Increase in Pappalysin Levels Could Promote IGF-1 Bioavailability in Children with Prader-Willi Syndrome

The increase in free insulin-like growth factor (IGF)-I levels in prepubertal children with Prader-Willi Syndrome (PWS) treated with exogenous growth hormone (GH) could be caused by increased pregnancy-associated plasma protein A (PAPP-A, PAPP-A2) levels and a reduction in stanniocalcins (STC-1, STC-2), according to a study recently published in The Journal of Clinical Endocrinology & Metabolism.

Researchers led by Jesus Argente, MD, PhD, professor of Pediatrics and Pediatric Endocrinology at Hospital Infantil Universitario Niño Jesús in Madrid, Spain, point out that children with PWS have decreased IGF-1 levels, independent of nutritional status, which indicates dysfunction of GH secretion. “Furthermore, the GH deficiency seen in PWS is independent of obesity, with low spontaneous and pharmacologically stimulated GH secretion observed in both children and adults,” the authors write.

The authors go on to note that while various studies have analyzed growth, body composition, metabolic alterations, and cognitive issues in these patients, as well as the effects of GH treatment on these processes, the changes in peripheral components of the IGF-1 axis in children with PWS remain unclear. They point to pappalysins and stanniocalcins, “new players,” which regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown.

“To our knowledge there are no studies in children and adolescents with PWS where the classical components of the GH-IGF axis have been analyzed together with these new players, PAPP-As and STCs, modulators of IGF actions,” the authors write. “Thus, the objectives of this study were to determine serum levels of PAPP-As and STCs in relationship with IGF axis components in children and adolescents with PWS, and the possible changes in the GH-IGF system after GH treatment in children with this syndrome.”

For this study, the researchers analyzed data from 40 children with PWS (18 Italian and 22 Spanish; 20 female and 20 male), as well as 38 adolescents (16 male and 22 female) with exogenous obesity and 120 healthy age- and sex-matched controls. How GH treatment affected 11 children was evaluated after six months.

“Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A,” the authors write. “Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio.”

The authors write that the finding of a direct relationship between standardized height with intact IGFBP-3 levels and the inverse relationship with the ratio of free/total IGF-I and serum PAPP-A and PAPP-A2 concentrations was surprising, but could possibly question that accuracy of using free IGF-I as a marker of growth and the response to GH administration, at least in these patients. “Moreover, Chen et al showed the temporal association between the increase in GH and reduction in free IGF-I levels, suggesting that circulating free IGF-I mediates the feedback regulation of GH secretion,” they write. “This finding, together with the short stature of the subjects with PWS included in this study and their rise in IGF-I levels, could indicate a certain degree of perturbation of the GH-IGF axis in PWS and therefore, its possible relationship with GH resistance.”

The study covers a lot, but the authors conclude that the increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. They also write that future studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients. “These results suggest that the differences in IGF-I bioavailability and IGFBP cleavage during childhood and adolescence, most likely due to changes in pappalysins and stanniocalcins, are relevant for understanding the disturbances in the GH-IGF axis in patients with PWS and could be helpful in clinical practice,” they write.