natriuretic-peptide--c-type and Dwarfism--Pituitary

Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia.

Topics: Achondroplasia; Androgens; Aromatase Inhibitors; Dwarfism, Pituitary; Gonadotropin-Releasing Hormone; Growth Disorders; Human Growth Hormone; Humans; Natriuretic Agents; Natriuretic Peptide, C-Type; Oxandrolone; Puberty, Precocious; Recombinant Proteins; Testosterone; Turner Syndrome

Studies from genetic modification and spontaneous mutations show that C-type natriuretic peptide (CNP) signalling plays an essential part in postnatal endochondral growth, but measurement of CNP proteins and changes in their abundance in tissues and plasma during normal growth has not been reported. Using rodent pups with GH deficiency, we now describe the pharmacodynamic response of CNP and rat amino-terminal proCNP (NTproCNP) in plasma and tissues, and relate these to changes in linear growth (nose-tail length, tibial length and tibial growth plate width) during the course of 1 week of GH or saline (control) administration. Compared with saline, significant increases in plasma and tissue CNP forms were observed after 24 h in GH-treated pups and before any detectable change in linear growth. Whereas CNP abundance was increased in most tissues (muscle, heart and liver) by GH, enrichment was the greatest in extracts from growth plates and kidney. Plasma and tissue concentrations in GH-treated pups were sustained or further increased at 1 week when strong positive associations were found between plasma NTproCNP and linear growth or tissue concentrations. High content of NTproCNP in kidney tissue strongly correlated with plasma concentrations, which is consistent with previous data showing renal extraction of the peptide. In showing a prompt and significant increase in CNP in tissues driving normal endochondral growth, these findings provide further rationale for CNP agonists in the treatment of growth disorders resistant to current therapies and support the use of CNP concentrations as biomarkers of linear growth.

Topics: Animals; Biomarkers; Body Weights and Measures; Bone and Bones; Bone Development; Disease Models, Animal; Dwarfism, Pituitary; Growth Hormone; Growth Plate; Hormone Replacement Therapy; Human Growth Hormone; Kidney; Male; Natriuretic Peptide, C-Type; Organ Specificity; Protein Precursors; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Recombinant Proteins