Adenohypophysial Changes in Mice Transgenic for Human Growth Hormone-Releasing Factor: A Histological, Immunocytochemical, and Electron Microscopic Investigation*

Abstract

The effect of protracted GH-releasing factor (GRF) stimulation on adenohypophysial morphology was investigated in six mice transgenic for human GRF (hGRF). All animals had significantly higher plasma levels of GH and GRF and greater body weights than controls. Eight-month-old mice were killed, and the markedly enlarged pituitaries were studied by histology, immunocytochemistry, electron microscopy, and immunogold method, using double labeling at ultrastructural level. In all pituitaries, a massive hyperplasia, chiefly of mammosomatotrophs, was found. These bihormonal cells, containing GH and PRL, were demonstrated by light microscopy and ultrastructural immunocytochemistry. Electron microscopy revealed the presence of cells with characteristics of GH cells in three pituitaries and cells resembling human adenomatous mammosomatotrophs in the other three glands. All of these cells, regardless of their ultrastructural features, contained secretory granules heavily labeled for GH by immunogold technique; PRL labeling varied from cell to cell, with the predominance of a weak immunostaining and was colocalized with GH in secretory granules. These results indicate that chronic exposure to GRF excess leads to mammosomatotroph hyperplasia. It is suggested that GH cells proliferate and transform to mammosomatotrophs in response to GRF stimulation. Focal PRL cell hyperplasia noted in three pituitaries could also be due to a GRF effect. Longer exposure to GRF is needed to clarify whether GRF can cause adenoma.

Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation

“…It would seem that in our patient altered responsiveness only affected the somatotrope but not the lactotrope in view of the stimulated prolactin secretion. Increased prolactin secretion has also been found in other states of endogenous GHRH excess, such as ectopic GHRH-secreting tumors (unpublished data) and hGHRH-transgenic mice (40).…”

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

“…An important role for GHRH in post-embryonic growth is suggested by clinical studies of tumors that secrete GHRH (Frohman and Szabo, 1981;Thorner et al, 1982;Frohman and Jansson, 1986), and by animal studies using transgenic mice that overexpress GHRH (Hammer et al, 1985;Stefaneanu et al, 1989). In both settings, growth hormone hypersecretion, pituitary somatotroph cell hyperplasia, and inappropriate patterns of growth (acromegaly or gigantism) are observed.…”

Pathophysiology and clinical aspects of the ectopic GH‐releasing hormone syndrome

“…In fact, it has been demonstrated that normal subjects show a rise in PRL after the intravenous administration of larger doses (600 mg) of GHRH (Sassolas et al, 1984). Furthermore, mice transgenic for hGHRH have an increased number of lactotrophs and mammosomatotrophs (Stefaneanu et al, 1989).…”