Single centre experience of using 6 monthly GnRH analogues in the paediatric population

Louise Apperley; Poonam Dharmaraj; Joanne Blair; Renuka Ramakrishnan; Urmi Das; Mohammed Didi; Peter Laing; Zoe Yung; Kelly Cassidy; Pauline Blundell; Charlotte Jarvis; Jennifer Parkinson; Senthil Senniappan

Background: Mounting evidence points to an association between increased glucocorticoid (GC) action and weight gain. However, the response to GCs is not only determined by GC serum concentrations, but also by individual differences in tissue-specific sensitivity, influenced by genetic and acquired (e.g. disease-related) factors. The extent to which differences in GC sensitivity may influence development of (abdominal) obesity, or vice versa, is poorly understood. In this study we investigate the relation between GC sensitivity and (abdominal) obesity.

Methods: Anthropometric data (BMI, weight, waist circumference and dual-energy X-ray absorptiometry (DXA) scans) and peripheral blood mononuclear cells (PBMCs) were obtained at baseline (T0) and completion of 10 weeks of treatment (T1) from 16 patients with obesity (BMI ≥ 30 kg/m²) undergoing a combined lifestyle intervention with cognitive behavioral therapy. The half maximal effective concentration of dexamethasone (DEX), mediating the transactivation (EC50) or transrepression (IC50) of responsive genes GC-induced leucine zipper (GILZ) or interleukin (IL)-2 and IL-6 respectively in PBMCs, was used as a measure of GC sensitivity. The associations of EC50 and IC50 with BMI, weight, waist circumference, DXA fat mass and DXA leans mass, were analysed using linear regressions.

Results: A lower IC50 of DEX-mediated transrepression of IL-6 at inclusion (higher sensitivity) was associated with higher DXA fat mass (% of total body mass) (β = -0.52, 95%CI = -0.86 to -0.19) and lower DXA lean mass (% of total body mass) (β = 0.52, 95%CI = 0.18 to 0.86). Interestingly, the lower the IC50 for DEX-mediated transrepression of IL-6 at inclusion, the higher was the weight loss in the first 10 weeks of lifestyle intervention (T1, β = 0.32, 95%CI = 0.04 to 0.60). Similar, but non-significant, associations were observed for IL-2. However, there were no associations between EC50 of DEX-mediated transactivation of GILZ and any of the above-mentioned anthropometrics variables.

Conclusion: This study suggests that increased GC sensitivity is associated with a less beneficial body composition in patients with obesity. Although, increased GC sensitivity at baseline was associated with weight loss at T1, further analysis of the data is in progress to determine whether this seeming contradiction is related to changes in GC sensitivity after lifestyle intervention.

ESPE Abstracts

P1-354