Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary complex formation throughout life

Measurement of the insulin-like growth factors (IGFs) and their binding pro teins has become commonplace in the indirect assessment of the integrity of the GH axis. However, the relative effect of GH deficiency (GHD) on each c omponent of the IGF axis and the merit of any one parameter as a diagnostic test have not been defined in a homogeneous population across all ages. We therefore measured IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 , IGFBP-3, and acid labile subunit (ALS) in 27 GHD subjects (aged 5-82 yr) from an extended kindred in Northeast Brazil with an identical GHRH recepto r mutation and in 55 indigenous controls (aged 5-80 yr). The effect of GHD on the theoretical distribution of IGFs between the IGFBPs and the ternary complex was also examined. All components of the IGF axis, measured and theoretical, showed complete s eparation between GHD and control subjects, except IGFBP-1 and IGFBP-2 conc entrations, which did not differ. The most profound effects of GHD were on total IGF-I, IGF-I in the ternary complex, and ALS. The proportion of IGF-I associated with IGFBP-3 remained constant throughout Life, but was signifi cantly lower in GHD due to an increase in IGF-I/IGFBP-2 complexes. IGF-I in the ternary complex was determined principally by concentrations of ALS in GHD and IGFBP-3 in controls, implying that ALS has greater GH dependency. In the controls, IGF-II was associated primarily with IGFBP-3 and to a less er extent with IGFBP-8, whereas in GHD the reverse was found. There was als o a dramatic decline in the proportion of free ALS in GHD adults that was n ot evident in controls. As diagnostic tests, IGF-I in the ternary complex a nd total IGF-I provided the greatest separation between GHD and controls in childhood. Similarly, in older adults the best separation was achieved wit h IGF-I in the ternary complex, with free ALS being optimal in younger adul ts. Severe GHD not only reduces the amounts of IGFs, IGFBP-3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic test s used in the investigation of GHD should be tailored to the age of the ind ividual. In particular, measurement of IGF-I in the ternary complex may pro ve useful in the diagnosis of GHD in children and older adults, whereas fre e ALS may be more relevant to younger adults.