title: Effects of an Antagonistic Analog of Growth Hormone-Releasing Hormone on Endometriosis in a Mouse Model and In Vitro.
abstract: Endometriosis is a benign gynecologic disorder causing dysmenorrhea, pelvic pain, and subfertility. Receptors for the growth hormone-releasing hormone (GHRH) were found in endometriotic tissues. Antagonists of GHRH have been used to inhibit the growth of endometriotic endometrial stromal cells. In this study, the GHRH receptor splice variant (SV) 1 was detected in human endometrial tissue samples by Western blots and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The highest messenger RNA (mRNA) and protein levels of SV1 were found in eutopic endometrium from patients with endometriosis compared to ectopic endometriotic tissues and endometrium from normal patients. The highest expression for GHRH mRNA was found by qRT-PCR in ectopic endometriosis lesions. In an in vivo mouse model with human endometrial explants from patients with endometriosis, 10 μg MIA-602 per day resulted in significantly smaller human endometrial xenotransplants after 4 weeks compared to mice treated with vehicle. The endometrial tissues expressed SV1 before and after xenotransplantation. The proliferation of endometrial stromal cells as well as the endometriosis cell lines 12-Z and 49-Z was decreased by exposure to 1 μM MIA-602 after 72 hours. The protein levels of epithelial growth factor receptors in 12-Z and 49-Z cell lines were reduced 48 and 72 hours after the administration of 1 μM MIA-602. MIA-602 decreased the activation of the MAP-kinases ERK-1/2. Our study demonstrates the presence of SV1 receptor as a target for treatment with GHRH antagonist in endometriosis. Endometrial tissues respond to MIA-602 with inhibition of proliferation in vitro and in vivo. The use of MIA-602 could be an effective supplement to the treatment strategies in endometriosis.
authors.affiliation: 1 Department of Gynecology and Obstetrics, University of Lübeck, Lübeck, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Köster
authors.affiliation: 2 Department of Gynecology and Obstetrics, The International Peace Maternity & Child Health Hospital of China Welfare Institute, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: 3 Department of Gynecology and Obstetrics, The Women's Hospital, School of Medicine, Zhejiang University, Zhejiang Province, People's Republic of China.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Shen
authors.affiliation: 4 Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA.|5 Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA.|6 Divisions of Hematology/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: 4 Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA.|5 Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA.|6 Divisions of Hematology/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Ren-Zhi
authors.initials: RZ
authors.lastname: Cai
authors.affiliation: 4 Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA.|5 Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA.|6 Divisions of Hematology/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: 7 Department of Gynecology and Obstetrics, Diakonissenkrankenhaus Karlsruhe Rüppurr, Karlsruhe, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hornung
authors.affiliation: 1 Department of Gynecology and Obstetrics, University of Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Marschner
authors.affiliation: 1 Department of Gynecology and Obstetrics, University of Lübeck, Lübeck, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Rody
authors.affiliation: 8 Department of Gynecology and Obstetrics, Krankenhaus Nordwest, Frankfurt am Main, Germany.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
authors.affiliation: 9 Department of Gynecology and Obstetrics, Evangelic Hospital Bielefeld, Bielefeld, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Finas
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D017337:Sermorelin / Q000031:analogs & derivatives; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: C550121:GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone
keywords: EGFR; ERK 1/2; Mus musculus; endometriosis; growth hormone-releasing hormone