Novel Insights into the Management of Growth Hormone Deficiency

Novel Insights into the Management of Growth Hormone Deficiency

Dattani Mehul
European Endocrine Review 2006
Published: October 2008
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Traditionally, short stature is defined as a height that lies more than two standard deviations (SD) below the mean for age compared with gender-specific standards based on an appropriate healthy population. In multi-ethnic societies, it is important to compare children with controls from an appropriate ethnically matched normal population. Additionally, the genetic background of an individual’s family is crucial. The majority of children with short stature do not have an underlying hormonal or genetic disease.1 Using the classical threshold of a height standard deviation score (SDS) equal to or below -2.0 identifies 14% of children as being of short stature with an organic cause, while reducing the threshold to -3.0 increases the yield to 58%.2,3 The genetic background is also crucial in determining the need for possible evaluation, and any child with a height more than 1.4 SD below the mid-parental height warrants assessment. Once familial short stature and organic causes of growth failure have been excluded, there remains a small number of children with unexplained short stature. Of these, a few will be found to have a hormonal cause for their growth failure.

Growth Hormone Deficiency
Growth hormone deficiency (GHD) is reported to occur in approximately one in 3,000–4,000 individuals, but this may be an overestimate given the reversibility of GH deficiency in 25–75% of patients with GHD (see below).1,4

Physiology
GH is secreted by somatotropes in the anterior pituitary gland in a pulsatile manner characterised by peaks and troughs. Secretion is age- and genderdependent. The human GH gene (GH-N or GH1) forms part of a cluster of five homologous genes (human GH (hGH)-N, human chorionic somatomammotropin-like (hCS)-L, hCS-A, hGH-V and hCS-B) located on the long arm of chromosome 17. Its expression is regulated by not only a proximal promoter, but also a locus control region (LCR) 15–32 kilobases (kb) upstream of the hGH-1 gene. The LCR confers pituitary-specific, high-level expression of hGH.5,6 The full-length transcript from the hGH-N gene encodes a 191-amino-acid 22 kilo Dalton (kDa) protein that accounts for 85–90% of circulating GH. Alternative splicing of the messenger RNA (mRNA) transcript generates a 20kDa form of GH that accounts for the remaining 10–15%.

Once GH has been secreted by the somatotropes, it binds to two binding proteins, high-affinity GHbinding protein (GHBP) and low-affinity GHBP, in the circulation.7 Little is known about low-affinity GHBP, while high-affinity GHBP is a 61kDa glycosylated protein that represents a soluble form of the extracellular domain of the GH receptor that can bind to both 20kDa and 22kDa hGH and thereby prolong the half-life of GH. GH then interacts with its receptor (GHR), which is present in a number of tissues. The hormone sequentially dimerises its receptor, activating the receptorassociated tyrosine kinase janus kinase 2 (JAK2) that, in turn, is auto-phosphorylated and also phosphorylates the GHR. This then leads to signal transduction using the mitogen-activated protein kinase (MAPK), signal transducers and activators of transcription (STAT) and phosphoinositide-3 (PI3) kinase pathways. The end-result is activation of a number of genes that mediate the effects of GH, such as c-jun, c-fos and c-myc, implicated in cell growth, proliferation and differentiation, and insulin-like growth factor 1 (IGF-1), which mediates the growth-promoting effects of GH.8,9

IGF-1 and -2 are single-chain polypeptide hormones that are widely expressed and, together with a family of specific binding proteins, are believed to mediate most of the actions of GH. Extensive and authoritative reviews cover this aspect of the GH axis.10

Aetiology
In the past, the majority of GHD cases were thought to be idiopathic. However, the last ten years have led to major advances in the understanding of pituitary and somatotrope development and, hence, the aetiology of some of these cases of idiopathic GHD (IGHD) and multiple pituitary hormone deficiency (MPHD). The pituitary gland consists of anterior, intermediate and posterior lobes and is a central regulator of growth, metabolism and development. Its complex functions are mediated via hormone signalling pathways that act to regulate the finely balanced homeostatic control in vertebrates by co-ordinating signals from the hypothalamus to peripheral endocrine organs (thyroid, adrenals and gonads). The mature anterior pituitary gland is populated by five neuroendocrine cell types, defined by the hormone produced, i.e. one of the following:


  • corticotropes (adrenocorticotropic hormone (ACTH));
  • thyrotropes (thyroid-stimulating hormone (TSH));
  • gonadotropes (luteinising hormone (LH), folliclestimulating hormone (FSH));
  • somatotropes (GH); and
  • lactotropes (prolactin (PRL)).

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