Urocortin (UCN) is a 40-amino acid neuropeptide sharing 45% sequence homology with corticotropin-releasing factor (CRF). The human endometrium expresses both UCN and CRF, and CRF/UCN receptors type-1 (CRF-R1) and -2 (CRF-R2). CRF-R1 activation inhibits cell growth and proliferation of a tumor cell line derived from the human endometrium, and the UCN signaling pathway has been implicated in tumorigenesis of several tissues. Therefore, we investigated whether UCN mRNA and peptide are expressed by human endometrial adenocarcinoma, and whether their expression changes compared to controls. Samples of well (grade 1; n = 6 endometrioid adenocarcinoma, of whom n = 1 with squamous differentiation, and n = 1 clear-cell carcinoma) and poorly differentiated (grade 3; n = 3 endometrioid adenocarcinoma) endometrial adenocarcinoma were collected from nine women (age range 61-79 years) enrolled at the time of diagnosis. Healthy endometrium was collected from postmenopausal women (controls; n = 13; age range 64-78 years), who underwent hysterectomy for uterine prolapse. Immunohistochemistry was used to evaluate cellular UCN localization, with the intensity of immunostaining scored on a subjective scale. Quantitative real-time reverse transcriptase (RT)-PCR analysis was used to estimate mRNA expression changes and restriction analysis was used to confirm PCR products identity. UCN mRNA expression was significantly reduced (P < 0.0001) in endometrial adenocarcinoma than in healthy controls. Immunoreactive UCN was found in luminal and glandular epithelial cells in healthy, but not in neoplastic samples. UCN mRNA and peptide expressions are decreased in endometrial adenocarcinoma. These data and the evidence that endometrial cancer expresses UCN receptors and UCN is involved in tumorigenesis of several tissues together suggest a role for UCN in endometrial tumoral cell growth and proliferation.