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Growth hormone — past, present and future

Key Points

  • The growth hormone (GH)–insulin-like growth factor (IGF) axis consists of central neuro-anatomical, regulatory and genetic systems, and the peripheral intracellular GH signalling pathway

  • The introduction of recombinant human GH (rhGH) in 1985 ended the phase of pituitary-derived human growth hormone (hGH) and its associated limitations and risks, opening the possibility of widespread clinical use

  • GH deficiency (GHD) is a syndrome with many different causes and is associated with alterations in growth, body composition and metabolism

  • In some non-GHD short stature disorders, rhGH has been proved effective and is used as a surrogate for the currently unknown, pathophysiologically appropriate treatment

  • Risks of hGH therapy might relate to its direct effects on growth, its anti-insulin action and its cell-proliferating activity; however, the safety profile of rhGH in children and adults is good

  • Current innovative treatment approaches relate to personalizing conventional rhGH, developing long-acting GH preparations, the prospect of gene therapy, GH–GH receptor antagonists and, potentially, new indications

Abstract

Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century, clinical observations and anatomical and biochemical studies formed the basis of the understanding of the structure of GH and its various metabolic effects in animals. The following period (1958–1985), during which pituitary-derived human GH was used, generated a wealth of information on the regulation and physiological role of GH — in conjunction with insulin-like growth factors (IGFs) — and its use in children with GH deficiency (GHD). The following era (1985 to present) of molecular genetics, recombinant technology and the generation of genetically modified biological systems has expanded our understanding of the regulation and role of the GH–IGF axis. Today, recombinant human GH is used for the treatment of GHD and various conditions of non-GHD short stature and catabolic states; however, safety concerns still accompany this therapeutic approach. In the future, new therapeutics based on various components of the GH–IGF axis might be developed to further improve the treatment of such disorders. In this Review, we describe the history of GH research and clinical use with a particular focus on disorders in childhood.

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Figure 1: Timeline of important discoveries in GH–IGF axis research until 1957.
Figure 2: Timeline of important discoveries in GH–IGF axis research from 1958 to present.
Figure 3: The GH–IGF axis and GH signalling pathway.

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Acknowledgements

The authors are grateful to L. Van den Brande and J. S. Parks, who inspired them as young scientists.

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Both authors contributed equally to this manuscript.

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Correspondence to Michael B. Ranke.

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Competing interests

M.B.R. declares that he is a member of the Pfizer advisory board for iGRO and has received honoraria for speaking from Pfizer and Sandoz. J.M.W. declares that he is a member of the Merck advisory board and has received honoraria for speaking from Sandoz, Merck-Serono, Pfizer, Versartis, Eli Lilly, Novo Nordisk and JCR.

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Supplementary information

Supplementary Table S1

Genes associated with disorders of the GH-IGF axis (PDF 395 kb)

Supplementary Box S2

Non-GH deficient medical conditions accepted as indications for GH treatment (PDF 305 kb)

Glossary

Hypothalamo–pituitary portal vessels

A system of blood vessels connecting the hypothalamus with the anterior pituitary.

Isolated GHD

(IGHD). Defined by the selective lack of pituitary growth hormone secretion in contrast to normal secretion of other pituitary hormones.

Agammaglobulinaemia

A term for deficiencies of immunoglobulins that electrophoretically migrate into the γ-fraction.

Laron syndrome

A growth disorder due to an insensitivity to growth hormone caused by a mutation in the growth hormone receptor.

Midparental height

(MPH). The average height of the father and mother after converting them to standard deviation scores.

International reference preparations

(IRPs). International standard preparations (for example, for human growth hormone) are established by WHO experts (National Institute for Biological Standards and Control (NIBSC)).

Turner syndrome

A dysmorphic syndrome with short stature caused by the (partial) loss of one X chromosome in females.

Idiopathic short stature

(ISS). Refers to short stature not explained by defined causes.

Chronic renal insufficiency

A term describing a severe form of renal failure that is associated with growth failure in children.

Prader–Willi syndrome

A congenital syndrome associated with severe obesity, mental retardation and short stature (OMIM 301900).

Noonan syndrome

A dysmorphic syndrome associated with phenotypical congenital heart defects and short stature (OMIM 615355).

Short bowel syndrome

The malabsorption disorder caused by the missing of functional small intestine.

HIV wasting syndrome

The severe loss of body mass due to an infection with HIV.

Creutzfeldt–Jakob disease

A prion-transmitted degenerative encephalopathy.

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Ranke, M., Wit, J. Growth hormone — past, present and future. Nat Rev Endocrinol 14, 285–300 (2018). https://doi.org/10.1038/nrendo.2018.22

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