**1. Introduction**

324 Endometriosis - Basic Concepts and Current Research Trends

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#### **1.1 Implantation failure in endometriosis**

The process of implantation is an interactive cascade of events between the embryo and the endometrium. It is a dynamic process consisting of three distinct phases. They are (i) apposition of embryo (ii) attachment with the epithelial lining of the endometrium and (iii) invasion into the endometrial stroma gaining access to the maternal circulatory system. Embryo implantation failure may occur due to embryonic defect or unsupportive endometrium. Advances in Assisted Reproductive Technology (ART) have made it possible to obtain good quality embryos; however, successful implantation remains the bottleneck for a successful pregnancy. The endometrium remodels before attaining a state of receptivity. Endometrium remains receptive during a limited period, when it is favourable for blastocyst attachment and implantation. In women, there is clinical evidence of a brief period of optimal uterine receptivity which allows for blastocyst implantation. This period, called the implantation window, is related to changes in the endometrial epithelial morphology. Inappropriate morphological development leads to unreceptive endometrium that causes defective endometrial /embryonic cross talk. This is generally agreed to be one of the main reasons for implantation failure. Endometriosis, characterized by benign growth of endometrial tissue outside the uterus, affects approximately 20%–48% of women during their reproductive years. The occurrence of aberrant hormonal, immunological, genetic and pathophysiological events associated with endometriosis is attributed to the heterogeneous etiology of the disease. The symptoms of endometriosis do not depend on the severity or stage of the disease. Women with even mildest degree of endometriosis can have a 3 – 4 fold reduction in their annual birth rate compared to normal non-endometriotic women.

Presence of endometriosis alters the characteristic of the endometrium. It also affects the expression of various factors and markers of receptivity during implantation window. All these result in dysfunctional endometrium. This can be a cause of higher implantation failure rates and lower pregnancy rates in endometriotic women due to failure of embryo implantation. However, alterations in endometrial remodeling in endometriosis resulting in impairment of the endometrial receptivity is still poorly understood. An understanding of endometrial receptivity in women with endometriosis is, therefore, crucial in understanding the fundamental causes of implantation failure which in turn, may have significant implications on fertility potential of these women.

Alteration in Endometrial Remodeling: A Cause for Implantation Failure in Endometriosis? 327

over the human reproductive cycle, VEGF is present in the stromal and glandular epithelium of the human endometrium throughout all phases of the menstrual cycle (Torry and Torry 1997, Smith 1998, Shifren et al., 1996, Charnock-Jones 1993, Popovici 1999, Lockwood 2002). However there exists a strong debate regarding its expression and angiogenesis. VEGF expression increased in the late secretory phase and heightened during menses (Torry and Torry 1997, Charnock-Jones 1993, Popovici 1999, Lockwood 2002, Bausero 1998). There is a marked increase even in the vascular network of the endometrium during the secretory phase over the proliferative phase (Ota 1998). But Nayak and Brenner reported that during proliferative phase there is a noted increase in the VEGF expression in stroma which shifts to glandular epithelium during the secretory phase (Nayak and Brenner 2002). However, contradictory report exist indicating that a gradual decline in angiogenesis occurs at the end of the cycle which rapidly increases with the start of a new cycle and reaching a maximum height during the mid cycle (Au and Rogers 1993). Other investigators have suggested that VEGF expression remains inconsistent (Sugino et al., 2002) or there is no change in the vascularity throughout the endometrial cycle (Rogers and Au 1993).

It is suggested that inappropriate regulation of sex steroids may lead to defect in implantation. The role of estradiol in embryo implantation is a subject of controversy and its association with pregnancy outcome in IVF cycle is an area of research for many years (Kyrou et al 2009). Several studies have shown that midluteal decline of serum estradiol do not affect the endometrial development, embryo implantation and IVF outcome (Friedler et al., 2005; Narvekar et al., 2010; Hung et al., 2000). This may be due to the fact that during follicular phase, estradiol induces growth of follicles, preparation of endometrium and production of specific proteins, growth factors and receptors of estrogen and progesterone. Additionally, adverse effect of high estradiol level on endometrial receptivity is still under debate (Kyrou et al., 2009). A number of investigators found no effect of high estradiol levels on the treatment outcome of IVF/ICSI cycle (Sharara and McClamrock 1999, Kosmas et al., 2004). Some studies have, however, suggested that elevated levels of estradiol may be responsible for impaired endometrial receptivity (Simon et al., 1995; Valbuena et al., 2001; Kyrou et al., 2009). After ovulation, progesterone is the main contributory sex hormone

executing the transformation of the endometrium during the secretory phase.

endometrial receptivity in women with endometriosis.

**2.4 Endometrial receptivity markers** 

It is evidenced that expression of cyclooxygenase-2 (COX-2), a molecule associated with angiogenesis and cell differentiation, promotes the release of MMP-2 (Xiong et al., 2005) and -9 (Itatsu et al., 2009), and angiogenic factor VEGF (Wang *et al.* (2010). COX-2, on the other hand, is regulated by female sexual hormone estradiol and progesterone (Li et al., 2007). Since the process of angiogenesis during endometrial remodelling shares similarities with the process of angiogenesis during metastasis in cancer, estradiol may also be involved in the up-regulation of the gene expression of COX-2 and MMPs during embryo implantation. Involvement of COX-2 gene in embryo implantation is a subject of interest among the researchers working on endometrial receptivity, and is suggested to play an important regulatory role in successful implantation. However, little is known about its role in

Inadequate uterine receptivity and poor embryo formation are two major factors responsible for implantation failure (Simon et al., 1998; Ledee-Bataille et al., 2002). Nowadays, using

**2.3 Regulation of matrix remodeling** 
