Reduced lymphocyte β2‐adrenoceptor density and impaired diastolic left ventricular function in patients with glucocorticoid deficiency
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Summary OBJECTIVE Patients with adrenal crisis are at risk of severe hypotension not responding to administration of catecholamines. As glucocorticoids may be a prerequisite for intact β‐adrenoceptor function, impaired adrenoceptor activity may explain the hypotension and reduced cardiac performance in adrenal insufficiency. The aim of our study was, therefore, to further elucidate the permissive action of glucocorticoids on adrenergic function and cardiac performance. DESIGN Prospective randomized controlled study. PATIENTS Nine patients with adrenal insufficiency were investigated before and 48 hours after glucocorticoid withdrawal. Mineralocorticoid therapy remained unchanged during the study period. MEASUREMENTS Lymphocyte β 2 ‐adrenoceptor density, intracellular c‐AMP response to isoprenaline, platelet α 2 ‐receptor density, plasma catecholamines, serum Cortisol, plasma ACTH, echocardiography. RESULTS Glucocorticoid depletion was demonstrated by a fall in serum Cortisol from mean ± SEM 441 ± 62 to 45 ± 18 nmoI/I. Glucocorticoid withdrawal decreased lymphocyte β 2 ‐receptor density from 798±111 to 498 ± 54 binding sites/cell ( P <0.05) and the intracellular c‐AMP response to isoprenaline from 15.0 ± 4.2 to 8.2 ± 1.7 pmol/10 6 cells ( P < 0.05). Echocardiography showed impaired diastolic relaxation after glucocorticoid withdrawal with prolongation of the rapid filling period (80.3 ± 12.5 vs 138.3 ± 11.8 ms, P < 0.05). Plasma catecholamines, platelet α 2 ‐receptor density and systolic left ventricular function were not affected by glucocorticoid deficiency. CONCLUSIONS This study demonstrates the importance of normal glucocorticoid levels for β 2 ‐adrenoceptor function and helps to explain the decreased responsiveness to catecholamines and the impaired cardiac performance in adrenal crisis.Keywords:
Isoprenaline
Mineralocorticoid
Corticosterone
Abstract Glucocorticoids are indispensable for mediating the response to stress, energy demands, development, and limiting inflammation. Once in the cell, these hormones exert their actions by activating nuclear receptors, transcription factors that regulate gene expression. The glucocorticoid receptor (GR) is the transcription factor that predominantly mediates both physiological and pharmacological glucocorticoid effects. Yet glucocorticoids can also bind and activate the mineralocorticoid receptor (MR), a transcription factor known to bind aldosterone thus maintaining whole-body fluid homeostasis. Phylogenetically, GR and MR are closely related and share a remarkable structural similarity. Indeed, the DNA-binding domain of MR is 96% identical to that of GR; thus MR is recruited to many of the same DNA response elements that bind GR. Moreover, GR has a low affinity for glucocorticoids but is expressed in nearly every cell, whereas MR shows a higher affinity for glucocorticoids although knowledge of MR’s expression levels is somewhat limited. These characteristics suggest that, while GR and MR can compensate for each other’s actions in many tissues, there are specific glucocorticoid and mineralocorticoid-mediated responses indicating GR-MR functional diversity. To investigate the similarities and differences between GR and MR signaling in the presence of glucocorticoid hormones, we generated U-2 OS (human osteosarcoma) cell lines stably expressing GR, MR, and both GR and MR (MRGR). Immunofluorescence analysis showed that the treatment of these cell lines with 1 nM of the synthetic glucocorticoid dexamethasone (Dex) induced nuclear translocation of both GR and MR. Moreover, Proximity Ligation Assay revealed that, in the absence of ligand, GR associated with MR in the cytoplasm and, upon 1 nM Dex exposure, GR-MR complexes were detected in the nucleus of MRGR cells. To decipher the functional contribution of GR-MR complexes in the transcriptional response to Dex, we performed RNA-seq in GR, MR, and MRGR cells treated with 1 nM of Dex. Transcriptome analysis revealed that Dex-activated GR regulated the transcription of 6180 genes. Co-expression of MR resulted in a greatly blunted Dex-mediated gene response which reduced the glucocorticoid-dependent transcriptome size by 75%. This phenomenon was also observed using a higher concentration of Dex. Indeed, 40% of genes commonly regulated by Dex in GR and MRGR cells showed a reduced magnitude of regulation when MR is co-expressed. These results suggest a functional antagonism between GR and MR in which MR inhibits GR function. Understanding the molecular mechanisms governing the cross-talk between GR and MR is crucial for the development of new therapies that address the adverse effects of glucocorticoid treatment as well as for the discovery of novel glucocorticoid-based therapeutics with minimal side effects.
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Mineralocorticoid
Primary Adrenal Insufficiency
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ACUTE adrenal insufficiency or Addisonian crisis is a life-threatening event in a patient whose physiological requirement for glucocorticoid and mineralocorticoid steroid hormones exceeds available supply. Prior to the availability of steroid therapy, acute adrenal insufficiency was the culmination of end-stage Addison disease. With an increasing use of maintenance glucocorticoid therapy, acute adrenal insufficiency has become more commonly recognized among patients with bilateral adrenalectomy, hypophysectomy, and in those on long-term glucocorticoid therapy for other disease processes. Precipitating events are various stressful situations—surgery, severe infection, and trauma—where the requirement for corticosteroids is increased and not met by the fixed steroid dosage that the patient is taking. Acute adrenal insufficiency is generally characterized by one or more of the following signs and symptoms1,2: (1) hypotension, (2) nausea and vomiting, (3) severe weakness, (4) hyperthermia, (5) hypoglycemia, and (6) hyponatremia and hyperkalemia. In addition, the intravascular volume depletion secondary to mineralocorticoid deficiency may
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ABSTRACT
Adrenal insufficiency is characterised by inadequate glucocorticoid production owing to destruction of the adrenal cortex or lack of adrenocorticotropic hormone stimulation. In primary adrenal insufficiency, lack of mineralocorticoids is also a feature. Patients can present with an insidious onset of symptoms, or acutely in adrenal crisis, which requires prompt recognition and treatment. Chronic glucocorticoid therapy is the most common cause of adrenal insufficiency. The diagnosis of adrenal insufficiency is made by demonstrating low basal and/or stimulated serum cortisol and should be followed by appropriate investigations to establish the underlying aetiology. Maintenance glucocorticoid replacement is usually given as a twice or thrice daily hydrocortisone preparation. Patients with primary adrenal insufficiency also require mineralocorticoid. Regular monitoring for features of under- and over- replacement is essential during follow-up. Patient education is a key feature of management of this condition.Mineralocorticoid
Primary Adrenal Insufficiency
Adrenal crisis
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ACUTE adrenal insufficiency or "Addisonian crisis" is a life-threatening event in a patient whose physiological requirement for glucocorticoid and mineralocorticoid steroid hormones exceeds available supply. Prior to the availability of steroid therapy, acute adrenal insufficiency was the culmination of end-stage Addison disease. With an increasing use of maintenance glucocorticoid therapy, acute adrenal insufficiency has become more commonly recognized among patients with bilateral adrenalectomy, hypophysectomy, and in those on long-term glucocorticoid therapy for other disease processes. Precipitating events are various stressful situations—surgery, severe infection, and trauma—where the requirement for corticosteroids is increased and not met by the fixed steroid dosage that the patient is taking. Acute adrenal insufficiency is generally characterized by one or more of the following signs and symptoms1,2: (1) hypotension, (2) nausea and vomiting, (3) severe weakness, (4) hyperthermia, (5) hypoglycemia, and (6) hyponatremia and hyperkalemia. In addition, the intravascular volume depletion secondary to mineralocorticoid deficiency may
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Adrenocortical Insufficiency
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Adrenal insufficiency is a life-threatening disorder. In the treatment of adrenal insufficiency, it is essential to administer the optimal medication at the optimal dose. Glucocorticoids are the main therapeutic approach in all forms of adrenal insufficiency. The recommended protocol for maintenance therapy is 15 – 25 mg of hydrocortisone, divided into two or three separate doses. Patients with primary adrenal insufficiency generally receive mineralocorticoid replacement comprised of fludrocortisone 0.05 – 0.2 mg/day. Recently, dehydroepiandrosterone has been proposed as a new therapeutic approach, despite the lack of strong evidence for beneficial effects. Additional glucocorticoid supplementation should be administered in stressful states. During critical illness, inadequate or no temporary increase in the dose of the replacement glucocorticoid can lead to acute adrenal failure. When acute adrenal failure occurs, it becomes necessary to administer intravenous hydrocortisone.
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Receptor expression
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ACUTE adrenal insufficiency or "Addisonian crisis" is a life-threatening event in a patient whose physiological requirement for glucocorticoid and mineralocorticoid steroid hormones exceeds available supply. Prior to the availability of steroid therapy, acute adrenal insufficiency was the culmination of end-stage Addison disease. With an increasing use of maintenance glucocorticoid therapy, acute adrenal insufficiency has become more commonly recognized among patients with bilateral adrenalectomy, hypophysectomy, and in those on long-term glucocorticoid therapy for other disease processes. Precipitating events are various stressful situations—surgery, severe infection, and trauma—where the requirement for corticosteroids is increased and not met by the fixed steroid dosage that the patient is taking. Acute adrenal insufficiency is generally characterized by one or more of the following signs and symptoms1,2: (1) hypotension, (2) nausea and vomiting, (3) severe weakness, (4) hyperthermia, (5) hypoglycemia, and (6) hyponatremia and hyperkalemia. In addition, the intravascular volume depletion secondary to mineralocorticoid deficiency may
Mineralocorticoid
Adrenal crisis
Fludrocortisone
Adrenocortical Insufficiency
Primary Adrenal Insufficiency
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