Pre-receptor metabolism and the control of hormone action

Lead Research Organisation: University of Birmingham
Department Name: Health and Population Sciences

Abstract

Hormones are chemicals that are released from endocrine glands into the circulation to act on a number of tissues and organs throughout the human body. However, different parts of the body respond differently to hormones, and one reason for this is that enzymes are present in tissues that can change hormones between active and inactive states. Thus an enzyme that activates a hormone will cause high levels of hormone action in that part of the body and this occurs independent of any change in circulating hormone levels. Our group has expertise in the workings of these enzymes and we now believe that they may be involved in causing human disease. Obesity and osteoporosis (thin bones), are major health hazards affecting up to 20% of the population. Breast and prostate cancers are also leading causes of death in the UK. In each case there are examples of hormones being important in causing these diseases, but in the majority of cases, hormone levels are normal within the blood. However, we have shown that an alteration in enzymes within key tissues such as cancers, fat and bone tissue may affect local hormone levels and contribute to the underlying disease. Importantly, new therapies that specifically target these enzymes may offer exciting future treatments for these common diseases. This research group will combine expertise to further define the role of a series of enzymes responsible for hormone action. In doing so, we believe we can make significant head way into the causes of, and therapy for, cancer, obesity and osteoporosis.

Technical Summary

Steroid and thyroid hormones play a pivotal role in the physiology and pathophysiology of diverse tissues. The transregulatory actions of steroid hormones are dependent on the expression of cognate intracellular receptors and post-receptor activator and repressor proteins. However, regulation of hormone action is also achieved at a pre-receptor level through a series of metabolic enzymes expressed in a tissue-specific fashion. This is particularly evident in tissues such as adipose and bone, as well as various tumours, where hormones such as cortisol, thyroid hormone and 1,25-dihydroxyvitamin D3 (1,25D3) exert pluripotent regulatory effects. In previous studies we have characterized the expression of enzymes involved in glucocorticoid, thyroid and vitamin D hormone metabolism;11b-hydroxysteroid dehydrogenases (11b-HSDs), iodothyronine deiodinases (deiodinase) and vitamin D-1a-/24-hydroxylases, respectively. Furthermore, as a consequence of functional studies in vivo and in vitro we have hypothesized that the autocrine production of glucocorticoids, thyroid hormone and vitamin D is involved in the pathogenesis of prevalent human diseases such as hypertension, obesity, osteoporosis and cancer. The aim of this Co-operative Group (COG) will be to develop a multidisciplinary collaborative group with a common interest in the metabolism of steroid/thyroid hormones. The COG will be to establish core facilities to undertake a sensitive analysis of steroid and thyroid hormones with the objective of elucidating new mechanisms and developing novel therapeutic targets, to a broad range of clinical problems central to the Health of the Nation.

Publications

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Arlt W (2006) Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. in The Journal of clinical endocrinology and metabolism

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Dineen R (2017) Acromegaly. in QJM : monthly journal of the Association of Physicians

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Gathercole LL (2007) Glucocorticoid modulation of insulin signaling in human subcutaneous adipose tissue. in The Journal of clinical endocrinology and metabolism

 
Description "11beta-hydroxysteroid dehydrogenase type 1, growth hormone and the pathophysiology of age related sarcopaenia". May 2007 for 3 years (MRC Fellowship to Dr Mark Sherlock) (Ref: G0601429).
Amount £371,657 (GBP)
Funding ID G0601429 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2007 
End 04/2010
 
Description "Corticosteroid hormone action in cardiomyocytes - impact on heart failure", October 2006 for 3 years (MRC Fellowship to Dr Fabian Hammer) (Ref: G0600432).
Amount £168,107 (GBP)
Funding ID G0600432 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description "Local glucocorticoid metabolism in inflammatory arthritis". October 2007 for 3 years (Ref: 18081).
Amount £159,135 (GBP)
Funding ID 082809 
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description Experimental Medicine grant "Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1: A novel treatment for the Metabolic Syndrome", April 2006 for 3 years (Ref: G0502165).
Amount £298,510 (GBP)
Funding ID G0502165 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2006 
End 03/2009
 
Description Steroid Profiling as a Biomarker Tool in the Diagnosis and Monitoring of Adrenal Tumours
Amount £916,094 (GBP)
Funding ID G0801473 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2009 
End 12/2012
 
Description Wellcome Trust Programme Grant (Hexose-6-phosphate dehydrogenase and Glucose-6-phosphate: novel regulators of corticosteroid hormone metabolism and adrenal function). (Ref: 082809).
Amount £1,032,652 (GBP)
Funding ID 082809 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2007 
End 09/2012
 
Title GC/MS 
Description Development of gas chromatography/ mass spectrometry analysis of steroids - helped human phenotyping 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2006 
Provided To Others? Yes  
Impact Adrenal biomarkers for diagnostic purposes 
 
Description New Biomarker analysis 
Organisation Waters Corporation
Country United States 
Sector Private 
PI Contribution Established GC/MS steroid technology.
Collaborator Contribution New Gas chromatography/ mass spectrometry platforms established. Helped pump prime new MRC Biomarkers grant on adrenal tumours
Impact New Gas chromatography/ mass spectrometry platforms established. Helped pump prime new MRC Biomarkers grant on adrenal tumours
Start Year 2007
 
Title 11HSD1 inhibitors 
Description Helped develop selective 11beta hydroxysteroid dehydrogenase 1 inhibitors for use in Obesity-Diabetes Mellitus. Several phase II trials have been conducted - none led by Stewart but Stewart involved in a few. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2006
Development Status Actively seeking support
Clinical Trial? Yes
Impact Many Pharma companies in development phase after our original pre clinical work. MRC-AZ collaboration now involves AZ 4017 which is an 11HSD1 inhibitor 
URL https://clinicaltrials.gov/show/NCT01277094
 
Title GC/MS 
Description In vivo assessment steroid metabolism in patients with Metabolic syndrome. Gold standard for diagnosis of inherited steroid disorders. Evaluation as diagnostic for adrenal cancer patients (see Arlt W ...... Stewart PM, J Clin Endocrinol Metab. 2011 Dec;96(12):3775-84) 
Type Diagnostic Tool - Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2006
Development Status Under active development/distribution
Impact Widespread adoption for drug efficacy studies 
 
Description plenary and symposia lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact Presentation to large audiences at International meetings

Local radio, press releases. Discipline specific press releases at conferences
Year(s) Of Engagement Activity 2006