The modulation of corticosteroid metabolism by hydrocortisone therapy in patients with hypopituitarism increases tissue glucocorticoid exposure.
BACKGROUND
Patients with hypopituitarism have increased morbidity and mortality. There is ongoing debate about the optimum glucocorticoid (GC) replacement therapy.


OBJECTIVE
To assess the effect of GC replacement in hypopituitarism on corticosteroid metabolism and its impact on body composition.


METHODS
We assessed the urinary corticosteroid metabolite profile (using gas chromatography/mass spectrometry) and body composition (clinical parameters and full body DXA) of 53 patients (19 female, median age 46 years) with hypopituitarism (33 ACTH-deficient/20 ACTH-replete) (study A). The corticosteroid metabolite profile of ten patients with ACTH deficiency was then assessed prospectively in a cross over study using three hydrocortisone (HC) dosing regimens (20/10 mg, 10/10 mg and 10/5 mg) (study B) each for 6 weeks. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was assessed by urinary THF+5α-THF/THE.


METHODS
Endocrine Centres within University Teaching Hospitals in the UK and Ireland.


METHODS
Urinary corticosteroid metabolite profile and body composition assessment.


RESULTS
In study A, when patients were divided into three groups - patients not receiving HC and patients receiving HC≤20 mg/day or HC>20 mg/day - patients in the group receiving the highest daily dose of HC had significantly higher waist-to-hip ratio (WHR) than the ACTH replete group. They also had significantly elevated THF+5α-THF/THE (P=0.0002) and total cortisol metabolites (P=0.015). In study B, patients on the highest HC dose had significantly elevated total cortisol metabolites and all patients on HC had elevated THF+5α-THF/THE ratios when compared to controls.


CONCLUSIONS
In ACTH-deficient patients daily HC doses of >20 mg/day have increased WHR, THF+5α-THF/THE ratios and total cortisol metabolites. GC metabolism and induction of 11β-HSD1 may play a pivitol role in the development of the metabolically adverse hypopituitary phenotype.
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK sherloma@tcd.ie.
Mark
M
Sherlock
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Lucy Ann
LA
Behan
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Mark J
MJ
Hannon
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Aurora Aragon
AA
Alonso
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Christopher J
CJ
Thompson
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Robert D
RD
Murray
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Nicola
N
Crabtree
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Beverly A
BA
Hughes
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Wiebke
W
Arlt
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Amar
A
Agha
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Andrew A
AA
Toogood
Centre for EndocrinologyDiabetes and Metabolism, University of Birmingham, Birmingham, UKDepartment of Endocrinology and DiabetesAdelaide and Meath Hospitals, Incorporating the National Children's Hospital and Trinity College, Tallaght Hospital, Dublin 24, IrelandDepartment of EndocrinologyDiabetes and Metabolism, Beaumont Hospital and RCSI Medical School, Dublin, IrelandDepartment of EndocrinologyLeeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, UKDepartment of Nuclear MedicineQueen Elizabeth Hospital, Birmingham, UKDepartment of Medicine and EndocrinologyUniversity of Leeds, Leeds, UK.
Paul M
PM
Stewart
D000324:Adrenocorticotropic Hormone / Q000172:deficiency*; D000328:Adult; D000368:Aged; D001823:Body Composition / Q000187:drug effects*; D018592:Cross-Over Studies; D003430:Cross-Sectional Studies; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D007018:Hypopituitarism / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D049629:Waist-Hip Ratio; D055815:Young Adult
D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone