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British Medical Journal Apr 1953
Topics: Addison Disease; Adrenal Insufficiency; Cortisone; Desoxycorticosterone; Hypoadrenocorticism, Familial
PubMed: 13032539
DOI: No ID Found -
Postgraduate Medical Journal Apr 1953
Topics: Addison Disease; Adrenal Insufficiency; Adrenocorticotropic Hormone; Cortisone; Desoxycorticosterone; Humans; Hypoadrenocorticism, Familial
PubMed: 13055541
DOI: 10.1136/pgmj.29.330.200 -
Toxicological Sciences : An Official... Mar 2019Many glucocorticoid receptor (GR) agonists have been detected in waste and surface waters domestically and around the world, but the way a mixture of these environmental...
Many glucocorticoid receptor (GR) agonists have been detected in waste and surface waters domestically and around the world, but the way a mixture of these environmental compounds may elicit a total glucocorticoid activity response in water samples remains unknown. Therefore, we characterized 19 GR ligands using a CV1 cell line transcriptional activation assay applicable to water quality monitoring. Cells were treated with individual GR ligands, a fixed ratio mixture of full or partial agonists, or a nonequipotent mixture with full and partial agonists. Efficacy varied (48.09%-102.5%) and potency ranged over several orders of magnitude (1.278 × 10-10 to 3.93 × 10-8 M). Concentration addition (CA) and response addition (RA) mixtures models accurately predicted equipotent mixture responses of full agonists (r2 = 0.992 and 0.987, respectively). However, CA and RA models assume mixture compounds produce full agonist-like responses, and therefore they overestimated observed maximal efficacies for mixtures containing partial agonists. The generalized concentration addition (GCA) model mathematically permits < 100% maximal responses, and fell within the 95% confidence interval bands of mixture responses containing partial agonists. The GCA, but not CA and RA, model predictions of nonequipotent mixtures containing both full and partial agonists fell within the same statistical distribution as the observed values, reinforcing the practicality of the GCA model as the best overall model for predicting GR activation. Elucidating the mechanistic basis of GR activation by mixtures of previously detected environmental GR ligands will benefit the interpretation of environmental sample contents in future water quality monitoring studies.
Topics: Biological Assay; Corticosterone; Desoxycorticosterone; Dexamethasone; Dose-Response Relationship, Drug; Drug Partial Agonism; Glucocorticoids; Ligands; Models, Biological; Prednisolone; Receptors, Glucocorticoid; Transcriptional Activation
PubMed: 30535411
DOI: 10.1093/toxsci/kfy290 -
Critical Care (London, England) Nov 2022Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients.
OBJECTIVES
We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis.
METHODS
An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality.
MEASUREMENTS AND MAIN RESULTS
Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality.
CONCLUSIONS
In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www.
CLINICALTRIALS
gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .
Topics: Adult; Humans; Adrenocorticotropic Hormone; Hydrocortisone; Hospital Mortality; Glucocorticoids; Mineralocorticoids; Corticosterone; Cortodoxone; Chromatography, Liquid; Tandem Mass Spectrometry; Sepsis; Shock, Septic; Desoxycorticosterone
PubMed: 36345013
DOI: 10.1186/s13054-022-04224-5 -
Cardiovascular Research Mar 2018
Topics: Acetates; Desoxycorticosterone Acetate; Female; Humans; Hypertension; Pregnancy; Spleen
PubMed: 29432537
DOI: 10.1093/cvr/cvy029 -
Critical Care Medicine Jan 2012Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have...
OBJECTIVE
Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia.
MEASUREMENTS AND MAIN RESULTS
Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression.
CONCLUSIONS
In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.
Topics: Animals; Blood Volume; Central Venous Pressure; Desoxycorticosterone; Dexamethasone; Dogs; Glucocorticoids; Heart; Interleukin-6; Lung; Mineralocorticoids; Platelet Count; Pneumonia, Staphylococcal; Serum Albumin; Shock, Septic; Sodium; Water-Electrolyte Balance
PubMed: 21926575
DOI: 10.1097/CCM.0b013e31822efa14 -
The Journal of Experimental Medicine Mar 1951The effect of desoxycorticosterone acetate (DCA) on the granulation tissue of healing and healed linear laparotomy wounds was studied in young adult male guinea pigs...
The effect of desoxycorticosterone acetate (DCA) on the granulation tissue of healing and healed linear laparotomy wounds was studied in young adult male guinea pigs maintained on a complete diet and on a known intake of ascorbic acid. DCA induces the production of an excessive amount of granulation tissue, as evidenced by a relatively great number of fibroblasts and by a larger amount of ground substance. This effect was accompanied by a slight to moderate lag in the maturation process of both cellular and intercellular elements. These changes were observed when DCA administration was begun 5 days prior to operation, but were less obvious or absent if DCA was injected, beginning on the 5th or 10th postoperative day. The results indicate that the action of DCA on immature, proliferating connective tissue is marked, and is considerably less or absent when connective tissue elements have reached partial or almost complete maturity. The effect of DCA on connective tissue does not appear to rest on the basis of an altered nutritional status. Chemical and histochemical studies of the adrenals suggest that the action of DCA on connective tissue is probably mediated through a disturbance of adrenocortical function, namely an imbalance between hormones of the zona glomerulosa (excess of DCA) and those of the zona fasciculata (deficiency of glucocorticoids). The presence of changes in granulation tissue and the lack of them in mature resting connective tissue of DCA-treated guinea pigs confirm the view that a profound difference in the response mechanism exists between resting and actively proliferating connective tissue.
Topics: Adrenal Cortex Hormones; Animals; Connective Tissue; Dermis; Desoxycorticosterone Acetate; Fibroblasts; Granulation Tissue; Guinea Pigs; Male; Wound Healing; Wounds and Injuries
PubMed: 14824397
DOI: 10.1084/jem.93.3.217 -
International Journal of Biological... 2014While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa), castration does not eliminate androgens from the prostate... (Review)
Review
While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa), castration does not eliminate androgens from the prostate tumor microenvironment, and residual intratumoral androgens are implicated in nearly every mechanism by which androgen receptor (AR)-mediated signaling promotes castration-resistant disease. The uptake and intratumoral (intracrine) conversion of circulating adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S) to steroids capable of activating the wild type AR is a recognized driver of castration resistant prostate cancer (CRPC). However, less well-characterized adrenal steroids, including 11-deoxcorticosterone (DOC) and 11beta-hydroxyandrostenedione (11OH-AED) may also play a previously unrecognized role in promoting AR activation. In particular, recent data demonstrate that the 5α-reduced metabolites of DOC and 11OH-AED are activators of the wild type AR. Given the well-recognized presence of SRD5A activity in CRPC tissue, these observations suggest that in the low androgen environment of CRPC, alternative sources of 5α-reduced ligands may supplement AR activation normally mediated by the canonical 5α-reduced agonist, 5α-DHT. Herein we review the emerging data that suggests a role for these alternative steroids of adrenal origin in activating the AR, and discuss the enzymatic pathways and novel downstream metabolites mediating these effects. We conclude by discussing the potential implications of these findings for CRPC progression, particularly in context of new agents such as abiraterone and enzalutamide which target the AR-axis for prostate cancer therapy.
Topics: Androgens; Antineoplastic Agents; Desoxycorticosterone; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 24948873
DOI: 10.7150/ijbs.8844 -
Clinical and Experimental Pharmacology... Apr 2021Hypertension is a multifaceted condition influenced by genetic and environmental factors and estimated to cause 9.4 million deaths globally every year. Recently, there...
Hypertension is a multifaceted condition influenced by genetic and environmental factors and estimated to cause 9.4 million deaths globally every year. Recently, there has been growing interest in understanding the gut microbe-host interaction in the maintenance of health or disease states, but relatively few studies have shown an association between the gut microbiome and specific types of hypertension. The deoxycorticosterone acetate (DOCA)-salt model of hypertension in rats is known to have a neurogenic component linked to increased sympathetic nervous system activity. As such, our lab has recently shown the hypertensive response in DOCA treated rats requires an intact organum vasculosum of the lamina terminalis (OVLT), a central hypothalamic circumventricular organ. Currently, we hypothesize the OVLT mediates changes in the gut microbiome associated with concomitant hypertension. Herein, we report that the hypertensive effects of DOCA-salt treatment were significantly attenuated throughout the 24-hour day/night cycle in OLVT lesioned rats on days 1, 3, and 9-21 of DOCA treatment compared with sham rats. Increased blood pressure (BP) in DOCA-salt treated rats was accompanied by specific changes in regional gut microbial populations yet was mitigated and offset by lesion of the OVLT. Furthermore, bacterial populations in OVLT-lesioned rats with attenuated hypertension more closely resembled those in normal control rats. We conclude that DOCA-salt hypertension is associated with specific microbiome changes in the gut, and the attenuated hypertensive effects of DOCA-salt in OVLT-lesioned rats is mediated in part through counteracting changes in these bacterial populations.
Topics: Animals; Blood Pressure; Desoxycorticosterone Acetate; Gastrointestinal Microbiome; Hypertension; Organum Vasculosum; Rats
PubMed: 33462863
DOI: 10.1111/1440-1681.13457 -
The Journal of Physiology May 2022Recently, studies have emerged suggesting that the skin plays a role as major Na reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. We...
Recently, studies have emerged suggesting that the skin plays a role as major Na reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. We investigated whether there were electrolyte gradients in skin and where Na could be stored to be inactivated from a fluid balance viewpoint. Na accumulation was induced in rats by a high salt diet (HSD) (8% NaCl and 1% saline to drink) or by implantation of a deoxycorticosterone acetate (DOCA) tablet (1% saline to drink) using rats on a low salt diet (LSD) (0.1% NaCl) on tap water as control. Na and K were assessed by ion chromatography in tissue eluates, and the extracellular volume by equilibration of Cr-EDTA. By tangential sectioning of the skin, we found a low Na content and extracellular volume in epidermis, both parameters rising by ∼30% and 100%, respectively, in LSD and even more in HSD and DOCA when entering dermis. We found evidence for an extracellular Na gradient from epidermis to dermis shown by an estimated concentration in epidermis ∼2 and 4-5 times that of dermis in HSD and DOCA-salt. There was intracellular storage of Na in skin, muscle, and myocardium without a concomitant increase in hydration. Our data suggest that there is a hydration-dependent high interstitial fluid Na concentration that will contribute to the skin barrier and thus be a mechanism for limiting water loss. Salt stress results in intracellular storage of Na in exchange with K in skeletal muscle and myocardium that may have electromechanical consequences. KEY POINTS: Studies have suggested that Na can be retained or removed without commensurate water retention or loss, and that the skin plays a role as major Na reservoir via regulation of the content of glycosaminoglycans and osmotic gradients. In the present study, we investigated whether there were electrolyte gradients in skin and where Na could be stored to be inactivated from a fluid balance viewpoint. We used two common models for salt-sensitive hypertension: high salt and a deoxycorticosterone salt diet. We found a hydration-dependent high interstitial fluid Na concentration that will contribute to the skin barrier and thus be a mechanism for limiting water loss. There was intracellular Na storage in muscle and myocardium without a concomitant increase in hydration, comprising storage that may have electromechanical consequences in salt stress.
Topics: Animals; Rats; Blood Pressure; Desoxycorticosterone; Desoxycorticosterone Acetate; Electrolytes; Glycosaminoglycans; Hypertension; Ions; Rats, Sprague-Dawley; Sodium; Sodium Chloride; Water
PubMed: 35377950
DOI: 10.1113/JP282715