Successful treatment with intrauterine delivery of dexamethasone for repeated implantation failure
Tao Zhang
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorChunyu Huang
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorYan Du
Office of Clinical Epidemiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
Search for more papers by this authorRuochun Lian
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorMeilan Mo
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorCorresponding Author
Yong Zeng
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Correspondence
Yong Zeng, Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China.
Email: [email protected]
Search for more papers by this authorGil Mor
Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
Search for more papers by this authorTao Zhang
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorChunyu Huang
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorYan Du
Office of Clinical Epidemiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
Search for more papers by this authorRuochun Lian
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorMeilan Mo
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Search for more papers by this authorCorresponding Author
Yong Zeng
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen, China
Correspondence
Yong Zeng, Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China.
Email: [email protected]
Search for more papers by this authorGil Mor
Division of Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
Search for more papers by this authorAbstract
Problem
Effective therapy for endometrial receptivity of patients with repeated embryo implantation failure (RIF) is far undeveloped. Whether intrauterine perfusion of dexamethasone (DXM), local administration of drugs with less systematic side-effects, benefit for embryo implantation by suppressing uterine NK (uNK) cells to improve endometrial receptivity remains unknown.
Method of study
Women with RIF were analyzed for the correlation between the percentage of uNK cells during implantation window and following clinical pregnancy rate to determine the appropriate range of uNK for embryo implantation. Women with RIF and extremely increased uNK cells were treated with transvaginal intrauterine perfusion of DXM. Quantification of uNK cells before and after this treatment was analyzed by immunohistochemistry staining for understanding potential underlying mechanism. Pregnancy outcome was evaluated for the efficiency and safety of this novel therapy.
Results
The clinical pregnancy rate was decreased if the percentage of uNK cells was higher than the 75th percentile (18.06%), which was considered as the cutoff value for increased uNK cells. All eight patients with increased uNK cells responded to DXM-induced decrease on uNK cells number, and seven got clinical pregnancy. Three delivered with a healthy baby at term without any pregnancy complication and three achieved an ongoing pregnancy, but one suffered from early miscarriage.
Conclusion
We report for the first time the beneficial effect of intrauterine perfusion of DXM for patients with RIF characterized by high number of uNK cells. The potential mechanism is downregulation of the proportion of uNK cells, which may improve endometrial receptivity and enhance embryo implantation.
REFERENCES
- 1Xie Y, Zhang T, Tian Z, et al. Efficacy of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) for infertile women with thin endometrium: a systematic review and meta-analysis. Am J Reprod Immunol. 2017; 78: e12701.
- 2Kwak-Kim J, Han AR, Gilman-Sachs A, Fishel S, Leong M, Shoham Z. Current trends of reproductive immunology practices in in vitro fertilization (IVF)—a first world survey using IVF-Worldwide.com. Am J Reprod Immunol. 2013; 69: 12-20.
- 3Nakagawa K, Kwak-Kim J, Ota K, et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015; 73: 353-361.
- 4Mekinian A, Cohen J, Alijotas-Reig J, et al. Unexplained recurrent miscarriage and recurrent implantation failure: Is there a place for immunomodulation? Am J Reprod Immunol. 2016; 76: 8-28.
- 5Ledee N, Petitbarat M, Chevrier L, et al. The uterine immune profile may help women with repeated unexplained embryo implantation failure after in vitro fertilization. Am J Reprod Immunol. 2016; 75: 388-401.
- 6Diaz-Gimeno P, Ruiz-Alonso M, Blesa D, et al. The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertil Steril. 2013; 99: 508-517.
- 7Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006; 12: 731-746.
- 8Chen X, Man GCW, Liu Y, et al. Physiological and pathological angiogenesis in endometrium at the time of embryo implantation. Am J Reprod Immunol. 2017; 78: e12693.
- 9Gnainsky Y, Dekel N, Granot I. Implantation: mutual activity of sex steroid hormones and the immune system guarantee the maternal-embryo interaction. Semin Reprod Med. 2014; 32: 337-345.
- 10Man GCW, Zhang T, Chen X, et al. The regulations and role of circadian clock and melatonin in uterine receptivity and pregnancy—an immunological perspective. Am J Reprod Immunol. 2017; 78: e12715.
- 11Dekel N, Gnainsky Y, Granot I, Racicot K, Mor G. The role of inflammation for a successful implantation. Am J Reprod Immunol. 2014; 72: 141-147.
- 12Dekel N, Gnainsky Y, Granot I, Mor G. Inflammation and implantation. Am J Reprod Immunol. 2010; 63: 17-21.
- 13Fujiwara H, Araki Y, Imakawa K, et al. Dual positive regulation of embryo implantation by endocrine and immune systems—step-by-step maternal recognition of the developing embryo. Am J Reprod Immunol. 2016; 75: 281-289.
- 14Quenby S, Nik H, Innes B, et al. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod. 2009; 24: 45-54.
- 15Quenby S, Farquharson R. Uterine natural killer cells, implantation failure and recurrent miscarriage. Reprod Biomed Online. 2006; 13: 24-28.
- 16Moraru M, Carbone J, Alecsandru D, et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol. 2012; 68: 75-84.
- 17Tuckerman E, Mariee N, Prakash A, Li TC, Laird S. Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF. J Reprod Immunol. 2010; 87: 60-66.
- 18Polanski LT, Barbosa MA, Martins WP, et al. Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature. Hum Reprod. 2014; 29: 65-75.
- 19Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril. 2005; 84: 980-984.
- 20Ogasawara M, Aoki K. Successful uterine steroid therapy in a case with a history of ten miscarriages. Am J Reprod Immunol. 2000; 44: 253-255.
- 21Raziel A, Schachter M, Strassburger D, Bern O, Ron-El R, Friedler S. Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure. Fertil Steril. 2007; 87: 198-201.
- 22Fauci AS. Mechanisms of corticosteroid action on lymphocyte subpopulations. II. Differential effects of in vivo hydrocortisone, prednisone and dexamethasone on in vitro expression of lymphocyte function. Clin Exp Immunol. 1976; 24: 54-62.
- 23Schwyzer R, Schiller PW. Hormone-receptor-relationships: synthesis and characteristics of N-epsilon-dansyllysine 21-adrenocorticotropin-(1–24)-tetrakosipeptide. Helv Chim Acta. 1971; 54: 897-904.
- 24Taniguchi F. Results of prednisolone given to improve the outcome of in vitro fertilization-embryo transfer in women with antinuclear antibodies. J Reprod Med. 2005; 50: 383-388.
- 25Robertson SA, Jin M, Yu D, et al. Corticosteroid therapy in assisted reproduction—immune suppression is a faulty premise. Hum Reprod. 2016; 31: 2164-2173.
- 26Hasegawa I, Yamanoto Y, Suzuki M, et al. Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization. Fertil Steril. 1998; 70: 1044-1048.
- 27Motteram C, Vollenhoven B, Hope N, Osianlis T, Rombauts LJ. Live birth rates after combined adjuvant therapy in IVF-ICSI cycles: a matched case-control study. Reprod Biomed Online. 2015; 30: 340-348.
- 28Ubaldi F, Rienzi L, Ferrero S, et al. Low dose prednisolone administration in routine ICSI patients does not improve pregnancy and implantation rates. Hum Reprod. 2002; 17: 1544-1547.
- 29Krigstein M, Sacks G. Prednisolone for repeated implantation failure associated with high natural killer cell levels. J Obstet Gynaecol. 2012; 32: 518-519.
- 30Santillan I, Lozano I, Illan J, et al. Where and when should natural killer cells be tested in women with repeated implantation failure? J Reprod Immunol. 2015; 108: 142-148.
- 31Kuroda K, Venkatakrishnan R, James S, et al. Elevated periimplantation uterine natural killer cell density in human endometrium is associated with impaired corticosteroid signaling in decidualizing stromal cells. J Clin Endocrinol Metab. 2013; 98: 4429-4437.
- 32Wong AW, Archer B, Mariee N, Li TC, Laird SM. Do uterine natural killer cell numbers in peri-implantation endometrium predict hypertensive disorder in pregnancy in women with a history of reproductive failure? J Reprod Immunol. 2014; 106: 34-40.
- 33Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006; 12: 1065-1074.
- 34Kwak-Kim J, Bao S, Lee SK, Kim JW, Gilman-Sachs A. Immunological modes of pregnancy loss: inflammation, immune effectors, and stress. Am J Reprod Immunol. 2014; 72: 129-140.
- 35Mor G, Aldo P, Alvero AB. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol. 2017; 17: 469-482.
- 36Pathare ADS, Zaveri K, Hinduja I. Downregulation of genes related to immune and inflammatory response in IVF implantation failure cases under controlled ovarian stimulation. Am J Reprod Immunol. 2017; 78: e12679.
- 37Senda T, Natsume N, Kuno J, Toyoda T, Shimozato K. Rate of occurrence of dexamethasone-induced cleft palate affected by uterine environment in the mouse. Plast Reconstr Surg. 2005; 115: 1208-1210.
- 38Bian X, Briggs MM, Schachat FH, Seidler FJ, Slotkin TA. Glucocorticoids accelerate the ontogenetic transition of cardiac ventricular myosin heavy-chain isoform expression in the rat: promotion by prenatal exposure to a low dose of dexamethasone. J Dev Physiol. 1992; 18: 35-42.
- 39Singh N, Toshyan V, Kumar S, Vanamail P, Madhu M. Does endometrial injury enhances implantation in recurrent in-vitro fertilization failures? A prospective randomized control study from tertiary care center. J Hum Reprod Sci. 2015; 8: 218-223.
- 40Hayashi T, Kitaya K, Tada Y, Taguchi S, Funabiki M, Nakamura Y. Single curettage endometrial biopsy injury in the proliferative phase improves reproductive outcome of subsequent in vitro fertilization-embryo transfer cycle in infertile patients with repeated embryo implantation failure. Clin Exp Obstet Gynecol. 2013; 40: 323-326.
- 41Narvekar SA, Gupta N, Shetty N, Kottur A, Srinivas M, Rao KA. Does local endometrial injury in the nontransfer cycle improve the IVF-ET outcome in the subsequent cycle in patients with previous unsuccessful IVF? A randomized controlled pilot study. J Hum Reprod Sci. 2010; 3: 15-19.
- 42Gnainsky Y, Granot I, Aldo P, et al. Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action. Reproduction. 2015; 149: 75-85.
- 43Gnainsky Y, Granot I, Aldo PB, et al. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril. 2010; 94: 2030-2036.
- 44Shahrokh-Tehraninejad E, Dashti M, Hossein-Rashidi B, Azimi-Nekoo E, Haghollahi F, Kalantari V. A randomized trial to evaluate the effect of local endometrial injury on the clinical pregnancy rate of frozen embryo transfer cycles in patients with repeated implantation failure. J Family Reprod Health. 2016; 10: 108-114.
- 45Kanazawa E, Nakashima A, Yonemoto K, et al. Injury to the endometrium prior to the frozen-thawed embryo transfer cycle improves pregnancy rates in patients with repeated implantation failure. J Obstet Gynaecol Res. 2017; 43: 128-134.