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Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer

Abstract

Since its discovery nearly a century ago, over 100,000 studies of growth hormone (GH) have investigated its structure, how it interacts with the GH receptor and its multiple actions. These include effects on growth, substrate metabolism, body composition, bone mineral density, the cardiovascular system and brain function, among many others. Recombinant human GH is approved for use to promote growth in children with GH deficiency (GHD), along with several additional clinical indications. Studies of humans and animals with altered levels of GH, from complete or partial GHD to GH excess, have revealed several covert or hidden actions of GH, such as effects on fibrosis, cardiovascular function and cancer. In this Review, we do not concentrate on the classic and controversial indications for GH therapy, nor do we cover all covert actions of GH. Instead, we stress the importance of the relationship between GH and fibrosis, and how fibrosis (or lack thereof) might be an emerging factor in both cardiovascular and cancer pathologies. We highlight clinical data from patients with acromegaly or GHD, alongside data from cellular and animal studies, to reveal novel phenotypes and molecular pathways responsible for these actions of GH in fibrosis, cardiovascular function and cancer.

Key points

  • Growth hormone (GH) is important for growth and tissue remodelling, extracellular matrix formation and fibrosis.

  • Patients with acromegaly, which is characterized by excessive circulating levels of GH, have increased cardiovascular mortality that is associated with hypertension and heart failure.

  • Patients with GH deficiency have an increased risk of cardiovascular morbidity and mortality that is associated with cardiovascular risk factors and premature atherosclerosis.

  • GH actions in cancer are particularly implicated in mechanisms of therapy resistance; for example, active drug efflux, the epithelial-to-mesenchymal transition, apoptosis inhibition and development of a tumour-supportive microenvironment.

  • GH has a ‘Goldilocks effect’, where too little or too much can lead to poor clinical outcomes.

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Fig. 1: GH overexpression in mice induces tissue fibrosis.
Fig. 2: The pleiotropic actions of GH–IGF1 on the cardiovascular system, and electrolyte and water balance in humans.
Fig. 3: Covert actions of GH in cancer.

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Acknowledgements

J.J.K. acknowledges the support of the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, NIH-R01AG059779, the AMVETS and the Edison Biotechnology Institute at Ohio University. D.E.B. acknowledges the support of ASPIRE funding from Pfizer, NIH-R01AG059779 and the Heritage College of Osteopathic Medicine at Ohio University. V.P. acknowledges the support of funds from Osteopathic Heritage Foundation’s Vision 2020 to Heritage College of Osteopathic Medicine at Ohio University, R01HL140836, R01MD012579 and RO1DK124126. The authors acknowledge J. Young, L. Householder, S. Zhu and A. Jara (Ohio University) for their assistance with the original version of Fig. 1.

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Kopchick, J.J., Basu, R., Berryman, D.E. et al. Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer. Nat Rev Endocrinol 18, 558–573 (2022). https://doi.org/10.1038/s41574-022-00702-6

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