Growth: III Growth Hormone
Clinical background
Growth hormone is necessary for the maintenance of good health in adult
life as well as for the promotion of growth in childhood. Adults with growth
hormone deficiency (GHD) are physically and psychologically less well than
normal subjects due to the diverse nature of GH action. The vast majority of
patients with adult GHD have pre-existing hypothalamic pituitary disease,
generally a pituitary adenoma. GHD may be part of the presenting illness or may
be induced by pituitary surgery or radiotherapy used in treatment. A small
percentage of patients with adult GHD will have presented with idiopathic GHD
in childhood.
The adult GHD syndrome is characterized by abnormalities of metabolism,
body composition and bone density and by psychological features of low mood,
poor self-esteem, anxiety and social isolation. Adults with GHD have increased
risk factors for cardiac disease reflected in reduced lean body mass, increased
central fat deposition, raised cholesterol and harmful low-density lipoprotein
concentrations and evidence of increased atheromatous deposits throughout the
arterial system. Bone mineral density is reduced and there is an increased risk
of fractures. The poor quality of life is a striking feature of the syndrome
and has been demonstrated using recognized assessments of psychological health.
GH replacement therapy is given as a daily subcutaneous injection of
recombinant human GH.
Growth hormone (GH)
Chemistry and synthesis
GH is synthesized in the somatotroph cells in the anterior pituitary
gland. GH is a member of a family of polypeptide hormones, including prolactin
(PRL) and placental lactogen (PL; Fig. 11a). GH is a single chain 191 amino
acid polypeptide, and has a high structural homology with PL and PRL. All three
are derived from a common precursor, even though each hormone has its own gene.
They share a common ancestral gene from which the GH/PL gene diverged about 400
million years ago, and divergence of GH and PL genes occurred about 85 to 100
million years ago. The GH and PL genes exist as multiple copies on chromosome
17, and the PRL gene is a single copy on chromosome 6. Mouse fibroblasts
synthesize a peptide called proliferin, which has significant structural
homology with GH, PRL and PL, suggesting that this family may be larger than
originally appreciated. GH and PRL exist in pituitary and plasma in more than
one form, that is they show structural heterogeneity.
Actions of growth hormone (Fig. 11b)
The most dramatic action of GH is on muscle and skeletal bone growth. The
actions may be conveniently divided into direct and indirect actions.
Indirect actions of growth hormone. GH acts in the liver to
stimulate the synthesis and secretion of the peptide IGF-1 which stimulates
bone growth. In fat cells, IGF-1 stimulates lipolysis and in muscle, it stimulates protein synthesis.
Functional GH receptors also exist in bone, stimulating local production of
IGF-1 in proliferative chondrocytes.
The direct actions of GH have been termed diabetogenic, since the
hormone’s actions oppose those of insulin, being lipolytic in fat and
gluconeogenic in muscle. These actions are implicated in disorders of GH
action.
Growth hormone receptor (Fig. 11c). The mechanism of action
of GH is still under investigation. It has a specific receptor on the membrane
of the target cell. The growth hormone receptor is a polypeptide of 619
residues which is organized into three distinct domains, viz. an extracellular
ligand binding domain, a single transmembrane segment and an intracellular
domain. It is part of the haematopoietic type I cytokine receptor family. The
extracellular domain of the GH receptor consists of 192 residues and has been
found on the receptor and as a circulating isoform protein called growth
hormone receptor binding protein, which is used as a marker of receptor number
integrity. It appears that each asymmetrical molecule of GH binds two
homologous binding domains on two separate GH receptors, and that there is a sequential
effect, in that one part of the GH molecule must bind first to its site on one
receptor followed by the other binding reaction to another receptor, for the
cell to respond appropriately.
Signal transduction. No changes in cAMP or phosphoinositol (the
PLC/IP3) systems have been reported. After the binding reactions have occurred,
the cytoplasmic domain of the receptor recruits the tyrosine kinase JAK2, and
phosphorylation of the receptor and the JAK2 occurs. Phosphotyrosine residues
on both JAK2 and the growth hormone receptor have docking sites for several
intracellular signalling proteins which possess phosphotyrosine motifs, for
example SH2 domains. Thus, the growth hormone receptor complex somehow enables
JAK2 to phosphorylate a number of different proteins, resulting in the cellular
response. The substrates for phosphorylation by JAK2 include the insulin receptor
substrate (IRS), the glucocorticoid receptor, the epidermal growth factor
receptor, signal transducers and activators of transcription (STATS) and
several others.
The cellular response depends on which of these molecules becomes
phosphorylated, and the result may be, for example, a metabolic change or
transcriptional activation or repression. For example activation of the insulin
receptor substrate results in the insulin-like actions of growth hormone, while
activation of STAT causes transcriptional activation. The growth hormone
receptor is regulated by inhibitory intracellular proteins which prevent
unregulated growth. Examples of regulators include: (i) SH2-domain-containing
protein tyrosine phosphatases which dephosphorylate the receptor and the JAK2
tyrosine kinase; and (ii) suppressors
of cytokine signalling (SOCS), which bind to JAK2 and block its kinase
activity. These basic research discoveries are of great interest as possible
new approaches to the treatment of
growth hormone-related diseases.
