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Update on adrenal steroid hormone biosynthesis and clinical implications.
Bacila, IA, Elder, C, Krone, N
Archives of disease in childhood. 2019;(12):1223-1228
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Abstract
Steroid biosynthesis is a complex process in which cholesterol is converted to steroid hormones with the involvement of multiple enzymes and cofactors. Inborn conditions affecting adrenal steroidogenesis are relatively common in paediatric practice and have serious implications on patient mortality and morbidity. This paper provides an overview of novel insights into human adrenal steroid biosynthesis. Inborn errors of steroidogenesis associated with congenital adrenal hyperplasia are discussed, with a particular focus on the pathophysiology and clinical features of 21-hydroxylase deficiency. The final section of the review presents more recent findings and clinical implications of adrenal-specific androgen biosynthesis.
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Steroids as Environmental Compounds Recalcitrant to Degradation: Genetic Mechanisms of Bacterial Biodegradation Pathways.
Olivera, ER, Luengo, JM
Genes. 2019;(7)
Abstract
Steroids are perhydro-1,2-cyclopentanophenanthrene derivatives that are almost exclusively synthesised by eukaryotic organisms. Since the start of the Anthropocene, the presence of these molecules, as well as related synthetic compounds (ethinylestradiol, dexamethasone, and others), has increased in different habitats due to farm and municipal effluents and discharge from the pharmaceutical industry. In addition, the highly hydrophobic nature of these molecules, as well as the absence of functional groups, makes them highly resistant to biodegradation. However, some environmental bacteria are able to modify or mineralise these compounds. Although steroid-metabolising bacteria have been isolated since the beginning of the 20th century, the genetics and catabolic pathways used have only been characterised in model organisms in the last few decades. Here, the metabolic alternatives used by different bacteria to metabolise steroids (e.g., cholesterol, bile acids, testosterone, and other steroid hormones), as well as the organisation and conservation of the genes involved, are reviewed.
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Polyphenolic natural products and natural product-inspired steroidal mimics as aromatase inhibitors.
Nielsen, AJ, McNulty, J
Medicinal research reviews. 2019;(4):1274-1293
Abstract
The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity. This review focuses on the ability of select polyphenolics and their synthetic derivatives to function as steroidal mimics in the inhibition of the enzyme aromatase, thereby lowering production of endogenous estrogen growth hormones. The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit compounds has led to the introduction of steroidal-based irreversible inhibitors, such as exemestane and reversible AIs such as anastrozole and letrozole, now standard therapy in the treatment of estrogen receptor-positive breast cancer and other hormone related indications. Pursuit of this strategy over the last few decades has been largely successful although complications and challenges remain. This review highlights the aromatase activity of natural stilbenes, chalcones, and flavanones and synthetically inspired versions thereof and draws attention to new and under-investigated areas within each class worthy of pursuit.
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Differentiation syndrome in acute promyelocytic leukaemia.
Stahl, M, Tallman, MS
British journal of haematology. 2019;(2):157-162
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Abstract
Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.
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Structural and Functional Biology of Aldo-Keto Reductase Steroid-Transforming Enzymes.
Penning, TM, Wangtrakuldee, P, Auchus, RJ
Endocrine reviews. 2019;(2):447-475
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Abstract
Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C enzymes acting as 3-ketosteroid, 17-ketosteroid, and 20-ketosteroid reductases are involved in the prereceptor regulation of ligands for the androgen, estrogen, and progesterone receptors and are considered drug targets to treat steroid hormone-dependent malignancies and endocrine disorders. In contrast, AKR1D1 is the only known steroid 5β-reductase and is essential for bile-acid biosynthesis, the generation of ligands for the farnesoid X receptor, and the 5β-dihydrosteroids that have their own biological activity. In this review we discuss the crystal structures of these AKRs, their kinetic and catalytic mechanisms, AKR genomics (gene expression, splice variants, polymorphic variants, and inherited genetic deficiencies), distribution in steroid target tissues, roles in steroid hormone action and disease, and inhibitor design.
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Steroids and Postoperative Complications in IBD.
López-Sanromán, A
Current drug targets. 2019;(13):1323-1326
Abstract
Corticosteroids are frequently used in the management of Inflammatory Bowel Disease. Although they can be very useful, their potential adverse effects have to be kept in mind. One of the situations in which these drugs should be avoided, if possible, is the perioperative setting. If a patient reaches surgery while on steroids, surgical complications will be more likely to occur, both infectious and non-infectious. Attention should be paid to this fact, within a multidisciplinary approach, that also takes into account other factors, such as nutrition.
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The immunobiology of autoimmune encephalitides.
Alexopoulos, H, Dalakas, MC
Journal of autoimmunity. 2019;:102339
Abstract
Autoimmune encephalitides, with an estimated incidence of 1.5 per million population per year, although described only 15 years ago, have already had a remarkable impact in neurology and paved the field to autoimmune neuropsychiatry. Many patients traditionally presented with aberrant behavior, especially of acute or subacute onset, and treated with anti-psychotic therapies, turn out to have a CNS autoimmune disease with pathogenic autoantibodies against synaptic antigens responding to immunotherapies. The review describes the clinical spectrum of these disorders, and the pathogenetic role of key autoantibodies directed against: a) cell surface synaptic antigens and receptors, including NMDAR, GABAa, GABAb, AMPA and glycine receptors; b) channels such as AQP4 water-permeable channel or voltage-gated potassium channels; c) proteins that stabilize voltage-gated potassium channel complex into the membrane, like the LGI1 and CASPR2; and d) enzymes that catalyze the formation of neurotransmitters such as Glutamic Acid Decarboxylase (GAD). These antibodies, effectively target excitatory or inhibitory synapses in the limbic system, basal ganglia or brainstem altering synaptic function and resulting in uncontrolled neurological excitability disorder clinically manifested with psychosis, agitation, behavioral alterations, depression, sleep disturbances, seizure-like phenomena, movement disorders such as ataxia, chorea and dystonia, memory changes or coma. Some of the identified triggering factors include: viruses, especially herpes simplex, accounting for the majority of relapses occurring after viral encephalitis, which respond to immunotherapy rather than antiviral agents; tumors especially teratoma, SCLC and thymomas; and biological cancer therapies (immune-check-point inhibitors). As anti-synaptic antibodies persist after viral infections or tumor removal, augmentation of autoreactive B cells which release autoantigens to draining lymph nodes, molecular mimicry and infection-induced bystander immune activation products play a role in autoimmunization process or perpetuating autoimmune neuroinflammation. The review stresses the importance of early detection, clinical recognition, proper antibody testing and early therapy initiation as these disorders, regardless of a known or not trigger, are potentially treatable responding to systemic immunotherapy with intravenous steroids, IVIg, rituximab or even bortezomid.
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Thyroid storm: a case of haemodynamic failure promptly reversed by aggressive medical therapy with antithyroid agents and steroid pulse.
Andrade Luz, I, Pereira, T, Catorze, N
BMJ case reports. 2018;(1)
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Abstract
Hyperthyroidism is a common metabolic disorder, although its presentation as an endocrine emergency called thyroid storm is rare. Here we review a case of a thyroid storm as the initial presentation of thyrotoxicosis, with multiple organ failure and haemodynamic collapse due to low-output cardiac dysfunction. Quick intervention with aggressive antithyroid therapy, including steroid pulse, and supportive intensive care measures led to an outstanding improvement and full recovery. The present case clearly shows the beneficial impact of initial clinical suspicion resulting in an early diagnosis and intensive therapy. Moreover, it supports the additional role of steroids to aggressive antithyroid strategy in order to control associated deleterious systemic inflammatory reactions.
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Eosinophilic esophagitis: short and long-term considerations.
Goyal, A
Current opinion in pediatrics. 2018;(5):646-652
Abstract
PURPOSE OF REVIEW Eosinophilic esophagitis (EoE) is a relatively new disease but its understanding is evolving over a period of time. This review highlights recent advances in the understanding of pathophysiology, diagnostic modalities, short and long-term goals of therapy and novel therapeutic agents. RECENT FINDINGS The prevalence of EoE is increasing. Upper endoscopy and biopsy remains the gold standard for diagnosing EoE but less invasive and more cost-effective testing has been under investigation. Scoring systems to assess symptoms, histology and endoscopic findings can distinguish between active and inactive disease. Step up therapy with 2-4-6 food elimination can result in early identification of triggering foods and reduce frequency of endoscopies. The term proton pump inhibitor (PPI) responsive eosinophilia should be avoided and PPI should be considered a therapeutic modality. Oral viscous budesonide has been more effective than fluticasone in achieving remission. Adrenal suppression should be looked for patients on swallowed steroids. IL-13 antagonists can be a promising therapy for EoE and dilation is a safe and effective treatment modality in patients with EoE but as is expected, does not decrease inflammation. SUMMARY EoE has been increasingly recognized as a cause of food impactions and dysphagia. Less invasive methods for diagnosis and to monitor treatment response have been studied but need validation in children. Short-term treatment goals include symptomatic and histological improvement, with prevention of fibrostenotic disease the primary long-term goal. Elemental diet and empiric elimination diet appear to be successful in inducing remission. PPI and swallowed steroids cause symptomatic improvement and histological remission but relapse is common after discontinuation of therapy.
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MECHANISMS IN ENDOCRINOLOGY: Rare defects in adrenal steroidogenesis.
Miller, WL
European journal of endocrinology. 2018;(3):R125-R141
Abstract
Congenital adrenal hyperplasia (CAH) is a group of genetic disorders of adrenal steroidogenesis that impair cortisol synthesis, with compensatory increases in ACTH leading to hyperplastic adrenals. The term 'CAH' is generally used to mean 'steroid 21-hydroxylase deficiency' (21OHD) as 21OHD accounts for about 95% of CAH in most populations; the incidences of the rare forms of CAH vary with ethnicity and geography. These forms of CAH are easily understood on the basis of the biochemistry of steroidogenesis. Defects in the steroidogenic acute regulatory protein, StAR, disrupt all steroidogenesis and are the second-most common form of CAH in Japan and Korea; very rare defects in the cholesterol side-chain cleavage enzyme, P450scc, are clinically indistinguishable from StAR defects. Defects in 3β-hydroxysteroid dehydrogenase, which also causes disordered sexual development, were once thought to be fairly common, but genetic analyses show that steroid measurements are generally unreliable for this disorder. Defects in 17-hydroxylase/17,20-lyase ablate synthesis of sex steroids and also cause mineralocorticoid hypertension; these are common in Brazil and in China. Isolated 17,20-lyase deficiency can be caused by rare mutations in at least three different proteins. P450 oxidoreductase (POR) is a co-factor used by 21-hydroxylase, 17-hydroxylase/17,20-lyase and aromatase; various POR defects, found in different populations, affect these enzymes differently. 11-Hydroxylase deficiency is the second-most common form of CAH in European populations but the retention of aldosterone synthesis distinguishes it from 21OHD. Aldosterone synthase deficiency is a rare salt-losing disorder. Mild, 'non-classic' defects in all of these factors have been described. Both the severe and non-classic disorders can be treated if recognized.