Growth hormone isoforms

Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms. The sources of this heterogeneity reside at the level of the genome, mRNA splicing, post-translational modification and metabolism. The GH gene cluster on chromosome 17q contains 2 GH genes (GH1 or GH-N and GH2 or GH-V) in addition to 2(-3) genes encoding the related chorionic somatomammotropin. Alternative mRNA splicing of the GH1 transcript yields two products: 22K-GH (the principal pituitary GH form) and 20K-GH. Post-translationally modified GH forms include N(alpha)-acylated, deamidated and glycosylated monomeric GH forms, as well as both non-covalent and disulfide-linked oligomers up to at least pentameric GH. GH fragments generated in the course of peripheral metabolism may be measured in immunoassays for GH. The GH-N gene is expressed in the pituitary, the GH-V gene in the placenta. Secretion of pituitary GH forms is pulsatile under control from the hypothalamus, whereas secretion of placental GH-V is tonic and rises progressively in maternal blood during the 2nd and 3rd trimester. Pituitary GH forms are co-secreted during a secretory pulse; no isoform-specific stimuli have been identified. There are minor differences in somatogenic and metabolic bioactivity among the GH isoforms, depending on species and assay system used. Both 20K-GH and GH-V have poor lactogenic activity. Oligomeric GH forms have variably diminished bioactivity compared to monomeric forms. GH isoforms cross-react in most immunoassays, but assays specific for 22K-GH, 20K-GH and GH-V have been developed. The metabolic clearance of 20K-GH and GH oligomers is delayed compared to that of 22K-GH. The heterogeneous mixture of GH isoforms in blood is further complicated by the presence of two GH-binding proteins, which form complexes with GH; isoform proportions also vary depending on the lag time from a secretory pulse because of different half-lives. GH forms excreted in the urine reflect monomeric GH isoforms in blood, but constitute only a minute fraction of the GH production rate. The heterogeneity of GH is one important reason for the notorious disparity among assay results. It also presents an opportunity for distinguishing endogenous from exogenous GH.