Ghrelin affects the release of luteolytic and luteotropic factors in human luteal cells

Context: Ghrelin, well-known modulator of food intake and energy balance, is a rather ubiquitous peptide involved in several endocrine and nonendocrine actions. A possible as-yet-unknown role for ghrelin in modulating luteal function has been suggested because both ghrelin and its receptor (GRLN-R) have been immunohistochemically detected in human corpus luteum. Objective: We first investigated GRLN-R mRNA expression in midluteal phase human luteal cells. Ghrelin effect on basal and human chorionic gonadotropin (hCG)-stimulated progesterone (P) release was then analyzed. Finally, we investigated whether ghrelin could affect luteal release of vascular endothelial growth factor (VEGF), prostaglandin (PG) E-2, both luteotropic factors, and PGF(2 alpha), luteolytic modulator. Ghrelin effect on both basal and hypoxia-stimulated VEGF luteal expression was analyzed. Methods: Human luteal cells were incubated for 24 h with ghrelin (10(-13) to 10(-7) M) or hCG (100 ng/ml) or CoCl2 (10 mu M), chemical hypoxia, or with hCG or CoCl2 in combination with ghrelin. Both GRLN-R mRNA and VEGF mRNA were evaluated by real-time RT-PCR. PGs and P release was assayed by RIA, whereas VEGF release by ELISA. Results: GRLN-R mRNA expression was demonstrated in human luteal cells. Both basal and hCG-stimulated P release was significantly decreased by ghrelin, which was able to reduce PGE(2) and increase PGF(2 alpha) luteal release. Both basal and hypoxia-stimulated VEGF release was significantly decreased by ghrelin, which did not affect VEGF mRNA luteal expression. Conclusions: The present in vitro study provides the first evidence of a direct inhibitory influence of ghrelin on human luteal function.