant (P < 0.05) increases in the concentration of hormones in the gonadosteroid [including dehydroepiandrosterone (DHEA), androstenedione, testosterone and estrone] and the corticosteroid (including cortisol, corticosterone and cortisone) families were demonstrated after both experimental resistance exercise sessions, irrespective of training status. Correlation analyses revealed relationships between the following hormones: (i) DHEA and androstenedione; (ii) DHEA and cortisol; (iii) androstenedione and estrone; and (iv) 11-deoxycortisol and cortisol. Testosterone appears to increase acutely and independently of other intermediary hormones after resistance exercise. In conclusion, lower-concentration intermediary gonadosteroids (e.g. estrone) and corticosteroids (e.g. corticosterone) respond robustly to resistance exercise in strength-trained men, although it seems that testosterone concentrations are regulated by factors other than the availability of precursor hormones and changes in plasma volume.

Mean platelet volume and response to the first line therapy in newly diagnosed adult immune thrombocytopenia patients: a retrospective study

Background/aim: Immune thrombocytopenia (ITP) is treated by corticosteroids and/or intravenous immune globulin as the first line treatment when necessary. Mean platelet volume (MPV) is a marker of platelet production and function. In this study, we aimed to search the relationship between the MPV and the treatment response in ITP patients and it was hypothesized that MPV can be used as a predictor of the response. Materials and methods: The 70 newly diagnosed adult primary ITP patients and 70 of healthy people were included. MPV between ITP and healthy population, MPV in the diagnosis and after the treatment between the responders and the nonresponders were compared. Results: The responders had significantly higher MPV and the nonresponders had significantly lower MPV than the healthy population (11.09 and 10.21 fL, P = 0.03; 9.38 and 10.21 fL, P = 0.001). MPV in the diagnosis was significantly higher in the responders than the nonresponders (11.09 and 9.38 fL, P = 0.005). MPV significantly changed after the treatment in the responders (11.09 to 9.32 fL, P = 0.004). Conclusion: MPV can be used as a predictor of early response to the first line treatment in newly diagnosed adult primary ITP patients.

A cross-sectional survey of adrenal steroid hormones among overweight/obese boys according to puberty stage.

BACKGROUND: Obesity is associated with many chronic diseases including cortisol rhythm disorder and low testosterone. Furthermore, studies on obese children are quite limited and no concordance results have been obtained, especially for boys in puberty. Moreover, the sample sizes of previous studies were small, and were not representative. METHODS: We conducted a cross-sectional survey including 1148 boys aged 6-14 years, they were divided into overweight/obesity (OW/OB) group and normal weight (NW) group. Puberty status was assessed according to Tanner scale and testicular volume. Serum levels of pregnenolone, 17-OH progesterone, corticosterone, dehydroepiandrosterone (DHEA), and androstenedione were detected by LC-MS. Serum free testosterone and sex hormone-binding globulin (SHBG) levels were measured by chemiluminescence immunoassay. RESULTS: The 17-OH progesterone, DHEA, androstenedione and free testosterone levels of OW/OB boys at prepubertal stage or at the age 6 = < 10 years group were higher than those of the NW boys (all the P values were < 0.01). Furthermore, androstenedione and free testosterone levels were lower in OW/OB boys at late puberty, and the trend continued at the post pubertal stage for FT (P < 0.01-0.05). DHEA, androstenedione, and FT levels persisted to be higher at the 10~ < 12 years in OW/OB boys but not for 17-OH progesterone. FT level was lower in the OW/OB group at the 12~ < 15 years group. The SHBG levels in the OW/OB boys were lower than those in the NW ones at the 6~12 years group, and prepubertal to early pubertal stage. CONCLUSIONS: Premature adrenarche is more likely in OW/OB boys. More attention should be given to the lower androgen levels of OW/OB boys at late pubertal and post pubertal stages.

Kleeb Bua Daeng, a Thai Traditional Herbal Formula, Ameliorated Unpredictable Chronic Mild Stress-Induced Cognitive Impairment in ICR Mice.

Thai traditional herbal formula ''Kleeb Bua Daeng (KBD)''consists of a 1:1:1 ratio (dry weight) of three medicinal plants: Piper nigrum fruit, the aerial part of Centella asiatica and the petals of Nelumbo nucifera. Oral administration of KBD to unpredictable chronic mild stress (UCMS) mice significantly improved their cognitive function caused by chronic mild stress. Daily administration of KBD significantly decreased the serum corticosterone (CORT) and malondialdehyde (MDA) levels but increased the catalase and superoxide dismutase activities in both frontal cortex and hippocampus. The effects of KBD were similar to those caused by oral administration of vitamin E. HPLC analysis of the KBD extract revealed the presence of piperine, madecassoside, asiaticoside, luteolin-7-O-glucoside, rutin, kaempferol-3-glucoside, quercetin, kaempferol and ferulic acid as major constituents.

Limited significance of repeated long-term radiological and hormonal examination in nonfunctioning adrenal incidentalomas.

PURPOSE: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. MATERIALS AND METHODS: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. RESULTS: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. CONCLUSIONS: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.

High-throughput profiling of the circulating proteome suggests sexually dimorphic corticosteroid signaling following ischemic stroke.

Increasing evidence suggests that there are innate differences between sexes with respect to stroke pathophysiology; however, the molecular mechanisms underlying these differences remain unclear. In this investigation, we employed a shotgun approach to broadly profile sex-associated differences in the plasma proteomes of a small group of male ( n = 6) and female ( n = 4) ischemic stroke patients. Peripheral blood was sampled during the acute phase of care, and liquid chromatography electrospray ionization mass spectrometry was used to quantify plasma proteins. We observed widespread differences in plasma composition, as 77 out of 294 detected proteins were significantly differentially expressed between sexes. Corticosteroid-binding globulin (CBG), a negative acute-phase reactant that inversely regulates levels of bioactive free cortisol, was the most dramatically differentially regulated, exhibiting 16-fold higher abundance in plasma from women relative to men. Furthermore, functional annotation analysis revealed that the remaining differentially expressed proteins were significantly enriched for those involved in response to corticosteroid signaling. Plasma CBG levels were further examined in an additional group of male ( n = 19) and female ( n = 28) ischemic stroke patients, as well as a group of male ( n = 13) and female ( n = 18) neurologically normal controls. CBG levels were significantly reduced in male stroke patients relative to male controls; however, no differences were observed between female stroke patients and female controls, suggesting that women may exhibit an attenuated cortisol response to stroke. Collectively, our findings reinforce the idea that there are sex-associated differences in stroke pathophysiology and suggest that cortisol signaling should be investigated further as a potential molecular mediator.

Perinatal exposure to venlafaxine leads to lower anxiety and depression-like behavior in the adult rat offspring.

Depression during pregnancy and in the post-partum period is a growing health issue. Venlafaxine, a representative of serotonin and noradrenaline reuptake inhibitors, is used to treat a wide spectrum of mood disorders. However, the limited number of prenatal and perinatal studies raises the question about the long-term consequences of venlafaxine therapy. The aim of this study was to investigate the effect of venlafaxine exposure during pregnancy and lactation on anxiety-like and depression-like behaviors, as well as adrenocortical hormone concentrations in the adult rat offspring. For this purpose, rat dams were treated orally with venlafaxine from day 15 of gestation to postnatal day 20 at doses of 7.5, 37.5, and 75 mg/kg. Administration of venlafaxine during gestation and lactation affected anxiety-like and depression-like behaviors in adult rat offspring of both sexes. The animals exposed through their mothers to venlafaxine, particularly at the lowest and middle doses, were less anxious and less depressive in several relevant behavioral tests, which can be considered a deviation from the normal state. At clinically relevant doses, venlafaxine did not alter circulating level of corticosterone and aldosterone in the adult offspring. In general, the consequences of venlafaxine were dose dependent and more apparent in females. Together, these results suggest that prenatal and early postnatal exposure to venlafaxine may interfere with functional development of the brain, though not necessarily in a negative way.

Relationship between adrenal steroid hormones in cord blood and birth weight: The Sapporo Cohort, Hokkaido Study on Environment and Children's Health.

OBJECTIVES: We investigated the relationship between steroid hormone levels in cord blood and birth weight. METHODS: Among 514 participants in a prospective birth cohort study in Sapporo, the following hormone levels were measured in 294 stored cord blood samples from 135 males and 159 females: androstenedione, dehydroepiandrosterone (DHEA), cortisol, and cortisone. Birth weight information was obtained from medical records. RESULTS: Androstenedione/DHEA was significantly higher in males than in females, while DHEA was significantly higher in females. Birth weight was significantly higher in males than in females. Regarding cortisone, androstenedione/DHEA, and cortisone/cortisol, a correlation was observed with birth weight in males but not in females. CONCLUSIONS: Prenatal adrenal steroids as well as converting enzymes such as 11ß-hydrosteroid dehydrogenase type 2 and 3ß-hydrosteroid dehydrogenase may have an impact on prenatal physical development.

A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts.

RATIONALE: Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy. OBJECTIVES: To determine the value of blood analysis to identify transcriptional differences between clinically defined asthma and nonasthma groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences. METHODS: Transcriptomic profiles were generated by microarray analysis of blood from 610 patients with asthma and control participants in the U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) study. Differentially expressed genes (DEGs) were identified by analysis of variance, including covariates for RNA quality, sex, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis. MEASUREMENTS AND MAIN RESULTS: A total of 1,693 genes were differentially expressed between patients with severe asthma and participants without asthma. The differences from participants without asthma in the nonsmoking severe asthma and mild/moderate asthma subgroups were significantly related (r = 0.76), with a larger effect size in the severe asthma group. The majority of, but not all, differences were explained by differences in circulating immune cell populations. Pathway analysis showed an increase in chemotaxis, migration, and myeloid cell trafficking in patients with severe asthma, decreased B-lymphocyte development and hematopoietic progenitor cells, and lymphoid organ hypoplasia. Cluster analysis of DEGs led to the creation of subgroups among the patients with severe asthma who differed in molecular responses to oral corticosteroids. CONCLUSIONS: Blood gene expression differences between clinically defined subgroups of patients with asthma and individuals without asthma, as well as subgroups of patients with severe asthma defined by transcript profiles, show the value of blood analysis in stratifying patients with asthma and identifying molecular pathways for further study. Clinical trial registered with www.clinicaltrials.gov (NCT01982162).

Nicotine exposure suppresses hyperinsulinemia and improves endothelial dysfunction mediators independent of corticosteroids in insulin-resistant oral contraceptive-treated female rats.

Estrogen-progestin oral contraceptives (COC) or tobacco smoking has been associated with hypertension and endothelial dysfunction resulting in increased risk of cardiovascular diseases (CVD). Contrasting effects of nicotine exposure on endothelial function have been reported. The effect of non-smoking nicotine exposure on endothelial dysfunction during COC treatment remains to be fully elucidated. We therefore, sought to determine the effects of nicotine exposure during COC treatment on endothelial dysfunction mediators and circulating corticosteroids. Female Wistar rats aged 10 weeks were given (po) vehicle, nicotine (1.0 mg/kg) with or without COC steroids (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) daily for 6 weeks. Nicotine exposure caused 113.3% increase in insulinemia whereas COC treatment led to 76.9% increased insulinemia compared with control. Furthermore, COC treatment or nicotine exposure led to glucose deregulation, insulin resistance, reduced nitric oxide bioavailability, elevated plasminogen activator inhibitor-1, uric acid, oxidative stress, atherogenic dyslipidemia, and corticosteroids. However, COC + NIC treatment led to 41.2% decrease in insulemina compared with COC-treated rats. Furthermore, all other alterations were alleviated by nicotine exposure in COC-treated female rats with the exception of corticosteroids.

Corticosteroid and Cortisol Serum Levels Following Intra-articular Triamcinolone Acetonide Lumbar Facet Joint Injections.

BACKGROUND: Facet joint steroid injections are used to treat chronic low back pain. However, little is known about the systemic absorption and serum levels of steroids following intra-articular facet joint injections. The primary objective of this preliminary study was to investigate the pharmacokinetics of triamcinolone acetonide following fluoroscopically guided intra-articular lumbar facet joint injections in a cohort of patients with chronic low back pain. A secondary aim was to investigate the effects of triamcinolone on serum cortisol levels following lumbar facet joint injections. METHODS: The study cohort included 5 patients undergoing fluoroscopically guided intra-articular lumbar facet joint injections at a pain medicine specialty clinic. Blood was collected prior to the injections and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injections. RESULTS: The terminal elimination half-life of triamcinolone in a noncompartmental analysis was 213 hours. The peak median triamcinolone concentration of 3.6 ng/mL was detected within 24 hours after the injections. Serum cortisol levels were < 30 ng/mL for an average of 4.4 days. The maximum effect of triamcinolone on cortisol suppression was observed with triamcinolone serum levels of > 1.9 ng/mL. CONCLUSIONS: The peak serum concentration of triamcinolone following intra-articular facet joint injections occurred within 24 hours. The median terminal elimination half-life was 213 hours, but baseline cortisol levels were suppressed for an average of 4.4 days. Clinically, the prolonged half-life and endocrine effects of triamcinolone could increase the risk for serious drug-drug interactions in patients taking medications that inhibit corticosteroid metabolism.

Equine fetal adrenal, gonadal and placental steroidogenesis.

Equine fetuses have substantial circulating pregnenolone concentrations and thus have been postulated to provide significant substrate for placental 5α-reduced pregnane production, but the fetal site of pregnenolone synthesis remains unclear. The current studies investigated steroid concentrations in blood, adrenal glands, gonads and placenta from fetuses (4, 6, 9 and 10 months of gestational age (GA)), as well as tissue steroidogenic enzyme transcript levels. Pregnenolone and dehydroepiandrosterone (DHEA) were the most abundant steroids in fetal blood, pregnenolone was consistently higher but decreased progressively with GA. Tissue steroid concentrations generally paralleled those in serum with time. Adrenal and gonadal tissue pregnenolone concentrations were similar and 100-fold higher than those in allantochorion. DHEA was far higher in gonads than adrenals and progesterone was higher in adrenals than gonads. Androstenedione decreased with GA in adrenals but not in gonads. Transcript analysis generally supported these data. CYP17A1 was higher in fetal gonads than adrenals or allantochorion, and HSD3B1 was higher in fetal adrenals and allantochorion than gonads. CYP11A1 transcript was also significantly higher in adrenals and gonads than allantochorion and CYP19 and SRD5A1 transcripts were higher in allantochorion than either fetal adrenals or gonads. Given these data, and their much greater size, the fetal gonads are the source of DHEA and likely contribute more than fetal adrenal glands to circulating fetal pregnenolone concentrations. Low CYP11A1 but high HSD3B1 and SRD5A1 transcript abundance in allantochorion, and low tissue pregnenolone, suggests that endogenous placental pregnenolone synthesis is low and likely contributes little to equine placental 5α-reduced pregnane secretion.

Elevated Steroid Hormone Production in the db/db Mouse Model of Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes have become a major public health problem worldwide. Steroid hormone dysfunction appears to be linked to development of obesity and type 2 diabetes and correction of steroid abnormalities may offer new approaches to therapy. We therefore analyzed plasma steroids in 15-16 week old obese and diabetic db/db mice using liquid chromatography-tandem mass spectrometry. Lean db/+ served as controls. Db/db mice developed obesity, hyperglycemia, hyperleptinemia, and hyperlipidemia. Hepatic triglyceride storage was increased and adiponectin and pancreatic insulin were lowered. Aldosterone, corticosterone, 11-deoxycorticosterone, and progesterone were respectively increased by 3.6-, 2.9-, 3.4, and 1.7-fold in db/db mice compared to controls. Ratios of aldosterone-to-progesterone and corticosterone-to-progesterone were respectively 2.0- and 1.5-fold higher in db/db mice. Genes associated with steroidogenesis were quantified in the adrenal glands and gonadal adipose tissues. In adrenals, Cyp11b2, Cyp11b1, Cyp21a1, Hsd3b1, Cyp11a1, and StAR were all significantly increased in db/db mice compared with db/+ controls. In adipose tissue, no Cyp11b2 or Cyp11b1 transcripts were detected and no differences in Cyp21a1, Hsd3b1, Cyp11a1, or StAR expression were found between db/+ and db/db mice. In conclusion, the present study showed an elevated steroid hormone production and adrenal steroidogenesis in the db/db model of obesity and type 2 diabetes.

Adrenal insufficiency associated with long-term use of inhaled steroid in asthma.

BACKGROUND: We previously reported that as many as one third of hospitalized patients with asthma treated with a low to medium daily dose of inhaled steroids (ICSs) for an average of 4.5 years showed adrenal insufficiency (AI). OBJECTIVE: To re-examine this issue in consecutive outpatients with asthma because of possible subject selection bias. METHODS: One hundred twenty-one consecutive adult patients with asthma under ICS treatment for at least 6 months underwent a rapid adrenocorticotrophic hormone stimulation test. AI was defined as a morning serum cortisol level no higher than 3 µg/dL or lower than 18 µg/dL before and after administration of 250 µg of adrenocorticotrophic hormone. RESULTS: The mean durations of ICS use in the short-term (less than the median) and long-term (at least the median) users were 3.8 and 11.5 years, respectively. The proportion of subjects affected by AI tended to increase with the increasing cumulative dose of ICS (short-term users at a low to medium daily dose: mean cumulative dose 502 mg [15 of 34, 44.1%]; short-term users at a high dose of 941 mg [16 of 26, 61.5%]; long-term users at a low to medium dose of 1,077 mg [25 of 41, 61.0%]; long-term users at a high dose of 2,805 mg [13 of 20, 65.0%]), although not significantly. In short-term users, daily and cumulative ICS doses were significantly related to serum cortisol levels 60 minutes after taking adrenocorticotrophic hormone (r = -0.300 and -0.287, respectively; P < .05). CONCLUSION: A large number of patients with asthma might have AI even with low- to medium-dose ICS treatment when ICSs are administered over a long period. Thus, it is essential that patients with asthma under ICS treatment be checked for AI much more frequently.

An Etomidate Analogue With Less Adrenocortical Suppression, Stable Hemodynamics, and Improved Behavioral Recovery in Rats.

BACKGROUND: ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue designed to alleviate the adrenocortical suppression caused by etomidate while retaining the rapid sedative-hypnotic onset and stable hemodynamic features of etomidate. This study compared the anesthetic effect, hemodynamic stability, and recovery profiles of ET-26HCl, etomidate, and the sedative-hypnotic drug propofol in rats. METHODS: The metabolic half-life of ET-26HCl was determined in vitro using high performance liquid chromatography analysis of samples of rat plasma and liver homogenates taken from 3 animals. Hypnotic median effective doses (HD50) of ET-26HCl, etomidate, and propofol were determined by up-and-down methods. Anesthesia effect and mean arterial pressure were estimated using equivalent intravenous (IV) doses of propofol, etomidate, and ET-26HCl in the rats. Serum concentrations of corticosterone were analyzed by enzyme-linked immunosorbent assay. The ability of rats to recover from the sedative-hypnotic effects of the drugs was evaluated using open field and Morris water maze tests at equipotent doses of propofol, etomidate, ET-26HCl, and normal saline. RESULTS: The metabolic half-life of ET-26HCl was 81 ± 6 minutes in rat plasma and 126 ± 12 minutes in incubation liver homogenate (mean ± standard deviation), respectively. In vivo experiments showed that the potency of ET-26HCl to cause a loss of righting reflex in rats was 3 times lower than that of etomidate in the rats. IV propofol caused a greater decrease in mean arterial pressure relative to the baseline (-27.9 mm Hg) than did ET-26HCl (-10.7 mm Hg) and etomidate (-19.4 mm Hg) at equipotent doses. Serum corticosterone levels after drug administration were significantly higher in the ET-26HCl group than in the etomidate group at equivalent doses when measured 15 (P < .001), 30 (P < .001), and 60 (P = .002) minutes after stimulation with adrenocorticotropic hormone (ACTH1-24). Recovery of spatial orientation from anesthesia induced by an IV bolus injection was faster with ET-26HCl than with propofol, but recovery of spontaneous activity was slower. CONCLUSIONS: ET-26HCl has anesthetic potency and hemodynamic stability similar to etomidate, but it caused less adrenocortical hormone synthesis suppression than etomidate and faster spatial orientation recovery from anesthesia than propofol, which was similar to etomidate.