In search for the new polypeptides responsible for energy homeostasis which are also involved in regulating the growth and function of the human prostate, we assessed the expression of orexins (OXs) and of orexin receptors (OXRs) in human normal prostate and in benign prostatic hyperplasia (BPH). Conventional RT-PCR revealed the expression of OXR2 in all studied samples obtained either from normal prostates or BPH ones while neither preproorexin (ppOX)nor OXR1 mRNA were detected. In adenomatous prostates, expression levels of OXR2 were 30- to 40-fold higher compared to controls. Western blot analysis demonstrated the presence of OXR2 protein in the studied samples and its expression levels were 4-fold higher in tissue samples from BPH. In normal glands, presence of OXR2-like immunoreactivity was found in the apical parts of epithelial cells as well as in smooth muscle cells of the stroma. Immunostaining for OXR2 was more intense in sections obtained from BPH. Immunohistochemistry did not detect the expression of OXR1-like protein. OXA serum concentrations were lowered in BPH patients (mean ± SE 56±4 ng/ml, n=12; P<0.01) and unaltered in prostate cancer (79±7 ng/ml, n=18) compared to the controls (69±2 ng/ml, n=16). On the contrary, serum OXB levels were similar in all studied groups of patients. We thus have demonstrated the mRNA and protein expression of OXR2, but not of ppOX and OXR1 in both normal and BPH human prostate glands. We also demonstrated notable up-regulation of OXR2 in benign prostatic hyperplasia, an alteration accompanied by lowered serum OXA concentrations. These findings suggest that both OXA and OXR2 may be involved in the pathogenesis and/or maintenance of BPH.