Adrenal Steroids, Metabolism, and Action Research Group

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Group leader: Professor Wiebke Arlt

Overview

Our group focuses on the pre-receptor regulation of androgen synthesis, metabolism and action, with a specific emphasis on the adrenal sex steroid precursor dehydroepiandrosterone (DHEA), thereby systematically exploring systemic and tissue-specific mechanisms underlying androgen excess and deficiency. Primary translational targets include adrenal and gonadal disorders, e.g. adrenal tumours and the polycystic ovary syndrome, a leading cause of female infertility and forerunner of the metabolic syndrome.

Our research group

Regulation of androgen synthesis and action

  • P450 oxidoreductase (POR) and co-factor regulation of androgen synthesis
  • Following up on our discovery of inactivating human P450 oxidoreductase (POR) mutations as the cause of a novel variant of congenital adrenal hyperplasia we have been systematically exploring the nature and significance of the alternative androgen pathway towards dihydrotestosterone synthesis we have discovered as the cause of virilisation in females affected by POR deficiency.
  • This work has recently led to an emerging programme around the role of this alternative pathway in prostate cancer. As part of this work we are aiming to develop novel inhibitors of the human 17β-HSD6 enzyme.
  • PAPS synthase type 2 (PAPSS2) as a regulator of DHEA sulfation and androgen action
  • DHEA is the principal precursor of androgen synthesis via the classic androgen synthesis pathway. Unconjugated DHEA can be converted directly to androgens, while the generation of DHEA sulphate (DHEAS) from DHEA represents an inactivation step. Our group has demonstrated inactivating mutations in the co-factor enzyme PAPS synthase 2 (PAPSS2) in a patient with androgen excess who presented with premature pubarche, subsequently progressing to early-onset PCOS. The identification of this important pre-receptor mechanism has highlighted the role of DHEA sulfation as a gate keeper for human androgen synthesis. Current research examines the role of these elements of the DHEA sulfation system in the pathogenesis of androgen excess disorders, including premature pubarche and PCOS, and underlying molecular mechanisms.
  • 5a-reductase as a therapeutic target in androgen excess
  • The conversion of testosterone to 5α-dihydrotestosterone by the 5α-reductase isozymes is a major androgen activation step. Increased 5α-reductase activity is characteristically observed in PCOS, but control of 5α-reductase activity is also of major importance in prostate cancer. We have recently identified a novel class of 5α-reductase inhibitors, which we are currently developing. Furthermore, we are examining the relationship between androgen excess, increased 5α-reductase activity and insulin resistance.

Steroid metabolomics as a biomarker tool for stratified diagnosis and therapy

We have recently developed a novel diagnostic tool, steroid metabolomics, i.e. the combination of urinary steroid metabolite profiling with mass spectrometry based techniques and computational analysis by machine learning, and have shown that this novel approach distinguishes between benign and malignant tumours with high sensitivity and specificity and we are currently evaluating this in a prospective trial in collaboration with a European consortium (European Network for the Study of Adrenal Tumours (ENSAT); www.ensat.org) (including lead roles for the ADIUVO and EURINE-ACT studies). We have extended this work to investigate its potential in the differential diagnosis of mineralocorticoid excess and we are also investigating whether we can contribute to investigating ovarian and testicular (Leydig cell) carcinoma. 

Current Projects

  • Clinical European study on the outcome of surgical and hormonal therapy and psychological intervention in disorders of sex development (DSD-Life)
  • Efficacy of adjuvant mitotane treatment in prolonging recurrence-free survival in patients with adrenocortical carcinoma at low-intermediate risk of recurrence (ADIUVO)
  • The role of DHEA sulfation in the pre-receptor regulation of androgen excess
  • European Network for the Study of Adrenal Tumours – Structuring clinical research on rare adrenal cancers in adults
  • P450 oxidoreductase: Novel regulator of steroid synthesis and metabolism in health and disease
  • Nicotinamide nucleotide transhydrogenase (NNT) as a novel target in the treatment of adrenocortical carcinoma.

Recent Publications

Staff

Principal Investigator
Professor Wiebke Arlt - School of Clinical and Experimental Medicine

Postdoctoral Researchers
Angela E Taylor - Postdoctoral fellow – Mass spectrometry (MDS)
Donna O’Neil - Research Technician – Mass spectrometry (FP7 ENS@T-Cancer)
Naeem Shafqat - Postdoctoral Fellow (MRC Programme Grant)
Hannah Ivison - Research Technician (MRC Programme Grant)
Jonathan Mueller - Postdoctoral Fellow (Wellcome Project Grant)
Ian T Rose - Research Technician (Wellcome Project Grant)
Marie Lebbe - MRC Clinical Research Fellow (MRC RTF)
Michael O’Reilly - Wellcome Trust Clinical Research Fellow (WT RTF)
Vasilis Chortis - Academic Clinical Fellow (ST3 – NIHR; CRTF from 1 Aug 2013)
Irina Bancos - Clinical Research Fellow (Mayo Clinic Foundation Scholarship)

PhD Students
Farrah Ali- BBSRC TPS; co-supervisor, primary supervisor Dagmar Scheel-Toellner)
Ana Vitlic - FP7 MC-NINA; co-supervisor, primary supervisor Anna Phillips
Jan Idkowiak - MRC CRTF; primary supervisor; co-supervisor Tim Barrett
Mark Foster - RCDM; co-supervisor, primary supervisor Janet Lord
Mick O’Reilly - Wellcome CRTF; primary supervisor; co-sup. Jeremy Tomlinson, Rob Semple
Marie Lebbe - MRC CRTF; primary supervisor; co-sup. Arri Commarasamy, Jackson Kirkman-Brown
Tracy MacLean - U21 University of Birmingham/University of Melbourne Joint PhD Studentship
Stephan Gloeckner - U21 University of Birmingham/University of Melbourne Joint PhD Studentship – both joint supervision together with Richard Sinnott, University of Melbourne, Australia
Vasilis Chortis - Wellcome CRTF; primary supervisor; co-supervisor Paul Foster
Orli Turgeman - UoB International Doctoral Elite Studentship; 3.5 years (primary supervisor; co-supervisor Paul Foster)

Internal Collaborators
Dr Vivek Dhir - School of Clinical and Experimental Medicine
Dr Gareth Lavery - School of Clinical and Experimental Medicine
Dr Nils Krone - School of Clinical and Experimental Medicine
Professor Arri Coomarasamy - School of Clinical and Experimental Medicine
Professor Janet Lord - School of Immunity and Infection
Dr Dagmar Scheel-Toellner - School of Immunity and Infection
Professor Gabriel Landini - School of Dentistry
Peter Tino
Professor Jon Deeks - Public Health, Epidemiology and Biostatistics
Professor Mark Viant - School of Biosciences
Dr Warwick Dunn - School of Biosciences
Dr Anna Phillips - School of Sport, Exercise and Rehabilitation Sciences
Professor Doug Carroll - School of Sport, Exercise and Rehabilitation Sciences
Ian Rowe
Emilio Porfiri
Kassiani Skordilis
Peter Nightingale
Dr Paul Foster - School of Clinical and Experimental Medicine