IGF-I bioavailability in congenital isolated growth hormone deficiency

The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity.

We evaluated the ISPa in: (1) GHD subjects with homozygous GHRH-R c.57 + 1G→A mutation, (2) heterozygotes (HTZ), and (3) homozygous wild-type controls (HMZ). Parameters from the ISPa were measured at LMU Klinikum, Munich. Additional biochemical parameters were analyzed at the Federal University of Sergipe, Brazil.

As expected, GHD subjects had markedly low GH, IGF-I, IGF-II, free IGF-I, and IGFBP 3 (P < .001), while HTZ resembled HMZ subjects. STC2, PAPP-A, and PAPP-A-STC2 complex concentrations did not differ between groups. However, PAPP-A2 and intact IGFBP 4 were higher in the GHD subjects (P < .05 and P < .01). Notably, IGF-I and IGFBP 3 positively correlated with IGF-II, whereas intact IGFBP 4 and PAPP-A2 showed inverse correlations with IGF-I and IGF-II.

Our findings suggest altered IGF-I bioavailability regulation via the ISPa in congenital lifetime GHD, leading to increased PAPP-A2 proteolytic activity, reduced PAPP-A enzymatic activity, and reduced sequestration of PAPP-A2 by STC2.