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Ghrelin Is Involved in the Decidualization of Human Endometrial Stromal Cells

Departments of Obstetrics and Gynecology and Pathology (T.Y.), Mie University School of Medicine, Mie 514-8507, Japan; Department of Molecular Genetics, Institute of Life Science, Kurume University (M.K.), Kurume, Fukuoka 839-0861, Japan; and Department of Biochemistry, National Cardiovascular Center Research Institute (K.K.), Suita, Osaka 565-8565, Japan

Address all correspondence and requests for reprints to: Hiroyuki Minoura, M.D., Ph.D., Department of Obstetrics and Gynecology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan. E-mail: hminoura{at}clin.medic.mie-u.ac.jp.

Successful implantation involves a complex interaction between the endometrium and the embryo. It is well known that several neuropeptides are expressed in the endometrium and placenta during embryonal implantation, suggesting an important role as chemical mediators of the feto-maternal relationship. Ghrelin has recently been identified as the endogenous ligand for the GH secretagogue receptor. Ghrelin is a peptide hormone with many physiological functions, and its expression in the human placenta has been reported. To investigate the involvement of ghrelin in embryonal implantation, we assessed the spatio-temporal expression pattern of ghrelin and its receptor in the human endometrium and placenta through the normal menstrual cycle and in early pregnancy. We also examined the effect of ghrelin on the decidualization of endometrial stromal cells (ESC). Weak expression of ghrelin mRNA was detected in the nonpregnant endometrium, and it was dramatically increased in the decidualized endometrium. A GH secretagogue receptor mRNA was detected in the endometrium throughout the normal menstrual cycle and in early pregnancy, but not in the first trimester placenta. Immunohistochemical analysis using an antighrelin antibody revealed strong signals in decidual cells and extravillous trophoblast cells. Coculture with first trimester placenta up-regulated ghrelin mRNA expression by primary cultured ESC, although sex steroids and 8-bromo-cAMP had no effect. In addition, ghrelin enhanced the decidualization of ESC induced by 8-bromo-cAMP (8-Br-cAMP) in vitro. Thus, ghrelin is a novel paracrine/autocrine factor that is involved in cross-talk between the endometrium and embryo during embryonal implantation.

Abbreviations: 8-Br-cAMP, 8-Bromo-cAMP; ESC, endometrial stromal cells; EVT, extravillous trophoblast; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GHS-R, GH secretagogue receptor; IR, implantation rate.

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