Infertility affects an estimated 2.4 million couples in the United States alone. Implantation failure may compromise fertility in as many as 20% of these couples, and effects even higher percentages of women with recurrent pregnancy loss. Preliminary data suggest that integrins, a family of cell adhesion molecules, participate in endometrial structure and function. These glycoproteins are present in the membranes of cells as heterodimeric alpha and beta subunits. The temporal and spatial expression of certain integrin receptor subunits are regulated during the menstrual cycle and preliminary studies suggest that these proteins are involved in endometrial receptivity. Specifically, we believe one integrin, alphav beta3, may be involved in the initial attachment of the embryo to the endometrial epithelium. The initial goal of this proposal is to prospectively map the expression of integrins in the normal endometrium throughout the menstrual cycle using immunohistochemistry and in situ hybridization, with special attention to those subunits that change their level of expression during the endometrial cycle. Using normal cycles as controls, we will then examine the distribution of integrins in women with luteal phase deficiency (LPD), recurrent pregnancy loss, an unexplained infertility. In addition the profile of integrins in stimulated cycles (with human menopausal gonadotropins) will be explored, as such medications have been reported to contribute to inadequate luteal phase endometrium. The vitronectin receptor subunit, Beta3, is expressed on epithelial cells during mid luteal phase and binds ligands known to be present on the developing trophoblast. This integrin subunit appears to be delayed in patients with disorders of endometrial maturation. Endometrial biopsies from infertility patients with LPD will be evaluated for the presence or absence of this cycle-specific integrin. The utility of this test as an inununohistochemical assay for the diagnosis luteal phase dysfunction will be determined. A third goal will be to determine what factors regulate integrin expression in normal endometrium. We will use an in vitro cell culture model of human endometrium (normal and transformed cells) to study the action of sex steroids, growth factors and the effects of mesenchyme (paracrine effects) and extracellular matrix on integrin expression. Using a series of proteins including steroid receptors, integrins and other cell specific markers, a fourth objective will be to develop a working reconstruction of endometrium, in vitro, to study the function of integrins in endometrial cells. Functionality studies will involve co-culture experiments to study endometrial/trophoblast interaction. A model of trophoblast-endometrial interaction is proposed and potential methods are presented to test the hypothesis that integrin-integrin interaction between endometrium and embryo forms the basis for cell-specific recognition and interaction, and defines the window of implantation.

Project Start
1992-07-01
Project End
1997-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Castelbaum, A J; Ying, L; Somkuti, S G et al. (1997) Characterization of integrin expression in a well differentiated endometrial adenocarcinoma cell line (Ishikawa). J Clin Endocrinol Metab 82:136-42
Somkuti, S G; Yuan, L; Fritz, M A et al. (1997) Epidermal growth factor and sex steroids dynamically regulate a marker of endometrial receptivity in Ishikawa cells. J Clin Endocrinol Metab 82:2192-7
Lessey, B A; Ilesanmi, A O; Castelbaum, A J et al. (1996) Characterization of the functional progesterone receptor in an endometrial adenocarcinoma cell line (Ishikawa): progesterone-induced expression of the alpha1 integrin. J Steroid Biochem Mol Biol 59:31-9
Somkuti, S G; Sun, J; Yowell, C W et al. (1996) The effect of oral contraceptive pills on markers of endometrial receptivity. Fertil Steril 65:484-8
Lessey, B A; Ilesanmi, A O; Lessey, M A et al. (1996) Luminal and glandular endometrial epithelium express integrins differentially throughout the menstrual cycle: implications for implantation, contraception, and infertility. Am J Reprod Immunol 35:195-204
Lessey, B A; Albelda, S; Buck, C A et al. (1995) Distribution of integrin cell adhesion molecules in endometrial cancer. Am J Pathol 146:717-26
Castelbaum, A J; Sawin, S W; Bellardo, L J et al. (1995) Endometrial integrin expression in women exposed to diethylstilbestrol in utero. Fertil Steril 63:1217-21
Lessey, B A (1994) The use of integrins for the assessment of uterine receptivity. Fertil Steril 61:812-4
Lessey, B A; Castelbaum, A J; Sawin, S W et al. (1994) Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab 79:643-9