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Independent Regulation of Matrix Metalloproteinase-9, Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), and TIMP-3 in Human Endometrial Stromal Cells by Gonadotropin-Releasing Hormone: Implications in Early Human Implantation¹

Department of Gynecology and Obstetrics, Reproductive Immunology Laboratory, Stanford University School of Medicine (F.R., E.M.C., Y.W., H.-Y.H., M.L.P.), Stanford, California 94305; the Department of Gynecology and Obstetrics, Valencia University School of Medicine and Center for Gynecology and Obstetrics (F.R., E.M.C., F.B.-M.), Valencia, Spain; and the Department of Gynecology and Obstetrics, Lin-Kou Medical Center, Chang Gung Memorial Hospital (H.-Y.H.), Taipei, Taiwan

Address all correspondence and requests for reprints to: Francisco Raga, M.D., Center for Gynecology and Obstetrics. Pedro Aleixandre 57–7, 46006 Valencia, Spain. E-mail: cegiob{at}interbook.net

Early human trophoblast shows dramatic invasive properties during early pregnancy. The simultaneous synthesis of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) in both human trophoblast and decidual membranes suggests that their controlled and balanced expression is crucial for the rapid matrix remodeling and controlled invasion during early pregnancy.

Recently, we have described the presence of an extrahypothalamic GnRH immunologically, biologically and chemically identical to the hypothalamic hormone in periimplantation human embryos. Moreover, the production of this decapeptide by the human trophoblast during the early stages of placentation is well documented.

TIMP-1 and -3 messenger ribonucleic acid (mRNA) expression in cultured stromal cells and protein secretion into the medium were significantly decreased by GnRH agonist compared to that in control groups. Moreover, expression of TIMP-1 was affected to a greater extent than that of TIMP-3. GnRH antagonist ablated the down-regulation of TIMPs by the GnRH agonist. MMP-9 mRNA expression was not detected in the control groups or in the groups treated with GnRH analogs.

Our results provide evidence that trophoblastic GnRH may play an important role in placental tissue organization and in the early embryo-maternal dialogue by enhancing trophoblast invasion through the specific inhibition of TIMPs.

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