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Ghrelin Affects the Release of Luteolytic and Luteotropic Factors in Human Luteal Cells

Cattedra di Fisiopatologia della Riproduzione Umana (A.T., F.Min., M.O., M.F.G., F.R., F.Mic., S.M., R.A.), Istituto Scientifico Internazionale "Paolo VI" (F.T.), and Instituto di Microbiologia (M.S.), Università Cattolica del Sacro Cuore, 00168 Roma, Italy; and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) "Associazione Oasi Maria SS.-Onlus" (S.C., A.L.), 94018 Troina (EN), Italy

Address all correspondence and requests for reprints to: Rosanna Apa, M.D., Cattedra di Fisiopatologia della Riproduzione Umana, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Roma, Italy. E-mail: krimisa{at}libero.it.

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) E₂, both luteotropic factors, and PGF₂, 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 µM), 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 PGE₂ and increase PGF₂ 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.