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Notes: We recently reported that galanin gene expression is markedly increased in the hyperplastic anterior pituitary gland of the human growth hormone-releasing hormone (hGHRH) transgenic mouse. To determine if another pituitary peptide hormone with putative growth-promoting activity is similarly affected, or if this effect is specific to the peptide galanin, we examined vasoactive intestinal polypeptide (VIP) gene expression in the hypothalamic-pituitary axis of male hGHRH transgenic and non-transgenic mice. The objectives were to: 1) assess VIP peptide concentrations, 2) estimate relative differences in VIP mRNA levels, 3) determine the effects of acute treatment with 17(3-estradiol on VIP peptide and mRNA levels, and 4) quantify the density of immunoreactive VIP pituitary cells by immunohistochemistry. Four to five month old male hGHRH transgenic mice and their non-transgenic siblings were identified by PCR. Immunoreactive VIP concentrations were decreased by 50% in the anterior pituitary glands of hGHRH transgenic mice as compared to non-transgenic siblings. In contrast, no differences in immunoreactive VIP concentrations were observed in the hypothalamus or frontal cerebral cortex of transgenic and non-transgenic mice. Treatment with 17β-estradiol significantly increased VIP concentrations in the anterior pituitary gland of both transgenic and non-transgenic mice; however, VIP peptide concentrations in the anterior pituitary glands of hGHRH transgenic mice remained 50% lower. Relative differences in VIP mRNA levels were estimated by RT-PCR, and were found to be 2.5-fold higher in the anterior pituitary glands of non-transgenic mice. In contrast, no differences in VIP mRNA levels in the cerebral cortex were detected between transgenic and non-transgenic mice. Treatment with 17(3-estradiol increased VIP mRNA levels in the anterior pituitary, but not in the cerebral cortex. In concert with the changes in VIP peptide and mRNA, the density of immunoreactive VIP pituitary cells was decreased approximately 50% in hGHRH transgenic mice. In conclusion, unlike galanin gene expression, VIP peptide and mRNA levels are significantly decreased in the anterior pituitary gland of hGHRH transgenic mice. Moreover, these changes appear to be tissue-specific and are likely due, in part, to the decrease in the density of VIP-containing pituitary cells in the hyperplastic pituitary. Although the pituitary cell type(s) synthesizing VIP remains unclear, these data suggest that VIP in the anterior pituitary is not stimulating pituitary tumor development in hGHRH transgenic mice.