The effect of in vivo growth hormone treatment on blood gene expression in adults with growth hormone deficiency reveals potential biomarkers to monitor growth hormone therapy

Abstract

Growth hormone (GH) replacement therapy is presently utilized in the treatment of adult GH deficiency (AGHD). Adult responses to GH treatment are highly variable and, apart from measurement of IGF-I, few tools are currently available for monitoring GH treatment progress. As GH receptors are expressed in certain blood cell types, changes in gene expression in peripheral blood can reflect perturbations induced as a result of GH therapy. We have carried out a pilot study to identify GH-responsive genes in blood, and have assessed the utility of GH-responsive genes in monitoring GH therapy in AGHD. Blood was collected from ten women diagnosed with AGHD syndrome both before and 4 weeks after initiation of GH substitutive therapy. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and changes in response to GH were detected using microarray-based gene analysis. All patients responded to GH replacement therapy, with serum levels of IGF-I increasing by an average of 307% (P = 0.0003) while IGFBP-3 increased by an average of 182% (P = 0.0002). Serum levels of triglycerides, LDL-C, HDL-C, APOA1 or APOB did not change after 1 month of GH treatment. By contrast, we detected an increase in Lp(a) serum levels (P = 0.0149). Using a stringent selection cutoff of P <or= 0.05, paired analysis identified a set of transcripts that correlated with GH administration. We applied the multivariate statistical technique PLS-DA to the changes in gene expression, demonstrating their utility in differentiating untreated patients and those undergoing GH replacement therapy. This study shows that GH-dependent effects on gene expression in PBMCs can be detected by microarray-based gene analysis, and our results establish a foundation for the further exploration of peripheral blood as a surrogate to detect exposure to GH therapy.