Elsevier

The Lancet

Volume 363, Issue 9425, 12 June 2004, Pages 1977-1987
The Lancet

Review
Growth hormone deficiency and related disorders: insights into causation, diagnosis, and treatment

https://doi.org/10.1016/S0140-6736(04)16413-1Get rights and content

Summary

Advances in molecular biology have led to the identification of mutations within several novel genes associated with the phenotype of isolated growth hormone deficiency, combined pituitary hormone deficiency, and syndromes such as septo-optic dysplasia. Progress has also been made in terms of the optimum diagnosis of disorders of stature and their treatment. The use of growth hormone for the treatment of adults with growth hormone deficiency and conditions such as Turner's syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure has changed the practice of endocrinology, although cost-benefit implications remain to be established.

Section snippets

Normal growth

Fetal growth is critical and has major implications for the ultimate stature of an individual. A crown-rump growth velocity of 50–60 cm per year represents the fastest rate of growth achievable. This growth is largely independent of growth hormone and is mediated by maternal nutrition and growth factors such as insulin-like growth factors (IGF-I and IGF-II), fibroblast growth factor, epidermal growth factor, transforming growth factors α and β, and insulin. Growth hormone does have a small role

Short stature

Traditionally, short stature is defined as a height that lies below -2SD for age compared with sex-specific standards based on an appropriate healthy population. In multiethnic societies, comparison of children with controls from the general population who are matched for ethnic background is important. Additionally, the genetic background of an individual's family is crucial. Investigators have shown that the expected height SD score (SDS) for a child should be calculated after adjustment for

Development of the anterior pituitary gland

The pituitary gland, which consists of anterior, intermediate, and posterior lobes, is a central regulator of growth, metabolism, and development. Its complex functions are mediated via hormone signalling pathways that regulate the finely balanced homoeostatic 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

The hypothalamo-pituitary-somatotroph axis

Somatotropes secrete growth-hormone in the anterior pituitary gland in a pulsatile manner. Secretion varies considerably with age,23, 24 and shows a sexually dimorphic pattern,25 with a greater average daily output in women. The pulsatility results from the interaction between the hypothalamic pep tides growth hormone-releasing hormone and somatostatin.

Recent use of synthetic growth-hormone-releasing peptides has led to the identification of a growth hormone secretagogue receptor (GHSR type

Epidemiology and causation

The frequency of growth hormone deficiency is reported to be about one in 3000 to one in 4000,5, 42 although this is probably an overestimate in view of the reversibility of this deficiency in 25–75% of patients. Anecdotally, the incidence of the deficiency is thought to vary substantially between countries. The incidence of isolated growth hormone deficiency relative to multiple pituitary hormone deficiencies is also believed to vary greatly. However, few reliable data exist; large

Treatment

Recombinant growth hormone is used for the treatment of growth hormone deficiency. In children treated early, catch-up growth is excellent, with a normal final height. A final height gain of 30 cm can be expected on average,75 but this figure is affected by variables such as birthweight, age at start of treatment, extent of this deficiency, duration of treatment, and frequency of growth hormone injections, height at start of treatment, and height at the start of puberty.76, 77, 78, 79, 80, 81

Bioinactive growth hormone syndrome

Some individuals who have a poor height velocity with normal growth hormone concentrations but low IGF-I have heterozygous mutations within the GH1 gene, resulting in the generation of abnormal growth hormone.135 These mutations are associated with a dominant negative effect, with a defect in dimerisation of the growth hormone receptor by growth hormone. The defect can be overcome by exogenous growth hormone treatment, with an increase in both the growth velocity and IGF-I concentration.

Conclusions

The past few years have led to major advances in our understanding of the development of the pituitary gland, and the genetics of isolated growth hormone deficiency and combined pituitary hormone deficiency. Additionally, growth hormone treatment is now used for several indications other than its deficiency. In the UK, 78% of growth hormone prescriptions were for licensed indications, whereas 22% were for unlicensed indications.155 Randomised controlled studies in which workers investigated the

Search strategy and selection criteria

We searched PubMed using the terms growth hormone and pituitary development as an initial screen. We refined the results with the terms: treatment, aetiology, diagnosis, clinical features, genes, and physiology. The search was not confined to English language publications, but no foreign language articles that justified translation were identified. The search was mostly concentrated over the past 10 years, although a few highly regarded and relevant earlier publications have been included

References (156)

  • T Rosen et al.

    Premature mortality due to cardiovascular disease in hypopituitarism

    Lancet

    (1990)
  • JW Tomlinson et al.

    Association between premature mortality and hypopituitarism: West Midlands Prospective Hypopituitary Study Group

    Lancet

    (2001)
  • S Stavrou et al.

    Diagnosis and management of growth hormone deficiency in adults

    Endocrinol Metab Clin North Am

    (2001)
  • KarlbergJ et al.

    Infancy growth pattern related to growth hormone deficiency

    Acta Paediatr Scand

    (1988)
  • J Karlberg

    On the modelling of human growth

    Stat Med

    (1987)
  • CM Wright et al.

    The strengths and limitations of parental heights as a predictor of attained height

    Arch Dis Child

    (1999)
  • LD Voss et al.

    Poor growth in school entrants as an index of organic disease: the Wessex growth study

    BMJ

    (1992)
  • MA Preece

    Childhood auxology

  • E Rao et al.

    Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome

    Nat Genet

    (1997)
  • RM Ayling et al.

    A dominant-negative mutation of the growth hormone receptor causes familial short stature

    Nat Genet

    (1997)
  • AD Goddard et al.

    Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature

    J Pediatr

    (1997)
  • JS Dasen et al.

    Signaling and transcriptional mechanisms in pituitary development

    Ann Rev Neurosci

    (2001)
  • N Takuma et al.

    Formation of Rathke's pouch requires dual induction from the diencephalon

    Development

    (1998)
  • J Ericson et al.

    Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary

    Development

    (1998)
  • D Lazzaro et al.

    The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain

    Development

    (1991)
  • HZ Sheng et al.

    Multistep control of pituitary organogenesis

    Science

    (1997)
  • M Treier et al.

    Multistep signaling requirements for pituitary organogenesis in vivo

    Genes Dev

    (1998)
  • MG Rosenfeld et al.

    Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo

    Recent Prog Horm Res

    (2000)
  • DM Simmons et al.

    Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors

    Genes Dev

    (1990)
  • MA Japon et al.

    In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development

    J Histochem Cytochem

    (1994)
  • PD Gluckman

    Maturation of hypothalamic-pituitary function in the ovine fetus and neonate

    Ciba Found Symp

    (1981)
  • PC Hindmarsh et al.

    Growth hormone secretion in children determined by time series analysis

    Clin Endocrinol (Oxf)

    (1988)
  • CA Jaffe et al.

    Regulatory mechanisms of growth hormone secretion are sexually dimorphic

    J Clin Invest

    (1998)
  • M Papotti et al.

    Growth hormone secretagogue binding sites in peripheral human tissues

    J Clin Endocrinol Metab

    (2000)
  • G Muccioli et al.

    Growth hormone-releasing peptides and the cardiovascular system

    Ann Endocrinol (Paris)

    (2000)
  • S Gnanapavan et al.

    The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans

    J Clin Endocrinol Metab

    (2002)
  • M Kojima et al.

    Ghrelin is a growth-hormone-releasing acylated peptide from stomach

    Nature

    (1999)
  • Y Date et al.

    Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

    Endocrinology

    (2000)
  • RG Smith et al.

    Growth hormone releasing substances: types and their receptors

    Horm Res

    (1999)
  • E Arvat et al.

    Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone

    J Clin Endocrinol Metab

    (2001)
  • K Takaya et al.

    Ghrelin strongly stimulates growth hormone release in humans

    J Clin Endocrinol Metab

    (2000)
  • IM Bennani-Baiti et al.

    DNase I-hypersensitive sites I and II of the human growth hormone locus control region are a major developmental activator of somatotrope gene expression

    Proc Natl Acad Sci USA

    (1998)
  • G Baumann

    Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins

    Endocr Rev

    (1991)
  • G Baumann

    Growth hormone binding protein. The soluble growth hormone receptor

    Minerva Endocrinol

    (2002)
  • RG Clark et al.

    Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat

    Endocrinology

    (1996)
  • C Carter-Su et al.

    Molecular mechanism of growth hormone action

    Annu Rev Physiol

    (1996)
  • LS Smit et al.

    The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH

    Mol Endocrinol

    (1996)
  • V Hwa et al.

    The insulin-like growth factor-binding protein (IGFBP) superfamily

    Endocr Rev

    (1999)
  • GV Vimpani et al.

    Differences in physical characteristics, perinatal histories, and social backgrounds between children with growth hormone deficiency and constitutional short stature

    Arch Dis Child

    (1981)
  • A Juul et al.

    European audit of current practice in diagnosis and treatment of childhood growth hormone deficiency

    Horm Res

    (2002)
  • Cited by (93)

    • The Hypothalamus

      2022, The Pituitary
    • Molecular diagnosis for growth hormone deficiency in Chinese children and adolescents and evaluation of impact of rare genetic variants on treatment efficacy of growth hormone

      2022, Clinica Chimica Acta
      Citation Excerpt :

      These variants could be contributory to GH response in the short-stature patients, however further functional analysis is needed to underpin their pathogenicity. In addition to comprehensive clinical, auxological, biochemical and radiological assessment, over 30 gene defects found by different genetic methods (WGSNP, aCGH, WES, WGS and GWAS) has greatly expanded our understanding of the etiology and pathogenesis of those with IGHD and combined pituitary hormone deficiencies (CPHD) [24–27]. Previous reports have revealed that most common causal genes for IGHD and CPHD from European and American studies were GH1, GHRHR and PROP1, respectively [12,28].

    • Genetic and hormonal control of growth

      2018, Encyclopedia of Endocrine Diseases
    • The Hypothalamus

      2017, The Pituitary: Fourth Edition
    • Hypothalamic Syndromes?

      2015, Endocrinology: Adult and Pediatric
    View all citing articles on Scopus
    View full text