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.
Adenohypophysial morphology in 12 mice transgenic for methallothionein-I-human (h) GH fusion gene was investigated by immunocytochemistry and electron microscopy. The sustained oversecretion of hGH stimulated body growth. The pituitary glands of 6-month-old transgenic mice were significantly decreased in weight and showed marked morphological changes in somatotrophs, lactotrophs, corticotrophs, and gonadotrophs. GH-immunoreactive cells were greatly reduced in size and midly decreased in number; by electron microscopy, the organelles implicated in hormone synthesis were inconspicuous in this cell type. Transgenic males were hypoprolactinemic, presumably due to lactogenic activity of hGH in rodents. Their pituitaries displayed few and slender PRL-immunoreactive cells; ultrastructurally, they belonged to immature (type II) lactotrophs. However, in females, PRL-containing cells showed no change in number, size, or distribution compared to controls. Prior biochemical studies demonstrated high blood levels of LH in males. Their pituitaries contained highly active gonadotrophs resembling gonadectomy cells, consistent with the view that these changes are related to PRL-like activity of hGH in mice. In both sexes, stimulated corticotrophs were present. The results indicate that some changes in adenohypophysial cells of mice transgenic for hGH can be attributed to protracted overproduction of the heterologous GH, whereas others can be explained by lactotrophic activity of hGH in mice. The divergent morphological responses of lactotrophs and gonadotrophs in the two sexes may reflect differences in the hormonal regulatory mechanisms between male and female mice.
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