Endometrium in Improving IVF Outcomes: Assessing its Behavior and Making an Ally from an Enemy

Siristatidis Charalampos1*, Vogiatzi Paraskevi1, Varytimiadi Angeliki1, Vrantza Tereza1, Zoe Iliodromiti2, Vrachnis Nikos2, Karatrasoglou Eleni3 and Chrelias Charalampos4 1Assisted Reproduction Unit, Department of Obstetrics and Gynaecology, University of Athens, Rimini-1, Chaidari-12642, Athens, Greece 2Department of Obstetrics and Gynaecology, University of Athens, Aretaieion Hospital, Athens, Greece 3Obstetric Gynecological Department, General-Maternity District Hospital “Helena-Venizelou”, Athens, Greece 4Department of Obstetrics and Gynaecology, University of Athens, Rimini 1, Chaidari, 12642, Athens, Greece

Specialized systems and protocols have been implemented in an effort to assist subfertile couples and this has led to the meticulous investigation of the factors affecting fertility at a macroscopical, microscopical and molecular level in order to establish the synergistic conditions that lead to successful reproduction. On this basis, the endometrium plays a crucial role in reproduction, as the tissue lining of the uterus is responsible for nurturing the developing embryo, but importantly and prior to implantation, it is the endometrial state, which is decisive of the fate of the early embryo. This state has been for a long time the subject of diagnostic and therapeutic interventions in the hope that through these, assisted reproduction specialists could improve the pregnancy rates. The current notion suggests that the inability of an embryo to implant is related to the asynchronous changes among itself and the endometrium.
The success of embryo implantation depends on the quality of the embryo, the endometrial receptivity and the synchronization between endometrial changes and embryonic development [1]. The endometrium is in a receptive state when it is capable to accept and support the embryo. Ovarian hormones control its preparation, and various protocols have been suggested [2]. Successful implantation occurs in a definite setting; a functional blastocyst "meets" a receptive endometrium and a synchronized "dialogue" between maternal and embryonic tissues begins [3,4]. The timing of this dialogue, referred as the "window of implantation", is characterized by significant changes at circulatory and tissue level, as well as in cellular and molecular level, with notable changes in steroid receptors and integrin expression [5][6][7].
During controlled ovarian hyperstimulation for IVF, the high E2 levels seem to cause differences in the development and receptivity of the endometrium, and they are considered to negatively affect the outcomes [8,9]. In contrast, other reports do not accept that receptivity is affected [10], whereas others have declined the endometrial receptivity to act as an ovarian stimulation biomarker: in this context, the study by Shapiro et al. [11] demonstrated equal probability of clinical pregnancy between fresh and frozen thawed embryos. Further confusion in the literature has been added when Richter et al. [12] reported reduced success rates in fresh transfers of later developing blastocyst, emphasizing that is the asynchrony of the developing embryo with endometrial receptivity and not the poor embryo quality that results in low IVF outcomes. Moreover, GnRH analogs have been considered as positively affecting the endometrial receptivity when compared to GnRH antagonists [13], but their comparison has yielded similar live birth rates in IVF cycles [14].
The current most simple way of monitoring a receptive endometrium is transvaginal ultrasonography and examination of the endometrial thickness, morphology and blood flow status (especially end-diastolic blood flow) [15,16]. The ideal range of all these parameters for implantation has been a matter of debate, when they were to be related to pregnancy outcomes on their own [3,[17][18][19][20][21]. Their combination though has been reported to be the most effective mean for evaluation of uterine receptivity [22], but still, their value remains unclear when coming to prediction of IVF outcomes. Hysteroscopy performed before an IVF cycle might be of essence, when surgically removing lesions altering the normal uterine cavity is the target. Intrauterine biopsy offers the opportunity to investigate the intrauterine microenvironment through the analysis of molecular factors that influence endometrial receptivity, but has the disadvantage of causing harm to a super-sensitive area, aiming to endorse a new organism that carries a foreign half-DNA.
To improve this, various pharmaceutical and interventional approaches have been implicated. The administration of periimplantation glucocorticoids in IVF cycles did not manage to significantly improve the clinical outcome, while insufficient evidence exists for the subgroups of women with autoantibodies, unexplained infertility or recurrent implantation failure [23]. Similarly, when the use of heparin was studied analyzing data from randomized trials, no improvement in clinical pregnancy and live birth rates was found [24]. In contrast the use of "mild" protocols for ovarian stimulation in IVF [25], and the mechanical damage of the endometrium prior to the IVF cycle [26] seem to improve the outcome parameters, both suggesting promising alternatives to conventional protocols and attitudes in IVF.
The hypothesis that individual factors (intrinsic properties of the endometrium) significantly affect endometrial growth [27], came to probability, but phenomenally, it gives an alibi to our inability to understand the underlying mechanisms and pathophysiology and to treat them. Most probably, the complexity of the transition into a receptive uterus, including various biochemical and molecular changes in the endometrium together with the modulated expression of different cytokines, growth factors, transcription factors and prostaglandins and hormone receptors [2], is a key area that has not yet elucidated.
In this article, we would express the urgent need of a better understanding of the underlying mechanisms that drive endometrial receptivity during the luteal phase, proliferation and thickness of the epithelium, the cellular modifications with respect to receptor regulation and expression, as well as signaling and communication patterns that occur at molecular level. That would add to our knowledge of how this complex system responds in hormonal alternation and fluctuation, how receptivity is defined in this framework, and what are the intrinsic factors that we could be allowed to experiment with in order to restore receptivity in non-responsive cases and cases with repeated implantation failures, as well as on how to preserve implantation and physiological embryo development. The prospective candidates range from pinopodes as potential markers of receptivity, progesterone responsiveness and integrin function, adhesion molecules with particular interest to RIF-associated mRNAs inflammatory and immunologically mediated byproducts [3,28].

Reproductive System and Sexual Disorders: Current Research
In conclusion, we still do not know fully the why and how, so we are not able to discover the way to improve it. Or isn't it so?
At the moment we could quote the suggestions of Revel [3], where endometrial biopsy samples, or samples obtained through secretions of the uterus, were proposed that could be used to identify molecules associated with uterine receptivity to obtain a better insight into human implantation. We would add that therapeutically, anatomical malformations should be treated by hysteroscopy, local injure prior to an IVF cycle [29] should be performed, while addition of various molecules to culture media, such as GC-CSF and gene therapy have the potential to constitute the future solutions. Finally, careful selection of patients to apply protocols and individualization of treatment strategies still constitute the cornerstone of success when improvement of IVF outcomes is the target.