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Dallagiovanna C, Di Stefano G, Reschini M, Invernici D, Comana S, Somigliana E. Re-embarking in ART while still breastfeeding: an unresolved question. Arch Gynecol Obstet 2025; 311:555-565. [PMID: 39828777 PMCID: PMC11890365 DOI: 10.1007/s00404-025-07933-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
Infertile women may request to embark on a new course of Assisted Reproductive Technologies (ART) in pursuit of a second child while still breastfeeding their first child. Breastfeeding is a time of profound hormonal changes that may interfere with ovarian physiology and uterine receptivity. Prolactin and oxytocin can mediate a plethora of potential detrimental effects. However, robust evidence to advise in favor or against ART during breastfeeding is lacking. In this narrative review, we reviewed the literature with the intent to shed light on this neglected issue. Possible adverse effects on ART success emerged for ovulatory mechanisms, folliculogenesis, uterine contractions, uterine peristalsis, and early embryo development. A negative impact of exogeneous hormones on infant health might be considered only for stimulation cycles. Overall, most concerns can be claimed for the clinical setting of ovarian stimulation, followed by the one of embryo transfer in a natural cycle and, finally, by the embryo transfer in a hormone replacement treatment preparation. However, in general, it seems wise to wait for breastfeeding to be discontinue before re-embarking on IVF, also considering that a too short interpregnancy interval may be deleterious to pregnancy outcomes. On the other hand, one must also recognize that available evidence is insufficient to deny access to treatments for women requesting earlier access. These women must be informed regarding the non-fully reassuring evidence.
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Affiliation(s)
- Chiara Dallagiovanna
- Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via M. Fanti, 6, 20122, Milan, Italy.
| | - Giorgia Di Stefano
- Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via M. Fanti, 6, 20122, Milan, Italy
| | - Marco Reschini
- Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via M. Fanti, 6, 20122, Milan, Italy
| | - Dalila Invernici
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Sabrina Comana
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Edgardo Somigliana
- Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via M. Fanti, 6, 20122, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Li J, Mo S, Lin Z, Shi Q. Atosiban application in fresh ET cycle is effective for women undergoing repeated embryo implantation failures, especially for advanced-age obese patients. Sci Rep 2023; 13:23044. [PMID: 38155160 PMCID: PMC10754826 DOI: 10.1038/s41598-023-49773-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/12/2023] [Indexed: 12/30/2023] Open
Abstract
To assess the effect of atosiban in pregnancy outcomes of the fresh embryo transfer (ET), the retrospective cohort study was conducted. Six hundred and eighty-nine cases (using atosiban) and 1377 age and ET cycle-matched controls were collected from the January 2016 to May 2022 to perform the fresh IVF-ET cycle. The essential characteristics and pregnancy outcomes were analyzed. Conditional logistic regression analysis and subgroup analysis were performed. In the whole samples, atosiban had no effects in the pregnancy outcomes. Subgroup analyses suggested that atosiban could improve the clinical pregnancy in more than 3 ET cycles (OR 1.667, 95% CI 1.108-2.509, P = 0.014). Moreover, the improvement of clinical pregnancy was mainly present in the advanced-age women (age ≥ 35 years: OR 1.851, 95% CI 1.136-3.014, P = 0.013), obesity (BMI ≥ 24 kg/m2: OR 2.550, 95% CI 1.105-5.883, P = 0.028) and cleavage stage embryo (D3 embryo: OR 1.721, 95% CI 1.098-2.696, P = 0.018) among the repeated implantation failures (RIF). Atosiban could also improve the live birth for the obese women. Further, in the RIF, atosiban application was strongly recommended for the advanced-age infertility women, who also had the risk of obesity with the implantation of the cleavage stage embryo. In conclusion, atosiban could improve pregnancy outcomes for the advanced-age and obese women in RIF, especially while implanting the cleavage stage embryo in fresh ET cycle.
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Affiliation(s)
- Jie Li
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
- The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Sien Mo
- The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Zhong Lin
- The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Qiuling Shi
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China.
- School of Public Health, Chongqing Medical University, Chongqing, China.
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Piróg M, Jach R, Ząbczyk M, Natorska J. Increased Serum Levels of Phoenixin-14, Nesfatin-1 and Dopamine Are Associated with Positive Pregnancy Rate after Ovarian Stimulation. J Clin Med 2023; 12:6991. [PMID: 38002606 PMCID: PMC10672044 DOI: 10.3390/jcm12226991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/30/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND We study the relationship between phoenixin (PNX-14), nesfatin-1 (NES-1), dopamine (DA) and oxytocin (OT) levels together with pregnancy rates in women after ovarian stimulation (OS). METHODS In a prospective case-control study, 56 infertile women were enrolled from the Department of Gynecological Endocrinology University Hospital. Infertile women age < 40 years old, with polycystic ovary syndrome (PCOS), confirmed tubal patency and suitable sperm quality were included. Blood samples were drawn twice-before the initiation of OS and before the human chorionic gonadotropin (hCG) administration. Assessments of PNX-14, NES-1, DA and OT serum levels were performed. Pregnancy rates after OS were observed. RESULTS Pregnant women showed higher baseline NES-1 and OT levels (+29.2% and +44%) but not PNX-14 and DA levels when compared to non-pregnant ones. In pregnant women, positive correlations between OT and prolactin, PRL (r = 0.47, p = 0.04), as well as between OT and NES-1 (r = 0.55, p = 0.02), were observed at baseline. At baseline, an OT level increase was associated with a positive pregnancy rate (per 100 pg/mL, OR = 1.39, 95% CI 1.04-1.74), while after OS, higher PNX-14 was a predictor of pregnancy (by 10 pg/mL, OR = 1.23, 95%CI 1.07-1.39). Post-stimulation PNX-14, NES-1 and DA concentrations were higher in pregnant women compared to non-pregnant ones (+17.4%, +26.1%, and +45.5%, respectively; all p < 0.05). In the pregnant group, OT levels were 2.7-times lower than in the remainder (p = 0.03). Moreover, in pregnant participants, a negative association between NES-1 and PNX (r = -0.53, p = 0.024) was observed. CONCLUSION Elevated PNX-14, NES-1 and DA along with decreased OT levels were observed in women who achieved pregnancy.
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Affiliation(s)
- Magdalena Piróg
- Gynecological Endocrinology Department, Jagiellonian University Medical College, 31-501 Krakow, Poland;
| | - Robert Jach
- Gynecological Endocrinology Department, Jagiellonian University Medical College, 31-501 Krakow, Poland;
| | - Michał Ząbczyk
- Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, 31-202 Krakow, Poland; (M.Z.); (J.N.)
- Krakow Centre for Medical Research and Technologies, St. John Paul II Hospital, 31-202 Krakow, Poland
| | - Joanna Natorska
- Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, 31-202 Krakow, Poland; (M.Z.); (J.N.)
- Krakow Centre for Medical Research and Technologies, St. John Paul II Hospital, 31-202 Krakow, Poland
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Cai H, Liu S, Chen L, Xie J, Yang C, Li W, Mol BW, Shi J. Effectiveness of atosiban in women with previous single implantation failure undergoing frozen-thawed blastocyst transfer: study protocol for a randomised controlled trial. BMJ Open 2023; 13:e076390. [PMID: 37844983 PMCID: PMC10582862 DOI: 10.1136/bmjopen-2023-076390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/22/2023] [Indexed: 10/18/2023] Open
Abstract
BACKGROUND Uterine contractions may interfere with embryo implantation in assisted reproductive technology. To reduce these contractions and improve success rates, the oxytocin antagonist atosiban has been suggested for administration during embryo transfer. The aim of this study is to evaluate the effectiveness of atosiban in increasing live birth rates among women who have previously experienced a single implantation failure and are scheduled for single blastocyst transfer. METHODS AND ANALYSIS We conduct a single-centre randomised controlled study comparing atosiban and placebo in women undergoing a single blastocyst transfer with a previous failed blastocyst transfer. Women with endocrine or systemic illnesses, recurrent miscarriages, uterine malformations or fibroids, untreated hydrosalpinx, endometriosis (stage III or IV) or uterine fibroids, as well as women undergoing preimplantation genetic testing, are ineligible. The primary outcome is live birth resulting from the frozen-thawed embryo transfer. Secondary outcomes include biochemical/clinical pregnancy, miscarriage, ectopic pregnancy, multiple pregnancies as well as maternal and perinatal outcomes. We plan to recruit 1100 women (550 women per group). This will allow us to demonstrate or refute an increase in live birth rate from 40% to 50%. Data analysis will follow the intention-to-treat principle. We will measure patterns of uterine peristalsis which will allow subgroup analysis for women with or without uterine peristalsis. ETHICS AND DISSEMINATION This study has been approved by the Institutional Review Board of Northwest Women's and Children's Hospital (No. SZ2019001). Written informed consent will be obtained from each participant before randomisation. The results of the trial will be presented at scientific meetings and reported in publications. TRIAL REGISTRATION NUMBER ChiCTR1900022333.
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Affiliation(s)
- He Cai
- The Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Shan Liu
- The Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
- Guangzhou Kapok Medical Group, Guangzhou, China
| | - Lijuan Chen
- The Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Jinlin Xie
- The Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Chen Yang
- The Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Wentao Li
- Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - Ben W Mol
- Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
- Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Juanzi Shi
- The Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
- Translational Medicine Center, Northwest Women's and Children's Hospital, Xi'an, China
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Tsuchiya H, Fujinoki M, Azuma M, Koshimizu TA. Vasopressin V1a receptor and oxytocin receptor regulate murine sperm motility differently. Life Sci Alliance 2023; 6:e202201488. [PMID: 36650057 PMCID: PMC9846835 DOI: 10.26508/lsa.202201488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 01/06/2023] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Specific receptors for the neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin, are present in the male reproductive organs. However, their exact roles remain unknown. To elucidate the physiological functions of pituitary hormones in male reproduction, this study first focused on the distribution and function of one of the AVP receptors, V1a. In situ hybridization analysis revealed high expression of the Avpr1a in Leydig cells of the testes and narrow/clear cells in the epididymis, with the expression pattern differing from that of the oxytocin receptor (OTR). Notably, persistent motility and highly proportional hyperactivation were observed in spermatozoa from V1a receptor-deficient mice. In contrast, OTR blocking by antagonist atosiban decreased hyperactivation rate. Furthermore, AVP stimulation could alter the extracellular pH mediated by the V1a receptor. The results highlight the crucial role of neurohypophyseal hormones in male reproductive physiology, with potential contradicting roles of V1a and OTR in sperm maturation. Our findings suggest that V1a receptor antagonists are potential therapeutic drugs for male infertility.
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Affiliation(s)
- Hiroyoshi Tsuchiya
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan
| | - Masakatsu Fujinoki
- Research Center for Laboratory Animals, Comprehensive Research Facilities for Advanced Medical Science, School of Medicine, Dokkyo Medical University, Mibu, Japan
| | - Morio Azuma
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan
| | - Taka-Aki Koshimizu
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan
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Wang YN, Zheng LW, Fu LL, Xu Y, Zhang XY. Heterotopic pregnancy after assisted reproductive techniques with favorable outcome of the intrauterine pregnancy: A case report. World J Clin Cases 2023; 11:669-676. [PMID: 36793642 PMCID: PMC9923848 DOI: 10.12998/wjcc.v11.i3.669] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/28/2022] [Accepted: 01/09/2023] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Heterotopic pregnancy (HP) is a rare condition in which both ectopic and intrauterine pregnancies occur. HP is uncommon after natural conception but has recently received more attention due to the widespread use of assisted reproductive techniques (ART) such as ovulation promotion therapy.
CASE SUMMARY Here, we describe a case of HP that occurred after ART with concurrent tubal and intrauterine singleton pregnancies. This was treated successfully with surgery to preserve the intrauterine pregnancy, resulting in the birth of a low-weight premature infant. This case report aims to increase awareness of the possibility of HP during routine first-trimester ultrasound examinations, especially in pregnancies resulting from ART and even if multiple intrauterine pregnancies are present.
CONCLUSION This case alerts us to the importance of comprehensive data collection during regular consultations. It is important for us to remind ourselves of the possibility of HP in all patients presenting after ART, especially in women with an established and stable intrauterine pregnancy that complain of constant abdominal discomfort and also in women with an unusually raised human chorionic gonadotropin level compared with simplex intrauterine pregnancy. This will allow symptomatic and timeous treatment of patients with better results.
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Affiliation(s)
- Ya-Nan Wang
- Department of Obstetrics and Gynecology, Reproductive Medical Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Lian-Wen Zheng
- Department of Obstetrics and Gynecology, Reproductive Medical Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Lu-Lu Fu
- Department of Obstetrics and Gynecology, Reproductive Medical Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Ying Xu
- Department of Obstetrics and Gynecology, Reproductive Medical Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Xue-Ying Zhang
- Department of Obstetrics and Gynecology, Reproductive Medical Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
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Pang WJ, Feng X, Wang X, Wang L, Sun NX. Analysis of the effect of phloroglucinol on pregnancy outcomes involving frozen embryo transfers in patients with endometriosis: A retrospective case-control study. Front Surg 2023; 9:994775. [PMID: 36684314 PMCID: PMC9852602 DOI: 10.3389/fsurg.2022.994775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/02/2022] [Indexed: 01/07/2023] Open
Abstract
Objective Abnormal contraction of uterus and vascular smooth muscle lead to the formation of hypoxia environment in uterus. Abnormal contraction may be the basis of dysmenorrhea, endometriosis, infertility and other diseases. Phloroglucinol is a non-atropine and non-papaverine smooth muscle spasmolytic agent, which can reduce the abnormal contraction of uterine smooth muscle. This study investigated the effect of phloroglucinol on frozen embryo transfer in patients with endometriosis. Methods The data of patients with endometriosis who underwent a frozen embryo transfer in Shanghai Changzheng Hospital from August 2018 to August 2021, comprising a total of 453 cycles, were retrospectively analyzed. The patients for whom phloroglucinol was included over 217 cycles were administered intramuscully 40 mg phloroglucinol starting on the day of progesterone administration, then once daily up to day 7 after the embryo transfer. Those for whom phloroglucinol was not administered over 236 cycles were used as the control group. The age of 35 years was used as a boundary in this study to observe the pregnancy outcomes of patients in the two different age groups. Results The biochemical pregnancy rate (63.13% vs. 51.27%), embryo implantation rate (44.64% vs. 33.60%), clinical pregnancy rate (59.64% vs. 48.30%), and live birth rate (52.99% vs. 36.86%) after the administration of phloroglucinol were higher than for patients in the control group, and the early abortion rate (7.75% vs. 20.18%) was also lower. The differences were statistically significant (P < 0.05). In particular, in the age group <35 years old, the embryo implantation rate (51.81% vs. 39.38%), clinical pregnancy rate (69.34% vs. 57.55%), and the live birth rate (63.50% vs. 44.60%) after phloroglucinol intervention rose significantly, and the abortion rate dropped (6.32% vs. 17.5%), indicating a statistically significant difference (P < 0.05). However, pregnancy outcomes showed no difference in the age group ≥35 years old (P > 0.05). Conclusion Continuous low-dose phloroglucinol pretreatment before and after frozen embryo transfer can improve both the clinical pregnancy and live birth rates and reduce the risk of abortion in younger infertile patients with endometriosis.
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Neumann K, Griesinger G. Is oxytocin receptor antagonist administration around embryo transfer associated with IVF treatment success? A systematic review and meta-analysis. Reprod Biomed Online 2021; 43:983-994. [PMID: 34686417 DOI: 10.1016/j.rbmo.2021.08.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/17/2021] [Accepted: 08/19/2021] [Indexed: 11/24/2022]
Abstract
A systematic literature review and meta-analysis was conducted to evaluate whether the administration of an oxytocin receptor antagonist (OTR-a) around embryo transfer is associated with live birth and pregnancy achievement in IVF treatment. Multiple databases were searched for randomized controlled trials (RCT) comparing the outcome of IVF treatment with administration of an OTR-a before, during or after embryo transfer versus administration of placebo/nil. The literature search identified 11 eligible RCT. The active compound was intravenous atosiban (n = 7), subcutaneous barusiban (n = 1) and oral nolasiban (n = 3). Clinical pregnancy rate was significantly higher in women receiving an OTR-a around embryo transfer (relative risk [RR] 1.31, 95% confidence interval [CI] 1.13-1.51, P = 0.0002, I2 = 61%, n = 11 studies, n = 3611); however, live birth rate was not statistically significantly affected (RR 1.09, 95% CI 0.98-1.20, P = 0.11, I2 = 25%, n = 5 studies, n = 2765). A sensitivity analysis on low risk of bias studies likewise indicates a higher clinical pregnancy chance (RR 1.11, 95% CI 1.01-1.22, P = 0.03, I2 = 5%, n = 5 RCT, n = 2765). OTR-a administration in IVF treatment has the potential to increase IVF efficacy, although the treatment effects observed so far are small and have not been sufficiently corroborated.
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Affiliation(s)
- Kay Neumann
- Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
| | - Georg Griesinger
- Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
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Craciunas L, Tsampras N, Kollmann M, Raine-Fenning N, Choudhary M. Oxytocin antagonists for assisted reproduction. Cochrane Database Syst Rev 2021; 9:CD012375. [PMID: 34467530 PMCID: PMC8408576 DOI: 10.1002/14651858.cd012375.pub2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Embryo transfer (ET) is a crucial step of in vitro fertilisation (IVF) treatment, and involves placing the embryo(s) in the woman's uterus. There is a negative association between endometrial wave-like activity (contractile activities) at the time of ET and clinical pregnancy, but no specific treatment is currently used in clinical practice to counteract their effects. Oxytocin is a hormone produced by the hypothalamus and released by the posterior pituitary. Its main role involves generating uterine contractions during and after childbirth. Atosiban is the best known oxytocin antagonist (and is also a vasopressin antagonist), and it is commonly used to delay premature labour by halting uterine contractions. Other oxytocin antagonists include barusiban, nolasiban, epelsiban, and retosiban. Administration of oxytocin antagonists around the time of ET has been proposed as a means to reduce uterine contractions that may interfere with embryo implantation. The intervention involves administering the medication before, during, or after the ET (or a combination). OBJECTIVES To evaluate the effectiveness and safety of oxytocin antagonists around the time of ET in women undergoing assisted reproduction. SEARCH METHODS We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in March 2021; and checked references and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) of the use of oxytocin antagonists for women undergoing ET, compared with the non-use of this intervention, the use of placebo, or the use of another similar drug. DATA COLLECTION AND ANALYSIS We used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth and miscarriage; secondary outcomes were clinical pregnancy and other adverse events. MAIN RESULTS We included nine studies (including one comprising three separate trials, 3733 women analysed in total) investigating the role of three different oxytocin antagonists administered intravenously (atosiban), subcutaneously (barusiban), or orally (nolasiban). We found very low- to high-certainty evidence: the main limitations were serious risk of bias due to poor reporting of study methods, and serious or very serious imprecision. Intravenous atosiban versus normal saline or no intervention We are uncertain of the effect of intravenous atosiban on live birth rate (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.88 to 1.24; 1 RCT, N = 800; low-certainty evidence). In a clinic with a live birth rate of 38% per cycle, the use of intravenous atosiban would be associated with a live birth rate ranging from 33.4% to 47.1%. We are uncertain whether intravenous atosiban influences miscarriage rate (RR 1.08, 95% CI 0.75 to 1.56; 5 RCTs, N = 1424; I² = 0%; very low-certainty evidence). In a clinic with a miscarriage rate of 7.2% per cycle, the use of intravenous atosiban would be associated with a miscarriage rate ranging from 5.4% to 11.2%. Intravenous atosiban may increase clinical pregnancy rate (RR 1.50, 95% CI 1.18 to 1.89; 7 RCTs, N = 1646; I² = 69%; low-certainty evidence), and we are uncertain whether multiple or ectopic pregnancy and other complication rates were influenced by the use of intravenous atosiban (very low-certainty evidence). Subcutaneous barusiban versus placebo One study investigated barusiban, but did not report on live birth or miscarriage. We are uncertain whether subcutaneous barusiban influences clinical pregnancy rate (RR 0.96, 95% CI 0.69 to 1.35; 1 RCT, N = 255; very low-certainty evidence). Trialists reported more mild to moderate injection site reactions with barusiban than with placebo, but there was no difference in severe reactions. They reported no serious drug reactions; and comparable neonatal outcome between groups. Oral nolasiban versus placebo Nolasiban does not increase live birth rate (RR 1.13, 95% CI 0.99 to 1.28; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence). In a clinic with a live birth rate of 33% per cycle, the use of oral nolasiban would be associated with a live birth rate ranging from 32.7% to 42.2%. We are uncertain of the effect of oral nolasiban on miscarriage rate (RR 1.45, 95% CI 0.73 to 2.88; 3 RCTs, N = 1832; I² = 0%; low-certainty evidence). In a clinic with a miscarriage rate of 1.5% per cycle, the use of oral nolasiban would be associated with a miscarriage rate ranging from 1.1% to 4.3%. Oral nolasiban improves clinical pregnancy rate (RR 1.15, 95% CI 1.02 to 1.30; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence), and probably does not increase multiple or ectopic pregnancy, or other complication rates (moderate-certainty evidence). AUTHORS' CONCLUSIONS We are uncertain whether intravenous atosiban improves pregnancy outcomes for women undergoing assisted reproductive technology. This conclusion is based on currently available data from seven RCTs, which provided very low- to low-certainty evidence across studies. We could draw no clear conclusions about subcutaneous barusiban, based on limited data from one RCT. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of atosiban and barusiban before ET. Oral nolasiban appears to improve clinical pregnancy rate but not live birth rate, with an uncertain effect on miscarriage and adverse events. This conclusion is based on a phased study comprising three trials that provided low- to high-certainty evidence. Further large, well-designed RCTs, reporting on live births and adverse clinical outcomes, should focus on identifying the subgroups of women who are likely to benefit from this intervention.
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Affiliation(s)
- Laurentiu Craciunas
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Nikolaos Tsampras
- Reproductive Medicine, St Marys Hospital, Central Manchester University Hospital NHS Trust, Manchester, UK
| | - Martina Kollmann
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Nick Raine-Fenning
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
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Selvi İ, Erdem M, Demirdağ E, Cevher F, Karakaya C, Erdem A. Comparison of frozen-thawed embryo transfer protocols in patients with previous cycle cancellation due to uterine peristalsis: a pilot study. Turk J Med Sci 2021; 51:1365-1372. [PMID: 33535734 PMCID: PMC8283447 DOI: 10.3906/sag-2012-149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 02/03/2021] [Indexed: 01/05/2023] Open
Abstract
Background/aim To investigate the optimal protocol for frozen-thawed embryo transfer (FET) cycles in patients who previously had a cycle cancellation due to uterine peristalsis (UP). Materials and methods Thirty-four patients with previous embryo transfer (ET) cancellation due to UP during artificial cycle (AC) were included retrospectively. In the proceeding cycle, endometrium was prepared with AC (n: 23) in AC-FET group or with stimulated cycle that contains letrozole (L) (n: 11) in L-FET group. Intravenous bolus dose of 6.75 mg atosiban (Tractocile; Ferring Pharmaceuticals, Switzerland) injection was performed to all patients of AC-FET group due to UP ≥ 4/min on the planned ET day of proceeding cycle. Atosiban was not used in L-FET group. Primary outcome was live birth rate (LBR) per ET. Secondary outcomes were clinical pregnancy rate (CPR) per ET, implantation rate (IR), cycle cancellation rate. Results The baseline characteristics such as age, body mass index, antral follicle count, duration of infertility, and the number of prior in vitro fertilization attempts of each group were similar. The IR, CPR per ET, LBR per ET, CPR per cycle and LBR per cycle were significantly higher; cycle cancellation rates were significantly lower in L-FET group as compared to the AC-FET group. Conclusion Endometrial preparation with letrozole significantly improves CPR and LBR in FET cycles of patients with previous cycle cancellations due to UP.
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Affiliation(s)
- İlknur Selvi
- Department of Obstetrics & Gynecology, Koru Hospital, Ankara, Turkey
| | - Mehmet Erdem
- Department of Obstetrics & Gynecology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Erhan Demirdağ
- Department of Obstetrics & Gynecology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Funda Cevher
- Department of Obstetrics & Gynecology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Cengiz Karakaya
- Department of Medical Biochemistry and IVF Unit, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ahmet Erdem
- Department of Obstetrics & Gynecology, Faculty of Medicine, Gazi University, Ankara, Turkey
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11
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Griesinger G, Blockeel C, Pierzynski P, Tournaye H, Višňová H, Humberstone A, Terrill P, Pohl O, Garner E, Donnez J, Loumaye E. Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials. Hum Reprod 2021; 36:1007-1020. [PMID: 33534895 DOI: 10.1093/humrep/deaa369] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
STUDY QUESTION Does a single oral dose of nolasiban 900 mg administered 4 h before embryo transfer (ET) increase pregnancy rates in women undergoing IVF? SUMMARY ANSWER In an individual patient data (IPD) meta-analysis of three clinical trials, a single oral dose of nolasiban 900 mg was associated with an increased ongoing pregnancy rate of an absolute 5% (relative 15%). WHAT IS KNOWN ALREADY Several clinical studies have shown that blocking activation of oxytocin receptors by an oxytocin receptor (OTR) antagonist has the potential to decrease uterine contractions, increase endometrial perfusion and enhance endometrial decidualisation and other parameters of endometrial receptivity. It has been hypothesised that antagonism of oxytocin receptors could improve the likelihood of successful embryo implantation and thus increase pregnancy and live birth rates following ET. STUDY DESIGN, SIZE, DURATION This is an analysis of three randomised, double-blind, placebo-controlled trials, which randomised 1836 subjects between 2015 and 2019. We describe the results of a meta-analysis of individual participant data (IPD) from all three trials and the pre-specified analyses of each individual trial. PARTICIPANT/MATERIAL, SETTING, METHODS Participants were patients undergoing ET following IVF/ICSI in 60 fertility centres in 11 European countries. Study subjects were below 38 years old and had no more than one previously failed cycle. They were randomised to a single oral dose of nolasiban 900 mg (n = 846) or placebo (n = 864). In IMPLANT 1, additional participants were also randomised to nolasiban 100 mg (n = 62) or 300 mg (n = 60). Fresh ET of one good quality embryo (except in IMPLANT 1 where transfer of two embryos was allowed) was performed on Day 3 or Day 5 after oocyte retrieval, approximately 4 h after receiving the study treatment. Serum hCG levels were collected at 14 days post oocyte retrieval (Week 2) and for women with a positive hCG result, ultrasound was performed at Week 6 post-ET (clinical pregnancy) and at Week 10 post-ET (ongoing pregnancy). Pregnant patients were followed for maternal (adverse events), obstetric (live birth, gestational age at delivery, type of delivery, incidence of twins) and neonatal (sex, weight, height, head circumference, Apgar scores, congenital anomalies, breast feeding, admission to intensive care and specific morbidities e.g. jaundice, respiratory distress syndrome) outcomes. MAIN RESULTS AND THE ROLE OF CHANCE In an IPD meta-analysis of the clinical trials, a single oral dose of nolasiban 900 mg was associated with an absolute increase of 5.0% (95% CI 0.5, 9.6) in ongoing pregnancy rate and a corresponding increase of 4.4% (95% CI -0.10, 8.93) in live birth rate compared to placebo. Similar magnitude increases were observed for D3 or D5 transfers but were not significantly different from the placebo. Population pharmacokinetics (PK) demonstrated a correlation between higher exposures and pregnancy. LIMITATIONS, REASON FOR CAUTION The meta-analysis was not a pre-specified analysis. While the individual trials did not show a consistent significant effect, they were not powered based on an absolute increase of 5% in ongoing pregnancy rate. Only a single dose of up to 900 mg nolasiban was administered in the clinical trials; higher doses or extended regimens have not been tested. Only fresh ET has been assessed in the clinical trials to date. WIDER IMPLICATIONS OF THE FINDINGS The finding support the hypothesis that oxytocin receptor antagonism at the time of ET can increase pregnancy rates following IVF. The overall clinical and population PK data support future evaluation of higher doses and/or alternate regimens of nolasiban in women undergoing ET following IVF. STUDY FUNDING/COMPETING INTERESTS The trials were designed, conducted and funded by ObsEva SA. A.H., O.P., E.G., E.L. are employees and stockholders of ObsEva SA. E.L. is a board member of ObsEva SA. G.G. reports honoraria and/or non-financial support from ObsEva, Merck, MSD, Ferring, Abbott, Gedeon-Richter, Theramex, Guerbet, Finox, Biosilu, Preglem and ReprodWissen GmbH. C.B. reports grants and honoraria from ObsEva, Ferring, Abbott, Gedeon Richter and MSD. P.P. reports consulting fees from ObsEva. H.T. reports grants and or fees from ObsEva, Research Fund of Flanders, Cook, MSD, Roche, Gedeon Richter, Abbott, Theramex and Ferring. H.V. reports grants from ObsEva and non-financial support from Ferring. P.T. is an employee of Cytel Inc., who provides statistical services to ObsEva. J.D. reports consulting fees and other payments from ObsEva and, Scientific Advisory Board membership of ObsEva. TRIAL REGISTRATION NUMBERS ClinicalTrials.gov: NCT02310802, NCT03081208, NCT03758885. TRIAL REGISTRATION DATES December 2014 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885). FIRST PATIENT’S ENROLMENT January 2015 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885).
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Affiliation(s)
- G Griesinger
- Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, 23538 Kiel, Germany
| | - C Blockeel
- Centre for Reproductive Medicine, Universitair Ziekenhuis, 1090 Brussel, Belgium
| | - P Pierzynski
- OVIklinika Warszawa Fertility Centre, 01-377 Warszawa, Poland
| | - H Tournaye
- Centre for Reproductive Medicine, Universitair Ziekenhuis, 1090 Brussel, Belgium.,Department of Obstetrics, Gynecology, Perinatology and Reproduction, Institute of Professional Education, Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Trubetskaya str., 8, b. 2, 119992, Moscow, Russia
| | - H Višňová
- IVF Cube, Prague 160 00, Czech Republic
| | | | - P Terrill
- Cytel Inc., Cambridge, MA 02139, USA
| | - O Pohl
- ObsEva Inc., Boston, MA, USA
| | | | - J Donnez
- Université Catholique de Louvain, 1150, Brussels, Belgium.,SRI (Société de recherches pour l'infertilité), 1150, Brussels, Belgium
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12
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Pierzyński P, Pohl O, Marchand L, Mackens S, Lorch U, Gotteland JP, Blockeel C. The mechanism of action of oxytocin antagonist nolasiban in ART in healthy female volunteers. Reprod Biomed Online 2021; 43:184-192. [PMID: 34167897 DOI: 10.1016/j.rbmo.2021.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/16/2020] [Accepted: 01/11/2021] [Indexed: 11/19/2022]
Abstract
RESEARCH QUESTION What are the effects of the oxytocin receptor (OTR) antagonist nolasiban on uterine contractions, endometrial perfusion and endometrial mRNA expression? DESIGN Randomized, double-blind, parallel-group, mechanism-of-action study with nolasiban. Forty-five healthy, pre-menopausal women were treated with placebo, 900 mg or 1800 mg nolasiban on the day corresponding to blastocyst transfer. Ultrasonographic uterine contraction frequency and endometrial perfusion were assessed, and endometrial biopsies analysed by next-generation sequencing. RESULTS Both doses of nolasiban showed decreased contraction frequency and increased endometrial perfusion depending on the time point assessed. At 1800 mg, 10 endometrial genes (DPP4, CNTNAP3, CNTN4, CXCL12, TNXB, CTSE, OLFM4, KRT5, KRT6A, IDO2) were significantly differentially expressed (adjusted P < 0.05). Of these, OLFM4, DPP4 and CXCL12 were regulated in the same direction as genes involved in implantation during the window of implantation. In addition, three genes (DPP4, CXCL12 and IDO2) were associated with decidualization and endometrial receptivity. CONCLUSIONS These data expand our knowledge of the mechanism of action of nolasiban in increasing pregnancy rates after embryo transfer. The results suggest more marked effects of nolasiban 1800 mg compared with the 900 mg dose, supporting testing at higher doses in IVF patients.
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Affiliation(s)
- Piotr Pierzyński
- Oviklinika Warszawa Fertility Centre, Połczyńska 31, Warszawa 01-377, Poland
| | - Oliver Pohl
- ObsEva SA, Chemin des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland
| | - Line Marchand
- ObsEva SA, Chemin des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland
| | - Shari Mackens
- Universitair Ziekenhuis Brussel, Centre for Reproductive Medicine, Laarbeeklaan 101, Brussel 1090, Belgium
| | - Ulrike Lorch
- Richmond Pharmacology Ltd, St George's University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK
| | | | - Christophe Blockeel
- Universitair Ziekenhuis Brussel, Centre for Reproductive Medicine, Laarbeeklaan 101, Brussel 1090, Belgium
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13
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Abstract
The uterine junctional zone represents the juncture between endometrium and myometrium. The junctional zone is hormonally dependent and displays continuous peristaltic activity throughout the menstrual cycle in the nonpregnant state which is concerned with sperm transport and embryo implantation. Peristalsis may be observed using various invasive and noninvasive modalities, of which ultrasound is the most readily applied in the clinical setting. Women with pelvic pathology display alterations in uterine peristalsis which may contribute to infertility. Characterization of peristalsis in infertility subgroups, the development of a subjective peristalsis tool, and the application of potential therapeutics to an assisted reproductive treatment setting are the subject of ongoing investigation. Meta-analysis indicates a potential role for oxytocin antagonist in the improvement of fertility treatments.
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14
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Schwarze JE, Crosby J, Mackenna A. Atosiban improves the outcome of embryo transfer. A systematic review and meta-analysis of randomized and non-randomized trials. JBRA Assist Reprod 2020; 24:421-427. [PMID: 32401462 PMCID: PMC7558905 DOI: 10.5935/1518-0557.20200016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE To estimate the effectiveness of Atosiban in improving the outcome after embryo transfer. The effectiveness of embryo transfer per cycle is still relatively low. One possible explanation might be uterine contractility that expels the transferred embryos. Atosiban improved the outcome of embryo transfer by reducing uterine contractility. METHODS Data sources: A systematic review of papers in English using MEDLINE and EMBASE (1990-2019). Search terms included Atosiban, embryo transfer. Study selection: We included studies that compared the outcomes of embryo transfer with Atosiban and a control group. Data Extracting: Independent extraction of papers by two authors, using predefined data fields, including study quality indicators. RESULTS All pooled analyses were based on a fixed-effect model. Four randomised controlled trials, including 1,025 women, and two non-randomised trials, including 686 patients, met our inclusion criteria. In both studies, the heterogeneity was moderate. Atosiban increased clinical pregnancy rates regardless of the indication for ART or type of embryo transferred. Pooled OR in randomized controlled trials reached 1.47 (1.18-1.82), and in non-randomised controlled trials it reached 1.50 (95% CI 1.10-2.05). CONCLUSION Atosiban appears to increase the clinical pregnancy rates in women undergoing embryo transfer.
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Affiliation(s)
- Juan Enrique Schwarze
- Reproductive Medicine at Clinica Las Condes, Santiago, Chile.,Obstetrics and Gynecology Department, Universidad de Santiago, Chile
| | - Javier Crosby
- Reproductive Medicine at Clinica Las Condes, Santiago, Chile
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15
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Tsuchiya H, Fujimura S, Fujiwara Y, Koshimizu TA. Critical role of V1a vasopressin receptor in murine parturition†. Biol Reprod 2020; 102:923-934. [PMID: 31836900 DOI: 10.1093/biolre/ioz220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 08/16/2019] [Accepted: 12/09/2019] [Indexed: 11/15/2022] Open
Abstract
The precise mechanisms of the reproductive physiological processes, such as labor initiation, are poorly understood. Oxytocin (OT) is one of the well-known uterotonics and is clinically adopted as a medication to facilitate childbirth. Vasopressin (VP), a posterior pituitary hormone similar to OT, has also been proposed to be involved in the reproductive physiology. In this study, we found that a total deficiency of V1a receptor subtype (V1aR) in mice resulted in a reduced number of pups, delayed labor initiation, and increased post-delivery hemorrhage compared with those in wild-type mice. Among the VP receptor subtypes, only V1aR was found to be expressed in the murine uterus, and its distribution pattern was different from that of the oxytocin receptor (OTR); V1aR expression was mainly distributed in the circular myometrium, whereas OTR was strongly expressed in both the circular and longitudinal myometrium. The maximum contractile force of the circular myometrium, induced by VP or OT, was attenuated in the pregnant uterus of Avpr1a-deficient mice. Contrarily, while OT expression was decreased in the Avpr1a-deficient uterus, OTR expression was significantly increased. These results suggest that V1aR deficiency not only reduces the uterine contractile force but also perturbs the expression of genes responsible for the reproductive physiology. Therefore, V1aR is necessary to exert the maximum contraction of the circular myometrium to deliver pups. This study revealed an important role of V1aR in physiological contraction and term parturition in mice.
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Affiliation(s)
- Hiroyoshi Tsuchiya
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Shyota Fujimura
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yoko Fujiwara
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Taka-Aki Koshimizu
- Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan
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16
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Li X, Zhang Z, Chen Y, Wan H, Sun J, Wang B, Feng B, Hu B, Shi X, Feng J, Zhang L, He F, Bai C, Zhang L, Tao W. Discovery of SHR1653, a Highly Potent and Selective OTR Antagonist with Improved Blood-Brain Barrier Penetration. ACS Med Chem Lett 2019; 10:996-1001. [PMID: 31223461 DOI: 10.1021/acsmedchemlett.9b00186] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 05/29/2019] [Indexed: 01/05/2023] Open
Abstract
The oxytocin receptor (OTR) plays a major role in the control of male sexual responses. Antagonists of the OTR have been reported to inhibit ejaculation in animal models and serve as a potential treatment for premature ejaculation (PE). Herein, we describe a novel scaffold featuring an aryl substituted 3-azabicyclo [3.1.0] hexane structure. The lead compound, SHR1653, was shown to be a highly potent OTR antagonist, which exhibited excellent selectivity over V1AR, V1BR, and V2R. This novel molecule was shown to have a favorable pharmacokinetic profile across species, as well as robust in vivo efficacy in a rat uterine contraction model. Interestingly, SHR1653 exhibited excellent blood-brain barrier penetration, which might be beneficial for the treatment of CNS-related PE.
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Affiliation(s)
- Xin Li
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Zhigao Zhang
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Yang Chen
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Hong Wan
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Jiakang Sun
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Bin Wang
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Bingqiang Feng
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Bing Hu
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Xingxing Shi
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Jun Feng
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Lei Zhang
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Feng He
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
- Chengdu Suncadia Medicine Co., LTD., 88 South Keyuan Road, Chengdu, Si Chuan 610000, China
| | - Chang Bai
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
| | - Lianshan Zhang
- Jiangsu Hengrui Medicine CO., LTD., Lianyungang, Jiangsu 222047, China
| | - Weikang Tao
- Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
- Chengdu Suncadia Medicine Co., LTD., 88 South Keyuan Road, Chengdu, Si Chuan 610000, China
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17
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Sztachelska M, Ponikwicka-Tyszko D, Sokolowska G, Anisimowicz S, Czerniecki J, Lebiedzinska W, Zbucka-Kretowska M, Zygmunt M, Wołczynski S, Pierzynski P. Oxytocin antagonism reverses the effects of high oestrogen levels and oxytocin on decidualization and cyclooxygenase activity in endometrial tissues. Reprod Biomed Online 2019; 39:737-744. [PMID: 31548121 DOI: 10.1016/j.rbmo.2019.06.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 05/30/2019] [Accepted: 06/04/2019] [Indexed: 11/27/2022]
Abstract
RESEARCH QUESTION What is the in-vitro effect of oxytocin receptor (OTR) antagonism on parameters of receptivity in human endometrial explants and endometrial stromal cell lines cultured in oestradiol-rich conditions mimicking ovarian stimulation? DESIGN Experimental in-vitro study on endometrial tissue explants collected by aspiration biopsy from 30 women undergoing fertility treatment and cultured endometrial tHESC cell line. The study examined the effects of high oestradiol, oxytocin and OTR antagonist on parameters of decidualization (cell viability and prolactin secretion) as well as cyclooxygenase-1/2 (COX-1/2) activity and prostaglandin F2α (PGF2α) secretion. Changes in expression of OXTR and COX-2 genes were examined using quantitative polymerase chain reaction (qPCR). RESULTS In experiments on cultured endometrial cell line, high oestradiol and oxytocin similarly limited the viability of cells. In cultured endometrial explants both also decreased the secretion of prolactin (a marker of decidualization) and augmented endometrial COX-2 activity and formation of PGF2α. Oxytocin antagonist atosiban was confirmed to reverse the above effects, both in the endometrial line and endometrial explants. Addition of atosiban to cultures acted analogously in experiments employing both oxytocin and high oestradiol. CONCLUSIONS Oxytocin antagonist reversed the effects of high oestradiol and oxytocin on parameters related to endometrial receptivity in conditions mimicking ovarian stimulation. This might point to a novel, endometrium-related mechanism to support embryo implantation achieved by the application of oxytocin antagonist prior to embryo transfer.
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Affiliation(s)
- Maria Sztachelska
- Department of Biology and Pathology of Human Reproduction, Białystok, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Tuwima 10, Olsztyn 10-748, Poland
| | - Donata Ponikwicka-Tyszko
- Department of Biology and Pathology of Human Reproduction, Białystok, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Tuwima 10, Olsztyn 10-748, Poland
| | - Gabriela Sokolowska
- Department of Reproduction and Gynecological Endocrinology, Medical University of Białystok, M. Sklodowskiej-Curie 24a, Białystok 15-276, Poland
| | | | - Jan Czerniecki
- Department of Biology and Pathology of Human Reproduction, Białystok, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Tuwima 10, Olsztyn 10-748, Poland
| | - Weronika Lebiedzinska
- Department of Reproduction and Gynecological Endocrinology, Medical University of Białystok, M. Sklodowskiej-Curie 24a, Białystok 15-276, Poland
| | - Monika Zbucka-Kretowska
- Department of Reproduction and Gynecological Endocrinology, Medical University of Białystok, M. Sklodowskiej-Curie 24a, Białystok 15-276, Poland
| | - Marek Zygmunt
- Department of Obstetrics and Gynecology, University of Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald D-17489, Germany
| | - Slawomir Wołczynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Białystok, M. Sklodowskiej-Curie 24a, Białystok 15-276, Poland
| | - Piotr Pierzynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Białystok, M. Sklodowskiej-Curie 24a, Białystok 15-276, Poland.
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18
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Yuan C, Song H, Fan L, Su S, Dong B. The Effect of Atosiban on Patients With Difficult Embryo Transfers Undergoing In Vitro Fertilization-Embryo Transfer. Reprod Sci 2019; 26:1613-1617. [PMID: 30791824 DOI: 10.1177/1933719119831791] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The purpose of this study was to evaluate the effect of atosiban on the outcomes of infertile women undergoing in vitro fertilization (IVF) with difficult embryo transfers (ETs). This randomized double-blind study enrolled 204 infertile women with difficult ETs during IVF treatment between June 2014 and June 2018. According to a computer-generated randomization list, participants were randomized into placebo (n = 102) and atosiban (n = 102) groups. In atosiban group, atosiban with a total dose of 37.5 mg was administered. All of the patients underwent IVF-ET using cryopreserved embryos. The clinical pregnancy rate per cycle and implantation rate per transfer (45.1% and 26.5%) in atosiban group were significantly higher than those of placebo group (15.6% and 9.7%, respectively; P < .05). This study showed that administration of atosiban during ET was extraordinarily effective for patients with difficult transfers.
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Affiliation(s)
- Caixia Yuan
- Department of Gynecology and Obstetrics, Qilu Hospital, Shandong University, Jinan, People's Republic of China.,Department of Reproductive Medicine, Shanxi Provincial People's Hospital, Taiyuan, People's Republic of China
| | - Haixia Song
- Department of Reproductive Medicine, Shanxi Provincial People's Hospital, Taiyuan, People's Republic of China
| | - Lingling Fan
- Department of Reproductive Medicine, Shanxi Provincial People's Hospital, Taiyuan, People's Republic of China
| | - Shili Su
- Department of Gynecology and Obstetrics, Qilu Hospital, Shandong University, Jinan, People's Republic of China
| | - Baihua Dong
- Department of Gynecology and Obstetrics, Qilu Hospital, Shandong University, Jinan, People's Republic of China
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19
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Ng KKL, Rozen G, Stewart T, Agresta F, Polyakov A. Does nifedipine improve outcomes of embryo transfer?: Interim analysis of a randomized, double blinded, placebo-controlled trial. Medicine (Baltimore) 2019; 98:e14251. [PMID: 30681617 PMCID: PMC6358362 DOI: 10.1097/md.0000000000014251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/22/2018] [Accepted: 01/03/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Implantation failure is the main factor affecting the success rate of in vitro fertilization (IVF) procedures. Studies have reported that uterine contractions (UC) at the time of embryo transfer (ET) were inversely related to implantation and pregnancy rate, hence reducing the success of IVF treatments. Various pharmacological agents, with the exception of calcium channel blockers, have been investigated to improve ET outcomes by reducing UC. Thus, a double-blinded randomized, placebo-controlled trial was conducted to determine whether nifedipine, a calcium channel blocker with potent smooth muscle relaxing activity and an excellent safety profile, can improve the outcome of patients undergoing ET treatments. METHODS Ninety-three infertile women were recruited into 1 of 2 groups: placebo (n = 47) or nifedipine 20 mg (n = 46). Study participants were admitted 30 minutes prior to ET and given either tablet after their baseline vital signs were recorded. They then underwent ET and were observed for adverse events for another 30 minutes post-ET. Follow up of the participants' outcomes was conducted via electronic medical records. The primary outcomes are implantation and clinical pregnancy rates. Secondary outcomes include any maternal or fetal adverse events, miscarriage, pregnancy, live births, and neonatal outcomes. Resulting data were then analyzed using t test, Pearson chi-square test, and Fisher exact test to compare outcomes between the 2 groups. RESULTS No statistical differences in the implantation rate (42.6% vs 39.1%, P = .737, rate ratio 0.868, 95% confidence interval [CI]: 0.379-1.986) and the clinical pregnancy rate (23.4% vs 26.1%, P = .764, rate ratio 1.155, 95% CI: 0.450-2.966) were detected between the placebo and the treatment groups. In addition, no statistical significance between the placebo and the treatment groups for any secondary outcomes were detected. CONCLUSIONS This double blinded, randomized, and placebo-controlled trial demonstrated that the single use of 20 mg nifedipine given 30 minutes before embryo transfer did not improve the implantation rate or the clinical pregnancy rate of the infertility treatment. Further studies are required to demonstrate the clinical benefits and risks of nifedipine usage in embryo transfer.
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Affiliation(s)
| | - Genia Rozen
- Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
| | | | - Franca Agresta
- Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
| | - Alex Polyakov
- Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
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Oxidative Stress in Women Treated with Atosiban for Impending Preterm Birth. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3919106. [PMID: 30622667 PMCID: PMC6304866 DOI: 10.1155/2018/3919106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/14/2018] [Accepted: 10/02/2018] [Indexed: 11/18/2022]
Abstract
Preterm birth is defined as delivery before 37 completed weeks of pregnancy, and it is the leading cause of neonatal morbidity and mortality. Oxidative stress is recognized as an important factor in the pathogenesis of premature labor. We conducted this analysis to investigate the safety of administration of the tocolytic drug Atosiban—a reversible, competitive antagonist of the oxytocin receptor in the treatment of preterm birth and its impact on the level of oxidative stress in pregnant women after 48 hours of tocolytic treatment. This prospective study was conducted between March 2016 and August 2017 at the Obstetric Clinic of the Polish Mother's Memorial Hospital Research Institute. Total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) values as well as 3-nitrotyrosine, carbonyl, and thiol group levels were measured using an ELISA test in serum and plasma of 56 pregnant women before and after 48 hours of continuous administration of Atosiban. We found that TAS levels decreased almost twice after the 48-hour drug administration (0.936 ± 0.360 mmol/L vs. 0.582 ± 0.305 mmol/L, P < 0.001) while TOS increased from 18.217 ± 16.093 μmol/L to 30.442 ± 30.578 μmol/L (P < 0.001). We also found a significant increase in OSI index—almost a threefold increase from 0.022 ± 0.022 to 0.075 ± 0.085, P < 0.001. In addition, statistically significant differences in the level of carbonyl groups were found. It increased from 65.358 ± 31.332 μmol/L to 97.982 ± 38.047 μmol/L (P < 0.001), which indicates increased oxidation of plasma proteins. Furthermore, patients who gave birth prematurely had higher levels of TOS after a 48-hour drug administration than the second group with labor after 37 weeks of pregnancy (42.803 ± 34.683 μmol/L vs. 25.792 ± 27.821 μmol/L, P < 0.031). The obtained results clearly indicate that pregnant women during tocolytic treatment with Atosiban are in a state of increased oxidative stress and occurrence of preterm birth can be associated with this phenomenon. This trial is registered with NCT03570294.
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Mishra V, Agarwal H, Goel S, Roy P, Choudhary S, Lamba S. A Prospective Case-control Trial to Evaluate and Compare the Efficacy and Safety of Atosiban versus Placebo in In vitro Fertilization-embryo Transfer Program. J Hum Reprod Sci 2018; 11:155-160. [PMID: 30158812 PMCID: PMC6094537 DOI: 10.4103/jhrs.jhrs_7_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Recent developments in assisted reproductive technology focus on potential advances to improve its success rate. Atosiban, a combined oxytocin/vasopressin V1a receptor antagonist, is a novel class of drug involved in basic priming of the uterus for successful implantation during embryo transfer (ET). Objectives The objective of this study is to evaluate the efficacy of atosiban (study group) in ET patients in comparison to placebo (control group) regarding implantation rate (IR), clinical pregnancy rate (CPR), and ongoing pregnancy rate and to assess the safety profile of atosiban. Materials and Methods A total of 320 women undergoing in vitro fertilization-ET at a tertiary care hospital were enrolled in the study. In the study group, atosiban was given as initial intravenous (IV) bolus injection 0.9 ml (6.75 mg), 30 min before ET followed by continuous IV infusion of atosiban. In the control group, placebo (normal saline) was infused at the same rate and dose. Pregnancy was confirmed 14 days after ET by β-human chronic gonadotropin level. IR and CPR were determined by doing transvaginal sonography 3 weeks and 6 weeks postET, respectively. Results In women with atosiban treatment, the positive pregnancy rate and CPRs were 41.25% and 36.25%, respectively. The IR per embryo transferred was 17.5%. No major side effects of atosiban were noted among enlisted patients. The miscarriage rate and ectopic pregnancy rate were low (12.12% and 4.54%, respectively). Forty-two women had singleton gestation, while twin and triplet pregnancies were encountered in 13 and 3 women, respectively. No congenital anomalies were observed during an antenatal scan at 18-20 weeks in ongoing pregnancies. The positive pregnancy rate, the CPR, and the IR in the control group was 35%, 30%, and 16.5%, respectively, which was significantly lower than the atosiban group. Conclusion Atosiban reduces uterine contractions and increases endomyometrial perfusion, both of which have potential benefits regarding improved IRs, CPR, and ongoing pregnancy rates. Atosiban has a good embryonic safety profile.
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Affiliation(s)
- Vineet Mishra
- Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India
| | - Himani Agarwal
- Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India
| | - Sugandha Goel
- Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India
| | - Priyankur Roy
- Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India
| | - Sumesh Choudhary
- Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India
| | - Sunita Lamba
- Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India
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Ng KKL, Rozen G, Stewart T, Agresta F, Polyakov A. A double-blinded, randomized, placebo-controlled trial assessing the effects of nifedipine on embryo transfer: Study protocol. Medicine (Baltimore) 2017; 96:e9194. [PMID: 29390463 PMCID: PMC5758165 DOI: 10.1097/md.0000000000009194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 11/20/2017] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION Implantation failure is the main factor affecting the success rate of in vitro fertilization (IVF) procedures. Studies have reported that uterine contractions (UCs) at the time of embryo transfer (ET) were inversely related to implantation and pregnancy rate, hence reducing the success of IVF treatment. Various pharmacological agents, with the exception of calcium channel blocker (CCB), have been investigated to reduce UC. In this regard, we are presenting a proposal for a double-blind randomized placebo-controlled trial. The trial aims to determine whether nifedipine, a CCB with potent smooth muscle relaxing activity and an excellent safety profile, can improve the outcome of ET. METHODS AND ANALYSES We will recruit 100 infertile women into one of 2 groups: placebo (n = 50) and nifedipine 20 mg (n = 50). Study participants will be admitted 30 minutes prior to ET and given either tablet after their baseline vital signs have been recorded. They will then undergo ET and be observed for adverse events for another 30 minutes post-ET. The primary outcome will be implantation rate and clinical pregnancy rate. Secondary outcomes include adverse events, miscarriage and pregnancy, and neonatal outcomes. Resulting data will then be analyzed using t test, Chi-square test, and multivariate test to compare outcomes between the 2 groups for any statistical significance. This protocol has been designed in accordance with the SPIRIT 2013 Guidelines.
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Affiliation(s)
- Kelvin KL Ng
- Melbourne Medical School, University of Melbourne
| | - Genia Rozen
- Department of Reproductive Services, Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
| | - Tanya Stewart
- Department of Reproductive Services, Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
| | - Franca Agresta
- Department of Reproductive Services, Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
| | - Alex Polyakov
- Department of Reproductive Services, Royal Women's Hospital, Parkville
- Melbourne IVF, East Melbourne, Victoria, Australia
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Florez Acevedo S, Cardenas Parra LF. Rol Modulador de la Oxitocina en la Interacción Social y el Estrés Social. UNIVERSITAS PSYCHOLOGICA 2017. [DOI: 10.11144/javeriana.upsy15-5.rmoi] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
La Oxitocina es un neuropéptido conocido por facilitar funciones del sistema nervioso periférico, relacionadas específicamente con el sistema reproductivo. Sin embargo, en las últimas décadas se ha reconocido la función moduladora de la Oxitocina en el comportamiento social, a través de su liberación en el sistema nervioso central. Así mismo, estudios han mencionado que la Oxitocina es un potencial ansiolítico cuando un individuo ha sido sometido a estrés social. Por lo tanto, el objetivo de esta revisión es presentar una caracterización de la Oxitocina y su relación con distintas formas de interacción social y el estrés social; a través de los resultados presentados en distintos estudios, tanto en modelos animales como en humanos. Además, se intenta mostrar la importancia de continuar con el estudio de la Oxitocina, dados los posibles vacíos teóricos y experimentales existentes, teniendo en cuenta las potenciales cualidades ansiolíticas de esta hormona.
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Huang QY, Rong MH, Lan AH, Lin XM, Lin XG, He RQ, Chen G, Li MJ. The impact of atosiban on pregnancy outcomes in women undergoing in vitro fertilization-embryo transfer: A meta-analysis. PLoS One 2017; 12:e0175501. [PMID: 28422984 PMCID: PMC5396917 DOI: 10.1371/journal.pone.0175501] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 03/26/2017] [Indexed: 12/01/2022] Open
Abstract
Background Atosiban is administered to women undergoing in vitro fertilization-embryo transfer (IVF-ET) to improve pregnancy outcomes. However, the results of this treatment were controversial. We conducted this meta-analysis to investigate whether atosiban improves pregnancy outcomes in the women undergoing in vitro fertilization (IVF). Methods Databases of PubMed, EMBASE, Web of Science, China BioMedicine, and Google Scholar were systematically searched. Meta-analyses were performed to investigate whether atosiban improves pregnancy outcomes in the women undergoing IVF. Results Our results showed that atosiban was associated with higher implantation (OR = 1.63, 95% CI: 1.17–2.27; P = 0.004) and clinical pregnancy (OR = 1.84, 95% CI: 1.31–2.57; P < 0.001) rates. However, atosiban showed no significant association with the miscarriage, live birth, multiple pregnancy or ectopic pregnancy rates. When a further subgroup analysis was performed in the women undergoing repeated implantation failure (RIF), implantation (OR = 1.93, 95% CI: 1.45–2.57; P < 0.001), clinical pregnancy (OR = 2.48, 95% CI: 1.70–3.64; P <0.001) and the live birth (OR = 2.89, 95% CI: 1.78–4.67; P < 0.001) rates were significantly higher in the case group. Nevertheless, no significant difference was detected in the miscarriage and multiple pregnancy rates between the case and control groups. Conclusion Atosiban may be more appropriate for women undergoing RIF and play only a limited role in improving pregnancy outcomes in the general population of women undergoing IVF. These conclusions should be verified in large and well-designed studies.
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Affiliation(s)
- Qian-Yi Huang
- Department of Reproductive Medical Research Center, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Min-Hua Rong
- Research Department, Affiliated Cancer Hospital, Guangxi Medical University, Nanning, China
| | - Ai-Hua Lan
- Department of Reproductive Medical Research Center, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiao-Miao Lin
- Department of Children Rehabilitation Medicine, Guangxi Matemal and Child Health Hospital, Nanning, China
| | - Xing-Gu Lin
- Center of Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China
| | - Rong-Quan He
- Center of Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Mu-Jun Li
- Department of Reproductive Medical Research Center, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- * E-mail:
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Kim SK, Han EJ, Kim SM, Lee JR, Jee BC, Suh CS, Kim SH. Efficacy of oxytocin antagonist infusion in improving in vitro fertilization outcomes on the day of embryo transfer: A meta-analysis. Clin Exp Reprod Med 2016; 43:233-239. [PMID: 28090463 PMCID: PMC5234285 DOI: 10.5653/cerm.2016.43.4.233] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 09/23/2016] [Accepted: 09/23/2016] [Indexed: 12/02/2022] Open
Abstract
Objective Uterine contraction induced by the embryo transfer (ET) process has an adverse effect on embryo implantation. The aim of this study was to determine the effect of oxytocin antagonist supplementation on the day of ET on in vitro fertilization outcomes via a meta-analysis. Methods We performed a meta-analysis of randomized controlled trials (RCTs). Four online databases (Embase, Medline, PubMed, and Cochrane Library) were searched through May 2015 for RCTs that investigated oxytocin antagonist supplementation on the day of ET. Studies were selected according to predefined inclusion criteria and meta-analyzed using RevMan 5.3. Only RCTs were included in this study. The main outcome measures were the clinical pregnancy rate, the implantation rate, and the miscarriage rate. Results A total of 123 studies were reviewed and assessed for eligibility. Three RCTs, which included 1,020 patients, met the selection criteria. The implantation rate was significantly better in patients who underwent oxytocin antagonist infusion (19.8%) than in the control group (11.3%) (n=681; odds ratio [OR], 1.92; 95% confidence interval [CI], 1.25–2.96). No significant difference was found between the two groups in the clinical pregnancy rate (n=1,020; OR, 1.57; 95% CI, 0.92–2.67) or the miscarriage rate (n=456; OR, 0.76; 95% CI, 0.44–1.33). Conclusion The results of this meta-analysis of the currently available literature suggest that the administration of an oxytocin antagonist on the day of ET improves the implantation rate but not the clinical pregnancy rate or miscarriage rate. Additional, large-scale, prospective, randomized studies are necessary to confirm these findings.
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Affiliation(s)
- Seul Ki Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea.; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - E-Jung Han
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sun Mie Kim
- Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Jung Ryeol Lee
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea.; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Chul Jee
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea.; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Chang Suk Suh
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Seok Hyun Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
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Mahar KM, Stier B, Fries M, McCallum SW. A single- and multiple-dose study to investigate the pharmacokinetics of epelsiban and its metabolite, GSK2395448, in healthy female volunteers. Clin Pharmacol Drug Dev 2016; 4:418-26. [PMID: 27137713 DOI: 10.1002/cpdd.210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 06/15/2015] [Indexed: 11/11/2022]
Abstract
An open-label single- and repeat-dose study was conducted to investigate the pharmacokinetics, safety, and tolerability of ascending doses of epelsiban in healthy female volunteers (n = 48). The pharmacokinetics of the epelsiban metabolite, GSK2395448, were also assessed. Epelsiban was readily absorbed and parent and metabolite readily appeared in plasma. The parent drug's median tmax was approximately 0.5 hours, and the metabolite's median tmax ranged from 0.5 to 1.0 hours post-parent dosing. Both epelsiban and GSK2395448 had rapid elimination half-lives, ranging between 2.66 and 4.85 hours. The metabolite:parent ratios for exposure (AUC and Cmax ) ranged from approximately 70% to greater than 100%, and therefore, GSK2395448 is considered a major metabolite of epelsiban. Mean epelsiban and GSK2395448 AUC values increased in a dose-proportional manner following both single-dose administration from 10 to 200 mg and repeat administration from 10 to 150 mg following twice daily or 4-times-daily dosing. Single-dose epelsiban pharmacokinetics in women was similar to single-dose pharmacokinetics previously observed in men. Epelsiban was generally well tolerated, and no events of clinical concern were observed in volunteers dosed in this study. The safety findings were consistent with the previous study in men, with headache the most commonly reported adverse effect.
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Affiliation(s)
- Kelly M Mahar
- Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, PA, USA
| | - Brendt Stier
- Clinical Pharmacology Science and Study Operations, GlaxoSmithKline, King of Prussia, PA, USA
| | - Michael Fries
- Clinical Statistics, GlaxoSmithKline, King of Prussia, PA, USA
| | - Stewart W McCallum
- Academic Discovery Performance Unit, GlaxoSmithKline, Collegeville, PA, USA
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Khairy M, Dhillon RK, Chu J, Rajkhowa M, Coomarasamy A. The effect of peri-implantation administration of uterine relaxing agents in assisted reproduction treatment cycles: a systematic review and meta-analysis. Reprod Biomed Online 2016; 32:362-76. [DOI: 10.1016/j.rbmo.2016.01.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 01/06/2016] [Accepted: 01/06/2016] [Indexed: 10/22/2022]
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Rombauts L, Motteram C, Berkowitz E, Fernando S. Risk of placenta praevia is linked to endometrial thickness in a retrospective cohort study of 4537 singleton assisted reproduction technology births. Hum Reprod 2014; 29:2787-93. [DOI: 10.1093/humrep/deu240] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Zhu L, Che HS, Xiao L, Li YP. Uterine peristalsis before embryo transfer affects the chance of clinical pregnancy in fresh and frozen-thawed embryo transfer cycles. Hum Reprod 2014; 29:1238-43. [DOI: 10.1093/humrep/deu058] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Decleer W, Osmanagaoglu K, Meganck G, Devroey P. Slightly lower incidence of ectopic pregnancies in frozen embryo transfer cycles versus fresh in vitro fertilization-embryo transfer cycles: a retrospective cohort study. Fertil Steril 2014; 101:162-5. [DOI: 10.1016/j.fertnstert.2013.10.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 09/16/2013] [Accepted: 10/03/2013] [Indexed: 01/27/2023]
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Xu A, Li Y, Zhu L, Tian T, Hao J, Zhao J, Zhang Q. Inhibition of endometrial fundocervical wave by phloroglucinol and the outcome of in vitro fertilization. Reprod Biol 2013; 13:88-91. [DOI: 10.1016/j.repbio.2013.01.165] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 01/04/2013] [Accepted: 01/07/2013] [Indexed: 10/27/2022]
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Kakourou G, Jaroudi S, Tulay P, Heath C, Serhal P, Harper JC, Sengupta SB. Investigation of gene expression profiles before and after embryonic genome activation and assessment of functional pathways at the human metaphase II oocyte and blastocyst stage. Fertil Steril 2012; 99:803-814.e23. [PMID: 23148922 DOI: 10.1016/j.fertnstert.2012.10.036] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 10/17/2012] [Accepted: 10/23/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To compare the oocyte versus the blastocyst transcriptome and provide data on molecular pathways before and after embryonic genome activation. DESIGN Prospective laboratory research study. SETTING An IVF clinic and a specialist preimplantation genetics laboratory. PATIENT(S) Couples undergoing or having completed IVF treatment donating surplus oocytes or cryopreserved blastocysts after patient consent. INTERVENTION(S) Sets of pooled metaphase II (MII) oocytes or blastocysts were processed for RNA extraction, RNA amplification, and analysis with the use of the Human Genome Survey Microarrays v2.0 (Applied Biosystems). MAIN OUTCOME MEASURE(S) Association of cell type and gene expression profile. RESULT(S) Totals of 1,909 and 3,122 genes were uniquely expressed in human MII oocytes and human blastocysts respectively, and 4,910 genes were differentially expressed between the two sample types. Expression levels of 560 housekeeping genes, genes involved in the microRNA processing pathway, as well as hormones and hormone receptors were also investigated. CONCLUSION(S) The lists of genes identified may be of use for understanding the processes involved in early embryo development and blastocyst implantation, and for identifying any dysregulation leading to infertility.
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Affiliation(s)
- Georgia Kakourou
- UCL Centre for Preimplantation Genetic Diagnosis, Institute for Women's Health, University College London, London, United Kingdom.
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Lan VTN, Khang VN, Nhu GH, Tuong HM. Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure. Reprod Biomed Online 2012; 25:254-60. [PMID: 22818095 DOI: 10.1016/j.rbmo.2012.05.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 05/25/2012] [Accepted: 05/29/2012] [Indexed: 11/29/2022]
Abstract
This prospective cohort study examined the effects of atosiban on uterine contraction, implantation rate (IR) and clinical pregnancy rate (CPR) in women undergoing IVF/embryo transfer. The study enrolled 71 women with repeated implantation failure (RIF; no pregnancies from an average of 4.8 previous embryo transfers with a mean of 12 top-quality embryos) undergoing IVF/embryo transfer using cryopreserved embryos. The total atosiban dose was 36.75 mg. The IR per transfer and CPR per cycle were 13.9% and 43.7%, respectively. Before atosiban, 14% of subjects had a high frequency of uterine contractions (≥ 16 in 4 min). The frequency of uterine contractions was reduced after atosiban. This reduction of uterine contractions in all cycles was significant overall (from 6.0 to 2.6/4 min; P<0.01), in cycles with ≥ 16 uterine contractions/4 min at baseline (from 18.8 to 5.1; P<0.01) and in cycles with <16 uterine contractions/4 min (from 3.9 to 2.2; P<0.01). IR and CPR improved in all subjects, irrespective of baseline uterine contraction frequency. This is the first prospective study showing that atosiban may benefit subjects with RIF undergoing IVF/embryo transfer with cryopreserved embryos. One potential mechanism is the reduction in uterine contractility, but others may also contribute. Many women undergoing IVF/embryo transfer do not achieve the outcome that they wish for. In fact, IVF/embryo transfer repeatedly fails for a subgroup of patients. There are limited options available to help these patients with repeat implantation failure (RIF) to become pregnant. This study looks at one potential new treatment option for women who experience RIF. A drug called atosiban is already being used to delay premature labour by inhibiting contractions of the uterus. In this study, atosiban was given at the time of embryo transfer to women undergoing IVF/embryo transfer. Atosiban reduced the number of uterine contractions in these patients and also increased the implantation and pregnancy rates. The pregnancy rate went from zero to 43.7%. The beneficial effects of atosiban were observed not only in patients who had a high frequency of uterine contractions at baseline but also in those who had a low frequency. These findings suggest that atosiban may have other benefits in addition to its effect on contractions of the uterus. More studies are required to find out exactly how atosiban works and to increase the knowledge of its use in patients with RIF undergoing IVF/embryo transfer.
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Affiliation(s)
- Vuong Thi Ngoc Lan
- Department of OB/GYN, University of Medicine and Pharmacy of Ho Chi Minh City, Ho Chi Minh City, 217 Hong Bang Street, District 5, Ho Chi Minh City, Vietnam.
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Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, Durroux T, Mouillac B, Corbani M, Guillon G. Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol 2012; 24:609-28. [PMID: 22375852 PMCID: PMC3490377 DOI: 10.1111/j.1365-2826.2012.02303.x] [Citation(s) in RCA: 328] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 02/17/2012] [Accepted: 02/17/2012] [Indexed: 01/08/2023]
Abstract
We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.
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Affiliation(s)
- M Manning
- Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH 43614-2598, USA.
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