Endometriosis and subfertility

Introduction

The lining of a woman’s uterus is made up of endometrial tissue that sheds in each menstrual cycle. In endometriosis, similar tissue develops on abnormal anatomical locations such as in the pelvis or abdominal cavity. This mislaid tissue shows a similar response to the hormonal changes of each cycle and sheds blood causing inflammation, swelling, and scarring. The discomfitures of endometriosis include dysmenorrhea, dyspareunia, chronic pelvic pain, irregular uterine bleeding, and/or subfertility based on the premise that the fecundity rate of women with endometriosis who have not been treated for it is lower, i.e., 2%–10%, as compared to the non-subfertile couples, which ranges from 15% to 20% per month.

Theories on pathophysiology of endometriosis

The pathologic process of endometriosis and a theory that explains this process are still poorly understood and remain controversial. Regarding the origin of endometriosis and its pathogenesis, several theories based on observations can be categorized into the implants that initiate from the uterus and those that arise from areas outside the uterus. A number of concepts and pathologic mechanisms are suggested ( Fig. 8.1 ) : implantation theory, metaplasia theory, induction theory, epigenetic theory, stem cell-based theory, and perineural theory.

Pathogenesis of endometriosis

While the debate of uterine or nonuterine origin of the disease is on, a number of factors and genetic susceptibilities have been identified to support the cause and effect mechanism of endometriosis such as endocrine-disrupting chemicals and endogenous/exogenous estrogens influencing endocrine, immune, stem/progenitor cells, epigenetic modifications ( Fig. 8.2 ).

Association between endometriosis and subfertility

Association between subfertility with minimal and mild endometriosis (stage I/II) is frequently seen in cases of unexplained infertility. Nevertheless, the impact of such lesions on fecundity is quite debatable. The literature suggests that although these lesions impair ovarian reserve, luteal function, and fertilization rate, the outcome is not affected in infertile females undergoing assisted reproductive technology (ART) treatment. On the other hand, the association between moderate and severe endometriosis (stage III/IV) seems more plausible, because of the presence of distorted uterine tubes and ovaries leading to blockage of embryos and gametes reaching the uterine cavity. Furthermore, there is an alteration in the structural tissue of seemingly normal ovarian cortex leading to reduced ovarian reserve. This could be as a result of complex interplay between various mechanisms including compromise in the vascular and nerve supply of whole ovarian complex, fibrosis changing the mechanical force and hence stimulating signaling pathways in follicular cells, and endometriotic cells themselves producing altered levels of substances, which can trigger granulosa cell activation and premature follicular development. Nevertheless, as a paradox, ovarian reserve evaluated by antral follicle count is not affected following surgical management of ovarian endometrioma, while it is reduced when evaluated by serum anti-Mullerian hormone (AMH), leading to uncertainties ( Fig. 8.3 ).

The endometrial factor can itself be a confounder or has interaction between the complex interplay of endometriosis and subfertility. The eutopic endometrium in women with endometriosis is different than others. Structural and ultrastructural analysis of endometrium suggests a proliferative phase defect among women with endometriosis leading to low endometrial plateau thickness and a heterogeneous response to endometriosis. Endometrial nerve fibers have been documented in women with endometriosis along with their presence in the myometrium, which may play a significant role in pain generation and pelvic adhesion formation. Increased concentrations of complement components have been reported, and dysregulation of these gene products could cause impaired implantation. On the one hand, endometrial receptivity and pregnancy rates are not reduced in oocyte donation recipients affected by endometriosis, while on the other, ovarian suppression with the use of a gonadotropin-releasing hormone (GnRH) agonist or oral contraceptive before the application of an ART significantly improved implantation rates leading to further uncertainties.

Issue of causality

“Endometriosis causes subfertility”—the establishment of this causal relationship requires the understanding of the type of association between these two, presence of temporal relationship, dose–response gradient, whether the association makes sense, and the effect of removal of cause. Evidence from experiments in animals suggests the presence of relationship, while data from experiments in humans are not available. The strength of the association in humans comes mainly from retrospective data, suggesting a greater prevalence of endometriosis in infertile females as compared to the fertile ones. There is moderate comparability of groups and outcomes for endometriosis and subfertility, and there is consistent association for endometriosis vs no endometriosis in terms of increase in prevalence, decrease in spontaneous conception, decrease in reproductive outcome of intrauterine insemination (IUI), and decrease in outcome of ART. The temporal relationship between endometriosis and subfertility has been shown in a large cohort study in which longitudinal prospective data were collected. Despite limitations of classification systems for endometriosis, a dose–response gradient cannot be disregarded as indicated in a systematic review and meta-analysis. Furthermore, epidemiological and biological data also make sense as reviewed in the synthesis literature. Lastly, the removal of endometriosis as the cause has shown that the spontaneous pregnancy rates were better after laparoscopic surgery as compared to expectant management.