The therapeutic use of growth hormone (GH), derived from human cadaveric pituitaries, was introduced in the late 1950s and early 1960s (1). The production of pituitary GH slowly increased over the next two decades, but supplies did not meet the treatment needs of all patients believed to have GH deficiency (GHD) due to difficulties in obtaining sufficient cadaveric pituitaries. The recognition of Creutzfeldt–Jakob disease (CJD) in recipients of pituitary-derived GH in 1985 led to its immediate discontinuation in most countries. The last two decades have seen a dramatic increase in worldwide availability of natural sequence recombinant human GH (rhGH), with improvement in treatment protocols for children with GHD. GH has been used increasingly for short children with non-GHD conditions in childhood and adolescence, including idiopathic short stature (ISS), intrauterine growth retardation (IUGR) or small for gestational age (SGA) infants, chronic renal failure (CRF), and genetic syndromes such as Turner syndrome (TS), Down syndrome (DS), and Prader–Willi syndrome (PWS). In addition, studies began in the 1990s on the adult population of childhood onset of GHD, as well as on adult-onset GHD and the elderly.

The human GH gene locus is on the long arm of chromosome 17 and encodes for both pituitary GH (hGH-N), a single polypeptide chain of 191 amino acid residues that is secreted from the pituitary, as well as placental hGH (hGH-V) (16). The GH gene locus is close to the gene locus for chorionic somatotropin or human placental lactogen derived from the placenta. The primary full-length 22-kDa peptide is alternately spliced to yield a 20-kDa peptide that is cosecreted with and circulates at 5% to 10% of 22-kDa GH levels. Isolated GHD attributed to GH gene mutations may be inherited as autosomal recessive, dominant or X-linked, with the last entity being associated with hypogammaglobulinemia. Deletions of hGH-N produce very severe autosomal recessive growth failure after birth (17).

GH exerts many of its physiologic functions by regulating the transcription of genes of a variety of proteins, including IGF-1, transcription factors, and metabolic enzymes (18). The GH receptor was cloned in 1987 and led to the study of GH signaling at a molecular level. The cDNA for the human GH receptor encodes a 638-amino acid protein that has single extracellular, transmembrane, and cytoplasmic domains. It is a member of the cytokine/hematopoietin receptor superfamily that binds more than 25 ligands, including prolactin and leptin. In the working model of GH action, a single molecule of GH binds to two molecules of the GH receptor in a sequential fashion to form a dimer, an event that is crucial to subsequent GH-signaling events. During activation, the extracellular domain undergoes proteolytic cleavage to yield a soluble GH-binding protein in plasma or GHBP. GH binding to two receptor molecules increases the affinity of each receptor for a nonreceptor tyrosine kinase termed JAK2. Activation of JAK2 induces phosphorylation of itself and of tyrosine residues on the cytoplasmic domain of the GH receptor, initiating a cascade of signaling molecules that are beyond the purview of this chapter (18).

Inactivating mutations of the GH receptor gene or downstream signaling pathways cause the GH insensitivity syndrome (GHIS). Laron syndrome or classical GHIS is rare; its phenotype resembles that of GHD except for the presence of high serum GH concentrations and low levels of IGF-1, IFG-2, and IGFBP-3. Subcutaneous injections of recombinant IGF-1 or recombinant IGF-1–recombinant IGFBP-3 complex offer some promise of significantly improving height growth (19). A patient with a post-GH-receptor defect in conjunction with a primary immunodeficiency was described, and a mutation in the STAT5b gene has been implicated (20).

GH is a powerful anabolic hormone, and has a broader spectrum of action than implied by its original name. The growth-promoting effects and metabolic effects of GH are mediated via interaction with the specific GH receptor and through the important intermediary IGF-1 and its receptor (18,21,22). Three general outcome measurements have been frequently assessed:

GH dose exerts a very significant positive influence on all parameters used to assess effects on growth and metabolism. Few of the tests just described can reliably predict and/or monitor response to GH therapy. Of these, serum IGF-1 appears to offer the best indicator of the action of GH throughout all age groups. Lack of GH action is seen in children with classical GHD. In these patients, there is a decrease in serum GH, IGF-1, and IGFBP-3; decreased height SDS and growth velocity; delayed skeletal maturation; delayed pubertal onset; and increased abdominal adiposity. These are reversed with GH therapy. Excessive GH action is classically seen in patients with acromegaly, who demonstrate increased serum GH not suppressed with glucose, increased serum IGF-1 and IGFBP-3, increased BMI, and acral enlargement. With treatment of acromegaly, clinical improvement is usually best correlated with reductions in serum levels of GH and IGF-1.