MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Abstract

Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 40-50 years. Work on the GH receptor (R) knock-out (GHRKO) mice and results of studies on GH resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition, and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.

The effects of growth hormone on therapy resistance in cancer

“…diabetic nephropathy [56][57][58] , and multi-organ failures leading to a significantly reduced lifespan [59] . Mouse models of GH excess -mice transgenic for bovine GH (bGH) -corroborate the above human data [2,42,[60][61][62] . These pleiotropic effects of GH action positions GH as a truly enigmatic biomolecule and a topic of intense research in human health for the last century.…”

“…On the other hand, resistance to cancer has been one of the consistent features of the two cohorts of LS patients in both Israel [34,63,82,83] and Ecuador [33] , with multiple studies focusing on the underlying molecular mechanisms [83][84][85] . Mouse models of dysregulated GH action -the bGH and the GHRKO mice -closely recapitulates the oncogenic profiles of the corresponding human patients [2] . A number of in vivo xenograft studies on bGH, GHRKO, as well as on mice transgenic for a GHR-antagonist (GHA mice) revealed an intrinsic resistance to tumor development and cancer progression due to abrogation of GHR function [2,3,86] .…”

“…A significant volume of research in vitro, in vivo, in clinical specimens and retrospective meta-analysis on human patients of GH-excess (acromegaly) and GH-resistance (LS) have established that a paracrine/ autocrine GH supports oncogenesis and drives neoplasms towards malignancy, metastasis or relapse in multiple tissues [2,3,63] . We refer our readers to a series of relevant reviews by us and colleagues in this regard, compiling the systematic comprehension of the overall and molecular details of how GHR-positive cancer cells exploit the versatile effects of GH action [2][3][4][64][65][66][67][68][69] . In relevance, the association between GH treatment and cancer incidence in GHD patients remains unclear and widely debated [70] .…”

“…On the other hand, the association between cancer risk in human patients of GH-excess/acromegaly has also been unclear. A confounding factor in this case are variations in IGF1normalizing medical interventions (surgery, GHR-inhibitors, somatostatin-analogs) the study participants underwent prior to the study [2] . However, a number of recent large-scale retrospective meta-analyses reveal a distinctly higher standardized incidence ratio for multiple cancers in these patients [52,78] .…”

Lifespan of long‐lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning

“…Mice with genetic deficiencies in somatotropic signaling, including the levels (Manini, ) and actions of growth hormone (GH) (Masternak & Bartke, ), have a major longevity advantage over genetically normal (“wild‐type”) animals (Bartke, ). Hypopituitary Ames dwarf (Prop1 df ) mice with deficiency of GH, thyroid‐stimulating hormone (TSH), and prolactin (Bartke & Brown‐Borg, ), and GH receptor knockout (GHRKO) mice with GH resistance (Zhou et al, ), are remarkably long‐lived and exhibit many features of the delayed, healthy aging, and extended longevity (Bartke & Brown‐Borg, ; Basu, Qian, & Kopchick, ). Many phenotypic characteristics shared by these mutants are believed to represent mechanisms of extended longevity.…”