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Division of Endocrinology and Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine (M.A., R.S.), Baltimore, Maryland 21287; and Endocrine and Polypeptide Cancer Institute, Veterans Affairs Medical Center and Tulane University School of Medicine (A.V.S.), New Orleans, Louisiana 70112
Address all correspondence and requests for reprints to: Dr. Roberto Salvatori, Division of Endocrinology, The Johns Hopkins University School of Medicine, 1830 East Monument Street #333, Baltimore, Maryland 21287. E-mail: salvator{at}jhmi.edu.
The proliferation of pituitary somatotroph cells and the synthesis and secretion of GH require the hypothalamic peptide GH-releasing hormone (GHRH). Accordingly, we have shown that mice with targeted disruption [knockout (KO)] of the GHRH gene (GHRHKO) have isolated GH deficiency (GHD) and anterior pituitary hypoplasia. The weight of GRHRKO mice is about 60% that of normal mice by 12 wk of age. The phenotype is strikingly similar to that observed in the mouse with mutated GHRH receptor (little). It is not known whether exposure to endogenous GHRH during intrauterine growth is necessary for postnatal GH secretion, and whether GHD due to congenital lack of GHRH activity would be reversible by treatment with GHRH during the postnatal period. To answer this question, we treated GHRHKO mice with a long-acting superactive GHRH analog (JI-38) at two ages: from wk 2–6 (2 µg, twice a day) and from wk 12–16 (4 µg, twice a day). Normal littermates served as controls. At both ages JI-38 caused growth acceleration, increase in size of the pituitary gland, increase in pituitary GH mRNA and GH protein levels and serum GH, and significant increase in liver IGF-I mRNA, although none of these parameters was fully normalized. Our findings demonstrate that GHD and pituitary hypoplasia in GHRHKO mice may be partially reversed by long-term treatment with a GHRH analog, and that somatotroph cells maintain responsiveness to GHRH even if this factor is absent during intrauterine development.
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