Role of Endometriosis in Infertility and Embryonic Loss: More than Anatomical Reasons

in an inappropriate milieu for sperm, oocytes, embryo development and uterine receptivity [5]. This milieu is characterized by a high concentration of inflammatory cytokines, oxidative stress products and reactive oxygen species (ROS). These substances affect spermatozoa membrane, leading to an impaired sperm function or rupture, including abnormal sperm- endosalpinx and sperm-oocyte interaction, low number of free spermatozoa in tubal ampulla, and loss of sperm fertilization potential. Women with endometriosis also have six-times more nuclear and cytoplasmic aberrations than other women and have been associated with disease severity [6]. These aberrations include polymorphisms, dysregulated micro-RNAs and epigenetic factors. Such factors are able to induce DNA hypomethylation with subsequent alteration of endometrial receptivity mediators and implantation failure [7]. Defects in blastocyst implantation could result due to altered hormonal levels, embryo anomalies orprogesterone-target genes dysregulation [7]. The last leads to a local progesterone resistance and to an inhospitable environment, which in turn impairs blastocyst implantation. This environment is characterized by a decreased or absent expression of implantation and regulators markers of endometrial receptivity, such as integrins, glycodelin A, leukemia inhibitory factor, osteopontin and lysophosphatidic acid receptor. Although hormone and inflammatory marker levels, and uterine cavity anatomy can easily be studied, there is insufficient evidence to recommend an appropriate assessment of endometrial receptivity. Some studies report that progesterone supplementation and endometrial biopsy may improve endometrial receptivity and pregnancy rates, especially in IVF-embryo transfer cycles [8]. However, the analysis of published evidence is difficult given the quality of the studies and the diversity of proposed treatments, especially those involving assisted- reproductive techniques. Progesterone administration for luteal phase support in embryo transfer protocols is effective when given on the day or the day- after oocyte pick-up (OR 1.87; 95% CI 1.13 to 3.08). On the other hand, increased endometrial implantation competency after endometrial biopsy are based on endometrial wound healing mechanisms, including secretion of cytokines and growth factors accompanied of stem cells recruitment, which are free of epigeneticdefects, favoring embryo implantation. Treatments with not conclusive efficacy are systemic administration of heparin, aspirin, prednisone, immunoglobulins or recombinant follicle-stimulant hormones. Future therapies involving immunomodulators or hormonal suppressive therapies could be useful to improve fertility and pregnancy rates [9].

As physicians and gynecologists, the better we understand the underlying causes of infertility, failure of uterine receptivity and impaired embryonic implantation associated to endometriosis, the more appropriate and secured therapies we can provide, although many of these pathophysiological mechanisms are right now not influenceable. Therefore more research is needed to design specific therapies capable of modulating the changeable ones, to improve fertility rates, and to reduce embryonic loss rates, especially when we are facing patients undergoing assisted-reproductive treatments.

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