Cortisol Resistance Research Articles

Use of Extracellular Monomeric Ubiquitin as a Therapeutic Option for Major Depressive Disorder.

Major depressive disorder (MDD) is a mood disorder that has become a global health emergency according to the World Health Organization (WHO). It affects 280 million people worldwide and is a leading cause of disability and financial loss. Patients with MDD present immunoendocrine alterations like cortisol resistance and inflammation, which are associated with alterations in neurotransmitter metabolism. There are currently numerous therapeutic options for patients with MDD; however, some studies suggest a high rate of therapeutic failure. There are multiple hypotheses explaining the pathophysiological mechanisms of MDD, in which several systems are involved, including the neuroendocrine and immune systems. In recent years, inflammation has become an important target for the development of new therapeutic options. Extracellular monomeric ubiquitin (emUb) is a molecule that has been shown to have immunomodulatory properties through several mechanisms including cholinergic modulation and the generation of regulatory T cells. In this perspective article, we highlight the influence of the inflammatory response in MDD. In addition, we review and discuss the evidence for the use of emUb contained in Transferon as a concomitant treatment with selective serotonin reuptake inhibitors (SSRIs).

THU037 Diagnostic Accuracy Of Bilateral Inferior Petrosal Sinus Sampling In Adrenocorticotropin-dependent Cushing’s Syndrome, And The Utility Of Maximum-stimulated Petrosal Sinus ACTH To Baseline Petrosal Sinus ACTH Ratio

Abstract Disclosure: A.N. Maldar: None. P.H. Chauhan: None. A. Kulkarni: None. N.F. Shah: None. B.K. Misra: None. M. Chadha: None. Methods: The diagnosis of Cushing’s Syndrome (CS) was made as per the prevalent endocrine society guidelines. CS patients with serum ACTH>15 pg/mL were considered as ACTH-dependent CS. Baseline ACTH (both inferior petrosal sinuses and peripheral) values were obtained, and since 2014, stimulated ACTH values (5 and 10 minutes post one unit iv vasopressin) were obtained as standard protocol. Prolactin corrected ACTH ratios were additionally being calculated since 2016. The highest central to peripheral ACTH gradient >2 in baseline samples (bC:P), >3 in samples after vasopressin stimulation (sC:P), and >0.8 in PRL-corrected ratios (pC:P) was used as reference value indicative of Cushing’s Disease (CD). An inter-petrosal gradient >1.4 was considered to be suggestive of an adenoma located on the side of the petrosal sinus with the higher ACTH concentration. Results: Of the 51 patients with ACTH-dependent CS who underwent BIPSS, four patients with incomplete data, one patient with unilateral petrosal sinus catheterization, one patient with Cortisol Resistance Syndrome were excluded from the analysis. Mean age of our cohort was 37.5 years, with 77.8% females. 39 patients had CD (positive histopathology-immunohistochemistry in 34, and remission post-surgery in additional five with hyperplasia), while six had ectopic CS (one each of bronchial carcinoid, lung NET, thymic NET, pancreatic NET, and two with undiagnosed ectopic source). bC:P>2 (N=45) demonstrated 92.3% sensitivity, 83.3% specificity, 97.3% PPV and 62.5% NPV, while sC:P>3 (N=31) demonstrated 96.3% sensitivity, 100% specificity, 100% PPV and 80% NPV to diagnose CD. pC:P>0.8 (N=20) improved the sensitivity and NPV to 100%, with a 75% specificity and 94.1% PPV. On ROC analysis, cut-point ratio of 2.55 for bC:P value gave a sensitivity of 89.7% and specificity of 100% (AUC=0.964); sC:P ratio of 2.95 had 96.3% sensitivity and 100% specificity (AUC=0.991); 0.93 for pC:P ratio provided a sensitivity of 93.8% and specificity of 100% for diagnosis of CD (AUC=0.984). Maximum-stimulated petrosal sinus ACTH to baseline petrosal sinus ACTH ratio of <1.11 provided a 100% sensitivity, while a ratio >1.75 provided 100% specificity towards diagnosis of CD. 71.4% (10/14) patients with left sided adenoma, and 85% (17/20) patients with right sided adenoma were correctly lateralised on BIPSS. In patients whom adenoma was detected on pituitary MRI, 66.7% (6/9) were correctly lateralised to the left side, and 94.1% (16/17) to the right side. Conclusion: BIPSS provides high sensitivity and specificity to diagnose CD. Vasopressin stimulation improves the sensitivity and specificity, while prolactin correction improves the sensitivity of BIPSS, as compared to baseline ratios. Maximum-stimulated petrosal sinus ACTH to baseline petrosal sinus ACTH ratio can be additionally used, especially in CD patients suspected of false negative localization. Presentation: Thursday, June 15, 2023

Cortisol resistance in the degu (Octodon degus)

Cortisol resistance has also been reported in the degu, Octodon degus, a New World hystricomorph endemic to central Chile. The degu is used as a model for studies of stress and diurnal rhythms, parental behaviour and female masculinization. Another New World hystricomorph, the guinea pig, also exhibits glucocorticoid resistance, a result of amino acid sequences that differ from other mammalian glucocorticoid receptors (GR). Mutations in the ligand-binding domain of the human GR have been identified in familial or sporadic generalised cortisol resistance as have variants in the guinea pig. To address the possibility that the high levels of cortisol observed in the degu are a result of the same or similar sequence variations observed in the guinea pig GR, we have cloned, expressed and characterised the ligand-binding domain (LBD) of the degu GR. Somewhat unexpectedly, neither the amino acids nor the region involved in the resistance observed in the guinea pig GR are relevant in the degu GR. The relative resistance to cortisol observed in the degu GR is conferred by the substitution of two isoleucine residues, which are highly conserved in the GR across species, with a valine doublet. These amino acids lie in the region between helices 5 and 6 of the GR LBD, a region known to be important in determining the affinity of ligand-binding in steroid receptors.

Molecular links between endocrine, nervous and immune system during chronic stress.

IntroductionThe stress response is different in various individuals, however, the mechanisms that could explain these distinct effects are not well known and the molecular correlates have been considered one at the time. Particular harmful conditions occur if the subject, instead to cope the stressful events, succumb to them, in this case, a cascade reaction happens that through different signaling causes a specific reaction named “sickness behaviour.” The aim of this article is to review the complex relations among important molecules belonging to Central nervous system (CNS), immune system (IS), and endocrine system (ES) during the chronic stress response.MethodsAfter having verified the state of art concerning the function of cortisol, norepinephrine (NE), interleukin (IL)‐1β and melatonin, we describe as they work together.ResultsWe propose a speculative hypothesis concerning the complex interplay of these signaling molecules during chronic stress, highlighting the role of IL‐1β as main biomarker of this effects, indeed, during chronic stress its increment transforms this inflammatory signal into a nervous signal (NE), in turn, this uses the ES (melatonin and cortisol) to counterbalance again IL‐1β. During cortisol resistance, a vicious loop occurs that increments all mediators, unbalancing IS, ES, and CNS networks. This IL‐1β increase would occur above all when the individual succumbs to stressful events, showing the Sickness Behaviour Symptoms. IL‐1β might, through melatonin and vice versa, determine sleep disorders too.ConclusionThe molecular links here outlined could explain how stress plays a role in etiopathogenesis of several diseases through this complex interplay.

Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas.

PurposeMost adrenal incidentalomas (AIs) are nonfunctioning adenomas (NFAs), but up to 30% may secrete cortisol autonomously without clinical evidence of Cushing syndrome (CS), which nevertheless may increase cardiovascular mortality. This subclinical hypercortisolism (SCH) is confirmed by cortisol resistance to a dexamethasone suppression test (DST). Cyclic cortisol secretion occurs in classic CS but was not reported in SCH.ObjectiveInvestigate cyclic cortisol production/autonomy in AIs using sequential DSTs.MethodsA total of 251 patients with AI underwent 487 DSTs over 12 years; patients with at least three DSTs were selected. DSTs were validated by measuring serum dexamethasone. Cyclic SCH was defined when at least two abnormal and two normal DSTs were documented.ResultsA total of 44 patients had three or more DSTs during follow-up: 9 of 44 patients (20.4%) had all negative test results (post-DST cortisol ≤1.8 μg/dL) and were classified as NFA; another nine patients had all positive results (cortisol >1.8 μg/dL) and were classified as sustained SCH. The remaining 26 (59.2%) had discordant responses: 8 of 44 (18.3%) had at least two positive and two negative tests, matching the criterion for cyclic SCH, whereas 18 of 44 (40.9%) had only one discordant test and were classified as possibly cyclic SCH. Eleven of 20 (55%) patients initially classified as NFA did not maintain their cortisol pattern.ConclusionsExtended follow-up with repeated DSTs uncovered an unusual subset of AIs with cyclic SCH. Recurring production of cortisol may affect determination of AI subtypes if based on just one DST. Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk.

Cushing\u2019s syndrome with no clinical stigmata \u2013 a variant of glucocorticoid resistance syndrome

BackgroundCortisol resistance syndrome is a very rare condition characterized by high cortisol levels, but without any clinical features of Cushing’s syndrome. Our objective is to present such a case.Case presentationA 41 year old female presented with mild hirsutism and elevated urinary cortisol levels. Plasma cortisol levels were elevated and were not suppressed by conventional doses of dexamethasone on multiple occasions, but decreased following administration of higher doses of dexamethasone. Adrenocorticotropic hormone (ACTH) levels were inappropriately elevated. Despite significantly elevated cortisol levels, she did not develop any clinical signs or symptoms of Cushing’s syndrome. Pituitary and adrenal imaging did not reveal any abnormalities. Genetic testing for human glucocorticoid receptor did not reveal any mutations.ConclusionsAlthough we were not able to identify any new mutations, we believe that our patient has a variant of cortisol resistance syndrome. This syndrome should be considered in the differential diagnosis of patients who present with high levels of cortisol but have no clinical features of Cushing’s syndrome.

The Influence of Cortisol and Age Differences on the Development of Insulin Resistance and Dyslipidemia in Euthyroid Patients

Objectives: The present study was planned to investigate the influence of serum cortisol and age differences on insulin resistance and the associated lipid disturbances in euthyroid adults. Methods: Hyperglycemic, hyperinsulinemic patients were recruited, and classified according to their insulin resistance (HOMA-IR) into: Normal insulin sensitivity (NIS), moderate- (MIR), high insulin resistance (HIR) with HOMA-IR 6, respectively. The patients were also classified into three age-range groups: young age (YA), middle age (MA), Old age (OA); with age ranges 40 yrs., respectively. Fasting serum was used for analysis. Results: The serum cortisol of HIR was higher than NIS by 17.64%, and insulin higher than NIS and MIR by 272% and 121%, respectively. On the other hand, serum glucose of OA was higher than YA by 28.87%, whereas, insulin was lower than YA and MA by 52.08%, and 31.10%. Similarly, HOMA-IR was lower than YA and MA by 45.97% and 24.11%, respectively. There was significant correlation between serum cortisol and HOMA-IR (R=0.59, P=0.02) at ages> 45 years. Serum triglyceride in HIR was higher than NIS and MIR by 38.59% and 18.79%, and VLDL by 116% and 20.37%, respectively, whereas, HDL was lower than NIS by 11.38%. Conclusion: Insulin resistant patients had elevated serum cortisol and insulin. There was significant correlation between cortisol and insulin resistance at older ages. The serum cortisol increased with age whereas insulin level decreased. Patients with high insulin resistance had dyslipidemia characterized by high serum TG, high VLDL-c and low HDL-c.

Screening for endocrine hypertension. An Endocrine Society scientific statement

Hypertension may be the initial clinical presentation for at least 15 endocrine disorders. An accurate diagnosis of endocrine hypertension provides clinicians with the opportunity to render a surgical cure or to achieve an optimal clinical response with specific pharmacologic therapy. It is challenging for the clinician to know when and how to perform case-detection testing for all the endocrine disorders in which hypertension may be the presenting symptom. Herein, we review the different forms of endocrine hypertension, with a focus on prevalence, clinical presentation, guidance on when to perform case detection testing, and currently available case-detection tests.Hypertension affects 28.6% of adults in United States. In most, hypertension is primary (essential or idiopathic), but a subgroup of approximately 15% has secondary hypertension. More than 50% of children who present with hypertension have a secondary cause. In young adults (< 40 years old), the prevalence of secondary hypertension is approximately 30%. The secondary causes of hypertension include renal causes (e.g., renal parenchymal disease) and endocrine causes. Hypertension may be the initial clinical presentation many endocrine disorders: pheochromocytoma and sympathetic paraganglioma, primary aldosteronism, hyperdeoxycorticosteronism (congenital adrenal hyperplasia – 11b-hydroxylase deficiency, 17a-hydroxylase deficiency, deoxycorticosterone-producing tumor, primary cortisol resistance), cushing syndrome, apparent mineralocorticoid excess / 11b-hydroxysteroid dehydrogenase deficiency, hyperparathyroidism, secondary hyperaldosteronism, renovascular hypertension, hypothyroidism, hyperthyroidism, obstructive sleep apnea and others.Clinical context is important. For example, case detection for endocrine hypertension may not be clinically important in an older patient with multiple life-limiting comorbidities. However, screening for endocrine hypertension may be key to enhancing and prolonging life in most patients with hypertension, especially younger patients.

Getting an Insight into the Complexity of Major Chronic Inflammatory and Degenerative Diseases: A Potential New Systemic Approach to Their Treatment.

As the modern society is troubled by multi-factorial diseases, research has been conducted on complex realities including chronic inflammation, cancer, obesity, HIV infection, metabolic syndrome and its detrimental cardiovascular complications as well as depression and other brain disorders. Deterioration of crucial homeostatic mechanisms in such diseases invariably results in activation of inflammatory mediators, chronic inflammation, loss in immunological function, increased susceptibility to diseases, alteration of metabolism, decrease of energy production and neuro-cognitive decline. Regulation of genes expression by epigenetic code is the dominant mechanism for the transduction of environmental inputs, such as stress and inflammation to lasting physiological changes. Acute and chronic stress determines DNA methylation and histone modifications in brain regions which may contribute to neuro-degenerative disorders. Nuclear glucocorticoids receptor interacts with the epigenoma resulting in a cortisol resistance status associated with a deterioration of the metabolic and immune functions. Gonadal steroids receptors have a similar capacity to produce epigenomic reorganization of chromatine structure. Epigenomic-induced reduction in immune cells telomeres length has been observed in many degenerative diseases, including all types of cancer. The final result of these epigenetic alterations is a serious damage to the neuro-endocrine-immune-metabolic adaptive systems. In this study, we propose a treatment with stem cells differentiation stage factors taken from zebrafish embryos which are able to regulate the genes expression of normal and pathological stem cells in a different specific way.

An analysis of the immune-endocrine changes occurring in tuberculosis patients from the time of disease diagnosis to treatment completion and clinical recovery

An analysis of the immune-endocrine changes occurring in tuberculosis patients from the time of disease diagnosis to treatment completion and clinical recovery

Social support modulates splenocyte glucocorticoid sensitivity in piglets exposed to social deprivation stress

There is growing evidence that positive social interactions can attenuate the effects of stressful life experiences. However, little is known about the benefits of social partners on stress responses in farm animals. Therefore, in this study we examined the effects of social support on the endocrine and immune stress responses to a single 4h social deprivation in domestic piglets at 7, 21 or 35days of age. The piglets were socially deprived of their mother and littermates. They were left alone (DA) or in the presence of a familiar (DF) or unfamiliar (DU) age-matched piglet. Non-socially deprived piglets served as a control. DA piglets displayed elevated plasma cortisol levels, higher lipopolysaccharide (LPS)-stimulated proliferation of splenocytes and increased TNF-α and IL-6 production in splenocyte cultures than the control piglets. There were no significant buffering effects of social partners on stress-induced plasma cortisol levels and splenocyte proliferation in response to LPS. However, the presence of an age-matched conspecific diminished the IL-6 production by splenocytes in younger, socially deprived piglets, and it reduced the TNF-α release in the older piglets. Compared to the controls, LPS-stimulated splenocytes from DA piglets were more resistant to the inhibitory effects of cortisol, which was demonstrated by a higher proliferative response and increased production of pro-inflammatory cytokines. The dose-dependent cortisol resistance was attenuated by the presence of a familiar or an unfamiliar conspecific at each of the three age categories. Indeed, in the present study, the familiarity level of the social partners did not seem to play a role in the alleviation of social stress-induced inflammatory activity and splenocyte cortisol resistance. In addition, the buffering effect of social support provided by an age-matched conspecific was more pronounced in older piglets. Conclusively, these findings suggest that social support is an important factor for enhancing piglets' abilities to cope with stressful challenges, and it may be a key approach needed to improve the health and welfare of farm animals.

The cocoa flavanol (−)-epicatechin protects the cortisol response

Various health benefits of the cocoa flavanol (−)-epicatechin (EC) have been attributed to its antioxidant and anti-inflammatory potency. In the present study we investigated whether EC is able to prevent deterioration of the anti-inflammatory effect of the glucocorticoid (GC) cortisol in the presence of oxidative stress. It was found that cortisol reduces inflammation in differentiated monocytes. Oxidative stress extinguishes the anti-inflammatory effect of cortisol, leading to cortisol resistance. EC reduces intracellular oxidative stress as well as the development of cortisol resistance. This further deciphers the enigmatic mechanism of EC by which it exerts its anti-inflammatory and antioxidant action. The observed effect of the cocoa flavanol EC will especially be of relevance in pathophysiological conditions with increased oxidative stress and consequential GC resistance and provides a fundament for the rational use of dietary antioxidants.

Further characterization of human glucocorticoid receptor mutants, R477H and G679S, associated with primary generalized glucocorticoid resistance

Objective. Primary generalized glucocorticoid resistance is a rare condition characterized by a generalized insensitivity to glucocorticoids, to some extent due to an impaired function of the glucocorticoid receptor. Our earlier genetic analysis of the human glucocorticoid receptor (hGR) in 12 unrelated patients with primary generalized glucocorticoid resistance revealed two new mutations, R477H in exon 4 and G679S in exon 8 in two patients. In order to further study the molecular mechanisms underlying the phenotype of these mutations we have investigated their effect on glucocorticoid signal transduction. Methods. We have studied the DNA-binding ability of the R477H mutant with an electrophoretic mobility shift assay (EMSA). The ability of the R477H and the G679S mutants to affect TNFα induced NF-κB activity and wild-type GR signalling was studied in transient transfection assays. Results. In EMSA the R477H mutation showed a reduced ability to bind to a glucocorticoid-response element compared to the wild-type GR. In transient transfection assays both the R477H mutant and the G679S mutant showed a dominant negative effect on co-transfected wild-type GR in Cos 7 cells. However, both mutants showed full capacity to repress TNFα-induced NF-κB activity. Conclusion. The impaired DNA-binding of the hGR, R477H mutant may explain the severe phenotype of cortisol resistance seen with this mutation. The dominant negative effects of both mutants on wild-type GR signalling probably contribute to the patients’ cortisol resistance.

Hiperaldosteronismo primario y secundario

Primary aldosteronism is the most common cause of secondary hypertension with and stimated prevalence ranging from 5 to 10% of all hypertensive patients. This entity presents with hypertension, in a minority of cases hypokalemia, and an increased risk of cardiovascular damage due to aldosterone excess. The diagnosis is made following a three-step approach: case-detection accomplished by measuring an ambulatory random plasmatic aldosterone concentration- renin activity ratio on standard testing conditions, aldosterone confirmatory supression testing, and then, an initial subtype classification by means of an adrenal imaging test (CT) to exclude potential malignant lesions. Unilateral laparoscopic adrenalectomy and mineralocorticoid receptor antagonist drugs are the choice treatment for patients with unilateral and bilateral disease, respectively. Other entities presenting with mineralocorticoid excess action but low aldosterone plasmatic concentration are apparent mineralocorticoid excess syndrome, primary cortisol resistance, Liddle's syndrome, deoxycorticosterone-producing tumors, certain types of congenital adrenal hyperplasia and hypertension exacerbated by pregnancy.

The N363S and I559N single nucleotide polymorphisms of the h-GR/NR3C1 gene in patients with bronchial asthma

Bronchial asthma is a disease of multifactorial etiology. The natural variability of the DNA sequence within the h-GR/NR3C1 gene affects both the conformation and the activity of glucocorticoid receptors. There are 2 major types of resistance to glucocorticoids (GCS)-resistant asthma failing to respond to treatment with high doses of inhaled and oral glucocorticoids. Type I GCS-resistant asthma is cytokine-induced or acquired. Type II GCS resistance involves generalized primary cortisol resistance, which affects all tissues and is likely to be associated with a mutation in the glucocorticoid receptor (GCR) gene or in genes that modulate GCR function. There are clear examples of glucocorticoid gene h-GR/NR3C1 polymorphisms that can influence responses and sensitivity to glucocorticosteroids. Among the numerous polymorphisms observed within this gene, N363S and I559N single nucleotide polymorphisms (SNPs) may play an important role in the development of bronchial asthma and in the alteration of sensitivity to GCS in severe bronchial asthma. The aim of this research project was to study the correlation between the N363S and I559N polymorphisms of the h-GR/NR3C1 gene and the occurrence of asthma in a population of Polish asthmatics. Peripheral blood was obtained from 210 healthy volunteers and 234 asthma patients. Structuralized anamnesis, spirometry and allergy skin prick tests were performed in all participants. Genotyping was carried out using the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR-HRM methods. In the healthy, non-atopic population, the GG variant of the N363S polymorphism was found with a 5.7% frequency. In asthma patients, GG SNP of N363S occurred with the frequency of 6.4%. In the groups of patients with uncontrolled moderate asthma and uncontrolled severe disease, the genotype distribution for the investigated polymorphisms were as follows: N363S, AA, AG, GG occurring with 0.8750/0.0834/0.0416 frequency and I559N, TT, TA, AA occurring with 1.000/0.000/0.000 frequency. The analysis demonstrated a significantly higher frequency of the A and G variants of the N363S polymorphisms in uncontrolled moderate asthma and uncontrolled severe disease than in the healthy population. No variant-related differences in the frequency of the studied I559N polymorphism were demonstrated in healthy controls and asthma patients. In conclusion, the N363S polymorphism of the h-GR/NR3C1 gene is significantly associated with an increased sensitivity to glucococorticoids in vivo and susceptibility to the development of a moderate to severe form of uncontrolled bronchial asthma in the Polish population. This observation needs to be confirmed in a larger group of subjects.

Effects of acute hypervolumic hemodilution with 6％ hydroxyethyl starch (130/0.4) on glycometabolism in patients with posterior lumbar decompression and bone graft fixation

Objective To investigate the effects of acute hypervolumic hemodilution (AHH) with 6％ hydroxyethyl starch (130/0.4) on glycometabolism in patients with posterior lumbar decompression and bone graft-fixation. Methods Sixty ASA Ⅰ -Ⅱ selective surgery patients were randomly divided into three groups(n=20): control group (group A), Ringer's solution group (group B) and voluven group (group C). In group B and C, 15 ml/kg Ringer's solution or voluven were infused respectively in 20 min-30 min after induction of anesthesia. The hemodynamics were continuously monitored in three groups. Blood samples were taken and the level of Hb, Hct, glucose(glu), cortisol(cor), glucagon(gln) and insulin(ins) were examined at different time points: prior to the AHH (T1), AHH finished immediately (T2), after surgery (T3), and 2 h after surgery (T4). Also the HOMA-insulin resistance index (HOMA-IRI) and insulin sensitivity index(ISI) were calculated. Results The hemodynamics of B and C groups remained stable at T2 compared with that at T1, but the level of glu, cor, gln and ins declined. At T3 and T4 in group A and B Hb, Hct and ISI significantly decreased(P＜0.05). Glu(11.6±2.3) mmol/L, ins(11.2±2.5) mIU/L, cor(347±39) μg/L, gln (230±19) ng/L and IRI increased markedly (P＜0.05). There were significant changes of glu, cor, gln, ins, IRI and ISI at T1. At T3 and T4 in group C, glu (8.0±2.0) mmol/L, ins (8.5±2.3) mIU/L, cot (282±21) μg/L, gln (197±28) ng/L and IRI elevated to a less degree than that observed in group A and B (P＜0.05). ISI decreased slightly in group C at post operation compared with that in other two groups (P＜0.05). Conclusion Implemented AHH with voluven before surgery can reduce posterior lumbar decompression and bone graft in patients with the concentration of stress hyperglycemia, cortisol, glucagon and insulin resistance. Key words: 6％ hydroxyethly starch; Hemodilution; Blood glucose; Glycometabolism

Q&amp;A: Primary generalized glucocorticoid resistance

What biological processes underlie this “resistance” to cortisol? Because this resistance includes the hypothalamicpituitary-adrenal (HPA) axis negative feedback regulatory centers in the brain and pituitary gland, this axis is activated to “overcome” or compensate for the glucocorticoid action defect (Figure 1). The production of hypothalamic corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and pituitary adrenocorticotropic hormone (ACTH) increase and the adrenal cortices hyperfunction, secreting large amounts of cortisol, adrenal steroid precursors and adrenal androgens. The adrenal steroid precursors include deoxy-corticosterone and corticosterone, both of which, as well as cortisol, have sodium-retaining activity through the mineralocorticoid receptor, which is normal in patients with cortisol resistance. Thus, the patient tissues are exposed to elevated levels of adrenal androgens and mineralocorticoids, which result in manifestations of hyperandrogenism and hypermineralocorticoidism.

Altered Immunomodulation by Glucocorticoids in Neonatal Pigs Exposed to a Psychosocial Stressor

Stressful early life experiences can have short- and long-term effects on neuroendocrine and immune mechanisms of adaptation, which are primarily modulated by glucocorticoids. This study aimed to examine how the stress and immune systems interact to cope with psychosocial stress induced by a single social isolation (4 h) in neonatal pigs at 7, 21, or 35 d of age. This social isolation provoked increased plasma ACTH and cortisol concentrations and reduced TNF-α levels but had no significant effect on IL-6 levels. Socially isolated piglets had a higher lipopolysaccharide (LPS)-stimulated proliferative response of peripheral blood mononuclear cells (PBMCs) than controls, whereas concanavalin A (ConA)-induced proliferation was not affected by isolation. A single social isolation also induced a dose-dependent cortisol resistance in ConA- and LPS-stimulated PBMCs compared with controls, which may be an adaptive response in the short term. Moreover, LPS-stimulated cultures from control piglets showed a reduction in cortisol sensitivity with increasing age. Conclusively, these findings provide stress-related measures for the psychophysiological assessment of livestock handling practices but might also have implications for stress and health studies in young animals and humans.

Familial Glucocorticoid Receptor Haploinsufficiency by Non-Sense Mediated mRNA Decay, Adrenal Hyperplasia and Apparent Mineralocorticoid Excess

Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11β-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension.

Serum corticosteroid binding globulin expression is modulated by fasting in polar bears ( Ursus maritimus)

Polar bears ( Ursus maritimus) from several subpopulations undergo extended fasting during the ice-free season. However, the animals appear to conserve protein despite the prolonged fasting, though the mechanisms involved are poorly understood. We hypothesized that elevated concentrations of corticosteroid binding globulin (CBG), the primary cortisol binding protein in circulation, lead to cortisol resistance and provide a mechanism for protein conservation during extended fasting. The metabolic state (feeding vs. fasting) of 16 field sampled male polar bears was determined based on their serum urea to creatinine ratio (> 25 for feeding vs. < 5 for fasting). There were no significant differences in serum cortisol levels between all male and female polar bears sampled. Serum CBG expression was greater in lactating females relative to non-lactating females and males. CBG expression was significantly higher in fasting males when compared to non-fasting males. This leads us to suggest that CBG expression may serve as a mechanism to conserve protein during extended fasting in polar bears by reducing systemic free cortisol concentrations. This was further supported by a lower serum glucose concentration in the fasting bears. As well, a lack of an enhanced adrenocortical response to acute capture stress supports our hypothesis that chronic hunger is not a stressor in this species. Overall, our results suggest that elevated serum CBG expression may be an important adaptation to spare proteins by limiting cortisol bioavailability during extended fasting in polar bears.