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Mark Sherlock, Lucy Ann Behan, Mark J Hannon, Aurora Aragon Alonso, Christopher J Thompson, Robert D Murray, Nicola Crabtree, Beverly A Hughes, Wiebke Arlt, Amar Agha, Andrew A Toogood, and Paul M Stewart

Context

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.

Design and patients

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.

Setting

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

Main outcome measures

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.

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Victoria S Sprung, Kelly A Bowden Davies, Juliette A Norman, Andrew Thompson, Katie L Mitchell, John P H Wilding, Graham J Kemp, and Daniel J Cuthbertson

Background

Data suggest that metabolic health status, incorporating components of metabolic syndrome (MetS), predicts cardiovascular disease (CVD) risk better than BMI. This study explored the association of MetS and obesity with endothelial function, a prognostic risk factor for incident CVD.

Methods

Forty-four participants were phenotyped according to BMI as non-obese vs obese (<30 or >30 kg/m2) and according to the International Diabetes Federation criteria of MetS: ≤2 criteria MetS (MetS−) vs ≥3 criteria MetS (MetS+); (1.)non-obese MetS− vs (2.) non-obese MetS+ and (3.) obese MetS vs (4.) obese MetS+. Flow-mediated dilation (FMD), body composition including liver fat (MRI and spectroscopy), dietary intake, intensities of habitual physical activity and cardio-respiratory fitness were determined. Variables were analysed using a one-factor between-groups ANOVA and linear regression; mean (95% CI) are presented.

Results

Individuals with MetS+ displayed lower FMD than those with MetS−. For non-obese individuals mean difference between MetS+ and MetS− was 4.1% ((1.0, 7.3); P = 0.004) and obese individuals had a mean difference between MetS+ and MetS− of 6.2% ((3.1, 9.2); P < 0.001). Although there was no association between BMI and FMD (P = 0.27), an increased number of MetS components was associated with a lower FMD (P = 0.005), and after adjustment for age and sex, 19.7% of the variance of FMD was explained by MetS, whereas only 1.1% was explained by BMI.

Conclusions

In this study cohort, components of MetS, rather than obesity per se, contribute to reduced FMD, which suggests a reduced bioavailability of nitric oxide and thus increased risk of CVD.