Use of biological and chemical molecules in regulating embryo implantation and endometrial receptivity : Reproductive and Developmental Medicine

Secondary Logo

Journal Logo

Special Issue: Updates on Research in Endometrium

Use of biological and chemical molecules in regulating embryo implantation and endometrial receptivity

Chen, Xian1; Sun, Shu-Ya1; Ng, Ernest Hung-Yu1,2; Li, Raymond Hang-Wun1,2; Yeung, William Shu-Biu1,2; Lee, Kai-Fai1,2,*

Author Information
Reproductive and Developmental Medicine 6(4):p 234-242, December 2022. | DOI: 10.1097/RD9.0000000000000027
  • Open

Abstract

Introduction

Embryo implantation is a critical and complex biological process in the establishment of pregnancy[1]. Successful implantation requires synchronization of the receptive endometrium and a development-competent blastocyst[2]. Endometrial receptivity is the capacity of the endometrium to allow implantation of the embryo. The short period during which the uterine endometrium is receptive to blastocyst implantation is called the window of implantation (WOI). During the early secretory phase of the menstrual cycle, rising progesterone levels transform the estrogen-primed pre-receptive endometrium to a receptive state on days 20 to 24 of the 28-day menstrual cycle[3]. During the WOI, blastocysts enter the uterine cavity and appose to the endometrium. Embryo-maternal crosstalk further promotes adherence of the blastocyst to the endometrium during the attachment process[4]. The trophoblastic cells of the blastocyst attach to and penetrate the luminal epithelium and basal lamina before invading the decidualized stromal cells[5]. However, not all development-competent blastocysts can be implanted, and it is estimated that approximately 75% of early pregnancy loss is due to implantation failure[6,7]. Although high-quality embryos are transferred in most in vitro fertilization (IVF) cycles, certain patients still suffer from implantation failures, suggesting that endometrial receptivity is a critical parameter for successful implantation and pregnancy[8,9].

Repeated implantation failure

There are various definitions of repeated implantation failure (RIF). Some define it as the failure of a woman below 40 years of age to achieve a clinical pregnancy after transferring a minimum of four good-quality embryos at the cleavage stage, or two blastocysts in at least three fresh or frozen cycles[10,11], and there remains no universal consensus. RIF is a major challenge in IVF treatment because the underlying causes are unknown in the majority of cases. The etiologies of RIF are complex, and the risk factors include advanced maternal age, smoking status, high body mass index, and stress[12]. Changes in endometrial microRNA and mRNA expression have been demonstrated in women with RIF[13,14].

Endometrial receptivity markers

Markers of endometrial receptivity have long been investigated. Morphological changes in glandular and stromal endometrial cells are the gold standard for a receptive endometrium[15–17]. Ultrasonography has been used to measure uterine blood flow and endometrial thickness, with some predictive value for pregnancy outcome[18–20]. An endometrial thickness of approximately 6 to 8 mm favors successful implantation[15,21,22], and a higher uterine blood flow resistance is associated with low pregnancy outcomes in women with RIF[23,24]. Resistance to blood flow in women with recurrent pregnancy loss is higher than that in women with normal pregnancies[25,26].

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 family. It is expressed in the luminal and glandular epithelia of the endometrium[27–29]. LIF binds to the LIF receptor, which works with gp130 to activate the signaling pathway via signal transducer and activator of transcription 3. Embryos cannot be implanted into LIF knockout mice[30–32]. Furthermore, LIF from the uterine glands contributes to endometrium-embryo crosstalk during implantation and stromal cell decidualization[33]. Patients with higher LIF expression have a better chance of conceiving[34]. Similarly, fertile women express higher endometrial LIF levels than infertile women do in the WOI[29,35,36]. Therefore, LIF is believed to be a potential predictor of successful pregnancy[34,37].

Non-hormonal molecules

An increase in endometrial thickness and decrease in endometrial blood flow resistance are associated with improved pregnancy outcomes (Table 1)[38]. Aspirin and low-molecular weight heparin (LMWH) have been used to improve endometrial microcirculation. Low-dose aspirin can increase blood flow in the uterine arteries by dilating the blood vessels and inhibiting platelet aggregation[39,40]. Heparin regulates insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) to promote decidualization during implantation[41]. Moreover, in certain studies, the anticoagulant action of heparin prevented thrombosis and increased implantation rates in women with thrombophilia and repeated IVF failures[59–61]. Although a recent meta-analysis did not show a significant impact of LMWH administration on both clinical pregnancy and live birth rates in non-thrombophilic women with RIF[38], the beneficial effects of LMWH in women with thrombophilia undergoing IVF warrant further investigation[62].

Table 1. - Summary of molecules that contribute to the blood flow or endometrial receptivity markers.
Groups Molecules Effects on
Blood flow Receptivity markers
Non-hormone molecules Aspirin +[39,40]
LMWH +[39,40] IGFBP-1, IGF-1[41]
Vitamin E +[42] LDLR, IL-1, TNFα[43]
Sildenafil +[44–47]
Atosiban +[48]
Hormones and cytokines hCG IGFBP-1, VEGF, MMP-9, TIMP[49–51]
GH +[52] IGF-I, VEGF, ITGB3[52]
Immunomodulatory molecules G-CSF
PBMC LIF, VEGF[53]
PRP MMP-1, MMP-3, MMP-7[54]
Intralipid
IVIG
Traditional Chinese Medicine Paeonia lactiflora LIF[55]
Perilla frutescens LIF[56]
Chinese Bushen Huoxue prescriptions ITGB3, LIF[57]
Wenshen Yangxue decoction + VEGF[58]
Presence or absence of characteristics represented as follows: present, plus (+) symbol; absent, minus (−) symbol.
G-CSF: granulocyte colony-stimulating factor; GH: growth hormone; hCG: intrauterine human chorionic gonadotrophin; IGF-I: insulin-like growth factor-I; IGFBP-1: insulin-like growth factor binding protein-1; IL-1: Interleukin-1; ITGB3: integrin subunit beta 3; IVIG: intravenous immunoglobulins; LDLR: low-density lipoprotein receptor; LMWH: Low-molecular weight heparin; MMP-1/3/7/9: matrix metalloproteinase 1/3/7/9; PBMC: peripheral blood mononuclear cell; PRP: platelet-rich plasma; TNFα: tumor necrosis factor alpha; VEGF: vascular endothelial growth factor; TIMP: matrix metalloproteinases.

Vitamin E may improve endometrial response because of its antioxidant and anticoagulant properties. Vitamin E appears to increase endometrial thickness and overcome the anti-estrogenic effect of clomiphene citrate in IVF treatment through its antioxidant effect[43,63,64]. Moreover, the anticoagulant effect of vitamin E may increase endometrial blood flow[42]. Supplementation with vitamin E improves the expression of low-density lipoprotein receptor, interleukin-1, and tumor necrosis factor alpha in patients with implantation failure[43]. A randomized controlled trial (RCT)[65] showed that the implantation rate was significantly higher in the treatment group of vitamin E and D3 in women with polycystic ovarian syndrome (PCOS) under intra-cytoplasmic sperm injection than in those PCOS infertile women without treatment; however, clinical support of vitamin E in the success of IVF is insufficient.

The use of vaginal sildenafil (Viagra) has gradually drawn attention as an adjuvant therapy for IVF. Sildenafil, an inhibitor of type 5-specific phosphodiesterase, can prevent cyclic guanosine monophosphate degradation and amplify the vasodilatory effects of nitric oxide[66]. Several studies have suggested the beneficial effects of vaginal sildenafil on endometrial receptivity through the improvement of uterine blood flow and an increase in endometrial thickness[44–47]. Atosiban, a mixed receptor antagonist of oxytocin and vasopressin V1a, can inhibit uterine contractions and increase endometrial perfusion[48]. In some studies, administration of atosiban improved implantation and pregnancy rates in patients with RIF[67,68], although other studies have indicated a limited role of atosiban in improving IVF success in unselected patients[69,70]. A previous study showed that atosiban treatment starting from the third embryo transfer (ET) cycle may be effective in improving embryo implantation and clinical pregnancy rates, because patients who have undergone three or more ET cycles were inclined to have higher uterine contractions and serum oxytocin levels[71]. Further investigation of the role of atosiban in embryo implantation is required.

Hormones

Steroid hormones regulate endometrial receptivity during the menstrual cycle. In IVF, hormone replacement therapy improves the implantation rate in patients with a thin endometrium (≤8 mm)[72]. It has been suggested that the administration of estrogen and progesterone helps patients with RIF to synchronize the uterine environment conducive to embryo implantation[73,74].

Intrauterine human chorionic gonadotropin (hCG) infusion can improve pregnancy outcomes during IVF cycles[75,76]. hCG is produced by syncytiotrophoblasts[77] and induces progesterone secretion by promoting the development of the corpus luteum in the ovary[78]. hCG may prolong endometrial receptivity to facilitate implantation by downregulating intrauterine IGFBP-1 expression[49,79] in the late luteal phase. IGFBP-1 is a well-identified decidualization marker that regulates implantation by interacting with trophoblast-derived IGFs. hCG may enhance the endometrial response by increasing vascular endothelial growth factor (VEGF) expression for endometrial angiogenesis[50]. Moreover, hCG can induce LIF[51] expression, upregulate matrix metalloproteinase 9 expression, and inhibit tissue inhibitors of matrix metalloproteinases expression, thereby facilitating embryo invasion in the endometrial tissue[50]. A recent meta-analysis, which included 15 RCTs with a total of 2763 participants, concluded that infertile patients receiving intrauterine hCG injection before ET had a significantly higher implantation (31.6% vs. 22.5%), clinical pregnancy (47.8% vs. 32.8%), and live birth rates (44.9% vs. 29.8%) than those of the untreated or placebo controls. In addition, the miscarriage rate was significantly lower (12.5% vs. 18.6%) than that in the control group[80].

Growth hormone (GH) can also enhance endometrial receptivity and improve oocyte quality by activating IGF-I or promoting steroidogenesis of follicle-stimulating hormone[81]. Administration of GH stimulates endometrial blood flow and expression of cytokines such as endometrial VEGF, IGF-1, and integrin subunit beta 3, resulting in endometrial gland proliferation, blood vessel formation, and thickening of the endometrium[52]. In fact, administration of GH in RIF or non-RIF patients undergoing IVF has a positive effect on pregnancy outcomes[82–84].

Melatonin is a neuroendocrine hormone that is secreted by the pineal gland. Melatonin may be an efficient antioxidant agent for oocyte maturation and embryonic development[85]. Besides, recent research has shown that melatonin receptors 1A and 1B were expressed in human endometria[86]. Melatonin significantly increased the implantation sites (16.0 ± 1.68 vs. 14.4 ± 1.91; P <0.01) and litter sizes (13.9 ± 1.23 vs. 12.6 ± 1.39, P <0.05) of mice. The increased effect of melatonin on implantation sites and litter sizes, possibly through upregulation of PRA, HB-EGF, and p53 expression in the uterus, may contribute to endometrial development and uterine receptivity[87]. In another study, melatonin treatment in mice upregulated genes involved in pregnenolone synthesis in the ovary and Ihh expression in the uterine endometrium, which may mediate endometrial development and improve endometrial receptivity[88].

Immunomodulatory molecules

The immune system plays a pivotal role in embryo implantation[89]. Immunomodulatory therapies, such as subcutaneous or intrauterine administration of granulocyte colony-stimulating factor (G-CSF), intrauterine infusion of peripheral blood mononuclear cells (PBMCs), autologous platelet-rich plasma (PRP), and intralipid and intravenous immunoglobulins (IVIG), have been used to treat patients with RIF[90–94].

G-CSF, as a hematopoietic-specific cytokine, improves embryonic development, implantation, and trophoblast invasion in patients with RIF[95,96]. Human recombinant G-CSF plays a regulatory role in endometrial remodeling, local immune modulation, and cellular adhesion pathways[97]. G-CSF increases phagocytosis and oxidative processes, which are important for embryo implantation, by regulating endometrial vascular remodeling, local immune modulation, and cellular adhesion[98]. A recent meta-analysis suggested that G-CSF administration increases implantation and clinical pregnancy rates in patients with RIF[99]. Transvaginal perfusion of G-CSF significantly increased clinical pregnancy rates compared with that of the placebo (risk ratio [RR] = 1.563, 95% confidence interval [CI] = 1.122–2.176). Implantation rates were also significantly increased in patients with thin endometrium or repeated IVF failure under G-CSF treatment (RR = 1.887, 95% CI = 1.256–2.833)[99]. However, there was no significant increase in endometrial thickness[99].

Intrauterine PBMC infusion is another treatment option for patients with RIF. Human PBMCs obtained from pregnant women can promote the spread and invasion of murine blastocysts in vitro[100]. Moreover, PBMCs promote the invasion of trophoblastic BeWo cells in vitro[101]. Intrauterine administration of PBMCs enhances endometrial receptivity in mice by stimulating the endometrial expression of LIF and VEGF[53]. A meta-analysis of three RCTs that investigated the effect of intrauterine PBMC infusion on IVF outcomes in women with RIF showed a significant increase in the chances of clinical pregnancy (fixed effects model, RR = 2.18; 95% CI = 1.58–3.00; P <0.00001; I2 = 0%) and live birth (RR = 2.41; 95% CI = 1.40–4.16; P = 0.002) in treated women[38]. In line with this, intrauterine administration of PBMCs increases clinical pregnancy rates in patients with RIF undergoing IVF-ET cycles[102–104], although a recently published meta-analysis study reported improvements in clinical pregnancy rates, but not live birth rates, in women with RIF after administration of PBMCs[91].

PRP infusion is a novel therapy in IVF[105]. PRP can facilitate embryo implantation by affecting endometrial thickness and vascularity[106]. Its therapeutic effect on endometrial growth and receptivity is due to the action of platelet-derived growth factors on cell proliferation and neo-endothelial cell generation for tissue growth, and also due to its anti-microbial and anti-inflammatory properties in uterine infections[107]. In two RCTs that investigated the effect of intrauterine PRP on IVF outcomes in women with RIF, clinical pregnancy rates were higher in the PRP group than in the control group (48.3% vs. 23.26%, P = 0.001; 44. 89% vs. 16.66%, P = 0.003, respectively)[55,56].

Intralipid, an intravenous fat emulsion, could be an effective and safe treatment for patients with RIF[108]. The benefits and efficacy of intravenous intralipid therapy in patients are controversial in clinical studies[109–111], however, a meta-analysis of 12 studies with 2676 participants in a recently published review[112] showed that treatment with intralipid improved implantation (odds ratio [OR]: 2.97, 2.05–4.29), pregnancy (OR: 1.64, 1.31–2.04), and live birth rates (OR: 2.36, 1.75–3.17), with a decrease in miscarriage rates (OR: 0.2, 0.14–0.30). This review highlights the benefits of intralipid in patients with poor reproductive history.

IVIG is considered a potential treatment for RIF and failed IVF. A previous study demonstrated that IVIG treatment increased the pregnancy rate of patients with RIF from 26% to 94% and the live birth rate from 18% to 80% compared with those not receiving IVIG[113]. A recent meta-analysis also showed that IVIG could improve implantation, pregnancy (OR = 1.82, 95% CI = 1.14–2.89; P = 0.01), and live birth rates (OR = 2.17, 95% CI = 1.30–3.61; P = 0.003) in patients with RIF to those of the control group[114]. Therefore, IVIG may be a good therapeutic agent for improving pregnancy outcomes in patients with RIF, particularly for those with immunological abnormalities[115].

Traditional Chinese medicine

Chinese herbs and acupuncture are adjuvant therapies used for patients undergoing IVF[116,117]. Accumulating data suggest that Chinese herbs increase endometrial thickness and improve embryo quality, which may benefit IVF treatment. Paeonia lactiflora (Chinese peony) and Perilla frutescens (Beefsteak plant) are Chinese herbs that increase LIF expression in endometrial epithelial cells and favor the adhesion of trophoblastic JAr cells in vitro[118,119]. Paeoniflorin, extracted from P. lactiflora, improves embryo implantation rates in a murine implantation failure model[120]. However, the clinical efficacy and safety of Chinese herbs require further investigation in clinical trials. In addition, several studies have shown that Chinese Bushen Huoxue prescriptions can upregulate the expression of endometrial receptors ER, PR, integrin β3, LIF, and other molecules, facilitating the development of pinopodes in the WOI and enhancing endometrial receptivity[57]. Another Traditional Chinese medicine (TCM), the Wenshen Yangxue decoction, could improve endometrial receptivity and promote endometrial angiogenesis by regulating the expression of PI3K, HIF-1α, and VEGF[58].

Emergency contraception

Birth control can be achieved through physical therapy and medication[121,122]. Emergency contraception (EC) is defined as the use of any drug or device after unprotected intercourse to prevent unwanted pregnancies[123]. In fact, >25% of all pregnancies are estimated to be unintended[124,125]; combined oral contraceptives (Yuzpe method), levonorgestrel, ulipristal acetate (UPA), and mifepristone (RU486) have commonly been used for medical abortion (Table 2).

Table 2. - Summary of the effects of molecules in emergency contraception.
Molecules Effects on
Human sperm function Follicular development and ovulation Endometrial receptivity and embryo implantation
Yuzpe ND +[126] ND
Levonorgestrel [127–129] +[130] ±[131–135]
Ulipristal acetate +[136,137] +[138,139] ±[131–135]
Mifepristone +[136,137] +[140–143] +[144,145]
Presence or absence of effects represented as follows: present, plus (+) symbol; absent, minus (−) symbol; conflicting data, plus/minus (±) symbol.
ND: not determined.

RU486 is an orally active progesterone antagonist that acts through progesterone receptors. It was developed to terminate pregnancies and was also used for EC[146]. RU486 functions by blocking the effects of progesterone[140]. RU486 administration also impairs the ovulatory process. In the pre-ovulatory phase, RU486 blocks or delays ovulation in a dose-dependent manner. At a dose of 10 mg RU486, the development of the dominant follicle can be arrested or continued without rupture[141]. In women treated with high RU486 (3 mg/kg, orally) doses for three consecutive days, follicle development is disrupted or the dominant follicle is functionally destroyed with inhibition of ovulation[142,143]. Both UPA and RU486 can suppress the acrosome reaction of sperm[136,137]. The contraceptive effect of RU486 is dose- and time-dependent. A single dose of oral RU486 from 10 to 600 mg is sufficient to prevent pregnancies[144,145,147,148]. A single low dose of RU486 delays or inhibits ovulation, whereas high doses affect endometrial receptivity and prevent embryo implantation[144,145]. In an in vitro co-culture model, RU486 treatment (10−5 mol/L) for 5 days significantly suppressed the attachment of human blastocysts to reconstituted endometrial tissue consisting of human endometrial stromal and epithelial cells[145].

Screening of small molecules on endometrial receptivity

The Library of Pharmacologically Active Compounds (LOPAC) is a commercially available source for high-throughput screening of targets. It contains 1280 pharmacologically active compounds, with 58% related to neurotransmission, 9% to cell signaling, 6% to ion channels, and 3% to hormones. All major target classes, such as kinases, proteases, G protein-coupled receptors, and molecules involved in gene regulation and neurotransmission, are included in these 1280 pharmacologically active compounds. This library includes marketed drugs and pharmaceutically relevant compounds. More than 100 related publications were found in PubMed. LOPAC has been used for antiviral and antifungal drug screening[149,150], neurotransmitter screening[151], drug discovery against hepatitis C and human immunodeficiency viruses[152], and neurological diseases[153]. Importantly, LOPAC has been used to identify inhibitors of the canonical Wnt signaling pathway in colon cancer cells by evaluating β-catenin stability in a high-throughput model[154], and neurological[155] and angiogenic factors[156] in zebrafish embryo screening.

We modified a high-throughput attachment assay[157] in our laboratory, to screen the LOPAC for small molecules that enhance and/or suppress embryo implantation. The screening procedures are shown in Fig. 1. By using receptive (Ishikawa and RL95-2) and non-receptive (HEC1-B and AN3CA) endometrial epithelial cells cocultured with trophoblastic (BeWo) spheroids generated using Aggrewell and labeled with a fluorescent dye, this assay can be used to study the effect of LOPAC on the attachment rate of spheroids in vitro. Our results showed that Nemadipine-A[158] decreased spheroid attachment. In line with this, molecules that control the function of ion channels have been reported to modulate endometrial receptivity and embryo implantation[159–163]. Further analysis and confirmation with in vitro and in vivo models were used to explore their clinical implications.

F1
Fig. 1.:
Schematic diagram showing the screening strategy of the LOPAC. (A) The endometrial epithelial cells were cultured in a culture flask (A1), trypsinized and plated on 96-well plates to form the monolayers (A2) with or without LOPAC treatment for 24 h. (B) Concurrently, BeWo spheroids were generated using AggreWell (B1) and labeled with calcein-AM (green), a fluorescence dye. (C) BeWo spheroids with fluorescence labels were transferred onto the monolayers using a multichannel pipette. (D) The endometrial monolayer was cocultured with green spheroids for 1 h. (E) The fluorescence signals of seeded spheroids were recorded using a plate reader. (F) The unattached spheroids were removed by phosphate-buffered saline. (G) The fluorescence signals of attached spheroids were then recorded. (H) The attachment effect was expressed as the calculation of the percentage of the ratio of fluorescence signals (attached/seeded).

Conclusion

Endometrial receptivity plays a vital role in successful implantation and pregnancy in women undergoing IVF. Ongoing research focuses on the use of non-hormonal molecules (aspirin, LMWH, vitamin E, sildenafil, and atosiban) to improve endometrial blood flow or vascularization. Hormonal factors, including hCG, GH, and melatonin, regulate the expression of receptivity markers. The effects of immunosuppressive or immunomodulatory agents, including G-CSF, PBMC, PRP, and IVIG, have been studied for their effects in modulating implantation. Laboratory studies have shown that P. lactiflora and P. frutescens increase LIF expression in endometrial epithelial cells. Certain TCM prescriptions improve endometrial receptivity by regulating hormone receptors and growth factors. Finally, the use of libraries of small molecules (eg, LOPAC) combined with a high-throughput screening method may provide an approach to screen for compounds that may potentially enhance or suppress embryo implantation. However, whether these biomedical findings translate into clinical applications requires further investigation.

Acknowledgments

None.

Author contribution

X.C., S.S., and K.L. conceived the concept of this study, designed and experimental approach. X.C. and S.S. performed the experiments. E.N., R.L., W.Y., and K.L. provided critical intellectual support, assisted with data analysis, and edited the manuscript. X.C., S.S., and K.L. wrote the manuscript. All authors contributed to the final editing and reviewed the manuscript.

Funding(s)

This work was partly supported by grants from the Sanming Project of Medicine in Shenzhen, China (SZSM201612083 to W.S.-B.Y.), Shenzhen Key Medical Discipline (SZXK2020089), General Research Fund, Research Grants Council, Hong Kong (17120720 to K.-F.L.), and internal research funding from the Department of Obstetrics and Gynaecology, the University of Hong Kong.

Conflicts of interest

All authors declare no conflict of interests.

References

[1]. Dey SK, Lim H, Das SK, et al. Molecular cues to implantation. Endocrinol Rev. 2004;25(3):341–373. doi:10.1210/er.2003-0020.
[2]. Kim SM, Kim JS. A review of mechanisms of implantation. Dev Reprod. 2017;21(4):351–359. doi:10.12717/DR.2017.21.4.351.
[3]. Hess AP, Nayak NR, Giudice LC. Oviduct and endometrium: cyclic changes in the primate oviduct and endometrium. Neill JD, ed. In: The Physiology of Reproduction. 3rd ed. St. Louis: Elsevier2006. p. 337–381.
[4]. Stavreus-Evers A, Aghajanova L, Brismar H, et al. Co-existence of heparin-binding epidermal growth factor-like growth factor and pinopodes in human endometrium at the time of implantation. Mol Hum Reprod. 2002;8(8):765–769. doi:10.1093/molehr/8.8.765.
[5]. Thie M, Denker HW. In vitro studies on endometrial adhesiveness for trophoblast: cellular dynamics in uterine epithelial cells. Cells Tissues Organs. 2002;172(3):237–252. doi:10.1159/000066963.
[6]. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345(19):1400–1408. doi:10.1056/NEJMra000763.
[7]. Bischof P, Campana A. Trophoblast differentiation and invasion: its significance for human embryo implantation. Early Pregnancy. 1997;3(2):81–95.
[8]. Comins-Boo A, Garcia-Segovia A, Nunez P. Evidence-based update: immunological evaluation of recurrent implantation failure. Reprod Immunol Open Acc. 2016;1(4):1–8. doi:10.21767/2476-1974.100024.
[9]. Lessey BA, Young SL. Structure, function, and evaluation of the female reproductive tract. In: Strauss J, Barbieri R. ed. Yen & Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management: 8th ed. Philadelphia: Elsevier. 2019;206–247.e13.
[10]. Coughlan C, Ledger W, Wang Q, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online. 2014;28(1):14–38. doi:10.1016/j.rbmo.2013.08.011.
[11]. Moustafa S, Young SL. Diagnostic and therapeutic options in recurrent implantation failure. F1000Research. 2020;9:208. doi:10.12688/f1000research.22403.1.
[12]. Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol. 2018;16(1):121. doi:10.1186/s12958-018-0414-2.
[13]. Shi C, Shen H, Fan LJ, et al. Endometrial microRNA signature during the window of implantation changed in patients with repeated implantation failure. Chin Med J. 2017;130(5):566–573. doi:10.4103/0366-6999.200550.
[14]. Rekker K, Altmäe S, Suhorutshenko M, et al. A two-cohort RNA-seq study reveals changes in endometrial and blood miRNome in fertile and infertile women. Genes. 2018;9(12):574–621. doi:10.3390/genes9120574.
[15]. Noyes N, Hampton BS, Berkeley A, et al. Factors useful in predicting the success of oocyte donation: a 3-year retrospective analysis. Fertil Steril. 2001;76(1):92–97. doi:10.1016/s0015-0282(01)01823-4.
[16]. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263. doi:10.1016/s0002-9378(16)33500-1.
[17]. Noyes RW, Haman JO. Accuracy of endometrial dating; correlation of endometrial dating with basal body temperature and menses. Fertil Steril. 1953;4(6):504–517. doi:10.1016/s0015-0282(16)31446-7.
[18]. Zhang T, He Y, Wang Y, et al. The role of three-dimensional power Doppler ultrasound parameters measured on hCG day in the prediction of pregnancy during in vitro fertilization treatment. Eur J Obstet Gynecol Reprod Biol. 2016;203:66–71. doi:10.1016/j.ejogrb.2016.05.016.
[19]. Mercé LT. Ultrasound markers of implantation. Ultrasound Obstet Gynecol. 2002;2(2):110–123. doi:10.3109/14722240208500468.
[20]. Raga F, Bonilla-Musoles F, Casan EM, et al. Assessment of endometrial volume by three-dimensional ultrasound prior to embryo transfer: clues to endometrial receptivity. Hum Reprod. 1999;14(11):2851–2854. doi:10.1093/humrep/14.11.2851.
[21]. Friedler S, Schenker JG, Herman A, et al. The role of ultrasonography in the evaluation of endometrial receptivity following assisted reproductive treatments: a critical review. Hum Reprod Update. 1996;2(4):323–335. doi:10.1093/humupd/2.4.323.
[22]. Khalifa E, Brzyski RG, Oehninger S, et al. Sonographic appearance of the endometrium: the predictive value for the outcome of in-vitro fertilization in stimulated cycles. Hum Reprod. 1992;7(5):677–680. doi:10.1093/oxfordjournals.humrep.a137718.
[23]. Khan MS, Shaikh A, Ratnani R. Ultrasonography and Doppler study to predict uterine receptivity in infertile patients undergoing embryo transfer. J Obstet Gynaecol India. 2016;66(Suppl 1):377–382. doi:10.1007/s13224-015-0742-5.
[24]. Tong R, Zhou Y, He Q, et al. Analysis of the guidance value of 3D ultrasound in evaluating endometrial receptivity for frozen-thawed embryo transfer in patients with repeated implantation failure. Ann Transl Med. 2020;8(15):944–953. doi:10.21037/atm-20-5463.
[25]. Nakatsuka M, Habara T, Noguchi S, et al. Impaired uterine arterial blood flow in pregnant women with recurrent pregnancy loss. J Ultrasound Med. 2003;22(1):27–31. doi:10.7863/jum.2003.22.1.27.
[26]. Lilic V, Tubic-Pavlovic A, Radovic-Janosevic D, et al. Assessment of endometrial receptivity by color Doppler and ultrasound imaging. Med Pregl. 2007;60(5-6):237–240. doi:10.2298/mpns0706237l.
[27]. Cullinan EB, Abbondanzo SJ, Anderson PS, et al. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA. 1996;93(7):3115–3120. doi:10.1073/pnas.93.7.3115.
[28]. Smith SK, Charnock-Jones DS, Sharkey AM. The role of leukemia inhibitory factor and interleukin-6 in human reproduction. Hum Reprod. 1998;13(Suppl 3):237–43; discussion 244. doi:10.1093/humrep/13.suppl_3.237.
[29]. Lass A, Weiser W, Munafo A, et al. Leukemia inhibitory factor in human reproduction. Fertil Steril. 2001;76(6):1091–1096. doi:10.1016/s0015-0282(01)02878-3.
[30]. Stewart CL, Kaspar P, Brunet LJ, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79. doi:10.1038/359076a0.
[31]. Daikoku T, Cha J, Sun X, et al. Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Dev Cell. 2011;21(6):1014–1025. doi:10.1016/j.devcel.2011.09.010.
[32]. Niwa H, Burdon T, Chambers I, et al. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 1998;12(13):2048–2060. doi:10.1101/gad.12.13.2048.
[33]. Kelleher AM, Milano-Foster J, Behura SK, et al. Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success. Nat Commun. 2018;9(1):2435. doi:10.1038/s41467-018-04848-8.
[34]. Serafini PC, Silva ID, Smith GD, et al. Endometrial claudin-4 and leukemia inhibitory factor are associated with assisted reproduction outcome. Reprod Biol Endocrinol. 2009;7:30. doi:10.1186/1477-7827-7-30.
[35]. Xiao Y, Sun X, Yang X, et al. Leukemia inhibitory factor is dysregulated in the endometrium and uterine flushing fluid of patients with adenomyosis during implantation window. Fertil Steril. 2010;94(1):85–89. doi:10.1016/j.fertnstert.2009.03.012.
[36]. Laird SM, Tuckerman EM, Dalton CF, et al. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum Reprod. 1997;12(3):569–574. doi:10.1093/humrep/12.3.569.
[37]. Mikolajczyk M, Wirstlein P, Skrzypczak J. The impact of leukemia inhibitory factor in uterine flushing on the reproductive potential of infertile women--a prospective study. Am J Reprod Immunol. 2007;58(1):65–74. doi:10.1111/j.1600-0897.2007.00492.x.
[38]. Busnelli A, Somigliana E, Cirillo F, et al. Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis. Sci Rep. 2021;11(1):1747–1778. doi:10.1038/s41598-021-81439-6.
[39]. Schisterman EF, Gaskins AJ, Whitcomb BW. Effects of low-dose aspirin in in-vitro fertilization. Curr Opin Obstet Gynecol. 2009;21(3):275–278. doi:10.1097/GCO.0b013e32832a0673.
[40]. Chi Y, He P, Lei L, et al. Transdermal estrogen gel and oral aspirin combination therapy improves fertility prognosis via the promotion of endometrial receptivity in moderate to severe intrauterine adhesion. Mol Med Rep. 2018;17(5):6337–6344. doi:10.3892/mmr.2018.8685.
[41]. Fluhr H, Spratte J, Ehrhardt J, et al. Heparin and low-molecular-weight heparins modulate the decidualization of human endometrial stromal cells. Fertil Steril. 2010;93(8):2581–2587. doi:10.1016/j.fertnstert.2009.10.025.
[42]. Cicek N, Eryilmaz OG, Sarikaya E, et al. Vitamin E effect on controlled ovarian stimulation of unexplained infertile women. J Assist Reprod Genet. 2012;29(4):325–328. doi:10.1007/s10815-012-9714-1.
[43]. Hashemi Z, Sharifi N, Khani B, et al. The effects of vitamin E supplementation on endometrial thickness, and gene expression of vascular endothelial growth factor and inflammatory cytokines among women with implantation failure. J Matern Fetal Neonatal Med. 2019;32(1):95–102. doi:10.1080/14767058.2017.1372413.
[44]. Hosseini A, Movaghar B, Abkenari SA, et al. Leukemia inhibitory factor enhanced the developmental and implantation compatibility of mouse embryos in co-culture with human endometrial epithelial cells. Reprod Dev Med. 2021;5(4):199–205. doi:10.4103/2096-2924.327881.
[45]. Takasaki A, Tamura H, Miwa I, et al. Endometrial growth and uterine blood flow: a pilot study for improving endometrial thickness in the patients with a thin endometrium. Fertil Steril. 2010;93(6):1851–1858. doi:10.1016/j.fertnstert.2008.12.062.
[46]. Bolnick JM, Kilburn BA, Bolnick AD, et al. Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3’,5’-cyclic monophosphate signaling. Fertil Steril. 2015;103(6):1587–95.e1–2. doi: 10.1016/j.fertnstert.2015.02.025.
[47]. Tao Y, Wang N. Adjuvant vaginal use of sildenafil citrate in a hormone replacement cycle improved live birth rates among 10,069 women during first frozen embryo transfers. Drug Des Devel Ther. 2020;14:5289–5297. doi:10.2147/DDDT.S281451.
[48]. Kalmantis K, Loutradis D, Lymperopoulos E, et al. Three dimensional power Doppler evaluation of human endometrium after administration of oxytocine receptor antagonist (OTRa) in an IVF program. Arch Gynecol Obstet. 2012;285(1):265–270. doi:10.1007/s00404-011-2019-2.
[49]. Fowler DJ, Nicolaides KH, Miell JP. Insulin-like growth factor binding protein-1 (IGFBP-1): a multifunctional role in the human female reproductive tract. Hum Reprod Update. 2000;6(5):495–504. doi:10.1093/humupd/6.5.495.
[50]. Licht P, Fluhr H, Neuwinger J, et al. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Molec Cell Endocrinol. 2007;269(1):85–92. doi:10.1016/j.mce.2006.09.016.
[51]. Perrier d’Hauterive S, Charlet-Renard C, Berndt S, et al. Human chorionic gonadotropin and growth factors at the embryonic-endometrial interface control leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) secretion by human endometrial epithelium. Hum Reprod. 2004;19(11):2633–2643. doi:10.1093/humrep/deh450.
[52]. Xu YM, Hao GM, Gao BL. Application of growth hormone in in vitro fertilization. Front Endocrinol. 2019;10:502. doi:10.3389/fendo.2019.00502.
[53]. Yu N, Yang J, Guo Y, et al. Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves endometrial receptivity in mice with embryonic implantation dysfunction. Am J Reprod Immunol. 2014;71(1):24–33. doi:10.1111/aji.12150.
[54]. Aghajanova L, Houshdaran S, Balayan S, et al. In vitro evidence that platelet-rich plasma stimulates cellular processes involved in endometrial regeneration. J Assist Reprod Genet. 2018;35(5):757–770. doi:10.1007/s10815-018-1130-8.
[55]. Nazari L, Salehpour S, Hosseini MS, et al. The effects of autologous platelet-rich plasma in repeated implantation failure: a randomized controlled trial. Hum Fertil. 2020;23(3):209–213. doi:10.1080/14647273.2019.1569268.
[56]. Zamaniyan M, Peyvandi S, Heidaryan Gorji H, et al. Effect of platelet-rich plasma on pregnancy outcomes in infertile women with recurrent implantation failure: a randomized controlled trial. Gynecol Endocrinol. 2021;37(2):141–145. doi:10.1080/09513590.2020.1756247.
[57]. Lyu BY, Li D, Zhang HL, et al. Effect and regulation mechanism of Chinese Bushen Huoxue prescriptions on endometrial receptivity. China J Chin Mater Med. 2018;43(10):2014–2019. doi:10.19540/j.cnki.cjcmm.20180226.001.
[58]. Xin M, He J, Yang W, et al. Wenshen Yangxue decoction improves endometrial receptivity recovery and promotes endometrial angiogenesis in a rat model. Pharm Biol. 2018;56(1):573–579. doi:10.1080/13880209.2018.1510973.
[59]. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update. 2008;14(6):623–645. doi:10.1093/humupd/dmn031.
[60]. Fiedler K, Würfel W. Effectivity of heparin in assisted reproduction. Eur J Med Res. 2004;9(4):207–214.
[61]. Qublan H, Amarin Z, Dabbas M, et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil. 2008;11(4):246–253. doi:10.1080/14647270801995431.
[62]. Hamdi K, Danaii S, Farzadi L, et al. The role of heparin in embryo implantation in women with recurrent implantation failure in the cycles of assisted reproductive techniques (without history of thrombophilia). J Family Reprod Health. 2015;9(2):59–64.
[63]. Acharya S, Yasmin E, Balen AH. The use of a combination of pentoxifylline and tocopherol in women with a thin endometrium undergoing assisted conception therapies--a report of 20 cases. Hum Fertil. 2009;12(4):198–203. doi:10.3109/14647270903377178.
[64]. Zingg JM. Modulation of signal transduction by vitamin E. Mol Aspects Med. 2007;28(5–6):481–506. doi:10.1016/j.mam.2006.12.009.
[65]. Fatemi F, Mohammadzadeh A, Sadeghi MR, et al. Role of vitamin E and D(3) supplementation in intra-cytoplasmic sperm injection outcomes of women with polycystic ovarian syndrome: a double blinded randomized placebo-controlled trial. Clin Nutr ESPEN. 2017;18:23–30. doi:10.1016/j.clnesp.2017.01.002.
[66]. Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod. 2000;15(4):806–809. doi:10.1093/humrep/15.4.806.
[67]. Liang YL, Kuo TC, Hung KH, et al. Oxytocin antagonist for repeated implantation failure and delay of delivery. Taiwan J Obstet Gynecol. 2009;48(3):314–316.
[68]. Lan VT, Khang VN, Nhu GH, et al. Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure. Reprod Biomed Online. 2012;25(3):254–260. doi:10.1016/j.rbmo.2012.05.014.
[69]. Huang QY, Rong MH, Lan AH, et al. The impact of atosiban on pregnancy outcomes in women undergoing in vitro fertilization-embryo transfer: a meta-analysis. PLoS One. 2017;12(4):e0175501. doi:10.1371/journal.pone.0175501.
[70]. Ng EH, Li RH, Chen L, et al. A randomized double blind comparison of atosiban in patients undergoing IVF treatment. Hum Reprod. 2014;29(12):2687–2694. doi:10.1093/humrep/deu263.
[71]. He Y, Wu H, He X, et al. Application of atosiban in frozen-thawed cycle patients with different times of embryo transfers. Gynecol Endocrinol. 2016;32(10):811–815. doi:10.1080/09513590.2016.1180680.
[72]. Zheng Y, Li Z, Xiong M, et al. Hormonal replacement treatment improves clinical pregnancy in frozen-thawed embryos transfer cycles: a retrospective cohort study. Am J Transl Res. 2013;6(1):85–90.
[73]. Shen MS, Wang CW, Chen CH, et al. New horizon on successful management for a woman with repeated implantation failure due to unresponsive thin endometrium: use of extended estrogen supplementation. J Obstet Gynaecol Res. 2013;39(5):1092–1094. doi:10.1111/j.1447-0756.2012.02070.x.
[74]. de Ziegler D, Meldrum DR. From in vitro fertilization (IVF) to menopause: physiologic hormone replacement adapted from donor egg IVF may be our best option for hormone therapy. Fertil Steril. 2003;80(3):485–487. doi:10.1016/s0015-0282(03)00995-6.
[75]. Mansour R, Tawab N, Kamal O, et al. Intrauterine injection of human chorionic gonadotropin before embryo transfer significantly improves the implantation and pregnancy rates in in vitro fertilization/intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril. 2011;96(6):1370–4.e1. doi:10.1016/j.fertnstert.2011.09.044.
[76]. Theofanakis C, Athanasiou V, Liokari E, et al. The impact of HCG in IVF Treatment: Does it depend on age or on protocol? J Gynecol Obstet Hum Reprod. 2019;48(5):341–345. doi:10.1016/j.jogoh.2019.02.012.
[77]. Hoshina M, Boothby M, Hussa R, et al. Linkage of human chorionic gonadotrophin and placental lactogen biosynthesis to trophoblast differentiation and tumorigenesis. Placenta. 1985;6(2):163–172. doi:10.1016/s0143-4004(85)80066-7.
[78]. Theofanakis C, Drakakis P, Besharat A, et al. Human chorionic gonadotropin: the pregnancy hormone and more. Int J Mol Sci. 2017;18(5):1059–1067. doi:10.3390/ijms18051059.
[79]. Licht P, Russu V, Lehmeyer S, et al. Intrauterine microdialysis reveals cycle-dependent regulation of endometrial insulin-like growth factor binding protein-1 secretion by human chorionic gonadotropin. Fertil Steril. 2002;78(2):252–258. doi:10.1016/s0015-0282(02)03226-0.
[80]. Gao M, Jiang X, Li B, et al. Intrauterine injection of human chorionic gonadotropin before embryo transfer can improve in vitro fertilization-embryo transfer outcomes: a meta-analysis of randomized controlled trials. Fertil Steril. 2019;112(1):89–97 e1. doi:10.1016/j.fertnstert.2019.02.027.
[81]. Hull KL, Harvey S. Growth hormone and reproduction: a review of endocrine and autocrine/paracrine interactions. Int J Endocrinol. 2014;2014:234014. doi:10.1155/2014/234014.
[82]. Wang XM, Hong J, Zhang WX, et al. The effects of growth hormone on clinical outcomes after frozen-thawed embryo transfer. Int J Gynaecol Obstet. 2016;133(3):347–350. doi:10.1016/j.ijgo.2015.10.020.
[83]. Altmäe S, Mendoza-Tesarik R, Mendoza C, et al. Effect of growth hormone on uterine receptivity in women with repeated implantation failure in an oocyte donation program: a randomized controlled trial. J Endocrinol Soc. 2017;2(1):96–105. doi:10.1210/js.2017-00359.
[84]. Cui N, Li AM, Luo ZY, et al. Effects of growth hormone on pregnancy rates of patients with thin endometrium. J Endocrinol Invest. 2019;42(1):27–35. doi:10.1007/s40618-018-0877-1.
[85]. Tamura H, Takasaki A, Taketani T, et al. Melatonin and female reproduction. J Obstet Gynaecol Res. 2014;40(1):1–11. doi:10.1111/jog.12177.
[86]. Mosher AA, Tsoulis MW, Lim J, et al. Melatonin activity and receptor expression in endometrial tissue and endometriosis. Hum Reprod. 2019;34(7):1215–1224. doi:10.1093/humrep/dez082.
[87]. He C, Wang J, Li Y, et al. Melatonin-related genes expressed in the mouse uterus during early gestation promote embryo implantation. J Pineal Res. 2015;58(3):300–309. doi:10.1111/jpi.12216.
[88]. Guan S, Xie L, Ma T, et al. Effects of melatonin on early pregnancy in mouse: involving the regulation of StAR, Cyp11a1, and Ihh expression. Int J Mol Sci. 2017;18(8):1637. doi:10.3390/ijms18081637.
[89]. King AE, Critchley HO, Kelly RW. Innate immune defences in the human endometrium. Reprod Biol Endocrinol. 2003;1:116. doi:10.1186/1477-7827-1-116.
[90]. Davari-Tanha F, Shahrokh Tehraninejad E, Ghazi M, et al. The role of G-CSF in recurrent implantation failure: A randomized double blind placebo control trial. Int J Reprod Biomed. 2016;14(12):737–742.
[91]. Yakin K, Oktem O, Urman B. Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: a systematic review and meta-analysis. Sci Rep. 2019;9(1):3897–3904. doi:10.1038/s41598-019-40521-w.
[92]. Nazari L, Salehpour S, Hoseini S, et al. Effects of autologous platelet-rich plasma on implantation and pregnancy in repeated implantation failure: a pilot study. Int J Reprod Biomed. 2016;14(10):625–628.
[93]. Plaçais L, Kolanska K, Kraiem YB, et al. Intralipid therapy for unexplained recurrent miscarriage and implantation failure: case-series and literature review. Eur J Obstet Gynecol Reprod Biol. 2020;252:100–104. doi:10.1016/j.ejogrb.2020.06.017.
[94]. Ahmadi M, Abdolmohammadi-Vahid S, Ghaebi M, et al. Regulatory T cells improve pregnancy rate in RIF patients after additional IVIG treatment. Syst Biol Reprod Med. 2017;63(6):350–359. doi:10.1080/19396368.2017.1390007.
[95]. Würfel W. Treatment with granulocyte colony-stimulating factor in patients with repetitive implantation failures and/or recurrent spontaneous abortions. J Reprod Immunol. 2015;108:123–135. doi:10.1016/j.jri.2015.01.010.
[96]. Santjohanser C, Knieper C, Franz C, et al. Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage. Arch Immunol Ther Exp. 2013;61(2):159–164. doi:10.1007/s00005-012-0212-z.
[97]. Rahmati M, Petitbarat M, Dubanchet S, et al. Granulocyte-colony stimulating factor related pathways tested on an endometrial ex-vivo model. PLoS One. 2014;9(10):e102286. doi:10.1371/journal.pone.0102286.
[98]. Weissman A, Horowitz E, Ravhon A, et al. Pregnancies and live births following ICSI with testicular spermatozoa after repeated implantation failure using ejaculated spermatozoa. Reprod Biomed Online. 2008;17(5):605–609. doi:10.1016/s1472-6483(10)60306-9.
[99]. Li J, Mo S, Chen Y. The effect of G-CSF on infertile women undergoing IVF treatment: a meta-analysis. Syst Biol Reprod Med. 2017;63(4):239–247. doi:10.1080/19396368.2017.1287225.
[100]. Nakayama T, Fujiwara H, Maeda M, et al. Human peripheral blood mononuclear cells (PBMC) in early pregnancy promote embryo invasion in vitro: HCG enhances the effects of PBMC. Hum Reprod. 2002;17(1):207–212. doi:10.1093/humrep/17.1.207.
[101]. Egawa H, Fujiwara H, Hirano T, et al. Peripheral blood mononuclear cells in early pregnancy promote invasion of human choriocarcinoma cell line, BeWo cells. Hum Reprod. 2002;17(2):473–480. doi:10.1093/humrep/17.2.473.
[102]. Okitsu O, Kiyokawa M, Oda T, et al. Intrauterine administration of autologous peripheral blood mononuclear cells increases clinical pregnancy rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. Am J Reprod Immunol. 2011;92(1):82–87. doi:10.1016/j.jri.2011.07.001.
[103]. Li S, Wang J, Cheng Y, et al. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol. 2017;119:15–22. doi:10.1016/j.jri.2016.11.006.
[104]. Nobijari FF, Arefi SS, Moini A, et al. Endometrium immunomodulation by intrauterine insemination administration of treated peripheral blood mononuclear cell prior frozen/thawed embryos in patients with repeated implantation failure. Zygote. 2019;27(4):214–218. doi:10.1017/S0967199419000145.
[105]. Chang Y, Li J, Chen Y, et al. Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in vitro fertilization. Int J Clin Exp Med. 2015;8(1):1286–1290.
[106]. Tandulwadkar SR, Naralkar MV, Surana AD, et al. Autologous intrauterine platelet-rich plasma instillation for suboptimal endometrium in frozen embryo transfer cycles: A pilot study. J Hum Reprod Sci. 2017;10(3):208–212. doi:10.4103/jhrs.JHRS_28_17.
[107]. Bos-Mikich A, de Oliveira R, Frantz N. Platelet-rich plasma therapy and reproductive medicine. J Assist Reprod Genet. 2018;35(5):753–756. doi:10.1007/s10815-018-1159-8.
[108]. Ehrlich R, Hull ML, Walkley J, et al. Intralipid immunotherapy for repeated IVF failure. Fertil Steril. 2019;01(04):154–160. doi:10.1142/S2661318219500178.
[109]. Lédée N, Vasseur C, Petitbarat M, et al. Intralipid® may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation. J Reprod Immunol. 2018;130:18–22. doi:10.1016/j.jri.2018.09.050.
[110]. Singh N, Davis AA, Kumar S, et al. The effect of administration of intravenous intralipid on pregnancy outcomes in women with implantation failure after IVF/ICSI with non-donor oocytes: a randomised controlled trial. Eur J Obstet Gynecol Reprod Biol. 2019;240:45–51. doi:10.1016/j.ejogrb.2019.06.007.
[111]. Al-Zebeidi J, Agdi M, Lary S, et al. Effect of empiric intravenous intralipid therapy on pregnancy outcome in women with unexplained recurrent implantation failure undergoing intracytoplasmic sperm injection-embryo transfer cycle: a randomized controlled trial. Gynecol Endocrinol. 2020;36(2):131–134. doi:10.1080/09513590.2019.1631280.
[112]. Kumar P, Marron K, Harrity C. Intralipid therapy and adverse reproductive outcome: is there any evidence? Reprod Fertil. 2021;2(3):173–186. doi:10.1530/RAF-20-0052.
[113]. Ramos-Medina R, García-Segovia A, Gil J, et al. Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion. Am J Reprod Immunol. 2014;71(5):458–466. doi:10.1111/aji.12217.
[114]. Abdolmohammadi-Vahid S, Pashazadeh F, Pourmoghaddam Z, et al. The effectiveness of IVIG therapy in pregnancy and live birth rate of women with recurrent implantation failure (RIF): a systematic review and meta-analysis. J Reprod Immunol. 2019;134-135:28–33. doi:10.1016/j.jri.2019.07.006.
[115]. Ruiz JE, Kwak JYH, Baum L, et al. Effect of intravenous immunoglobulin G on natural killer cell cytotoxicity in vitro in women with recurrent spontaneous abortion. J Reprod Immunol. 1996;31(1):125–141. doi:10.1016/0165-0378(96)00969-2.
[116]. Jiang D, Li L, Wan S, et al. Acupuncture and Chinese herbal medicine effects on assisted reproductive technology: six cases and their clinical significance. Med Acupunct. 2019;31(6):395–406. doi:10.1089/acu.2019.1338.
[117]. Guo J, Li D, Liu C, et al. Effects of Chinese herbs combined with in vitro fertilization and embryo transplantation on infertility: a clinical randomized controlled trial. J Tradit Chin Med. 2014;34(3):267–273. doi:10.1016/s0254-6272(14)60089-3.
[118]. Kim EY, Choi HJ, Chung TW, et al. Water-extracted Perilla frutescens increases endometrial receptivity though leukemia inhibitory factor-dependent expression of integrins. J Pharmacol Sci. 2016;131(4):259–266. doi:10.1016/j.jphs.2016.07.004.
[119]. Choi HJ, Chung TW, Park MJ, et al. Paeonia lactiflora enhances the adhesion of trophoblast to the endometrium via induction of leukemia inhibitory factor expression. PLoS One. 2016;11(2):e0148232. doi:10.1371/journal.pone.0148232.
[120]. Park HR, Choi HJ, Kim BS, et al. Paeoniflorin enhances endometrial receptivity through leukemia inhibitory factor. Biomolecules. 2021;11(3):439–443. doi:10.3390/biom11030439.
[121]. Hatcher RA, Kowal D. Birth control. Walker HK, Hall WD, Hurst JW, ed. In: Clinical Methods: The History, Physical, and Laboratory Examinations 3rd edition. Boston: Butterworths1990.
[122]. Curtis KM, Tepper NK, Marchbanks PA. Contraceptive use: guidelines and effectiveness. Shoupe D. ed. In: Contraception. Blackwell Publishing Ltd2011. p. 1–12. doi: 10.1002/9781444342642.
[123]. Upadhya KK. Emergency contraception. Pediatrics. 2019;144(6):e20193149. doi:10.1542/peds.2019-3149.
[124]. Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am J Public Health. 2014;104(S1):S43–S48. doi:10.2105/AJPH.2013.301416.
[125]. Krisberg K. Deaths due to unintended pregnancies on the rise. Nations Health. 2002;32(10):12.
[126]. Yuzpe AA, Lancee WJ. Ethinylestradiol and dl-norgestrel as a postcoital contraceptive. Fertil Steril. 1977;28(9):932–936.
[127]. do Nascimento JA, Seppala M, Perdigão A, et al. In vivo assessment of the human sperm acrosome reaction and the expression of glycodelin-A in human endometrium after levonorgestrel-emergency contraceptive pill administration. Hum Reprod. 2007;22(8):2190–2195. doi:10.1093/humrep/dem119.
[128]. Munuce MJ, Nascimento JA, Rosano G, et al. In vitro effect of levonorgestrel on sperm fertilizing capacity and mouse embryo development. Contraception. 2005;72(1):71–76. doi:10.1016/j.contraception.2004.12.003.
[129]. Hermanny A, Bahamondes MV, Fazano F, et al. In vitro assessment of some sperm function following exposure to levonorgestrel in human fallopian tubes. Reprod Biol Endocrinol. 2012;10:8. doi:10.1186/1477-7827-10-8.
130]. Shohel M, Rahman MM, Zaman A, et al. A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception. BMC Womens Health. 2014;14:54. doi:10.1186/1472-6874-14-54.
[131]. Rosato E, Farris M, Bastianelli C. Mechanism of action of ulipristal acetate for emergency contraception: A systematic review. Front Pharmacol. 2015;6:315. doi:10.3389/fphar.2015.00315.
[132]. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64(4):227–234. doi:10.1016/s0010-7824(01)00250-5.
[133]. Gemzell-Danielsson K, Svalander P, Swahn ML, et al. Effects of a single post-ovulatory dose of RU486 on endometrial maturation in the implantation phase. Hum Reprod. 1994;9(12):2398–2404. doi:10.1093/oxfordjournals.humrep.a138458.
[134]. Mozzanega B, Nardelli GB. UPA and LNG in emergency contraception: the information by EMA and the scientific evidences indicate a prevalent anti-implantation effect. Eur J Contracept Reprod Health Care. 2019;24(1):4–10. doi:10.1080/13625187.2018.1555662.
[135]. Matsuo M, Hirota Y, Fukui Y, et al. Levonorgestrel inhibits embryo attachment by eliminating uterine induction of leukemia inhibitory factor. Endocrinology. 2019;161(2):bqz005. doi:10.1210/endocr/bqz005.
[136]. Dalal J, Kumar P, Chandolia RK, et al. A new role for RU486 (mifepristone): it protects sperm from premature capacitation during cryopreservation in buffalo. Sci Rep. 2019;9(1):6712. doi:10.1038/s41598-019-43038-4.
[137]. Ko JK, Huang VW, Li RH, et al. An in vitro study of the effect of mifepristone and ulipristal acetate on human sperm functions. Andrology. 2014;2(6):868–874. doi:10.1111/j.2047-2927.2014.00261.x.
[138]. Brache V, Cochon L, Jesam C, et al. Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture. Hum Reprod. 2010;25(9):2256–2263. doi:10.1093/humrep/deq157.
[139]. Brache V, Cochon L, Deniaud M, et al. Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens. Contraception. 2013;88(5):611–618. doi:10.1016/j.contraception.2013.05.010.
[140]. Gemzell-Danielsson K, Marions L. Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception. Hum Reprod Update. 2004;10(4):341–348. doi:10.1093/humupd/dmh027.
[141]. Marions L, Cekan SZ, Bygdeman M, et al. Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function. Contraception. 2004;69(5):373–377. doi:10.1016/j.contraception.2003.11.018.
[142]. Liu JH, Garzo G, Morris S, et al. Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486. J Clin Endocrinol Metab. 1987;65(6):1135–1140. doi:10.1210/jcem-65-6-1135.
[143]. Jamin C. Emergency contraception: efficacy difference between levonorgestrel and ulipristal acetate depending on the follicular size at the time of an unprotected sexual intercourse. Gynecol Obstet Fertil. 2015;43(3):242–247. doi:10.1016/j.gyobfe.2015.01.010.
[144]. Marions L, Hultenby K, Lindell I, et al. Emergency contraception with mifepristone and levonorgestrel: mechanism of action. Obstet Gynecol. 2002;100(1):65–71. doi:10.1016/s0029-7844(02)02006-9.
[145]. Lalitkumar PG, Lalitkumar S, Meng CX, et al. Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model. Hum Reprod. 2007;22(11):3031–3037. doi:10.1093/humrep/dem297.
[146]. Ho PC, Yu Ng EH, Tang OS. Mifepristone: contraceptive and non-contraceptive uses. Curr Opin Obstet Gynecol. 2002;14(3):325–330. doi:10.1097/00001703-200206000-00013.
[147]. Sarkar NN. The potential of mifepristone (RU-486) as an emergency contraceptive drug. Acta Obstet Gynecol Scand. 2005;84(4):309–316. doi:10.1111/j.0001-6349.2005.00418.x.
[148]. Jin J, Weisberg E, Fraser IS. Comparison of three single doses of mifepristone as emergency contraception: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2005;45(6):489–494. doi:10.1111/j.1479-828X.2005.00483.x.
[149]. Watamoto T, Egusa H, Sawase T, et al. Screening of pharmacologically active small molecule compounds identifies antifungal agents against Candida biofilms. Front Microbiol. 2015;6:1453. doi:10.3389/fmicb.2015.01453.
[150]. Xu M, Lee EM, Wen Z, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016;22(10):1101–1107. doi:10.1038/nm.4184.
[151]. Sherman SP, Bang AG. High-throughput screen for compounds that modulate neurite growth of human induced pluripotent stem cell-derived neurons. Dis Model Mech. 2018;11(2):dmm031906. doi:10.1242/dmm.031906.
[152]. Chamoun AM, Chockalingam K, Bobardt M, et al. PD 404,182 is a virocidal small molecule that disrupts hepatitis C virus and human immunodeficiency virus. Antimicrob Agents Chemother. 2012;56(2):672–681. doi:10.1128/AAC.05722-11.
[153]. Al Haj Zen A, Nawrot DA, Howarth A, et al. The retinoid agonist Tazarotene promotes angiogenesis and wound healing. Mol Ther. 2016;24(10):1745–1759. doi:10.1038/mt.2016.153.
[154]. Perusini SJ. High-throughput screen to identify small molecule inhibitors of the canonical Wnt signaling pathway [MSc_thesis]: University of Toronto2008.
[155]. Vliet SM, Ho TC, Volz DC. Behavioral screening of the LOPAC1280 library in zebrafish embryos. Toxicol Appl Pharmacol. 2017;329:241–248. doi:10.1016/j.taap.2017.06.011.
[156]. Tran TC, Sneed B, Haider J, et al. Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish. Cancer Res. 2007;67(23):11386–11392. doi:10.1158/0008-5472.CAN-07-3126.
[157]. Ho H, Singh H, Aljofan M, et al. A high-throughput in vitro model of human embryo attachment. Fertil Steril. 2012;97(4):974–978. doi:10.1016/j.fertnstert.2012.01.116.
[158]. Chen X, Fernando SR, Lee YL, et al. High-throughput in vitro screening identified nemadipine as a novel suppressor of embryo implantation. Int J Mol Sci. 2022;23(9):5073. doi:10.3390/ijms23095073.
[159]. Ruan YC, Chen H, Chan HC. Ion channels in the endometrium: regulation of endometrial receptivity and embryo implantation. Hum Reprod Update. 2014;20(4):517–529. doi:10.1093/humupd/dmu006.
[160]. Ruan YC, Guo JH, Liu X, et al. Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation. Nat Med. 2012;18(7):1112–1127. doi:10.1038/nm.2771.
[161]. Ruan YC, Wang Z, Du JY, et al. Regulation of smooth muscle contractility by the epithelium in rat vas deferens: role of ATP-induced release of PGE2. J Physiol. 2008;586(20):4843–4857. doi:10.1113/jphysiol.2008.154096.
[162]. Banerjee A, Padh H, Nivsarkar M. Role of the calcium channel in blastocyst implantation: a novel contraceptive target. J Basic Clin Physiol Pharmacol. 2009;20(1):43–53. doi:10.1515/jbcpp.2009.20.1.43.
[163]. Choi Y, Jang H, Seo H, et al. Changes in calcium levels in the endometrium throughout pregnancy and the role of calcium on endometrial gene expression at the time of conceptus implantation in pigs. Mol Reprod Dev. 2019;86(7):883–895. doi:10.1002/mrd.23166.
Keywords:

Embryo implantation; Endometrial receptivity; In vitro fertilization; Repeated implantation failure; Birth control; Emergency contraception

Copyright © 2022 Reproductive and Developmental Medicine, Published by Wolters Kluwer Health, Inc.