Evidence for growth hormone (GH) autoregulation in pituitary somatotrophs in GH antagonist-transgenic mice and GH receptor-deficient mice

Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone; however, there has been no evidence of GH autoregulat ion on the pituitary somatotroph. To determine the effects of GH on its own regulation, we examined the pituitaries of giant transgenic mice expressin g a GH agonist (E117L), dwarf transgenic mice expressing a GH antagonist (G 119K), and dwarf mice devoid of the GH receptor/binding protein (GHR/BP). I n the E117L, transgenic mice, the number and distribution of pituitary GH-i mmunoreactive cells were unchanged from nontransgenic littermate controls; an ultrastructural examination revealed typical, densely granulated somatot rophs. In contrast, the pituitaries of the G119K mice contained both modera tely granulated somatotrophs and a sparsely granulated (SG) population with well-developed synthetic organelles and a distinct juxtanuclear globular G H-staining pattern, GHR/BP-deficient mice exhibited a marked reduction in t he intensity of cytoplasmic GH immunoreactivity; however, prominent GH stai ning in the juxtanuclear Golgi was seen. GH-immunoreactive cells were incre ased in number, and the reticulin network pattern was distorted; stains for proliferating cell nuclear antigen confirmed mild hyperplasia, Electron mi croscopy showed that the somatotrophs were hyperactive SG tells with promin ent endoplasmic reticulum membranes, large Golgi complexes, and numerous mi tochondria, These findings are consistent with synthetic and secretory hype ractivity in pituitary somatotrophs due to the reduced GH feedback regulati on, The changes are most striking in animals that are devoid of GHR/BP and less marked in animals expressing a GH antagonist; both models had reduced insulin-like growth factor-I levels, but the more dramatic change in the GH R/BP animals can be explained by abrogated GH signaling, This represents th e first evidence of direct GH feedback inhibition on pituitary somatotrophs , which may have implications for the use of GH analogs in different clinic al settings.