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Submitted on August 10, 2004
Accepted on November 19, 2004
Division of Endocrinology, and The Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore MD 21287 (M.A., R.S.); Endocrine and Polypeptide Cancer Institute, Veterans Affairs Medical Center and Tulane University School of Medicine, New Orleans, LA (A.V. S.)
* To whom correspondence should be addressed. 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 (knock out, KO) of the GHRH gene (GHRHKO) have isolated GH deficiency (GHD) and anterior pituitary hypoplasia. The weight of the GRHRKO mice is about 60% of normal mice by the 12th week of age. The phenotype is strikingly similar to the one observed in the mouse with mutated GHRH receptor (little).
It is unknown whether exposure to endogenous GHRH during the 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 different times of life: from week 2 to week 6 (2 µg twice a day) and from week 12 to 16 (4 µg twice a day). Normal littermates served as control. At both ages JI-38 caused growth acceleration, increase in size of the pituitary gland, increase in pituitary GH mRNA and GH protein, and in serum GH, and significant increase in liver IGF-1 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 intra-uterine development.
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