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
ReviewGrowth hormone deficiency and related disorders: insights into causation, diagnosis, and treatment
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
References (156)
Fetal programming of coronary heart disease
Trends Endocrinol Metab
(2002)- et al.
Utah growth study: growth standards and the prevalence of growth hormone deficiency
J Pediatr
(1994) Growth hormone therapy for the short normal child: who needs it and who wants it?-the case against growth hormone therapy
J Pediatr
(2000)- et al.
How many homeobox genes does it take to make a pituitary gland?
Trends Genet
(1998) - et al.
Early steps in pituitary organogenesis
Trends Genet
(1999) - et al.
Pit-1 binding sites at the somatotrope-specific DNase I hypersensitive sites I, II of the human growth hormone locus control region are essential for in vivo hGH-N gene activation
J Biol Chem
(1999) - et al.
Congenital idiopathic growth 50 hormone deficiency associated with prenatal and early postnatal growth failure. The International Board of the Kabi Pharmacia International Growth Study
J Pediatr
(1992) - et al.
Diagnosis and management of growth hormone deficiency in childhood and adolescence: part 1-diagnosis of growth hormone deficiency
Growth Horm IGF Res
(2001) - et al.
Results of early reevaluation of growth hormone secretion in short children with apparent growth hormone deficiency
J Pediatr
(2002) - et al.
Diagnosis and management of growth hormone deficiency in childhood and adolescence: part 2-growth hormone treatment in growth hormone deficient children
Growth Horm IGF Res
(2002)
Premature mortality due to cardiovascular disease in hypopituitarism
Lancet
Association between premature mortality and hypopituitarism: West Midlands Prospective Hypopituitary Study Group
Lancet
Diagnosis and management of growth hormone deficiency in adults
Endocrinol Metab Clin North Am
Infancy growth pattern related to growth hormone deficiency
Acta Paediatr Scand
On the modelling of human growth
Stat Med
The strengths and limitations of parental heights as a predictor of attained height
Arch Dis Child
Poor growth in school entrants as an index of organic disease: the Wessex growth study
BMJ
Childhood auxology
Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome
Nat Genet
A dominant-negative mutation of the growth hormone receptor causes familial short stature
Nat Genet
Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature
J Pediatr
Signaling and transcriptional mechanisms in pituitary development
Ann Rev Neurosci
Formation of Rathke's pouch requires dual induction from the diencephalon
Development
Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary
Development
The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain
Development
Multistep control of pituitary organogenesis
Science
Multistep signaling requirements for pituitary organogenesis in vivo
Genes Dev
Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo
Recent Prog Horm Res
Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors
Genes Dev
In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development
J Histochem Cytochem
Maturation of hypothalamic-pituitary function in the ovine fetus and neonate
Ciba Found Symp
Growth hormone secretion in children determined by time series analysis
Clin Endocrinol (Oxf)
Regulatory mechanisms of growth hormone secretion are sexually dimorphic
J Clin Invest
Growth hormone secretagogue binding sites in peripheral human tissues
J Clin Endocrinol Metab
Growth hormone-releasing peptides and the cardiovascular system
Ann Endocrinol (Paris)
The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans
J Clin Endocrinol Metab
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
Nature
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
Growth hormone releasing substances: types and their receptors
Horm Res
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
Ghrelin strongly stimulates growth hormone release in humans
J Clin Endocrinol Metab
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
Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins
Endocr Rev
Growth hormone binding protein. The soluble growth hormone receptor
Minerva Endocrinol
Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat
Endocrinology
Molecular mechanism of growth hormone action
Annu Rev Physiol
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
The insulin-like growth factor-binding protein (IGFBP) superfamily
Endocr Rev
Differences in physical characteristics, perinatal histories, and social backgrounds between children with growth hormone deficiency and constitutional short stature
Arch Dis Child
European audit of current practice in diagnosis and treatment of childhood growth hormone deficiency
Horm Res
Cited by (93)
The Hypothalamus
2022, The PituitaryMolecular 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 ActaCitation 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].
Using modern human cortical bone distribution to test the systemic robusticity hypothesis
2018, Journal of Human EvolutionGenetic and hormonal control of growth
2018, Encyclopedia of Endocrine DiseasesThe Hypothalamus
2017, The Pituitary: Fourth EditionHypothalamic Syndromes?
2015, Endocrinology: Adult and Pediatric