The long term goal of our research is to unravel root and proximal mechanisms by which endometriosis decreases fecundity in women. Evidence supports an association between endometriosis and reduced fecundity. Tragically, a cause and effect relationship has not been established, hence effective treatments for infertility in women with endometriosis are woefully lacking. Our overall hypothesis is that endometriosis causes reduced fecundity. The rationale for our hypothesis is based on clinical observations and published evidence supporting an association between endometriosis and reduced fecundity. As studies of fertility are ethically limited in women, we have used an established endometriosis animal model to begin to understand how endometriosis reduces fecundity. We have reported that endometriotic lesions de novo synthesize and secrete tissue inhibitor of metalloproteinase-1 (TIMP-1) and that two-fold more endometriotic TIMP-1 localizes in the ovarian follicular theca in endometriosis (Endo) rats compared to Sham rats. As it is known that TIMP-1 highly regulates matrix metalloproteinase enzymes (MMPs) critical for follicular development, ovulation and embryo development, we propose endometriotic TIMP-1 is blocking ovarian MMPs required for follicular development and ovulation. Others have shown that TIMP-1 inhibition of MMPs, both in vivo and in vitro, causes embryo growth retardation and reduction in embryo survival. Our newest and most exciting preliminary data shows Sham rat embryos develop endometriosis-like anomalies by addition of TIMP-1 to culture media or by intra-abdominal injection of TIMP-1. Collectively, these data are compatible with the notion that endometriosis causes ovarian, oocyte and embryo anomalies and that endometriotic TIMP-1 may be part of the mechanism causing them. Two hypothesis-driven Specific Aims have been designed and will be performed with this established model of endometriosis in the rat and validated by comparison to data from human ovaries, oocytes and embryos.
Specific Aim 1 : Endometriotic lesions diminish follicular development and impede ovulation via a TIMP-1 modulated mechanism thereby reducing fecundity.
Specific Aim 2 : Endometriotic lesion TIMP-1 causes specific anomalies in oocyte quality and embryo development contributing to reduced fecundity in endometriosis. Determining the specific phenotype of reduced fecundity in endometriosis is the first step towards understanding mechanisms whereby endometriosis exerts its pathological effects, novel, targeted approaches for restoration of fertility may be developed. Such approaches are paramount to shift from surgical or chemical obliteration of lesions or repeated attempts at IVF. Using an endometriosis model which emulates human disease and comparing the data to that from women will facilitate mechanistic studies to determine how endometriosis reduces fecundity and provide an avenue to test the safety and efficacy of novel therapeutic approaches for endometriosis, and a rapid translation of data into knowledge of human endometriosis. 7. PROJECT NARRITAVE Evidence supports an association between endometriosis and reduced fecundity yet a cause and effect relationship has not been established, hence effective treatments for infertility in women with endometriosis are woefully lacking. We hypothesize that endometriosis reduces fecundity via its ability to synthesize and secrete TIMP-1. As it is known that TIMP-1 highly regulates MMPs critical for follicular development, ovulation and embryo development, we propose endometriotic TIMP-1 is blocking MMPs required for normal function and reducing fecundity.
|Birt, Julie A; Nabli, Henda; Stilley, Julie A et al. (2013) Elevated peritoneal fluid TNF-* incites ovarian early growth response factor 1 expression and downstream protease mediators: a correlation with ovulatory dysfunction in endometriosis. Reprod Sci 20:514-23|
|Birt, Julie A; Taylor, Kristen H; Davis, J Wade et al. (2013) Developmental exposure of fetal ovaries and fetal germ cells to endometriosis in an endometriosis model causes differential gene expression in the preimplantation embryos of the first-generation and second-generation embryos. Fertil Steril 100:1436-43|
|Stilley, Julie A W; Birt, Julie A; Nagel, Susan C et al. (2010) Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development. Biol Reprod 83:185-94|
|Stilley, Julie A W; Woods-Marshall, Renita; Sutovsky, Miriam et al. (2009) Reduced fecundity in female rats with surgically induced endometriosis and in their daughters: a potential role for tissue inhibitors of metalloproteinase 1. Biol Reprod 80:649-56|