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Systems Biology in Reproductive Medicine

Volume 66, 2020 - Issue 2
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Review Article

The impact of hyaluronan-enriched culture medium and intrauterine infusion of human chorionic gonadotropin on clinical outcomes in blastocyst transfer cycles.

Hanna Balakier CReATe Fertility Centre, Toronto, ON, CanadaCorrespondencehanna@createivf.com
,
Iryna Kuznyetsova CReATe Fertility Centre, Toronto, ON, Canada
&
Clifford L. Librach CReATe Fertility Centre, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada; Department of Gynecology, Women’s College Hospital, Toronto, Ontario, Canada
Pages 79-88
Received 19 Nov 2019
Accepted 02 Feb 2020
Published online: 04 Mar 2020

Review Article

The impact of hyaluronan-enriched culture medium and intrauterine infusion of human chorionic gonadotropin on clinical outcomes in blastocyst transfer cycles.

ABSTRACT

ABSTRACT

Over the last few decades, advances in ovarian hormonal stimulation, embryology laboratory technologies and embryo genetic testing, have significantly enhanced clinical outcomes in human assisted reproduction technologies (ART). However, embryo implantation remains a major bottleneck in achieving better pregnancy and live birth rates. Thus, there is growing interest in establishing new approaches to enhance implantation efficiency after embryo transfer. With advanced molecular techniques, many promising biomarkers associated with embryonic and endometrial changes occurring prior to and during embryo implantation have been identified. However, despite the progress in applying novel procedures into IVF practice, clinical evaluation of those biomarkers has so far reached modest predictive value for enhancing blastocyst developmental potential and endometrial receptivity. Therefore, other simpler strategies have also been introduced to increase the rates of successful clinical pregnancies and live births. One of these approaches is to investigate the impact of using embryo transfer medium containing high concentrations of an adherence compound, such as hyaluronic acid (HA), on IVF outcomes. Additionally, intrauterine infusion of a small volume of human chorionic gonadotropin (hCG) at the time of embryo transfer (ET) has also been proposed as a technique that might be advantageous for increasing the clinical outcomes, considering the fact that hCG plays a critical role in synchronizing endometrial and fetal development. However, the current findings from both interventions remain controversial, demonstrating a mixture of positive and indifferent results of these treatments in ART cycles. Further research will be crucial for a better understanding of the molecular mechanism of cross-talk between the blastocyst and the maternal endometrium during the optimal implantation period when using either hyaluronan-enriched medium or hCG infusion before embryo transfers. Therefore, this review aims to present existing literature related to both treatments, emphasizing their effects on blastocyst implantation.

Abbreviations: ART: assisted reproduction technologies; HA: hyaluronic acid; hCG: human chorionic gonadotrophin; IVF: in vitro Fertilization; ET: embryo transfer; pH: hydrogen ions; CO2: Carbone dioxide; O2: Oxygen; PGT: pre-implantation genetic testing; FET: frozen embryo transfer; PCOS: Polycystic ovarian syndrome; DNA: deoxyribonucleic acid; miRNA: micro-ribonucleic acid; EVs: extracellular vesicles; ERA: endometrial receptivity array; CD44 and RHAMM: primary hyaluronan surface receptors; RCT: randomized clinical trials; LBR: life birth rate; CPR: clinical pregnancy rate; IR: implantation rate.

Introduction

Despite significant advances in clinical and laboratory techniques achieved in human ART, the pregnancy and live birth success rates remain relatively low and it is estimated that about 50% to 70% of lost pregnancies are mainly caused by implantation failure (Norwitz et al. 2001; Mansour et al. 2011; Kushnir et al. 2017; De Geyter et al. 2018). It is a well-known fact that implantation is not a single event, but, rather an extremely complex process that is precisely controlled at the molecular and cellular level. However, the mechanisms underlying a comprehensive understanding of the nature of embryo implantation remain to be fully explored (Zhang et al. 2013; Teh et al. 2016). Fundamentally, successful implantation depends on sequential and synchronized interactions between the embryo while it is acquiring developmental competence and the receptive uterus in a repetitive, cyclical manner (Teh et al. 2016; Salamonsen et al. 2016; Lessey and Young 2019; Kliman and Frankfurter 2019). Embryo implantation occurs at the blastocyst stage when the blastocyst first weakly opposes and then tightly adheres to the surface of the endometrial epithelium, followed by trophoblast invasion through the epithelium into the endometrial stroma (Zhang et al. 2013; Kliman and Frankfurter 2019).

It took about 30 years to understand embryo metabolism and accordingly develop more effective culture media, as well as optimize culture conditions (pH, CO2 and O2 levels, embryo scope etc.) to sustain prolonged embryo viability in vitro. These important improvements have enabled embryo transfers to be moved from cleavage stage on day 2/3 to blastocyst transfers on day 5/6 (Gardner et al. 1996, 1998; Swain 2015; Wale and Gardner 2016). Such changes in practice have improved embryo selection with higher implantation potential and allowed transfer of blastocysts into a uterine microenvironment that more closely resembles physiological events in vivo, where embryos only enter the uterus via the fallopian tubes at the morula or blastocyst stage, on day 4 post fertilization when the uterus is at a more receptive state (Gardner et al. 1996; Blake et al. 2007; Mangalraj et al. 2009; Glujovsky et al. 2016; De Carvalho et al. 2017; Kontopoulos et al. 2019). In addition, the application of blastocyst freezing using vitrification and the introduction of blastocyst pre-implantation genetic testing (PGT) have collectively contributed to improving implantation, pregnancy and live birth rates (Evans et al. 2014; Sullivan-Pyke and Dokras 2018).

Blastocyst implantation takes place only during an optimal, time-limited period of uterine receptivity, referred to as the ‘implantation window’ (Gómez et al. 2015; Teh et al. 2016; Kliman and Frankfurter 2019). The length of this implantation window varies, and it appears to be extended to 3–5 days within the secretory mid-luteal phase in most women. However, in certain gynecologic disorders, including endometriosis, tubal disease, and polycystic ovary syndrome, it can be narrowed or shifted, leading to infertility or pregnancy losses (Koot et al. 2012; Gomez et al. 2015; Teh et al. 2016; Lessey and Young 2019; Kilman et al. 2019). There is also an indication that the high, supra-physiologic hormonal levels that are created during routine ovarian stimulation protocols could alter the normal intrauterine environment causing the asynchrony in dialog between embryonic and maternal tissues, thus reducing the chance of blastocyst implantation in fresh IVF cycles (Ozgur et al. 2015; Roque 2015; Teh et al. 2016). Indeed, several studies comparing clinical results from fresh and frozen-thawed (FET) blastocyst transfers have revealed better pregnancy, implantation and possible fetal growth outcomes in the former, suggesting superior endometrial receptivity and placentation in FET cycles which may be attributed to the possibly minor hormonal intrauterine milieu disruptions (Shapiro et al. 2014; Roque 2015; Ozgur 2015). There are also contradictory reports that did not detect a difference in clinical pregnancy and live birth rates when comparing frozen-thawed and fresh blastocyst transfer procedures (Wirleitner et al. 2015; Pereira et al. 2016).

Such inconsistent results and slow progress in decreasing implantation failures, led to the general awareness that the evaluation of endometrial receptivity by standard methods like ultrasonography, endometrial histology and monitoring blood hormone levels, remain unreliable, and current efforts to clinically define the implantation window have limited utility (Craciunas et al. 2019). Therefore, new molecular techniques have recently been developed to identify specific biomarkers for both embryonic and endometrial changes occurring prior to and during the implantation window (Chan et al. 2013; Craciunas et al. 2019). Although human data is limited, a promising source of embryo-derived biomarkers has been discovered in embryo culture-conditioned medium which is in contact with the embryo for 5–6 days. However, metabolomic and proteomic analysis of the media have, thus far, reached modest predictive value for prediction of an embryo’s quality and implantation potential (Dominguez et al. 2015; Capalbo et al. 2016). It has also been found that human preimplantation embryos in prolonged in vitro culture release various nucleic acids, both DNA (Kuznyetsov et al. 2018) and microRNA (miRNA) (Rosenbluth et al. 2014; Capalbo et al. 2016) into the media that may reflect blastocyst health and were positively (miR-20a/miR-30c; Capalbo et al. 2016) or negatively (miR-661; Cuman et al. 2015) correlated with blastocyst implantation. It is thought that these miRNAs regulate endometrial receptivity. Often these potential biomarker molecules are packaged in extracellular vehicles (EVs) that facilitate their transfer and communication between the cells/tissues. EVs have been observed in human embryos from early cleavage to blastocyst stage (day3/5) when traversing the perivitelline space and zona pellucida into the surrounding culture media (Vyas et al. 2019). Interestingly, the uptake of human blastocyst-derived EVs by endometrial epithelial and stromal cells has been demonstrated recently, suggesting that EV exchange is a possible means of communication at the maternal-fetal interface during implantation (Giacomini et al. 2017).

Extensive research aiming to define biomarkers that identify the optimal implantation window in women undergoing embryo transfer after IVF is ongoing. An endometrial receptivity array (ERA) test, has been designed based on the expression of 238 selected genes, presumably involved in blastocyst implantation, which could accurately determine receptive and non-receptive endometrial status, thus potentially allowing personalized adjustment of the optimal day for blastocyst transfer (Dominguez et al. 2009; Dıaz-Gimeno et al. 2011, Dıaz-Gimeno et al. 2013; Ruiz-Alonso et al. 2013; Enciso et al. 2018). Although, several studies have reported promising results, there is still insufficient data to evaluate the clinical value of the ERA in its ability to predict successful pregnancy in good prognosis patients, patients with recurrent implantation failure, and others undergoing the ART procedures (Enciso et al. 2018; Craciunas et al. 2019). It is also evident that a number of available biomarkers are not fully reliable and predictive of endometrial receptivity and blastocyst potential, and require further validation before clinical use. Therefore, in parallel with the search for specific biomarkers, other strategies have been introduced to ART to potentially improve clinical outcomes of ETs. In this review we aimed to present data on the impact of the use of: 1) embryo transfer medium containing a high concentration of hyaluronic acid, and 2) on intrauterine infusion of human chorionic gonadotropin at the time of blastocyst transfer, on IVF clinical outcome.

The impact of hyaluronan-enriched culture medium on blastocyst transfers

A large number of studies have focused on developing different strategies for enhancing successful and effective attachment of the human embryo to the uterine wall, and one of these approaches is to investigate whether using embryo transfer medium containing a high concentration of an adherence compound, such as hyaluronic acid (HA), may increase the likelihood of embryo implantation, thereby improving pregnancy and live birth rates. Hyaluronan, a naturally existing molecule, is abundant in many tissues and fluids of mammals, including the human reproductive system, and it plays an important role in various processes; from folliculogenesis through oocyte maturation, fertilization and early embryo development to pregnancy (Friedler et al. 2007; Babayan et al. 2008; Fouladi-Nashta et al. 2017 review). It has been shown that synthesis of HA is increased dramatically on the day of implantation in mice (Gardner et al. 1999). In the human endometrium, HA undergoes cycle-dependent fluctuations in its expression levels, with two peaks, one around the mid-proliferative and one during the mid-to late secretory phase (Salamonsen et al. 2001), suggesting that HA is involved in the process of implantation. Moreover, HA promotes cell-to-cell and cell-to-matrix adhesion, suggesting it also plays a role in the initial stages of blastocyst apposition and attachment to the maternal endometrium. Thus, HA has been evaluated as a potential implantation-enhancing molecule for clinical use (Turley and Moore 1984; Gardner et al. 1999).

The actions of HA are mainly mediated through its cell surface receptors CD44 and RHAMM. The presence of CD44 has been detected in mature oocytes and throughout all embryonic preimplantation development, from early cleavage embryo to the blastocyst stage, in several animal species, such as bovine (Furnus et al. 2003), porcine (Toyokawa et al. 2005) and murine, (Wheatley et al. 1993) as well as in humans (Campbell et al. 1995). Confocal examination of human blastocysts demonstrated the presence of CD44 receptors on the surface of individual cells of both the inner cell mass and trophectoderm, and their subsequent loss from trophoblast cells was observed after implantation during the first trimester (Campbell et al. 1995). Based on these results, it was concluded that this cell adhesion molecule may be involved in the first invasion phase of implantation, but that it is then down-regulated at the fetal-maternal interface. CD44 hyaluronan receptors are also localized on stromal cells of the human endometrium during the middle to late secretory phases, which again suggests the importance of HA in the implantation process (Yaegashi et al. 1995).

The role of HA in reproductive biology and its clinical application have gained widespread interest since studies in various animal models (bovine, murine, porcine and sheep) indicated that HA supplementation of culture media improves embryo development and blastocyst quality, and may result in increased implantation and live birth rates (Gardner et al. 1999; Fouladi-Nashta et al. 2017). In clinical practice, HA was introduced as EmbryoGlue® (VitroLife AB, Goteborg, Sweden), a commercial embryo transfer medium containing a higher concentration (0.5 mg/ml) of this adherence compound in comparison to standard culture medium which contains a much lower concentration of HA (0.125 mg/ml) and usually served as a control in clinical studies. The findings of numerous clinical studies on the routine use of EmbryoGlue® remain, however, controversial and demonstrate a mixture of positive and indifferent results of this treatment. Some reports of studies where embryo transfers were performed at the cleavage or blastocyst stage showed significant increases in clinical pregnancy and/or implantation rates (Urman et al. 2008; Friedler et al. 2007; Korosec 2007; Balaban et al. 2011; Nakagawa et al. 2012; Singh et al. 2015; Kandari 2019; Pereze et al. 2019), while others contradicted the beneficial effects of HA-medium, when compared to conventional culture media (Loutradi et al. 2007; Hazlett et al. 2008; Hambiliki et al. 2010; Fancsovits et al. 2015; Chun et al. 2016). Such discrepancies among studies most likely arose due to considerable variables in study design and inclusion criteria, and also from the small sample sizes in some studies.

Nonetheless, a Cochrane meta-analysis of randomized clinical trials (RCT) has revealed moderate quality evidence suggesting improved clinical pregnancy and live birth rates with the use of HA-enhanced transfer medium (Bontekoe et al. 2014). The report also emphasized the fact of increased multiple pregnancy rates as a possible result of combined action of an adherence compound and a policy of transferring more than one embryo. Indeed, most studies included cases where multiple embryos were transferred per treatment cycle. Only one early study examined the use of HA rich transfer medium in fresh or frozen single blastocyst transfers (Korosec 2007). Overall, pregnancy rates were similar in both trial and control groups but in a subgroup of women with previous implantation failure, use of HA in fresh elective single blastocyst transfer resulted in higher pregnancies rates. Recently, the use of HA medium in fresh elective single blastocyst ET in PCOS patients resulted in a significant increase in implantation (39.2% vs. 23.8%) and LBRs (39.9% vs. 17.3%) with lower miscarriage rates (8.3% vs. 17.3%) compared with conventional embryo transfer medium (Kandari 2019). Strong evidence of increased pregnancy and take-home baby rates (LBR: 63.4% vs. 52.2% in HA vs. control) has been presented by Balaban’s group (2011) following fresh blastocyst transfers involving high concentrations of HA. Similarly, the beneficial effect of HA-enriched medium was also reported for fresh blastocyst transfers in the study by Urman et al. (2008). Analysis of their data showed a significant increase in the clinical pregnancy and implantation rates in women ≥35 years of age, and in women with previous implantation failures. Furthermore, it was observed that the implantation efficiency was enhanced in EmbryoGlue® (HA) transfers not only in good but also in poor-quality blastocysts. In addition, EmbryoGlue® medium had a positive effect in frozen-thawed blastocyst cycles, and a 14% and 18% increase in pregnancy and implantation rates, respectively, was demonstrated in comparison to embryo transfers in control groups (Wang et al. 2019). In contrast, three other studies did not show significant improvement in clinical outcomes following day 5 transfers using EmbryoGlue® when patients were analyzed according to embryo recipient age (Loutradi et al. 2007) and previous implantation failure (Chun et al. 2016), or in a non-selected patient cohort (Hazlett 2008).

It is important to note, that two reports have suggested a negative influence of HA application. One paper, although detailed results were not included, found significantly lower pregnancies in blastocyst treatment with Embryo Glue® medium versus standard control (total 150 patients; Morbeck 2007). In the second article, the authors noted that clinical outcomes are associated with the duration of embryo pre-equilibration time in HA transfer medium (Wang et al. 2019). Although, the developmental stages (cleavage or blastocyst) were not specified, it was suggested that prolonged embryo exposure to HA (>60 minutes) may reduce the efficacy of HA use, since such treatment led to a considerable decrease of IVF results; clinical pregnancy, implantation and live birth rates. However, most published studies did not find any cytotoxic effects of high concentrations of this adherence compound, (Embryo Glue). Therefore, these two studies with negative correlations should be interpreted with caution, but at the same time cannot be ignored.

In summary, the results of existing studies on HA’s ability to promote embryo implantation remain inconsistent. Thus, further investigations are necessary to draw solid conclusions regarding the role of HA in endometrial preparation and blastocyst implantation, and confirm the safety and efficacy of this procedure. These studies will also be essential to determine whether EmbryoGlue® is beneficial in a selected patient population. Finally, more clinical trials with elective single embryo transfer and live birth rates need to be undertaken, possibly considering an optimal implantation window.

The impact of intrauterine infusion of hCG on blastocyst transfers

Currently, intrauterine infusion of a small volume of human chorionic gonadotropin (hCG) just prior to embryo transfer has been proposed as a technique that might be advantageous for increasing the clinical outcomes of human embryo transfers in sub-fertile women undergoing assisted reproduction. This is an interesting concept since hCG is one of the first embryonic products and it plays a crucial role in embryo-maternal cross-talk during implantation and placental development (Cole 2010; Bourdiec et al. 2013; Evans 2016). hCG is a glycoprotein hormone composed of an alpha-subunit and beta-subunit, which due to post-translational modifications, forms 5 unique isoforms (Cole 2012a; Evans 2016). All these 5 variants of hCG (all called ‘hCG forms’) are produced by different cells and have distinct, independent functions. The main hCG molecule and its variants have a remarkably wide spectrum of diverse and complex biological functions (Cole 2010, Cole 2012b; Evans 2016). The list of the numerous actions of hCG is long, including but not limited to the following: stimulates progesterone secretion in the corpus luteum, promotes trophoblast invasion and decidualization of the endometrial stroma cells, stimulates endometrial angiogenesis, signals the endometrium about forthcoming implantation, regulates embryonic autocrine and maternal paracrine factors involved in blastocyst attachment and endometrial remodeling, regulates immune mechanisms around implanting blastocysts, and it has many other important key functions in placental, uterine and fetal development in the course of pregnancy (Cole 2010; Evans 2016).

Importantly, hCG is considered to be one of the earliest embryonic signals and its isoform βhCG is the first to be expressed by the human embryo (Butler et al. 2013). Gene expression studies have discovered the initiation of βhCG transcription at the 2-cell and 8-cell stage blastomeres (Bonduelle et al. 1988; Jurisicova et al. 1999), and the secretion of βhCG into the culture media has been detected from the 2-pronuclear (2PN), one cell stage embryo throughout embryo development to the blastocyst stage when different secretome-sensitive immunoassay methods were employed (Lopata and Hay 1989; Lopata et al.1997; Butler et al. 2013; Xiao-Yan et al. 2013; Chen et al. 2019). More detailed analysis of the presence of different hCG isoforms (hCG, hCGh, hCGβ, hCGββ) during all preimplantation embryonic developmental stages has revealed that prior to blastocyst hatching, the production of hCG is almost solely attributed to isoform hCGβ while after hatching hCG/hCGh variants become the predominantly secreted molecules by the hatched blastocyst (Lopata et al. 1997; Butler et al. 2013). The fact that hCGh is produced by hatched but not unhatched blastocyst (Lopata et al. 1997), and that it comprises up to 90% of the total hCG measurable in blood and urine during the first 2–3 weeks of pregnancy, suggests a specific involvement of hCGh in endometrial function. It is probable that hCG/hCGh secreted by embryonic blastocyst cells may directly modulate endometrial receptivity and differentiation during the process of early implantation (Fluhr et al. 2008; Evans 2016). Therefore, it has been hypothesized that high concentrations of hCG/hCGh are stored within the zona pellucida and then released close to the endometrial epithelium initiating, attachment, invasion and implantation of the hatched blastocyst (Butler et al. 2013). This scenario seems to be quite realistic since hCGh is recognized as the main promotor of trophoblast invasion and its low levels have been associated with inadequate implantation and pregnancy loss (Cole and Khanlian 2007). Furthermore, blastocysts leading to successful implantation and pregnancy showed better morphological grading and were positively correlated with higher levels of hCG-β in spent culture media when compared to embryos that did not implant (Jurisicova et al.1999; Xiao-Yan et al. 2013; Wang et al. 2014; Chen et al. 2019). It has also been suggested that such variability in hCG concentration, especially the hCGh variant, might be indicative of blastocyst viability and its developmental competence, and could be used as a clinical biomarker(s) of blastocyst quality and implantation success (Butler et al. 2013).

Present knowledge about the multiple roles of hCG in endometrial receptivity and recent findings of the signaling properties of different embryo-derived hCG isoforms inspired researchers to investigate the effect(s) of intrauterine hCG infusion before ET, aiming to enhance embryonic-endometrial interactions and improve IVF-ET outcomes. Several meta-analyses of randomized controlled trials (RCTs; Ye et al. 2015; Osman et al. 2016; Gao et al. 2019), Cochrane review (Craciunas et al. 2018) and critical review (Zhang et al. 2019) were conducted to evaluate the efficacy and usefulness of this treatment. However, these comparative studies have revealed considerable clinical and statistical heterogeneity among published articles. This has been attributed to wide variations in study populations (donor vs non-donor, patients ages, low number of cases etc.) and experimental design (fresh vs frozen ETs, different doses & time of hCG, day 3 vs. day 5 etc.), and importantly indicating contradictory results. Thus, to date there is not enough evidence to draw solid conclusions on the use of intrauterine hCG infusion. A search for the source of these discrepancies identified two key variables as important determinants: stage of ET (cleavage vs. blastocyst) and dose of injected hCG (<500IU vs. ≥500IU) (Craciunas et al. 2018). The majority of studies were related to cleavage stage embryos and, according to the Cochrane summary (2018), there is moderate quality evidence that women undergoing transfer at this stage (day 2/3) using intrauterine hCG infusion with a dose ≥500IU have an improved live birth rate. However, there is insufficient evidence for similar treatment benefit related to blastocyst transfer. Furthermore, one meta-analysis focusing on LBR did not find any support for the use of intrauterine hCG administration regardless of embryonic stage at transfer (n = 8 RCTs; Osman et al. 2016). On the contrary, the other two papers have presented opposite findings showing that infusion of 500IU of hCG can be beneficial and may significantly improve LBR, CPR and IR when compared to the control groups (n = 5 RCTs, Ye et al. 2015 and n = 17 RCTs; Gao et al. 2019).

Interestingly, there were only a few studies that investigated blastocyst transfers exclusively. With the exception of two reports (Mostajeran et al. 2017; Liu et al. 2019), all others did not find any improvement in clinical outcomes after routine intrauterine hCG infusion (Hong et al. 2014; Wirleitner et al. 2015; Volovsky et al. 2018). Of note, the positive data were based on relatively low numbers of either fresh (46 vs. 48; hCG vs control) or frozen-thawed (87 vs. 87; hCG vs control) cycles. In the case of fresh ETs, infusion of 700IU of hCG showed a trend towards improved PR rate compared to the control group (28.6% vs.12.5%) but this difference was not statistically different (Mostajeran et al. 2017). In another study, injection of 500IU of hCG into the uterine cavity 3 days before frozen blastocyst transfers, significantly increased clinical pregnancy (41.4% vs. 26.4%), implantation (42.2% vs. 26.1%) and live birth rates (33.3% vs. 17.2%) in patients with recurrent implantation failures (RIF; Liu et al. 2019). It should be mentioned that in the study by Hong et al. (2014), when data was stratified for day 6 transfers of chromosomally screened euploid blastocysts of younger patients (35 years old), no differences in implantation rates were observed between hCG infusion and control groups (respectively 50.6%, 43/85 and 48.1%, 39/81). In contrast, our own pilot retrospective observational study has indicated that intrauterine infusion of hCG prior to FETs moderately improves the likelihood of achieving pregnancy in euploid blastocyst transfers in patients of age ranging from 20 to 43 years (48.6%; 53/109 vs. 32.9%; 54/164) in hCG vs. control group; unpublished data).

While existing findings suggest that intrauterine hCG infusion is a rather safe procedure for both cleavage and blastocyst stage transfers, there remains a concern for potential adverse effects of this intervention. The basis for this is clinical investigations showing that prolonged exposure to hCG may be detrimental to endometrial receptivity, resulting in down regulation of its receptors and making endometrial cells unresponsive to secreted hCG by hatched blastocyst (Evans and Salamonsen 2013). In line with this cautionary notice, a recent report suggests a possible negative effect of intrauterine hCG injections at the time of fresh blastocyst transfers for selected patients without RIF (Volovsky et al. 2018). In those without RIF, a significant reduction in clinical PR rates by 8.1% and in LB rates by 7.2% was observed, whereas no differences in IVF-ET outcomes were detected in the RIF’s cohort. It is possible then, that additional quantities of injected hCG beyond a certain threshold may have harmful, rather than beneficial or neutral effects, on the success of pregnancy.

The current findings indicate that the intrauterine hCG administration at the time of ET appears to moderately improve the success rate of cleavage stage human embryos. There is not sufficient evidence to support that hCG infusion at the blastocyst stage has any beneficial effect on IVF-ET outcomes. More research will be crucial to improve our understanding of the molecular mechanisms of cross-talk between the blastocyst and maternal endometrium via hCG variants and other factors. It will also be critical to determine the time and dose of hCG administration, and to identify the patient population that could benefit from this therapy.

In summary, the current findings from multiple clinical trials on the efficacy of using HA transfer media and intrauterine hCG administration at the time of ET to improve embryo implantation remain controversial, with questions remaining. Further basic research will be crucial to advance our understanding of the molecular mechanisms of cross-talk between the blastocyst and maternal endometrium. It will also be important to determine the role of exogenous HA and hCG or other factors that might enhance or reduce these mutual interactions, as well as to identify the patient population that could benefit the most from such treatments. Prospective randomized and well-designed clinical trials are necessary to provide high-quality evidence that the procedures are beneficial and effective.

Acknowledgments

We would like to thank Parshvi Vyas and Andree Gauthier-Fisher for editing the manuscript.

Disclosure statement

The authors report no conflict of interest.

Authors’ contributions

Wrote and critically reviewed the manuscript: HB. Critically reviewed the manuscript: IK, CLL. All authors have approved the final version of the manuscript.

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