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Corticotropin-releasing hormone (CRH) and its receptors have been identified in female reproductive tissues. CRH regulates follicular maturation, ovulation, luteolysis and steroidgenesis. A CRH-related peptide stresscopin (SCP), or urocortin III (Ucn3), has recently been identified, but its functions in the ovary remain to be elucidated. In the present study, we investigated the effects of SCP/Ucn3 on progesterone production in cultured human granulosa-lutein cells.The presence of SCP/Ucn3 and CRH type-2 receptor (CRHR2) in cultured granulosa-lutein cells from 21 infertile women (aged 22-36 years) was examined by RT-PCR and immunocytochemistry. The concentration of SCP/Ucn3 in follicular fluid, human serum and culture medium was examined by radioimmunoassay. Progesterone production by cultured granulosa-lutein cells treated with SCP/Ucn3 was examined by enzyme-linked immunosorbent assay.SCP/Ucn3 and CRHR2 mRNAs and proteins were expressed in granulosa-lutein cells. SCP/Ucn3 was detected in culture media of granulosa-lutein cells and follicular fluid. Treatment of cultured granulosa-lutein cells with 0.1, 1.0 or 10 nM SCP/Ucn3 decreased progesterone secretion when compared with untreated control (all P0.05). Concomitant treatment with the CRHR2 antagonist antisauvagine-30 counteracted the inhibitory effects of SCP/Ucn3 on progesterone secretion, suggesting a mediatory role of CRHR2.The present results suggest that the SCP/CRHR2 system is present in human ovaries and treatment with SCP/Ucn3 inhibits progesterone production by cultured granulosa-lutein cells through interaction with CRHR2.