Pituitary GH secretion is regulated by hypothalamic hormones and peripheral factors. Cell-cell contact may also have an important role in regulating pituitary hormone expression and secretion. The role of pituicyte cell-cell contact mediated by N-cadherin and neural cell adhesion molecule (N-CAM) was studied in the regulation of GH secretion. RT-PCR showed N-cadherin mRNA expression in eight of 12 of GH-secreting adenomas compared with one of seven of prolactin-cell adenomas. N-cadherin and N-CAM were similarly expressed in adenomas and in adult and fetal normal pituitary tissues. The effects of CAM homophilic binding on GH secretion from dispersed human fetal pituitary cultures were studied by manipulating CAM mediated cell-cell contact using either soluble N-cadherin-Fc or pituitary cells cocultured with NIH-3T3 cells stably expressing CAMs. CAM stimulation increased GH secretion from pituitary fetal cultures by 40-60% (P < 0.05) and also from cultured GH adenoma cells by 40-75% (P < 0.05). Disrupting N-cadherin homophilic binding by anti-N-cadherin antibody decreased fetal, but not tumorous GH secretion by 40% (P < 0.05). This study indicates that pituitary cell-cell contact mediated by homophilic interactions between adhesion molecules regulates human GH secretion.