Abstract

Endometrial receptivity disorder is the leading cause for failed embryonic implantation. Recently, the methods to ameliorate endometrial receptivity, to improve the success rate and increase the clinical pregnancy rate of in vitro fertilization-embryo transfer (IVF-ET) technology has become a research hotspot. In this article, we describe the treatment methods and elaborate the latest progress made in improving endometrial receptivity in the recent years.

Keywords: Repeated implantation failure (RIT); In vitro fertilization-embryo transfer (IVF-ET); Endometrial receptivity; Therapies

Introduction

Repeated implantation failure (RIF) implies at least 3 consecutive treatment cycles of failed in vitro fertilization-embryo transfer (IVF-ET), in which 1 or 2 quality embryos are implanted in each treatment cycle. RIF has gradually become the major problem that undermines the pregnancy rate of IVF [1]. A good endometrial tolerance is an important factor to ensure the implantation, growth and development of embryos; defective endometrial receptivity is one of the principal causes of RIF [2]. Previous studies have shown that endometrial thickness varies periodically within the menstrual cycle, and that maintaining a certain thickness of the endometrium during the planting window is conducive to increasing the success rate of embryo implantation [3]. The etiology and the underlying mechanism of low endometrial receptivity remain unclear. Clinically treatments are carried out to increase endometrial thickness, ameliorate endometrial blood flow, induce the secretion of regulative cytokines, and enhance the expression of pinopodes, which is the marker of endometrial receptivity in clinical practice.

Chemical Medicine and Hormone-Replacement Therapy

The human endometrium is a fluctuating and complex multicellular tissue that is affected by ovarian-derived steroid hormones. In the event of reduced ER level caused by low estrogen levels in the body and intrauterine adhesions, high doses of estrogen are used to promote endometrial regeneration [4]. Estrogen binds to the estrogen receptor and regulates cell-specific transcription of the target tissue, thereby exerting its cell proliferative effect. Under the effect of estrogen, the endometrium becomes thicker; with the synergistic effect of progesterone, the hyperplastic endometrium is transformed to enter the secretory phase [5]. Shen MS et al. [6] reported one case of patient receiving IVF-ET with repetitive failed implantation due to thin endometrium, and that the extended treatment of estrogen effectively guarantees the pregnancy and the subsequent delivery of twins. Currently, the medications used to improve endometrial microcirculation include aspirin, low molecular weight heparin (LMWH), microbial E and so on [7].

In recent years, the application of aspirin in assisting reproduction has received increasing attention. Studies indicate that [4], aspirin increases the blood flow of the uterine artery by inhibiting platelet aggregation. LMWH can prevent thrombosis formation in embryonic sites and placenta attachment sites in patients with thrombotic tendency during early pregnancy. Moreover, Aspirin can regulate the expression of certain cytokines and growth factors in the endometrium, thereby promoting its decidualization and providing a good environment for embryo implantation [8]. As one of the most important antioxidants in the human body, Vitamin E also exhibits the effect of dilating blood vessels. Wilkens [9] observed that vitamin E increases the endometrial glands of patients and promote the development of blood vessels, to improve endometrial receptivity.

Surgical Treatment

Hysteroscopic surgery can detect and treat small lesions in the uterine cavity, therefore it has become an important means for the diagnosis and treatment of uterine cavity abnormalities [10]. The operation of Hysteroscopic surgery is simple. Under the visual condition, it can reveal whether there is an anatomical abnormality in the uterine cavity with good recognition and great accuracy. Studies have confirmed that [11] hysteroscopic endometrial minimally invasive surgery can clarify the morphological classification of endometrium, improve the distribution of blood flow and induce the development of endometrial vesicle, thereby enhancing endometrial receptivity. The clinical application value of hysteroscopic endometrial minimally invasive surgery has been corroborated regarding improving endometrial receptivity.

Stem Cells and Granulocyte Colony-Stimulating Factor (G-CSF)

Bone marrow mesenchymal stem cells (BMSCs) can differentiate into tissue cells belonging to three germ layers under specific induction conditions [12]. Zhao [13] injected BMSCs into the uterine cavity of SD rats with thin endometrium and found that the endometrium of rats was significantly thickened. Therefore, the researchers rationally speculated that BMSCs can differentiate directly into endometrial cells in the uterine cavity or stimulate the proliferation of endometrial cells through the secretion of cytokines and immune regulation. The effect stimulates proliferation of endometrial cells. It is suggested that stem cell perfusion not only improves the regeneration ability of the endometrium, but also raises endometrial receptivity. However, the perfusion of BMSCs is constrained in animal experiments only. More clinical trials are needed to confirm the effectiveness and safety of transplantation in vivo.

G-CSF is also used to treat RIF, owing to the main mechanism of stimulating the maturation of granulocyte and macrophage, promote the release of mature cells to the peripheral blood, and stimulate the multiple functions of macrophages and eosinophils [14]. Kunicki M et al. [15] conducted clinical study on 37 patients with thin endometrium (<7mm during ovulation) who received IVF-ET treatment, reporting that G-CSF intrauterine significantly increased the thickness of endometrium from 6.74±1.75 mm to 8.42 ±1.73 mm (mean ± SD). G-CSF is of great significance in endometrial regulation throughout the human menstrual cycles. However, due to its distressing side effects and high price, G-CSF has not yet been widely used in clinical practice. In addition, therapies of growth hormone (Gn), biofeedback (BF), and platelet-rich plasma (PRP) [16] are currently used to enhance endometrial receptivity.

Traditional Chinese Medicine (TCMs)

The history of using traditional Chinese medicine in treating gynecological diseases dates to long ago. The efficacy of numerous TCMs to improve endometrial receptivity has been confirmed. Wu Xiaoyu [17] observed that human placenta shows a certain effect on improving the endometrial receptivity of rats in an apparent dose-dependent manner. Ma Rong et al. [18] believe that Bushen Tiaochong recipe can improve the endometrial receptivity of patients with the obesity PCOS infertility.

Acupuncture

A plethora of evidence in recent years have highlighted the significant effect of acupuncture in assisting the treatment of infertility, especially regarding its low side effects in improving endometrial receptivity. Yan Honglian [19] suggested that performing acupuncture treatment 24 hours before transplantation and 30 minutes after transplantation alleviated the blood supply in the endometrium of patients who underwent IVF-ET. In addition, it is found that transcutaneous acupoint electrical stimulation (TAES) [20] can improve endometrial blood supply and regulate estrogen levels in the serum, thereby improving endometrial receptivity and enhancing clinical pregnancy rate.

Conclusion

At present, achievements have been made in the researches of improving endometrial receptivity and clinical pregnancy rate. These results bring good news to infertile patients, especially to those who have suffered from repeated failed implantations. Some patients have achieved favorable clinical efficacy. Nevertheless, given the lack of in-depth experimental researches and the limited number of clinical cases, the clinical application of some newly emerged methods is under constraint. In clinical applications, these methods should be handled with great discretion, with special attention paying to the possible side effects of medications and operational complications.

Acknowledgement

None.

References

• Cao H, You D, Yuan M, Xi M (2018) Hysteroscopy after repeated implantation failure of assisted reproductive technology: A meta‐analysis. Journal of Obstetrics and Gynaecology Research 44(3): 365-373.
• Wang W-j, Zhang H, Chen Z-q, Zhang W, Liu X-m, et al. (2019) Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis. Reproductive Biology and Endocrinology 17(1): 2.
• Wu F, Chen X, Liu Y, Liang B, Xu H, et al. (2018) Decreased MUC1 in endometrium is an independent receptivity marker in recurrent implantation failure during implantation window. Reproductive Biology and Endocrinology 16(1): 60.
• Chi Y, He P, Lei L, Lan Y, Hu J, et al. (2018) Transdermal estrogen gel and oral aspirin combination therapy improves fertility prognosis via the promotion of endometrial receptivity in moderate to severe intrauterine adhesion. Molecular Medicine Reports 17(5): 6337-6344.
• de Ziegler D, Pirtea P, Fanchin R, Ayoubi JM (2018) Ovarian reserve in polycystic ovary syndrome: more, but for how long? Fertility and Sterility 109(3): 448-449.
• Shen MS, Wang CW, Chen CH, Tzeng CR (2013) New horizon on successful management for a woman with repeated implantation failure due to unresponsive thin endometrium: use of extended estrogen supplementation. Journal of Obstetrics and Gynaecology Research 39(5): 1092-1094.
• Quao ZC, Tong M, Bryce E, Guller S, Chamley LW, et al. (2018) Low molecular weight heparin and aspirin exacerbate human endometrial endothelial cell responses to antiphospholipid antibodies. American Journal of Reproductive Immunology 79(1).
• Sadowski R, Gadzała-Kopciuch R, Buszewski B (2019) Recent Developments in the Separation of Low Molecular Weight Heparin Anticoagulants. Current Medicinal Chemistry 26(1): 166-176.
• Wilkens J, Male V, Ghazal P, Forster T, Gibson DA, et al. (2013) Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil. The Journal of Immunology 191(5): 2226-2235.
• Franchini M, Lippi G, Calzolari S, Giarrè G, Gubbini G, et al. (2018) Hysteroscopic endometrial polypectomy: clinical and economic data in decision making. Journal of Minimally Invasive Gynecology 25(3): 418-425.
• Li X-C, Liang C-X, Li J, Li P-F, Zhao Y (2016) Effect of hysteroscopic adhesiolysis combined with growth hormone on endometrial blood flow and volume as well as Smad2/3 expression. Journal of Hainan Medical University 22(6): 1-4.
• Jing H, Su X, Gao B, Shuai Y, Chen J, et al. (2018) Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis. Cell Death & Disease 9(2): 176.
• Zhao J, Zhang Q, Wang Y, Li Y (2015) Uterine infusion with bone marrow mesenchymal stem cells improves endometrium thickness in a rat model of thin endometrium. Reproductive Sciences 22(2): 181-188.
• Kamath MS, Chittawar PB, Kirubakaran R, Mascarenhas M (2017) Use of Granulocyte-colony stimulating factor in assisted reproductive technology: A systematic review and meta-analysis. European Journal of Obstetrics & Gynecology and Reproductive Biology 214: 16-24.
• Kunicki M, Łukaszuk K, Woclawek-Potocka I, Liss J, Kulwikowska P, et al. (2014) Evaluation of granulocyte colony-stimulating factor effects on treatment-resistant thin endometrium in women undergoing in vitro fertilization. BioMed Research International 2014(3): 913235.
• Bos-Mikich A, Ferreira MO, de Oliveira R, Frantz N (2019) Platelet-rich plasma or blood-derived products to improve endometrial receptivity? Journal of Assisted Reproduction and Genetics 36(4): 613-620.
• Wu XY, Shi XL, Ling N (2017) Experimental study on endometrial receptivity of chinese medicine zihe che to superovulation rats. Journal of Liaoning University of Traditional Chinese Medicine (11): 46-48.
• Ma R, Wang XM, Zhu XL (2018) Effect of Bushen Tiaochong Recipe on infertility in obese polycystic ovary syndrome and its influence on endometrial receptivity. Chinese Journal of Experimental Formulaology (5): 188-192.
• Yan HL, He SZ, Xing YJ, Luo XD, Lin B, et al. (2015) Clinical application of acupuncture treatment in in vitro fertilization-embryo transfer. Guangzhou Pharmaceutical 46(1): 13-16.
• Yang J, Feng TT, Sun W, Feng XJ, Xu D, et al. (2017) Effect of endometrial light scraping combined with percutaneous acupoint electrical stimulation on thawed embryo transfer in patients with repeated implantation failure. Journal of Reproductive Medicine 26(3): 238-243.

Abstract

Endometrial receptivity disorder is the leading cause for failed embryonic implantation. Recently, the methods to ameliorate endometrial receptivity, to improve the success rate and increase the clinical pregnancy rate of in vitro fertilization-embryo transfer (IVF-ET) technology has become a research hotspot. In this article, we describe the treatment methods and elaborate the latest progress made in improving endometrial receptivity in the recent years.

Keywords: Repeated implantation failure (RIT); In vitro fertilization-embryo transfer (IVF-ET); Endometrial receptivity; Therapies