**1. Introduction**

382 Endometriosis - Basic Concepts and Current Research Trends

Pezzone, M. A., R. Liang, et al. (2005). "A model of neural cross-talk and irritation in the

Zimmermann, M. (2001). "Pathobiology of neuropathic pain." Eur J Pharmacol 429(1-3): 23-

Gastroenterology 128(7): 1953-1964.

37.

pelvis: implications for the overlap of chronic pelvic pain disorders."

Investigation of one complex pathological condition is definitively a challenging task, but trying to find the connection(s) between two is even more difficult. This is very true in the case of infertility and endometriosis. Both conditions have numerous symptoms, very diverse clinical pictures and multifactorial etiologies. The first step toward understanding the connection between the two is to prove the correlation between them. The next task is to try to understand the mechanisms by which they affect each other, which involves examination and comparison of numerous variables specific for each condition. The results are still the subject of many controversies.

#### **1.1 Endometriosis and infertility**

At present, there is little debate that endometriosis and infertility are actually associated. For example, early retrospective studies (Hasson, 1976; Drake & Grunet, 1980; Strathy et al., 1982) and one more recent prospective study (Mahmood & Templeton, 1991) performed in women who underwent laparoscopy (for various reasons) showed that endometriotic lesions were significantly more frequent in women who were treated for infertility than in those who requested laparoscopy for tubal sterilization. Prevalence of endometriosis in infertile women ranged from 21 - 48% which was in clear contrast to the prevalence of 1.3 – 5% in fertile women (Hasson, 1976; Drake & Grunet, 1980; Strathy et al., 1982). Another line of evidence of the existence of a link between endometriosis and infertility came from studies in women who underwent donor insemination because of severe male infertility. In these studies, women with endometriosis had significantly fewer conceptions per procedure than women without this condition (Hammond et al., 1986; Yeh & Seibel, 1987). In studies where peritoneal endometriosis was induced in rabbits (Schenken & Asch, 1980), primates (Schenken et al., 1984) and rodents (Vernon & Wilson 1985; Barragan et al., 1992) it was clearly demonstrated that endometriosis was strongly associated with infertility regardless of localization and/or extension of the lesions.

While it is relatively easy to document the link between the two conditions, defining precise pathophysiologic mechanisms and proving a causal relationship between endometriosis and infertility is much more difficult.

Embryo Quality and Pregnancy Outcome in Infertile Patients with Endometriosis 385

Quality of the embryo may be described using many direct and indirect measures. For example, parameters which could be used for indirect assessment of embryo quality are number of embryos on Day 2, total number of blastocysts, number of frozen blastocysts, but also the implantation rate and early pregnancy loss rate. The only direct measure of embryo quality is embryo quality score based on morphological characteristics of a developing embryo. However, this parameter is quite difficult to use in practice. One reason for this difficulty is the absence of uniformity of scoring systems used by different laboratories. Another is a consequence of two facts: (1) quality score is a categorical variable and (2) it is (still) a common practice to transfer more than one embryo (blastocyst) at a time. In other words, if two or more embryos of different qualities have been transferred, it is not possible to calculate "the mean embryo quality score" or to determine exactly which one of

Researchers who would come across this issue tried to overcome it in various ways. The simplest was to exclude from the study those patients in whom embryos with different quality scores were transferred (La Sala et al., 2005). The main drawback of this approach was a significant reduction of observed cycles, i.e. of the sample size. Also, this tactic prevented incorporation of some other important variables (namely the number of transferred embryos) in the final analysis. On the other hand, some of the authors (Lambers et al, 2007) used a cumulative embryo score, previously introduced by Steer (Steer et al., 1992). Cumulative embryo score was defined as an additive parameter (i.e. following the transfer of two embryos with scores of 1 and 3, the total score of embryos transferred was 4). Other investigators (Winter et al., 2002) assessed embryo quality with relation to the number of embryos transferred and the possibility of elective transfer. According to this system, embryos were scored 1 in the case of an elective transfer of one or two embryos (highest score); elective transfer of 3 embryos yielded a score of 2; if two or three embryos had been transferred non-electively, the score was 3, and if only a single embryo was transferred non-

In our research, we adopted yet another approach. If multiple embryos of different quality were transferred, we assumed that (1) implanting embryo was the best quality embryo (the so-called leading embryo) and (2) the leading embryo determined embryo quality score of the entire group of transferred embryos. The first assumption was well documented in the literature (Hourvitz et al., 2006) and the second one was additionally

Despite the fact that important hypothesis blames defective early embryo development for poorer IVF-ET outcome in patients with endometriosis, relatively few studies have analyzed the association between quality of transferred embryo(s) and endometriosis. We will briefly

A group of Spanish investigators conducted three separate retrospective analyses of the success of their IVF-ET and oocyte donation program in patients and donors with and

**2.2 Relevant studies encompassing the measures of embryo quality** 

**2.1 Measures of embryo quality** 

transferred embryos has eventually implanted.

electively, it was scored 4 (worst score).

present several important studies on the subject.

tested in our sample.

In severe cases of endometriosis, the seriously distorted anatomy of pelvic organs is the obvious cause of impaired fertility. In the absence of pelvic adhesions and scarring, when only mild to moderate endometriotic lesions are present, finding the cause and the consequence is anything but an easy task. Many confounding factors make these studies both controversial and difficult to interpret. One of the main problems is the choice of the appropriate control group. The common practice has been to choose women with tubal factor infertility or those with unexplained infertility as controls. The problem with this choice is our inability to identify women with inherently reduced potential for conception (fertilization and implantation) and to exclude them from the control group. Also, the common practice is to make observations on the patients with endometriosis who are treated by one of the techniques of assisted reproductive technologies (ART). This practice is problematic because the use of ART creates a non-physiologic environment and many subtle but important *in vivo* effects of endometriosis on the process of conception may be hidden in *in vitro* conditions.

Hypotheses on mechanisms by which mild to moderate endometriosis could impair fertility potential are numerous and will be mentioned here only briefly. One group of investigators tested hypotheses that endocrine abnormalities in women with mild and moderate endometriosis might be the cause of reduced fertility. As was already conveniently summarized in the literature (Garrido et al., 2000; Hunter et al., 2004), proposed mechanisms were hypersecretion of prolactin in patients with endometriosis (Muse et al., 1982), impaired folliculogenesis (Tummon et al., 1988), altered ovulation (Dmowski et al., 1986) and luteal phase defects (Grant, 1966). The other line of investigation was directed towards immune dysfunctions as potential causes of infertility in patients with endometriosis. Proposed mechanisms were chronic inflammatory reaction and altered immune responses induced by endometriosis (Harada et al., 2001), including increased production of cytokines and other soluble immunomodulators in the peritoneal fluid. These altered immune responses could further affect motility and velocity of the sperm, lead to sperm phagocytosis (Soldati et al., 1989), accelerate ovum transport (Croxato et al., 1978), impair the process of fertilization (Mahadevan et al., 1983), display direct embryo toxicity (Damewood et al., 1990) or adversely affect the process of implantation (Yovich et al., 1985; Matson & Yovich, 1986). Unfortunately, results of these studies were usually contradicting and no definitive conclusion could be made so far. It is likely that there is more than one answer to this complex problem.
