During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

I. Introduction II. Characteristics of the IGFBPs III. Target Cell Actions of the IGFBPs A. To modulate IGF actions B. To facilitate storage of IGFs in extracellular matrices C. To exert IGF-independent effects IV. IGF-IGFBP Complexes in Biological Fluids A. Serum B. Milk C. Urine D. Cerebrospinal fluid (CSF) E. Follicular fluid F. Amniotic fluid G. Lymph H. Seminal fluid I. Other biological fluids V. Assays for Circulating Levels of IGFBP A. Western ligand blotting B. Western immunoblotting C. RIA D. Immunoradiometric assay (IRMA) VI. Relative Distribution of IGFBPs in Serum VII. Regulation of Serum IGFBPs A. Physiological conditions B. Development and aging C. Hormonal effects: mechanisms D. Pathological conditions VIII. IGFBP Proteases in Circulation A. Proteases under normal conditions B. Pregnancy-associated proteases C. Proteases under catabolic and disease states IX. Endocrine Functions of IGFBPs in Serum A. To prevent insulin-like effects B. To increase the half-lives of IGFs C. To control the tra...

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Insulin-Like Growth Factor-Binding Proteins in Serum and Other Biological Fluids: Regulation and Functions

Insulin-like growth factor I (IGF-I) mediates the majority of the growth-promoting effects of growth hormone (GH) after birth.1 In the prenatal period, GH does not appear to have a major influence on fetal growth, whereas IGF-I does. Infants with congenital GH deficiency and defects in the GH-receptor gene have only mild retardation of growth at birth,2–4 whereas transgenic mice with a homozygous defect of the IGF-I gene (IGF-I knockout mice) have profound embryonic and postnatal growth retardation.5–7 Although there is no direct evidence that IGF-I has a prominent role in human fetal growth, fetal tissues express IGF-I from . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199610313351805

Intrauterine Growth Retardation and Postnatal Growth Failure Associated with Deletion of the Insulin-Like Growth Factor I Gene

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.

https://www.pnas.org/content/pnas/94/24/13215.full.pdf

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

This report documents that the syndrome of growth hormone insensitivity (severe short stature, increased secretion of growth hormone, but low serum concentrations of insulin-like growth factor I [IGF-I] and IGF–binding protein 3) in a teenage girl was due to a homozygous missense mutation in the gene for STAT5b, an essential component of the actions of growth hormone, as well as many other cytokine-induced functions.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa022926

Growth hormone insensitivity associated with a STAT5b mutation.

Twenty-seven patients with GH insensitivity were identified from 44 possible cases, using a scoring system based on height standard deviation score (SDS), basal GH, insulin-like growth factor-I (IGF-I), IGF-I response to IGF-I generation test, and GH-binding protein (GH-BP) determinations. The 27 cases were from 8 European countries and Australia. Clinical features were as follows: age 2.8-22.6 yr; 12 male, 15 female, 19 prepubertal. Birth weight was median -0.72 SDS (1.75(-)-3.29) and birth length, median -1.59 SDS (0.63(-)-3.63). Hypoglycemia had been documented in 33% of the cases, and micropenis was present in 58% of the males. At assessment, height was median -6.1 SDS (-3.8(-)-10.2), weight was median -3.2 SDS (-0.1 to -5.2), and percentage weight for height, median 111.3 (72-271). Puberty was absent in 2 boys aged 15 yr and in 3 girls aged 13 yr. Bone age was delayed in 19 of the 27 patients. Endocrine investigations showed basal serum GH median 17 micrograms/L (0.5-79), IGF-I values less than 5th p...

Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome).

GH insensitivity syndrome (GHIS) is associated with many different mutations of the GH receptor (GHR) gene. We examined the phenotypic and biochemical features in 82 GHIS patients from 23 countries, each fulfilling diagnostic criteria of GHIS. There were 45 males and 37 females [mean age, 8.25 yr; mean height, −6.09 sd score, and mean insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3),− 7.99 sd score]. Sixty-three were GH-binding protein (GHBP) negative; 19 were GHBP positive (>10% binding). The mean height in GHBP-negative subjects was −6.5 sd score, and that in GHBP-positive patients was −4.9 sd score (P = <0.001). Clinical and biochemical heterogeneity was demonstrated by the wide range of height (−2.2 to− 10.4 sd score) and IGFBP-3 (−1.4 to −14.7 sd score) values, which were positively correlated (r2 = 0.45; P = <0.001). This contrasted with the lack of correlation between mean parental height sd score and height sd score (r2 = 0.01). Fifteen different GH receptor gene mutations were identif...

/pdf/phenotype-genotype-relationships-in-growth-hormone-1lycewgcqd.pdf

Phenotype: genotype relationships in growth hormone insensitivity syndrome.

Laron syndrome (LS) is a severe autosomal recessive form of GH resistance resulting from molecular defects in the GH receptor (GHR). Affected individuals have extreme short stature and a typical facial phenotype. The point mutations in the GHR gene identified in this condition have until now been confined to the region encoding the extracellular domain of the receptor. We report here the first homozygous point mutation within the intracellular domain of the GHR in two LS cousins distinguishable from classical LS patients only by the presence of elevated GH-binding protein (GHBP) in their serum. A G to C transversion at the vital - 1 position in the splice donor site of exon 8 disrupts normal splicing, resulting in the complete skipping of exon 8, producing a mutant GHR protein lacking transmembrane and intracellular domains. We predict that this mutant protein would not be anchored in the cell membrane and would be measurable in the circulation as GHBP, hence explaining the phenotype of severe GH resistan...

A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein.

Defects of the growth hormonereceptor and their clinical implications

Twenty-seven patients with GH insensitivity were identified from 44 possible cases, using a scoring system based on height standard deviation score

M. C. Postel-Vinay

Papers

Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome).

Phenotype: genotype relationships in growth hormone insensitivity syndrome.

A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein.

Defects of the growth hormonereceptor and their clinical implications

Clinical Features and Endocrine Status in Patients with Growth Hormone Insensitivity