Abstract
Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p<0.0001, unadjusted paired t-test), which nevertheless did not retain significance after adjustment for multiple testing. An individualized evaluation strategy led to the identification of 2350 CpG and 3 CpH sites showing methylation differences of at least 10% in more than 2 of the 24 analyzed sample pairs. To investigate the long term effects of rhGH treatment on the DNA-methylome, we analyzed peripheral blood cells from an independent cohort of 36 rhGH treated children born small for gestational age (SGA) as compared to 18 untreated controls. Median treatment interval was 33 months. In line with the groupwise comparison in the short-term treated cohort no differentially methylated targets reached the level of significance in the long-term treated cohort. We identified marked intra-individual responses of DNA-methylation to short-term rhGH treatment. These responses seem to be predominately associated with immunologic functions and show considerable inter-individual heterogeneity. The latter is likely the cause for the lack of a rhGH induced homogeneous DNA-methylation signature after short- and long-term treatment, which nevertheless is well in line with generally assumed safety of rhGH treatment.
Highlights
Recombinant human growth hormone has been introduced in 1985 for the treatment of children with short stature [1]
Current indications include among others growth hormone (GH) deficiency, children born small for gestational age (SGA), Turner syndrome, Prader– Willi syndrome, chronic renal insufficiency and short stature homeobox (SHOX) gene deficiency [2]
The rise of insulin-like growth factor 1 (IGF1) concentration in the peripheral blood following Recombinant human growth hormone (rhGH) treatment serves, in the clinical setting as basic laboratory parameter to estimate the response to rhGH treatment in vivo [12]
Summary
Recombinant human growth hormone (rhGH) has been introduced in 1985 for the treatment of children with short stature [1]. Current indications include among others growth hormone (GH) deficiency, children born small for gestational age (SGA), Turner syndrome, Prader– Willi syndrome, chronic renal insufficiency and short stature homeobox (SHOX) gene deficiency [2]. GH is secreted from pituitary somatotrophic cells. It regulates postnatal growth through a complex network of direct and indirect effects involving amongst others the stimulation of insulin-like growth factor 1 (IGF1) synthesis and release in the liver [11]. Analogous to the physiologic GH effect, treatment with rhGH enhances circulating IGF1 levels. The rise of IGF1 concentration in the peripheral blood following rhGH treatment (so called IGF1 generation test, IGFGT) serves, in the clinical setting as basic laboratory parameter to estimate the response to rhGH treatment in vivo [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
