Effects of growth hormone overexpression and growth hormone resistance on neuroendocrine and reproductive functions in transgenic and knock-out mice

Transgenic mice overexpressing growth hormone (GH) exhibit alterations in t he function of the hypothalamic-pituitary-gonadal (HPG) axis and the H-P-ad renal axis. Alterations in the turnover of hypothalamic neurotransmitters, in plasma hormone levels, and in regulation of their release are associated with reproductive deficits, particularly in females. Results reported afte r publication of our minireview on this subject provided evidence that GH-t ransgenic mice have increased binding of GH to GH binding proteins in plasm a, are hyperinsulinemic and insulin resistant, and have major alterations i n energy budgets with increased allocation to growth. Reduced life span and fertility of these animals may be related to insufficient allocation of en ergy to reproduction and maintenance. Growth hormone resistance induced by transgenic expression of an antagonistic bGH analog or by targeted disrupti on (knock-out, KO) of the GH receptor (GH-R) gene leads to dramatic suppres sion of plasma levels of insulin-like growth factor-1 (IGF-I), and dwarf ph enotype due to reduced growth and increased adiposity, In both models of GH resistance, there are marked reproductive deficits in females, decline of breeding performance of males, and alterations in the function of the HPG a xis. In GH-R-KO females, puberty is delayed, and litter size is reduced. Fe tal weights are reduced whereas placental weights are increased, and the we ight of newborn pups is reduced despite an increase in the length of gestat ion. In GH-R-KO males, copulatory behavior and fertility are reduced, plasm a PRL is elevated, and responses to lutenizing hormone releasing hormone (L HRH) in vivo and to LH in vitro are suppressed. However, reproductive defic its in GH-R-KO mice are very mild when compared to those described previous ly in IGF-KO animals. Apparently, the amounts of IGF-1 that may be produced locally in the absence of GH stimulation are sufficient for sexual maturat ion and fertility in both sexes, whereas quantitative deficits in reproduct ive function reflect absence of GH-dependent IGF-1 production and other con sequences of eliminating GH signaling. The reproduction phenotype of the GH -R-KO mice is also mild when compared to dwarf mice that lack GH, prolactin (PRL), and thyroid stimulating hormone (TSH). This is presumably related t o the presence of redundant mechanisms in the stimulatory control of the go nads by the pituitary and the ability of animals capable of producing PRL a nd TSH to compensate partially for the absence of GH signaling.