Implantation biology is one of the most important yet least understood women's health issues. Failure of the human embryo to implant or faulty implantation resulting in subsequent pregnancy loss is a major clinical problem in human reproductive biology. One of 9 couples in the United States is involuntarily childless and it is estimated that only 1/3 of potentially fertile cycles result in a child with approximately 30% of embryos never reaching the stage of uterine implantation ad another 30% which implant but are morphologically abnormal and non-viable. More recently, sensitive assays for human chorionic gonadotropin (hCG) have documented that 22% of all pregnancies detected by hCG assay fail to survive long enough to be clinically recognized. Thus, the incidence of clinically unrecognized implantation failure is high. In addition, spontaneous abortion rates are 15-25% for clinically diagnosed pregnancies. Recently, several immunologic etiologies for pregnancy wastage and habitual abortion have been proposed but little is actually known about the possible immunologic pathogenesis of pregnancy wastage. In this proposal, we will investigate the hypothesis that the IL-1 system --IL - 1beta, its receptor antagonist -- are critical in the process of human implantation. Our first goal is to study the regulation of IL-1 receptor type I (IL-1R tI) in human endometrial stromal and glandular cell cultures. These studies will examine the ability of IL-1beta and other cytokines and growth factors to modulate and upregulate protein and RNA expression of endometrial IL-IR tI. In addition, the ability of growth factors and cytokines secreted by the human embryo to modulate endometrial IL-IR tI levels will be assessed using human embryo-conditioned media. The second goal will examine the ability of IL-1beta to modulate the plasminogen activator system as an important mechanism of endometrial response permitting embryonic invasion and implantation. The third goal of this study is to examine the endometrial localization and in vitro regulation of both IL-1 receptor antagonist (IL- 1ra) mRNA and protein in human endometrial glandular and stromal cell cultures and the ability of IL-1ra to ablate upregulation of the IL-1 receptor by IL-Ibeta and other growth factors. The fourth goal is to study the in vivo effect of Il-1ra on implantation by examining its ability to interfere with implantation and pregnancy when injected into PMSG/hCG stimulated and mated mice. Our hypothesis is that appropriate activation and upregulation of the IL-1 receptor by IL-1beta and by other embryonically generated cytokines is critical to successful human embryo implantation. A corollary is that IL- 1ra is capable of interfering with successful implantation. Elucidation of the cytokine mediated relationship between the embryo and endometrium during early implantation is critical to the understanding of the clinically important entities of infertility related to implantation failure and habitual abortion; such knowledge will broaden our understanding of the events of early implantation and has potential clinical application in syndromes of pregnancy wastage.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Reproductive Endocrinology Study Section (REN)
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Stanford University
Obstetrics & Gynecology
Schools of Medicine
United States
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Huang, Hong-Yuan; Raga, Francisco; Wen, Yan et al. (2003) Interleukin-1beta regulation of gonadotropin-releasing hormone messenger ribonucleic acid in cultured human endometrial stromal cells. Fertil Steril 79:399-406
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Krussel, J S; Casan, E M; Raga, F et al. (1999) Expression of mRNA for vascular endothelial growth factor transmembraneous receptors Flt1 and KDR, and the soluble receptor sflt in cycling human endometrium. Mol Hum Reprod 5:452-8
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