Characterization of egfl7 expression during endometrial preparation to implantation and its implications in infertility conditions

Implantation of the embryo into the endometrium is one of the most critical events in human reproduction. The establishment of pregnancy is limited to a specific period of the menstrual cycle called the “window of implantation” (WOI) and requires a perfect and complex crosstalk between a competent blastocyst and a receptive endometrium. The complex network of signalling involved in implantation is one of the major limiting steps in mammalian reproduction. Alterations of these signalling pathways may determine pathological conditions leading to infertility (Massimiani et al., 2019). Implantation efficiency in humans is estimated to be only 30% per cycle (Kim and Kim, 2017; Wilcox et al., 1988), one in every six couples is subfertile, and 25% of these conditions are classified as unexplained infertility (Su and Fazleabas, 2015). Infertility is a health issue that affects males and females worldwide and it may be a consequence of several factors including male problems, female dysfunctions or embryo quality. About 20–35% of infertility cases is due to female problems and may derive from an heterogeneity of causes such as age, anatomical and immunological problems, and several pathological conditions including ovulation disorders (premature ovarian failure, polycystic ovary syndrome, hyperprolactinemia, poor egg quality, thyroid problems) and endometrium or fallopian tube problems (pelvic or cervix surgery, endometriosis, submucosal fibroids, cancer) (Abrao et al., 2013; Mekinian et al., 2016; Ticconi et al., 2019). Many of these pathological conditions may lead to implantation failure, a common cause of impaired fertility (Larsen et al., 2013). The term “implantation failure” refers to conditions in which the blastocyst is not able to implant in the maternal endometrium after both spontaneous and in vitro fertilization (IVF) (Bashiri et al., 2018; Massimiani et al., 2019). Many couples undergo to assisted reproductive technology (ART) to conceive and give birth to a live and healthy baby. ART includes medical procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes or embryos and offers treatments for several infertility conditions. Although over the last decades ART has greatly improved the rate of live births, implantation failure remains a substantial problem to overcome, considering that only around 25% of transferred blastocysts will successfully implant (Edwards, 2006). The condition when implantation failure occurs after the transfer of three or more good quality embryos is defined recurrent implantation failure (RIF) (Coughlan et al., 2014; Bashiri et al., 2018; Ochoa-Bernal and Fazleabas, 2020). Besides the 4 defects that might occur during the initial phases of embryo development, other pathological conditions may affect pregnancy success at later stages, leading to recurrent pregnancy loss (RPL). RPL is defined as the loss of 2 or more consecutive clinical pregnancies prior to 20/ 24 weeks of gestation, according to ASRM and ESHRE, respectively (Bashiri et al., 2018). Up to 5% of women experience two consecutive miscarriages and in only 50% of RPL specific causes are identified (Rai and Regan, 2006; Branch et al., 2010; Strug et al., 2018). For example, dysregulated immune functions with high levels of cytotoxic cytokines, such as IFN-γ, infections, genetic, endocrine and anatomic factors may contribute to RPL. (Ford and Schust, 2009; Comba et al., 2015; Liang et al., 2015; Strug et al., 2018). For those reasons, understanding the underlying problems, which may lead to RPL or RIF, remains an issue to be explored