17.1.1 Infertility and Endometriosis

Almost 50% of adolescents with intractable dysmenorrhea or pelvic pain are diagnosed with endometriosis, but it is not yet clear why only certain women develop the condition.

The monthly fecundity rate in normal couples of reproductive age is known to be 15–20%, whereas the rate in infertile women with endometriosis ranges from 2 to 10% [8].

A meta-analysis proposed that the chance of achieving pregnancy was lower for patients with endometriosis compared to those with tubal factor infertility (OR 0.56; 95% CI, 0.44–0.70) [9].

However, the association between infertility and early-stage disease, from minimal endometriosis [stage I] and mild endometriosis [stage II], according to the ASRM score (Fig. 17.3), in which no substantial pelvic anatomical changes are identified, remains controversial [10].

The improvement of Controlled Ovarian Hyperstimulation (COH) with GnRH-a downregulation and the application of ICSI technology may suppress some negative influences of endometriosis on pregnancy [11, 12].

Dong et al. investigated the impact of endometriosis on the IVF/ICSI outcomes, comparing ovarian stimulation parameters and IVF/ICSI outcomes. Patients with stage I-II and stage III-IV endometriosis required higher dosage and longer duration of gonadotropins, but had lower day 3 high-quality embryos rate, when compared to patients with tubal infertility. In addition, the number of oocytes retrieved, the number of obtained embryos, the number of day 3 high-quality embryos, serum E2 level on the day of hCG, and fertilization rate were lower in patients with stage III-IV endometriosis than those in tubal factors group. Except reduced implantation rate in stage III-IV endometriosis group, no differences were found in other pregnancy parameters. This study concluded that IVF/ICSI yielded similar pregnancy outcomes in patients with different stages of endometriosis and patients with tubal infertility [13].

Barbosa et al. evaluated whether the presence or severity of endometriosis affects the outcome of ART in a systematic review, investigating all studies comparing the outcome of ART in women with and those without endometriosis, or at different stages of the disease. Women with endometriosis undergoing ART have practically the same chance of achieving clinical pregnancy and live birth as do women with other causes of infertility. No relevant difference was observed in the chance of achieving clinical pregnancy and live birth following ART when comparing stage-III/IV with stage-I/II endometriosis [14].

In a recent review, Tanbo and Fedorcsak affirmed that medical or hormonal treatment alone has little or no effect and should only be used in conjunction with ART. Of the various methods of ART, intrauterine insemination, due to its simplicity, can be recommended in women with minimal or mild peritoneal endometriosis, even though insemination may yield a lower success rate than in women without endometriosis. IVF is an effective treatment option in less-advanced disease stages, and the success rates are similar to the results in other causes of infertility. However, women with more advanced stages of endometriosis have lower success rates with IVF [15].

How endometriosis affect infertility? The most widely accepted theory, which was developed by Sampson, holds that that endometrial tissue refluxed to the fallopian tubes fails to be cleared and attaches to the peritoneum. Some 70% of women who menstruate regularly exhibit bleeding reflux, but only 10% develop endometriosis [16] (Figs. 17.4, 17.5, and 17.6).

Recently, it has been suggested that abnormal immune function and dysregulation of immune mediators are responsible for the poor response to treatment, and poor clearance, of ectopic endometrium. Immune status is now considered to play an important role in the initiation and progression of endometriosis. Several studies have shown that the levels of activated macrophages, T cells, B cells, and inflammatory cytokines are increased in women with endometriosis [17, 18].

Reductions in NK cell cytotoxic function have been observed in the peritoneal fluid (PF) of patients with endometriosis implying that a defect in NK cell cytotoxic function, preventing elimination of endometrial cells from ectopic sites, may cause endometriosis [19, 20].

17.1.2 Endometriosis-Related Infertility

Endometriosis may contribute to infertility by impairing ovarian and tubal function and reducing uterine receptivity (Fig. 17.6); in fact, 35–50% of women with infertility have endometriosis [10], and about 30–50% of patients with endometriosis have impaired fertility [21].

Endometriosis is also associated with a reduced rate of pregnancy after IVF, which may be due to the poor qualities of oocytes and embryos [22].

Despite the advances in the research of endometriosis role in infertility, there are still no clearly defined treatment protocols. Low pregnancy rates after IVF are observed in patients with endometriosis, compared to those with tubal factor of infertility. The detrimental impact, if any, of endometriosis on IVF outcome would be expected to be on embryo “quality” and/or endometrial receptivity [23].

Analyzing retrospective studies on in vitro fertilization (IVF) and oocyte donation programs showed that women with endometriosis have significantly reduced pregnancy rates per cycle and per transfer as well as reduced implantation rates. Moreover, studies reported that healthy ovum donation to patients with endometriosis produces the same rate of implantation and pregnancy compared to controls [23].

Retrospective and prospective clinical trials on IVF success rate have shown decreased oocyte and embryo quality and low ovarian reserves in women with endometriosis compared to controls [24].

Nevertheless, human studies indicate poor oocyte and embryo quality and lower pregnancy rates in women with endometriosis, addressing the problem on pro-inflammatory cytokines and chemokines that negatively interact with the oocyte and embryo, with damage to the oocyte and embryo [25].

In fact, intrafollicular levels of IL-8, IL-12, and adrenomedullin are elevated in women with endometriosis undergoing IVF and are indicators of impaired embryo and oocyte quality [26].

Poor oocyte quality was observed and measured, in retrospective IVF studies, by diminished blastomere cleavage rates, increased numbers of arrested embryos, and impaired cytosolic events [27].

In addition, reports also suggest that other etiological factors, such as in utero exposure to diethylstilbestrol, environmental exposure to endocrine disrupting agents, low birth weight, and dietary choices may play significant roles in the development of endometriosis [28].

Outcomes of in vitro fertilization cycles in women with endometriosis are significantly worse than in patients without this condition. The impact of endometriosis on ovarian reserve and the quality of retrieved oocytes seems evident. Lower implantation rates, however, raise the question whether this finding is purely the consequence of lower number and poorer quality of embryos, or whether it also reflects compromised endometrial receptivity [29].

Accumulating evidence indicates that endometriosis is associated with aberrant transcriptional profiles in the eutopic endometrium of women and baboons resulting in dysregulation of critical signaling pathways [30].

Endometriosis is known to be associated with several deregulated molecules related to the pathogenesis of the disease, such as cyclooxygenase-2 (COX-2) and aromatase. The COX-2 enzyme, encoded by the PTGS2 gene (prostaglandin–endoperoxide synthase 2), is naturally induced by aromatase and is involved in the conversion of arachidonic acid into prostaglandins, which, in turn, regulate aromatase levels in endometriotic tissue [31].

In the endometrial tissue of patients with endometriosis, aberrant aromatase is induced via cyclooxygenase-2 prostaglandin-2 (COX-2–PGE2) pathway deregulation, with a positive feedback cycle. It is also related to proliferative and inflammatory properties of ectopic implants [32].

The PTGS2 gene, which encodes cyclooxygenase 2 (COX-2), is deregulated in endometriotic lesions and plays a crucial role in the acquisition of oocyte competence [33].

17.1.3 Peritoneal Fluid of Patient with Endometriosis

Endometrial fragments refluxed during menstruation induce inflammation within the peritoneal cavity [34].

Normally, neutrophils and macrophages are among the first immune cells (Fig. 17.7) to be recruited to this area and, both, are primary contributors to the elevations in pro-inflammatory and chemotactic cytokine levels found in the peritoneal fluid (PF) [35].

In addition to encouraging the growth of peritoneal implants, macrophages are a major source of angiogenic mediators, including TNF-𝛼 and IL-8 [36].

Endometriosis also involves significant disarray in the production and metabolism of nitric oxide (NO), a ubiquitous free radical in the oocyte microenvironment that plays a vital role in virtually every step of oocyte development, including meiotic maturation, fertilization, embryonic cleavage, and implantation [37].

Authors demonstrated a significant role of NO in delaying oocyte aging and maintaining the integrity of the spindle apparatus.

Decreased bioavailability of NO under certain pathologic conditions could therefore result in abnormalities in oocyte viability and developmental capacity [38].

Further, sperm, travelling through the uterus and fallopian tubes, also interact with inflammatory cytokines in the PF and similarly encounter damage.

Moreover, endometriosis is linked to the Natural Killer (NK) cells dysfunction; NK cells comprise 15% of all circulating lymphocytes, particularly those of the innate immune system, and protect against tumor development and viral infections.

Most studies have found that the numbers of cytotoxic NK cells are functionally defective and reduced in the PF and peripheral blood of patients with endometriosis and that this is accompanied by an overall decrease in NK cell activity [16] (Fig. 17.8).

In such patients, the populations of NK cells (CD32CD56+) are significantly decreased, whereas the proportions of immature NK cells (CD272CD11b2) among CD32CD56+ NK cells are increased in the PF. Functional impairment and diminished cytotoxicity of NK cells within the peritoneal cavity have also been well documented in such patients [39].

In addition, the levels of the inflammatory cytokines IL-6, IL-8, IL-1b, IFN-𝛾, and TNF-𝛼 increase in the PF of patients with endometriosis, which is consistent with the elevated levels noted in the serum [16].

Inflammatory cytokines including TNF-α and oxidative stress has been shown to directly hinder sperm motility [25, 26].

Similarly, murine embryos incubated in the PF from women with endometriosis have shown diminished growth rates of embryos, increased rates of apoptosis, DNA fragmentation, and increased number of embryos arrested in development [40].

Dexamethasone reduced the observed embryotoxic effect of the PF from women with endometriosis-associated infertility. Dexamethasone is a glucocorticoid that has been shown to reduce the expression of prostaglandins and other inflammatory mediators dysregulated in endometriosis [41].

Additionally, inhibiting TNF-α reduces embryotoxic effect on mouse embryos incubated with PF from infertile women with endometriosis [42].

Collectively, these studies link inflammation in the PF, specifically TNF-α, with embryo toxicity. Studying the toxicity of PF from women with endometriosis is limited by ethical constraints as interfering with human embryos violates moral and ethical considerations. However, this murine model provides a convincing argument to suggest the PF from women with endometriosis produces a damaging effect on the embryo [40].

17.1.4 The Oocyte Quality

Patients with endometriosis continue to pose difficulties in achieving pregnancy. Studies have shown lower implantation rates in non-endometriotic patients who received oocytes from women with endometriosis, whereas healthy donated oocytes have proven to contribute to a pregnancy with similar chances in women without the disease. The question still to be answered is whether this situation applies for natural cycles or whether it is the use of gonadotropin-releasing hormone analogs and hormonal replacement therapy used for endometrial priming in oocyte recipients that reestablishes an adequate uterine environment [29].

Endometriosis, especially at the ovarian site has been shown to have a detrimental impact on ovarian physiology. Indeed, sonographic and histologic data tend to support the idea that ovarian follicles of patients with endometriosis are decreased in number and more atretic. Moreover, the local intrafollicular environment of patients affected is characterized by alterations of the granulosa cell compartment including reduced P450 aromatase expression and increased intracellular reactive oxygen species generation [24].

Assessment of oocyte morphology is obligatory for the evaluation of oocyte quality and it has been known that quality of the oocyte has an impact on the fertilization outcomes [43].

Oocyte quality is determined by its morphological, cellular, and molecular evaluations [44].

Advances in reproductive medicine have made clear that one of the most important factors determining the outcome of embryo development is oocyte quality [45].

Many prognostic factors based on morphological characteristics of the oocyte have been devised that may allow prediction of oocyte quality, fertilization rates, and embryo development.

However, currently available techniques are not very reliable in predicting which metaphase II (MII) oocyte will lead to an embryo which will implant and result in a clinical pregnancy [46] (Fig. 17.9).

One way indirectly to assess oocyte quality is to analyze markers in cumulus cells (CCs). During follicular development, the granulosa cells differ in the mural population, limiting the follicular antrum and in the CC population, which surrounds the oocyte. Mural cells are responsible for estrogen production and rupture of the follicle, whereas CCs are intimately associated with oocyte development. CCs are regulated, in part, by factors derived from the oocyte, while contributing to oocyte maturation and development potential.

In this context, some studies have suggested that the analysis of gene expression in CCs can be used as an indirect predictor of oocyte quality and outcomes of assisted reproduction technologies, with possible clinical applications [23].

Traditionally, poor oocyte quality has been held responsible for poor ART outcome in women with endometriosis.

Barnhart et al. observed lower number of oocytes retrieved and lower fertilization rates in oocytes recovered from women with endometriosis as compared to controls of tubal factor infertility but other authors have reported conflicting results [9].

Other researches have found no difference in folliculogenesis or the number of oocytes retrieved in patients with endometriosis, as compared to other etiologies such as tubal factor infertility [47, 48].

Adverse influence on the oocyte is therefore a likely central aspect in endometriosis-related infertility. This concept is strengthened by a study reporting significant improvement in the pregnancy rate in patients with endometriosis who received donated oocytes compared with their own oocytes. Conversely, the pregnancy rates were lower in subjects without endometriosis who received donor oocytes from subjects with endometriosis [49–51].

Moreover, a recent meta-analysis on IVF outcomes in endometriosis indicates that live birth rates were not altered in patients with minimal/mild endometriosis, whereas patients with moderate and severe endometriosis patients had poorer outcomes including lower retrieved oocytes, implantation rates, and birth rates [52].

When retrieved oocyte number is considered as ovarian response to controlled ovarian stimulation (COS) and as a success parameter, data in the literature are more conflicting.

The acquisition of oocyte competence is known to depend on adequate cytoplasmic and nuclear maturation, the latter being dependent on the presence of a normal spindle. The meiotic spindle of human oocytes in metaphase II, a temporary and dynamic structure composed of microtubules, is associated with the oocyte cortex and its subcortical microfilaments network and is essential to ensure the fidelity of chromosome segregation during meiosis. The meiotic spindle, however, is extremely sensitive to the action of various factors such as oxidative stress, which can promote meiotic abnormalities and chromosome instability, increase apoptosis and impair the development of the preimplantation embryo [23].

17.1.5 Impact of Endometriosis on Oocyte Quality

A systematic review of the literature showed that the retrieved oocytes from women affected by endometriosis are more likely to fail in vitro maturation and to show altered morphology and lower cytoplasmic mitochondrial content compared to women with other causes of infertility (Fig. 17.10). Results from meta-analyses addressing IVF outcomes in women affected would indicate that a reduction in the number of mature oocytes retrieved is associated with endometriosis while a reduction in fertilization rates is more likely to be associated with minimal/mild rather than with moderate/severe disease [24].

Women with endometriosis ovulate fewer oocytes than healthy women and those oocytes ovulated by women with endometriosis are both sometimes compromised, so that endometriosis negatively impacts embryo development [25].

Xu et al. examined the ultrastructure of oocytes from patients with minimal or mild endometriosis and control females undergoing IVF treatment by transmission electron microscopy (TEM) to investigate the physiological significance of oocyte quality for patients with minimal or mild endometriosis. The TEM results revealed that the oocytes from women with minimal or mild endometriosis exhibited abnormal mitochondrial structure and decreased mitochondria mass. Quantitative real-time PCR analysis revealed that the mitochondrial DNA copy number was significantly reduced in the oocytes from women with minimal or mild endometriosis compared with those of the control subjects. Their results suggested the decreased oocyte quality because of impaired mitochondrial structure and functions, probably an important factor affecting the fertility of patients with endometriosis [53].

A recent study has shown that women with endometriosis exhibit an increase in apoptosis of the cumulus cells surrounding the oocyte and apoptosis in ovarian cells is a good indicator of poor oocyte quality [54].

Death of cumulus cells probably leads to reduced oocyte quality and maturation attributable to the loss of the essential support that the cumulus cells give to the oocyte [55].

Aberrant nuclear and cytoplasmic events in embryos from women with endometriosis are six times more likely compared with women without endometriosis [56] (Fig. 17.11).

These events include cytoplasmic fragmentation, darkened cytoplasm, reduced cell numbers, and increased frequency of arrested embryos, leading to significantly fewer transferable blastocysts. Additionally, the quality of embryos that develop from patients with endometriosis has been shown to be reduced [57].

Treatment with a gonadotropin-releasing hormone agonist that temporarily causes regression of the endometriotic lesions and cessation of reproductive cyclicity helps to improve embryo quality in these patients [58].

Embryo quality and embryo implantation are also of particular concern in women with endometriosis. In a normal embryo, there are proteins called L-selectin that normally coat the trophoblast on the surface of the blastocyst. This protein is involved in binding of the embryo to the endometrium. Low levels of the enzyme involved in the synthesis of the endometrial ligand for L-selectin have been observed and is a possible etiology of decreased embryo receptivity in patients with endometriosis [59–61].

In addition, endometriosis-free patients who have oocytes donated from women with a known history of moderate to severe endometriosis have decreased implantation rates and reduced embryo quality. This decrease in implantation rate and embryo quality is in comparison with women with moderate to severe endometriosis that receive oocytes from endometriosis-free women [62].

The hormonal milieu was altered in the follicular fluid of patients with endometriosis, such as a decreased estradiol concentration [63].

A dysregulated intrafollicular hormone milieu, as well as an abnormal intrafollicular cytokine profile, might therefore be a cause of reduced fertility in endometriosis.

Table 17.1

Change in OS concentration in oocytes after retrieval in patients with endometriosis

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