Leptin is a circulating hormone secreted by adipose and a few other tissues. The leptin receptor consists of a single transmembrane-spanning polypeptide that is present as a long physiologically important form as well as in several short isoforms. Recent studies have suggested that the anterior pituitary may have a role in the regulatory effects of leptin in animal models. To test this possibility in human pituitaries, we examined the expression of leptin and OB-R in normal and neoplastic pituitaries, and the possible functions of leptin in the pituitary were also analyzed. Leptin was present in 20-25% of anterior pituitary cells and was expressed in most normal anterior pituitary cells, including ACTH (70% of ACTH cells), GH (21%), FSH (33%), LH (29%), TSH (32%), and folliculo-stellate cells (64%), but was colocalized with very few PRL cells (3%), as detected by double labeling immunohistochemistry with two different antileptin antibodies. In addition, leptin expression was detected by RT-PCR in some pituitary tumors, including ACTH (three of four), GH (one of four), null cells (two of four), and gonadotroph (one of four) tumors as well as in normal pituitary. Immunohistochemical staining showed greater immunoreactivity for leptin in normal pituitaries compared to adenomas. Treatment of an immortalized cultured anterior pituitary cell line, HP75, with leptin stimulated pancreastatin secretion in vitro. Leptin also inhibited cell growth in the human HP75 and in the rat pituitary GH3 cell lines. Both long (OB-Rb) and common (OB-Ra) forms of the leptin receptor messenger ribonucleic acid and leptin receptor protein were expressed in normal and neoplastic anterior pituitary cells. These findings show for the first time that leptin is expressed by most human anterior pituitary cell types and that there is decreased leptin protein immunoreactivity in pituitary adenomas compared to that in normal pituitary tissues. We also show that OB-Rb is widely expressed by normal and neoplastic anterior pituitary cells, implicating an autocrine/paracrine loop in the production and regulation of leptin in the pituitary.