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Gurkan N, Alper T. The effect of endometrial PRP on fertility outcomes in women with implantation failure or thin endometrium. Arch Gynecol Obstet 2025; 311:1195-1204. [PMID: 39939464 DOI: 10.1007/s00404-025-07948-1] [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: 10/06/2024] [Accepted: 01/02/2025] [Indexed: 02/14/2025]
Abstract
OBJECTIVE To evaluate the effect of intrauterine platelet-rich plasma (PRP) treatment on frozen-thawed embryo transfer (FET) cycles in patients with recurrent implantation failure. MATERIALS AND METHODS The study group consisted of 150 patients. The patients were grouped only as those with thin endometria, those with recurrent implantation failure (RIF), and those with both thin endometria and RIF. All participants underwent frozen embryo transfer. The control group consisted of a total of 150 patients who had normal endometrial thickness and did not have a history of RIF and who presented to the clinic due to unexplained infertility. The rates of biochemical pregnancy, clinical pregnancy, miscarriage and live birth were compared among the groups in terms of fertility outcomes. RESULTS In 150 patients with a thin endometrium or a history of RIF who underwent PRP, the endometrial thickness was significantly greater than the pre-PRP endometrial thickness, and this value was found to be statistically significant (7.38 mm vs. 7.96 mm, p < 0.001). In the thin endometrium group, there was also a statistically significant difference between the endometrial thickness measured before and after PRP (5.85 mm vs 6.65 mm, p < 0.001). The rate of not achieving pregnancy in the RIF group without PRP was found to be significantly greater than that in the control group (53.1% vs 28.7%, p < 0.05). There was no significant difference in pregnancy rates between the PRP groups. Morever, no statistically significant relationship was found between pregnancy status and whether or not PRP was performed in RIF patients (p value > 0.05). Overall, although there was an increase in clinical pregnancy and live birth rates in the PRP group compared with the control group, this difference did not reach statistical significance. CONCLUSION In patients suffering from a thin endometrium or RIF, although endometrial PRP increases endometrial thickness, it does not significantly improve fertility outcomes.
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Affiliation(s)
- Naziye Gurkan
- VM Medical Park Hospital, Gynecology and Obstetrics Clinic, Samsun, Turkey.
| | - Tayfun Alper
- VM Medical Park Hospital, Gynecology and Obstetrics Clinic, Samsun, Turkey
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Tiwari S, Poojari VG, Mundkur A, Adiga P, Kumar P, Bhatele P, Palanivel V. Efficacy of intrauterine autologous blood cell derivatives in enhancing endometrial thickness and IVF outcomes for women with recurrent implantation failure: a retrospective cohort study. J Assist Reprod Genet 2024; 41:2667-2680. [PMID: 39235518 PMCID: PMC11535134 DOI: 10.1007/s10815-024-03231-5] [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: 07/09/2024] [Accepted: 08/12/2024] [Indexed: 09/06/2024] Open
Abstract
PURPOSE The purpose of this study was to determine the effects of intrauterine infusion of autologous blood cell derivative (ABCD) on endometrial thickness and pregnancy outcomes in a group of patients who underwent IVF with recurrent implantation failure (RIF) and who had either a normal endometrium or thin endometrium. METHODS This retrospective study included 63 patients who experienced RIF at the Department of Reproductive Medicine and Surgery, KMC, Manipal, between January 2021 and March 2024 and who received three doses of intrauterine ABCD infusion to prepare the endometrium for frozen embryo transfer (FET). RESULTS We enrolled 63 RIF patients, 30 with a normal endometrium (NEM) and 33 with a thin endometrium (TEM). The endometrial thickness (EMT) significantly increased across all the groups. After 3 cycles of intrauterine ABCD infusion, the mean increases in EMT in the NEM and TEM groups were 0.77 mm and 1.36 mm, respectively, which were statistically significant. Among the 62 completed FET cycles, 40.3% were positive for beta-hCG. The clinical pregnancy rate was 33.8% (40% in the NEM group, 28.1% in the TEM group), and the live birth rate was 24.2% (30% in the NEM group, 18.8% in the TEM group). A total of 9.7% of pregnancies had spontaneous miscarriages. Moreover, the EMT did not differ between the pregnant and nonpregnant groups. CONCLUSION Intrauterine ABCD infusion improves the pregnancy outcomes of patients with RIF, regardless of the EMT. The results of this study revealed that endometrial receptivity improved significantly along with the EMT.
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Affiliation(s)
- Shivangi Tiwari
- Department of Reproductive Medicine and Surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Vidyashree G Poojari
- Department of Reproductive Medicine and Surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Anjali Mundkur
- Department of Reproductive Medicine and Surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104.
| | - Prashanth Adiga
- Department of Reproductive Medicine and Surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Pratap Kumar
- Department of Reproductive Medicine and Surgery, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Prashant Bhatele
- Department of Neurology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Vasanthi Palanivel
- Seragen Biotherapeutics Pvt Ltd, Bangalore Bioinnovation Centre, Helix , Biotech Park Electronic City, Phase-1, Bangalore, India
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Ebrahimi F, Omidvar-Mehrabadi A, Shahbazi M, Mohammadnia-Afrouzi M. Innate and adaptive immune dysregulation in women with recurrent implantation failure. J Reprod Immunol 2024; 164:104262. [PMID: 38823361 DOI: 10.1016/j.jri.2024.104262] [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: 11/11/2023] [Accepted: 05/13/2024] [Indexed: 06/03/2024]
Abstract
Recurrent implantation failure (RIF) is a condition where a woman fails to obtain pregnancy after multiple embryo transfer cycles, even with superior-quality blastocysts. There are various factors that can contribute to RIF, including immunologic disturbances. The immune system is extremely important during pregnancy. Immune cells such as T cells, B cells, natural killer (NK) cells, and macrophages (MQ) are present in the female reproductive tract and are accountable for regulating the immune response to invading pathogens and maintaining tissue homeostasis. Dysregulation of these immune cells can lead to inflammation, which can impair fertility. One of the most common immunological disturbances observed in RIF is an altered Th1/Th2 ratio, along with changes in NK cell and macrophage numbers. In addition, the presence of some antibodies, such as anti-ovarian antibodies, can also contribute to RIF. Interleukins have been implicated in the development of an inflammatory response that can interfere with successful embryo implantation. As a result, a comprehensive understanding of immunological compartments in RIF women could assist us in determining the immunological origins of this disease. We will discuss immunological factors that might contribute to RIF etiology, including cellular and molecular components.
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Affiliation(s)
- Fateme Ebrahimi
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Mehdi Shahbazi
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Abbassi R, Haddad S, Haneyah F, Nakawa W, Murad MS, Issa AM, Alkheder A, Azar A, Dakhalalah Bani Hani M, Abbassi H. Treating refractory thin endometrium through a novel way of activation and administration of Platelet-rich plasma in sexually active women: An interventional prospective cohort clinical study. Medicine (Baltimore) 2024; 103:e38554. [PMID: 38875415 PMCID: PMC11175857 DOI: 10.1097/md.0000000000038554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/16/2024] Open
Abstract
A prospective cohort study investigated the effectiveness of platelet-rich plasma (PRP) infusion for refractory thin endometrium in 38 infertile patients. Patients showed significant improvement in endometrial thickness post-PRP injection, leading to successful implantation and pregnancy. The study revealed a negative correlation between antimullerian hormone (AMH) levels and the need for PRP interventions, suggesting higher ovarian reserve may reduce the necessity for repeated treatments. This implies AMH levels could serve as a prognostic indicator for treatment outcomes, aiding clinicians in optimizing protocols and reducing patient burden. Further research is needed to confirm these findings in larger and more diverse populations, along with exploring long-term reproductive success rates post-PRP treatment.
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Affiliation(s)
- Rasha Abbassi
- University Hospital of Obstetrics and Gynecology in Damascus, Damascus, Syrian Arab Republic
| | - Sultaneh Haddad
- Children's Hospital Damascus, Damascus, Syrian Arab Republic
- Stemosis for Scientific Research, Damascus, Syrian Arab Republic
| | | | - Wael Nakawa
- Damascus University, Faculty of Medicine, Damascus, Syria
| | | | | | - Ahmad Alkheder
- Department of Otorhinolaryngology, Al Mouwasat University Hospital, Faculty of Medicine, Damascus University, Damascus, Syria
- Faculty of Medicine, Syrian Private University, Damascus, Syria
| | - Adel Azar
- Department of Otorhinolaryngology, Al Mouwasat University Hospital, Faculty of Medicine, Damascus University, Damascus, Syria
| | | | - Haitham Abbassi
- University Hospital of Obstetrics and Gynecology in Damascus, Damascus, Syrian Arab Republic
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徐 少, 马 黔, 张 耀, 安 银, 何 玮, 马 瑛, 李 俊, 李 丹, 路 巍, 马 琴, 雍 佳, 赖 婷, 苏 莲, 向 鸿. [Effect of Intrauterine Perfusion of Granulocyte Colony-Stimulating Factor on Endometrium and Blood Flow Parameters in Patients With Thin Endometrium: A Prospective Controlled Clinical Trial]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2024; 55:574-579. [PMID: 38948297 PMCID: PMC11211764 DOI: 10.12182/20240560504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Indexed: 07/02/2024]
Abstract
Objective To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF) on the endometrial thickness, volume, and blood flow parameters of patients with thin endometrium and their clinical outcomes. Methods We designed a prospective non-randomized synchronous controlled trial and recruited patients with thin endometrium who underwent frozen-thawed embryo transfer (FET) at Mianyang Central Hospital between September 1, 2021 and September 1, 2023. They were divided into two groups, an experimental group of patients who received the experimental treatment of intrauterine perfusion with G-CSF and a control group of patients who did not receive the experimental treatment. The general data and the clinical outcomes of the two groups were analyzed and compared. The endometrial thickness, volume and blood flow parameters of patients in the experimental group before and after intrauterine perfusion with G-CSF were analyzed. Results The clinical data of 83 patients were included in the study. The experimental group included 51 cases, while the control group included 31 cases. There were no significant differences in the baseline data between the two groups. The clinical pregnancy rate of the experimental group (56.86%) was higher than that of the control group (50.00%) and the rate of spontaneous abortion in the experimental group (27.59%) was lower than that in the control group (37.50%), but the differences were not statistically significant (P>0.05). In the experimental group, the postperfusion endometrial thickness ([0.67±0.1] cm) was greater than the preperfusion endometrial thickness ([0.59±0.09] cm), the postperfusion ([1.84±0.81] cm3) was greater than the preperfusion endometrial volume ([1.54±0.69] cm3), and the postperfusion vascularization flow index (VFI) (1.97±2.82) was greater than the preperfusion VFI (0.99±1.04), with all the differences being statistically significant (P<0.05). Conclusion Intrauterine perfusion with G-CSF can enhance the endometrial thickness, volume, and some blood flow parameters in patients with thin endometrium.
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Affiliation(s)
- 少蓉 徐
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 黔红 马
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 耀 张
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 银华 安
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 玮 何
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 瑛 马
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 俊林 李
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 丹 李
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 巍 路
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 琴芹 马
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 佳嘉 雍
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 婷 赖
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 莲 苏
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
| | - 鸿 向
- 电子科技大学医学院附属绵阳医院·绵阳市中心医院 生殖中心 (绵阳 621000)Reproductive Medicine Center, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China
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Wang Y, Tang Z, Teng X. New advances in the treatment of thin endometrium. Front Endocrinol (Lausanne) 2024; 15:1269382. [PMID: 38745960 PMCID: PMC11092375 DOI: 10.3389/fendo.2024.1269382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 03/22/2024] [Indexed: 05/16/2024] Open
Abstract
Thin endometrium (TE) is defined as a mid-luteal endometrial thickness ≤7mm. TE can affect endometrial tolerance, leading to lower embryo implantation rates and clinical pregnancy rates, and is also associated with impaired outcomes from assisted reproductive treatment. Herein, we systematically review TE causes, mechanisms, and treatments. TE pathogenesis has multiple causes, with the endometrium becoming thinner with age under hormonal influence. In addition, uterine cavity factors are important, as the inflammatory environment may affect expressions of certain genes thereby inhibiting endometrial stromal cell proliferation and promoting apoptosis. Long-term oral contraceptive use or the use of ovulation-promoting drugs are also definite factors contributing to endometrial thinning. Other patients have primary factors, for which the clinical etiology remains unknown. The main therapeutic strategies available for TE are pharmacological (including hormonal and vasoactive drugs), regenerative medicine, intrauterine infusion of growth factor-granulocyte colony-stimulating factor, autologous platelet-rich plasma, and complementary alternative therapies (including traditional Chinese herbal medicine and acupuncture). However, the associated mechanisms of action are currently unclear. Clinical scholars have proposed various approaches to improve treatment outcomes in patients with TE, and are exploring the principles of efficacy, offering potentials for novel treatments. It is hoped that this will improve TE tolerance, increase embryo implantation rates, and help more couples with infertility with effective treatments.
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Affiliation(s)
- Yidi Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zunhao Tang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiuxiang Teng
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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Su Q, Pan Z, Yin R, Li X. The value of G-CSF in women experienced at least one implantation failure: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2024; 15:1370114. [PMID: 38694938 PMCID: PMC11061619 DOI: 10.3389/fendo.2024.1370114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/22/2024] [Indexed: 05/04/2024] Open
Abstract
Objective Despite the developments of in vitro fertilization (IVF) protocols, implantation failure remains a challenging problem, owing to the unbalance between the embryo, endometrium, and immune system interactions. Effective treatments are urgently required to improve successful implantation. Recently, many researchers have focused on granulocyte colony-stimulating factor (G-CSF) to regulate immune response and embryo-endometrium cross-talk. However, previous studies have reported inconsistent findings on the efficacy of G-CSF therapy on implantation failure. The objective of this review was to further explore the effects of G-CSF according to administration dosage and timing among women who experienced at least one implantation failure. Methods We systematically searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Scopus, and Web of Science for randomized controlled trials of G-CSF on implantation failure up to July 21, 2023. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and the heterogeneity of the studies with the I2 index was analyzed. Results We identified a total of 2031 studies and finally included 10 studies in the systematic review and meta-analysis. G-CSF administration improved the clinical pregnancy rate (CPR), implantation rate (IR), biochemical pregnancy rate (BPR), and live birth rate (LBR) in women with at least one implantation failure. Subgroup analyses showed that G-CSF treatment could exert good advantages in improving CPR [OR=2.49, 95%CI (1.56, 3.98), I2 = 0%], IR [OR=2.82, 95%CI (1.29, 6.15)], BPR [OR=3.30, 95%CI (1.42, 7.67)] and LBR [OR=3.16, 95%CI (1.61, 6.22), I2 = 0%] compared with the blank control group. However, compared with placebo controls, G-CSF showed beneficial effects on CPR [OR=1.71, 95%CI (1.04, 2.84), I2 = 38%] and IR [OR=2.01, 95%CI (1.29, 3.15), I2 = 24%], but not on LBR. In addition, >150μg of G-CSF treatment increased CPR [OR=2.22, 95%CI (1.47, 3.35), I2 = 0%], IR [OR=2.67, 95%CI (1.47, 4.82), I2 = 0%] and BPR [OR=2.02, 95%CI (1.17, 3.47), I2 = 22%], while ≤150μg of G-CSF treatment improved miscarriage rate (MR) [OR=0.14, 95%CI (0.05, 0.38), I2 = 0%] and LBR [OR=2.65, 95%CI (1.56, 4.51), I2 = 0%]. Moreover, G-CSF administration on the day of embryo transfer (ET) could increase CPR [OR=2.81, 95%CI (1.37, 5.75), I2 = 0%], but not on the day of ovum pick-up (OPU) or human chorionic gonadotropin (HCG) injection. Conclusion G-CSF has a beneficial effect on pregnancy outcomes to some extent among women who experienced at least one implantation failure, and the administration dosage and timing influence the effect size.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023447046.
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Affiliation(s)
- Qing Su
- Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
| | - Zhuo Pan
- Center for Reproductive Medicine, Chongqing Key Laboratory of Human Embryo Engineering, Chongqing Reproduction Genetics Institute, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Rong Yin
- Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
| | - Xuemei Li
- Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
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Jinno M, Tamaoka Y, Teruya K, Watanabe A, Hatakeyama N, Goda T, Kimata H, Jinno Y. Granulocyte colony-stimulating factor priming improves embryos and pregnancy rate in patients with poor ovarian reserve: a randomized controlled trial. Reprod Biol Endocrinol 2023; 21:29. [PMID: 36944952 PMCID: PMC10029156 DOI: 10.1186/s12958-023-01082-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/13/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Granulocyte colony-stimulating factor (G-CSF) administration increased ovarian preantral follicles and anti-Müllerian hormone (AMH) in animal models with diminished ovarian reserve. We investigated whether G-CSF priming before treatment with assisted reproductive technology (ART) improved embryo development and pregnancy rate while increasing serum AMH in patients with poor ovarian reserve. METHODS In this prospective randomized open-label controlled trial, 100 patients 20 to 42 years old with AMH below 2 ng/mL were randomized to priming or control groups (50 patients each). None had over 1 ART failure, day-3 follicle-stimulating hormone (FSH) above 30 IU/L, uterine anomalies, or a partner with azoospermia. All patients initially underwent conventional infertility treatment for 2 consecutive cycles in which the priming group but not controls received a subcutaneous G-CSF priming injection during the early luteal phase. Each group then underwent 1 cycle of in vitro fertilization/intracytoplasmic sperm injection and fresh embryo transfer (IVF/ICSI-fresh ET), followed by cryopreserved ET if needed until live birth or embryo depletion. AMH was measured before and after priming. RESULTS Fertilization rate, embryonic development, and implantation rate by fresh ET were significantly improved by priming. Clinical and ongoing pregnancy rates by IVF/ICSI-fresh ET were significantly higher with priming (30% and 26% in 47 ART patients; 3 delivered with conventional treatment) than in controls (12% and 10% in 49 ART patients; 1 dropped out). With priming, significantly more patients achieved cryopreservation of redundant blastocysts. The cumulative live birth rate was 32% in 50 patients with priming, significantly higher than 14% in 49 controls (relative risk, 2.8; 95% confidence interval, 1.04-7.7). Infants derived from priming had no congenital anomalies, while infant weights, birth weeks, and Apgar scores were similar between groups. Among 4 variables (age, day-3 FSH, AMH, and priming), logistic regression significantly associated age and priming with cumulative live birth. Priming significantly increased serum AMH. No adverse effects of priming were observed. CONCLUSION G-CSF priming improved embryonic development and pregnancy rate during ART treatment and increased AMH in patients with poor ovarian reserve. Enhanced preantral follicle growth likely was responsible. TRIAL REGISTRATION UMIN registration in Japan (UMIN000013956) on May 14, 2014. https://www.umin.ac.jp/ctr/index.htm .
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Affiliation(s)
- Masao Jinno
- Women's Clinic Jinno, 3-11-7 Kokuryou-Chou, Choufu City, Tokyo, 182-0022, Japan.
| | - Yukoku Tamaoka
- Ikebukuro Metropolitan Clinic, Toshima-Ku, Tokyo, 171-0021, Japan
- Department of Obstetrics and Gynecology, Inagi Municipal Hospital, Inagi City, Tokyo, 206-0801, Japan
| | - Koji Teruya
- Faculty of Health Sciences, Kyorin University, Mitaka City, Tokyo, 181-8612, Japan
| | - Aiko Watanabe
- Women's Clinic Jinno, 3-11-7 Kokuryou-Chou, Choufu City, Tokyo, 182-0022, Japan
| | - Naohisa Hatakeyama
- Women's Clinic Jinno, 3-11-7 Kokuryou-Chou, Choufu City, Tokyo, 182-0022, Japan
| | - Tomoya Goda
- Women's Clinic Jinno, 3-11-7 Kokuryou-Chou, Choufu City, Tokyo, 182-0022, Japan
| | - Hayato Kimata
- Women's Clinic Jinno, 3-11-7 Kokuryou-Chou, Choufu City, Tokyo, 182-0022, Japan
| | - Yuichi Jinno
- Women's Clinic Jinno, 3-11-7 Kokuryou-Chou, Choufu City, Tokyo, 182-0022, Japan
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Rai S, Yasaswi K, Raj R, Hiremath R, Singh S. Can intrauterine infusion of granulocyte colony-stimulating factor or platelet-rich plasma increase implantation rate in women undergoing in vitro fertilization with normal endometrium: boon or bane? JOURNAL OF MARINE MEDICAL SOCIETY 2023. [DOI: 10.4103/jmms.jmms_89_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023] Open
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10
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Etrusco A, Buzzaccarini G, Cucinella G, Agrusa A, Di Buono G, Noventa M, Laganà AS, Chiantera V, Gullo G. Luteinised unruptured follicle syndrome: pathophysiological background and new target therapy in assisted reproductive treatments. J OBSTET GYNAECOL 2022; 42:3424-3428. [PMID: 36469701 DOI: 10.1080/01443615.2022.2153297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Luteinised unruptured follicle syndrome (LUFS) is a cause of infertility consisting in the unruptured of the dominant follicle after the LH-surge. In fact, during assisted reproductive treatments (ART) clomiphene citrate and letrozole are frequently administered in order to achieve ovulation. However, considering the pathophysiology of LUFS, new possible therapy can be proposed. On this scenario, we performed a review of the literature searching for LUFS recurrency and its impact in infertility and ART. An inflammation theory has been proposed that can be fuel for further therapeutic possibilities. In particular, considering the increase in granulocytes accumulation, the granulocyte colony-stimulating factor (G-CSF) administration has been proposed as target therapy in IUI cycles hampered by LUFS. Although data are encouraging, randomised controlled trials are needed in order to confirm the efficacy of G-CSF administration for LUFS patients.
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Affiliation(s)
- Andrea Etrusco
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, IVF Unit, University of Palermo, Palermo, Italy
| | - Giovanni Buzzaccarini
- Department of Women’s and Children’s Health, Gynaecologic and Obstetrics Clinic, University of Padua, Padua, Italy
| | - Gaspare Cucinella
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, IVF Unit, University of Palermo, Palermo, Italy
| | - Antonino Agrusa
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Giuseppe Di Buono
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Marco Noventa
- Department of Women’s and Children’s Health, Gynaecologic and Obstetrics Clinic, University of Padua, Padua, Italy
| | - Antonio Simone Laganà
- Unit of Gynecologic Oncology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), ARNAS “Civico – Di Cristina – Benfratelli”, University of Palermo, Palermo, Italy
| | - Vito Chiantera
- Unit of Gynecologic Oncology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), ARNAS “Civico – Di Cristina – Benfratelli”, University of Palermo, Palermo, Italy
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, IVF Unit, University of Palermo, Palermo, Italy
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11
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Benkhalifa M, Joao F, Duval C, Montjean D, Bouricha M, Cabry R, Bélanger MC, Bahri H, Miron P, Benkhalifa M. Endometrium Immunomodulation to Prevent Recurrent Implantation Failure in Assisted Reproductive Technology. Int J Mol Sci 2022; 23:ijms232112787. [PMID: 36361577 PMCID: PMC9654171 DOI: 10.3390/ijms232112787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 12/02/2022] Open
Abstract
After more than four decades of assisted reproductive technology (ART) practice worldwide, today more than 60% of women undergoing in vitro fertilization (IVF) treatments fail to become pregnant after the first embryo transfer and nearly 20% of patients are suffering from unexplained recurrent implantation failures (RIFs) and repeated pregnancy loss (RPL). The literature reported different causes of RIF–RPL, mainly multifactorial, endometrial and idiopathic. RIF remains a black box because of the complicated categorization and causes of this physio-pathological dysregulation of implantation and pregnancy process after ovarian stimulation. Many options were suggested as solutions to treat RIF–RPL with controversial results on their usefulness. In this article, we reviewed different possible therapeutic options to improve implantation rates and clinical outcomes. Based on our experience we believe that endometrium immunomodulation after intrauterine insemination of activated autologous peripheral blood mononuclear cells (PBMCs) or platelet-rich plasma (PRP) can be a promising therapeutic solution. On the other hand, peripheral lymphocyte balance typing, specific cytokines and interleukins profiling can be proposed as predictive biomarkers of implantation before embryo transfer.
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Affiliation(s)
- Mustapha Benkhalifa
- HB Laboratory, Tunis TN 1007, Tunisia
- Faculty of Sciences of Bizerte, University of Carthage, Bizerte TN 7021, Tunisia
| | - Fabien Joao
- Fertilys Reproductive Center, Laval, QC H7S 1Z5, Canada
| | - Cynthia Duval
- Fertilys Reproductive Center, Laval, QC H7S 1Z5, Canada
| | | | - Molka Bouricha
- Department of Reproductive Medicine, Reproductive Biology & Genetics, University Hospital and School of Medicine Picardie University Jules Verne, 80054 Amiens, France
| | - Rosalie Cabry
- Department of Reproductive Medicine, Reproductive Biology & Genetics, University Hospital and School of Medicine Picardie University Jules Verne, 80054 Amiens, France
| | | | | | - Pierre Miron
- Fertilys Reproductive Center, Laval, QC H7S 1Z5, Canada
| | - Moncef Benkhalifa
- Department of Reproductive Medicine, Reproductive Biology & Genetics, University Hospital and School of Medicine Picardie University Jules Verne, 80054 Amiens, France
- PeriTox Laboratory, CURS, Amiens Sud, 80480 Salouël, France
- Correspondence: ; Tel.: +33-677-867-390
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12
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Che JH, Zheng ZM, Li MQ, Yao X. Macrophage Polarization in Placenta Accreta and Macrophage-trophoblast Interactions. Am J Reprod Immunol 2022; 88:e13611. [PMID: 36000792 DOI: 10.1111/aji.13611] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 08/01/2022] [Accepted: 08/08/2022] [Indexed: 11/26/2022] Open
Abstract
PROBLEM Placenta accreta (PA) is defined by an abnormal invasion of placental trophoblasts into the myometrium, which can lead to serious postpartum complications. Macrophages play an important role in the regulation of trophoblast function. Both granulocyte colony-stimulating factor (G-CSF) and its receptor (granulocyte colony-stimulating factor receptor, G-CSFR) have effects on trophoblast invasion. However, the current understanding of G-CSF secretion, G-CSFR expression, abnormal polarization of decidual macrophages (dMϕ) in PA and the abnormal invasion of placental trophoblasts into the myometrium are limited. METHOD OF STUDY The polarization of dMϕ in PA was analyzed by flow cytometry (FCM), and the expression of G-CSFR in placental trophoblasts in PA was evaluated by immunohistochemistry. In an in vitro co-culture model, we investigated the effects of HTR-8/SVneo trophoblasts cell line (HTR-8) on macrophage human monocyte cell line (THP-1) polarization and G-CSF secretion, and we also analyzed the effects of THP-1 cells, especially M2-like subtype, on primary trophoblasts and HTR-8 proliferation, invasion, and adhesion. FCM, transwell assays, adhesion assays, and proliferation assays were used in the above model. RESULTS Compared with controls (n = 9), dMϕ showed significantly lower levels of M1 markers CD80 and CD86 and higher levels of the M2 markers CD163 and CD206, and G-CSFR expression of placental trophoblasts was increased in PA(n = 5). In vitro experiments showed that the trophoblast HTR-8 cell line induced polarization of THP-1 cells to an M2-like subtype and increased their secretion of G-CSF. Furthermore, IL-4/IL-13-induced M2-like THP-1 macrophages were able to increase the expression of G-CSFR, proliferation, invasion and adhesion of both primary trophoblasts and HTR-8 trophoblasts. CONCLUSIONS There is an altered immune imbalance at the maternal-fetal interface in PA, which further may lead to abnormal trophoblast function. G-CSF and its receptors may play important roles in abnormal polarization of macrophages and abnormal invasion of trophoblasts. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Jia-Hui Che
- Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Zi-Meng Zheng
- Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China
| | - Ming-Qing Li
- Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Fudan University, Shanghai, China
| | - Xiaoying Yao
- Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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13
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Jacobs EA, Van Voorhis B, Kawwass JF, Kondapalli LA, Liu K, Dokras A. Endometrial thickness: How thin is too thin? Fertil Steril 2022; 118:249-259. [PMID: 35878944 DOI: 10.1016/j.fertnstert.2022.05.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 11/04/2022]
Affiliation(s)
- Emily A Jacobs
- Division of Reproductive Endocrinology and Infertility, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Brad Van Voorhis
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Jennifer F Kawwass
- Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Emory Reproductive Center, Atlanta, Georgia
| | | | - Kimberly Liu
- Mount Sinai Fertility, University of Toronto, Toronto, Ontario, Canada
| | - Anuja Dokras
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Aramesh S, Azizi Kutenaee M, Najafi F, Ghaffari P, Taghavi SA. Granulocyte colony stimulating factor (GCSF) did not affect the fertility outcomes in women with unexplained infertility after intrauterine insemination: a randomised clinical trial. J OBSTET GYNAECOL 2022; 42:2480-2485. [PMID: 35787135 DOI: 10.1080/01443615.2022.2080534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
This study aimed to evaluate the effect of granulocyte colony stimulating factor (GCSF) on fertility outcomes in women with unexplained infertility after intrauterine insemination (IUI). This study is a randomised clinical trial that was conducted on unexplained infertile women referred to infertility Clinic in Yasuj, Iran. All participants were stimulated by letrozole, clomiphene and HMG during the cycle. When at least one follicle was greater than 18 mm, 5000 IU hCG intramuscularly was administered for ovulation induction and then IUI was performed 34-36 hours later. In GCSF group, 300 μg GCSF subcutaneously administrated in two days after IUI. Control group received routine IUI. The main outcome measures were biochemical pregnancy, clinical pregnancy, abortion and ongoing pregnancy rate. Our results showed no statistically significant difference in the biochemical pregnancy (16.3% vs. 12.2%; P=.56), clinical pregnancy (16.3% vs. 8.2%; P=.21), abortion (0 vs. 2.04%; P=.55) and ongoing pregnancy rates (8.2% vs. 14.2%; P=.32) between the control and the G-CSF groups. The results of the current study suggest that systemic administration of 300 μg GCSF in the two days after receiving IUI in patients with unexplained infertility does not offer any beneficial clinical related implantation, and pregnancy rates. IRCT registration number: IRCT20160524028038N4 Impact statementWhat is already known on this subject? Unexplained infertility means to the inability of couples in pregnancy after a year without obvious male and female infertility factors. Some patients have not been justified in endometrial function, which leads to the defect of the dialogue between the foetus and endometrium and may lead to implantation failure. Granulocyte colony stimulating factor is produced at the maternal-foetal interface during embryo implantation and is the main part of the uterine-cytokine network that is needed to create and maintain pregnancy.What do the results of this study add? The current study suggests that systemic administration of 300 μg granulocyte colony stimulating factor in the two days after receiving IUI in patients with unexplained infertility does not offer any beneficial clinical related implantation and pregnancy rates.What are the implications of these findings for clinical practice and/or further research? These results may not be generalised to all patients and more randomised controlled trials are needed for the comparison of granulocyte colony stimulating factor effects on women with thin and normal endometrial thickness, efficacy, side effects, and pregnancy outcomes of the intrauterine perfusion versus systemic subcutaneous administration of granulocyte colony stimulating factor in unexplained infertility treated with intrauterine insemination.
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Affiliation(s)
- Shahintaj Aramesh
- Gynecologic and Obstetrics Department, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Maryam Azizi Kutenaee
- Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fataneh Najafi
- Gynecologic and Obstetrics Department, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Parvin Ghaffari
- Gynecologic and Obstetrics Department, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
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15
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Belapurkar P, Jaiswal A, Madaan S. Comparison of Efficacy Between Vaginal Sildenafil and Granulocyte-Colony Stimulating Factor (G-CSF) in Improving Endometrial Thickness (ET) in Infertile Women. Cureus 2022; 14:e26415. [PMID: 35911259 PMCID: PMC9335401 DOI: 10.7759/cureus.26415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2022] [Indexed: 11/05/2022] Open
Abstract
Background Infertility is presently an emanating preventive medicine issue with some severe societal repercussions associated with it. In India, approximately a score percent of couples bear the burden of infertility. Moreover, the declining fertility rates despite effective artificial reproductive techniques and increasing development of modern reproductive medicine from the last two censuses pose an alarm to the demographic progression data. Many studies have highlighted the importance of shifting the research focus to endometrial receptivity for increasing clinical pregnancy. Objective This research aims to compare the efficacy of treatments of vaginal sildenafil citrate and granulocyte-colony stimulating factor (G-CSF) intrauterine injection in increasing endometrial thickness (ET). Methodology This was a randomized control trial (RCT) conducted over a two months period. Women seeking infertility treatment were recruited from the hospital's gynecological outpatient department (OPD). After the subjects gave informed consent, their history, clinical examination, and investigations were assessed. From the sixth day of the menstrual cycle, group A and group B had serial trans-vaginal ultra-sonographic evaluations for baseline endometrial thickness measurements. From day six to day 12 of the menstrual cycle, patients of group A were requested to self-administer per vaginal sildenafil citrate 25 mg every six hours. ET was evaluated sonographically on day 12 and day 14 of their menstrual cycle. Patients of group B received G-CSF 300 mcg/ml as intrauterine instillation on day 10 and were evaluated sonographically on day 12 and day 14 of their menstrual cycle. Patients then underwent additional therapy in the form of intrauterine injection (IUI), intracytoplasmic sperm injection with/without embryo transfer (ICSI/ET), or a natural cycle. Paired as well as unpaired t-tests were applied to the study groups to detect significant differences in the measurement of endometrial thickness before and after treatment. Results It was noticed that both sildenafil and G-CSF are agents for increasing endometrial thickness. The mean increase in endometrial thickness in the sildenafil treated group was 3.87 mm, while the mean increase in endometrial thickness in G-CSF treated group was 3.27 mm. Conclusion This study has evidence of better results in improving endometrial thickness in infertile women by using vaginal sildenafil with respect to endometrial growth with an intrauterine infusion of granulocyte colony-stimulating factor (filgrastim, G-CSF).
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16
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Ding J, Wang J, Cai X, Yin T, Zhang Y, Yang C, Yang J. Granulocyte colony-stimulating factor in reproductive-related disease: Function, regulation and therapeutic effect. Biomed Pharmacother 2022; 150:112903. [PMID: 35430390 DOI: 10.1016/j.biopha.2022.112903] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/14/2022] [Accepted: 03/27/2022] [Indexed: 11/16/2022] Open
Abstract
Granulocyte colony-stimulating factor (G-CSF) is one of the cytokines which plays important roles in embryo implantation and normal pregnancy. At the maternal-fetal interface, G-CSF can be synthesized by multiple cells, and participates in regulation of trophoblast development, endometrial decidualization, placental metabolism and angiogenesis. Moreover, as an important medium of intercellular communication, G-CSF has also been shown to exert key roles in crosstalk between cellular components at the maternal-fetal interface. Recently, our study demonstrated that G-CSF derived from M2 macrophage could promote trophoblasts invasion and migration through activating PI3K/AKT/Erk1/2 pathway, thereby involving in normal pregnancy program. Herein, we will summarize the role and regulation of G-CSF in normal pregnancy and reproductive-related disease, and the clinical applications of G-CSF in patients undergoing in vitro fertilization with thin endometrium, repeated implantation failure, and women suffered with recurrent spontaneous abortion.
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Affiliation(s)
- Jinli Ding
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430060, China
| | - Jing Wang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430060, China
| | - Xiaopeng Cai
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center & The Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan 430071, China
| | - Tailang Yin
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430060, China
| | - Yan Zhang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center & The Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan 430071, China.
| | - Jing Yang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430060, China.
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Evidence for the effectiveness of immunologic therapies in women with subfertility and/or undergoing assisted reproduction. Fertil Steril 2022; 117:1144-1159. [PMID: 35618357 DOI: 10.1016/j.fertnstert.2022.04.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 01/23/2023]
Abstract
Implantation is a critical step in the establishment of a successful pregnancy, depending on a complex immune-endocrine dialogue between the developing embryo and maternal endometrium. Research suggests that altered immunity in the maternal decidua results in implantation impairment and failure. Immunomodulatory drugs have, thus, been widely used in assisted conception to aid embryo implantation, despite an absence of consensus on their effectiveness and safety. We conducted a systematic review and meta-analysis of interventional studies investigating the use of immunomodulators in women undergoing assisted reproduction. Evidence was uncertain of an effect for most of the included interventions, owing to heterogeneous findings and a paucity of high-quality studies. For certain patient subgroups, however, the use of specific immunomodulatory therapies may offer some benefit. There is a need for further large randomized controlled trials to corroborate these findings.
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18
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Gao P, Zha Y, Wei L, Zhou X, Zhu S, Zhang H, Gao X, Jiang Y, Chen Y, Li J, Zhang J, Yu J, Wang S, Liu H, Feng L. G-CSF: A vehicle for communication between trophoblasts and macrophages which may cause problems in recurrent spontaneous abortion. Placenta 2022; 121:164-172. [DOI: 10.1016/j.placenta.2022.03.125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 02/26/2022] [Accepted: 03/25/2022] [Indexed: 12/20/2022]
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19
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Banerjee K, Singla B, Verma P. Efficacy of subcutaneous granulocyte colonystimulating factor infusion for treating thin endometrium. Clin Exp Reprod Med 2022; 49:70-73. [PMID: 35255660 PMCID: PMC8923628 DOI: 10.5653/cerm.2021.04833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 10/14/2021] [Accepted: 11/13/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE This study was conducted to assess the efficacy of subcutaneous granulocyte colony-stimulating factor (G-CSF) for treating thin endometrium. METHODS Data from 88 infertile women with thin endometrium (<7 mm) aged 23 to 40 years were evaluated retrospectively over a period of 1 year. In group 1, subcutaneous infusion of G-CSF (300 μg/mL) was administered to 44 women along with other supplemental treatments. If the lining did not exceed 7 mm within 72 hours, a second infusion was administered. In group 2, which also had 44 women, only estradiol valerate and sildenafil were administered, while subcutaneous G-CSF infusion was not. Embryo transfers were performed once the lining exceeded 7.5 mm. The efficacy of G-CSF was evaluated by assessing the thickness of the endometrium before embryo transfer, pregnancy rates, and clinical pregnancy rates. RESULTS There were no differences between the groups regarding demographic variables, egg reserves, sperm parameters, the number of embryos transferred, and embryo quality. The pregnancy rate was significantly higher in group 1 (60%, 24 of 40 cases) than in group 2 (31%, 9 of 29 cases) (p<0.001). The clinical pregnancy rate was also significantly higher in group 1 (55%) than in group 2 (24%) (p<0.001). CONCLUSION Subcutaneous G-CSF infusion improved the thickness of the endometrium when it was thin. To the best of our knowledge, this is the first documented study to clearly demonstrate the benefits of subcutaneous G-CSF infusion for treating thin endometrium.
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Affiliation(s)
| | - Bhavana Singla
- Advance Fertility and Gynaecology Centre, New Delhi, India
| | - Priyanka Verma
- Advance Fertility and Gynaecology Centre, New Delhi, India
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Gharibeh N, Aghebati-Maleki L, Madani J, Pourakbari R, Yousefi M, Ahmadian Heris J. Cell-based therapy in thin endometrium and Asherman syndrome. Stem Cell Res Ther 2022; 13:33. [PMID: 35090547 PMCID: PMC8796444 DOI: 10.1186/s13287-021-02698-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 12/24/2021] [Indexed: 12/17/2022] Open
Abstract
Numerous treatment strategies have so far been proposed for treating refractory thin endometrium either without or with the Asherman syndrome. Inconsistency in the improvement of endometrial thickness is a common limitation of such therapies including tamoxifen citrate as an ovulation induction agent, acupuncture, long-term pentoxifylline and tocopherol or tocopherol only, low-dose human chorionic gonadotropin during endometrial preparation, aspirin, luteal gonadotropin-releasing hormone agonist supplementation, and extended estrogen therapy. Recently, cell therapy has been proposed as an ideal alternative for endometrium regeneration, including the employment of stem cells, platelet-rich plasma, and growth factors as therapeutic agents. The mechanisms of action of cell therapy include the cytokine induction, growth factor production, natural killer cell activity reduction, Th17 and Th1 decrease, and Treg cell and Th2 increase. Since cell therapy is personalized, dynamic, interactive, and specific and could be an effective strategy. Despite its promising nature, further research is required for improving the procedure and the safety of this strategy. These methods and their results are discussed in this article.
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Affiliation(s)
- Nastaran Gharibeh
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Javad Madani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Pourakbari
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
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21
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Zhang Y, Chen X, Chen S, Wei C, Li B, Wang Z, Shen X, Lin X. OUP accepted manuscript. Hum Reprod 2022; 37:725-733. [PMID: 35147195 DOI: 10.1093/humrep/deac023] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 12/03/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Yanling Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China
| | - Xuanyu Chen
- Department of Obstetrics and Gynecology, Wenzhou People's Hospital, Wenzhou, Zhejiang Province, P. R. China
| | - Sijia Chen
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China
| | - Cheng Wei
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China
| | - Baijia Li
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China
| | - Zilian Wang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China
| | - Xiaolu Shen
- Department of Obstetrics and Gynecology, Wenzhou People's Hospital, Wenzhou, Zhejiang Province, P. R. China
| | - Xiaona Lin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China
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Wen J, Hou B, Lin W, Guo F, Cheng M, Zheng J, He P, Ji W. 3D-printed hydrogel scaffold-loaded granulocyte colony-stimulating factor sustained-release microspheres and their effect on endometrial regeneration. Biomater Sci 2022; 10:3346-3358. [DOI: 10.1039/d2bm00109h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
After injury, the endometrium cannot self-repair or regenerate because damages of the basal layer of the uterine, which often lead to intrauterine adhesions (IUAs), which can cause serious problems such...
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Zhu YC, Sun YX, Shen XY, Jiang Y, Liu JY. Effect of intrauterine perfusion of granular leukocyte-colony stimulating factor on the outcome of frozen embryo transfer. World J Clin Cases 2021; 9:9038-9049. [PMID: 34786386 PMCID: PMC8567495 DOI: 10.12998/wjcc.v9.i30.9038] [Citation(s) in RCA: 4] [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: 03/12/2021] [Revised: 08/04/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Treatment of thin endometrium with granular leukocyte-colony stimulating factor (G-CSF) remains controversial.
AIM To investigate the effect of G-CSF on the outcome of frozen embryo transfer in patients with thin endometrium.
METHODS A retrospective propensity score matching (PSM) study was performed to assess patients administered frozen embryo transfer at the Reproductive Medicine Center of the Affiliated Drum Tower Hospital of Nanjing University Medical School, in 2012-2018. The patients were divided into G-CSF intrauterine perfusion (G-CSF) and non-G-CSF groups, and clinical pregnancy, implantation, ectopic pregnancy, and early abortion rates between the two groups were compared.
RESULTS Before PSM, 372 cycles were enrolled, including 242 and 130 cycles in the G-CSF and non-G-CSF groups, respectively. Age (34.23 ± 5.76 vs 32.99 ± 5.59 years; P = 0.047) and the blastula/cleavage stage embryo ratio (0.68 vs 0.37; P = 0.011) were significantly elevated in the G-CSF group compared with the non-G-CSF group; however, clinical pregnancy (46.28% vs 51.54%; P = 0.371) and embryo implantation (35.21% vs 35.65%; P = 0.910) rates were similar in both groups. After PSM by age and blastula/cleavage stage embryo ratio, 244 cycles were included (122 cases each in the G-CSF and non-G-CSF groups). The clinical pregnancy (50.82 % vs 48.36%; P = 0.701) and embryo implantation (37.38% vs 34.11%; P = 0.480) remained similar in both groups.
CONCLUSION Intrauterine infusion of G-CSF does not improve the clinical outcome of frozen embryo transfer in patients with thin endometrium.
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Affiliation(s)
- Ying-Chun Zhu
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Yan-Xin Sun
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Xiao-Yue Shen
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Yue Jiang
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - Jing-Yu Liu
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
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Kashani L, Moini A, Esfidani T, Yamini N, Mohiti S. Effect of intrauterine granulocyte-colony stimulating factor administration on in vitro fertilization outcome in women with moderate-to-severe endometriosis: An RCT. Int J Reprod Biomed 2021; 19:733-740. [PMID: 34568734 PMCID: PMC8458918 DOI: 10.18502/ijrm.v19i8.9621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/12/2020] [Accepted: 01/12/2021] [Indexed: 11/24/2022] Open
Abstract
Background Nearly 25-50% of infertile women have endometriosis. There are reports of disorders in the expression of granulocyte colony-stimulating factor (G-CSF) receptors in women with endometriosis. Objective To examine the effect of intrauterine administration of G-CSF in in vitro fertilization (IVF) cycles on the fertility rate of infertile women with moderate-to-severe endometriosis. Materials and Methods This clinical trial was conducted on 66 infertile women with moderate-to-severe endometriosis, undergoing IVF and intracytoplasmic sperm injection (ICSI). The participants were allocated into two groups via simple randomization: the G-CSF (n = 27) and control (n = 39) groups. In the G-CSF intervention group, on the oocyte pick-up day, immediately after an ovarian puncture, 300 μg of G-CSF was injected through a transcervical catheter under abdominal ultrasound guide to visualize flushing into the uterine cavity. Women in the control group received no intervention. The two groups were evaluated for clinical pregnancy. Results No significant difference was noted in the demographic characteristics of the two groups. The rate of clinical pregnancy was 28.2% in the control group and 25.9% in the G-CSF group, indicating no significant difference (p = 0.83). Conclusion The results showed that the intrauterine injection of G-CSF had no effects on pregnancy in women with stage-3/4 endometriosis undergoing IVF.
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Affiliation(s)
- Ladan Kashani
- Department of Obstetrics and Gynecology, Arash Womens' Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ashraf Moini
- Department of Obstetrics and Gynecology, Arash Womens' Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Esfidani
- Department of Obstetrics and Gynecology, Arash Womens' Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazila Yamini
- Department of Obstetrics and Gynecology, Arash Womens' Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Mohiti
- Department of Obstetrics and Gynecology, Arash Womens' Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Li W, Cao Z, Yu X, Hu W. Effect of growth hormone on thin endometrium via intrauterine infusion. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1325. [PMID: 34532462 PMCID: PMC8422125 DOI: 10.21037/atm-21-3583] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022]
Abstract
Background A thin endometrium has become a common reason for the repeated implantation failure. Growth hormone (GH) can regulate the proliferation and metabolism of endometrial cells. The aim of this study was to explore the effect of GH on thin endometrium. Methods A total of 48 female Sprague-Dawley (SD) rats were randomly assigned to the following 4 groups with 12 rats in each group: blank control, model, subcutaneous, and GH groups. The blank control group was untreated and maintained in a routine manner. The model, subcutaneous, and GH groups were intrauterine perfused with 95% ethanol during estrus. After 6–8 h, the model group was intrauterine perfused with 0.2 mL normal saline, the subcutaneous group received subcutaneous injection of 0.12 mg/kg GH dissolved in 0.2 mL normal saline, and the GH group was intrauterine perfused with 0.12 mg/kg GH dissolved in 0.2 mL normal saline. Hematoxylin and eosin (HE) staining was used to examine the thickness of the endometrium. The expression of cytokeratin and vimentin was detected by western blotting and immunohistochemistry. Results The intima thickness in the GH group and blank control group was increased compared with that in the model group (P<0.01). The intima thickness in the subcutaneous group was increased compared with that in the model group, but there was no significant difference. The expression of vimentin and cytokeratin was increased in the GH (P<0.01) and blank control (P<0.01) groups compared with that in the model group. Conclusions Intrauterine perfusion of GH can promote the regeneration and repair of thin endometrium in rats. The therapeutic effect of uterine infusion of GH is better than that of subcutaneous injection of GH.
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Affiliation(s)
- Wenjie Li
- Center of Reproductive Medicine, the First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Zhiwen Cao
- Center of Reproductive Medicine, the First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Xiaoying Yu
- Center of Reproductive Medicine, the First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Weihua Hu
- Center of Reproductive Medicine, the First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, China
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Hou Z, Jiang F, Yang J, Liu Y, Zha H, Yang X, Bie J, Meng Y. What is the impact of granulocyte colony-stimulating factor (G-CSF) in subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles on recurrent implantation failure: a systematic review and meta-analysis? Reprod Biol Endocrinol 2021; 19:125. [PMID: 34388994 PMCID: PMC8361788 DOI: 10.1186/s12958-021-00810-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 07/25/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Among recurrent implantation failure (RIF) patients, the rate of successful implantation remains relatively low due to the complex etiology of the condition, including maternal, embryo and immune factors. Effective treatments are urgently needed to improve the outcomes of embryo transfer for RIF patients. In recent years, many researchers have focused on immunotherapy using granulocyte colony-stimulating factor (G-CSF) to regulate the immune environment. However, the study of the G-CSF for RIF patients has reached conflicting conclusions. The aim of this systematic review and meta-analysis was performed to further explore the effects of G-CSF according to embryo transfer cycle (fresh or frozen) and administration route (subcutaneous injection or intrauterine infusion) among RIF patients. METHOD The PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for literature published from the initial to October 2020. The meta-analysis, random-effects model and heterogeneity of the studies with I2 index were analyzed. Stata 15 was used for statistical analysis. RESULTS A total of 684 studies were obtained through the databases mentioned above. Nine RCTs included 976 RIF patients were enrolled in this meta-analysis. Subgroup analysis indicated that G-CSF improved the clinical pregnancy rate for both the fresh and frozen embryo transfer cycles (fresh RR: 1.74, 95% CI: 1.27-2.37, I2 = 0.0%, n = 410; frozen RR: 1.44, 95% CI: 1.14-1.81, I2 = 0.0.%, n = 366), and for both subcutaneous injection and intrauterine infusion (subcutaneous RR: 1.73, 95% CI: 1.33-2.23, I2 = 0.0%, n = 497; intrauterine RR: 1.39, 95% CI: 1.09-1.78, I2 = 0.0%, n = 479), but the biochemical pregnancy rate of the RIF group was also higher than that of the control group (RR: 1.85, 95% CI: 1.28-2.68; I2 = 20.1%, n = 469). There were no significant differences in the miscarriage rate (RR: 1.13, 95% CI: 0.25-5.21: I2 = 63.2%, n = 472) and live birth rate (RR: 1.43, 95% CI: 0.86-2.36; I2 = 52.5%; n = 372) when a random-effects model was employed. CONCLUSION The administration of G-CSF via either subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles for RIF patients can improve the clinical pregnancy rate. However, whether G-CSF is effective in improving livebirth rates of RIF patients is still uncertain, continued research on the utilization and effectiveness of G-CSF is recommended before G-CSF can be considered mainstream treatment for RIF patients.
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Affiliation(s)
- Zhijin Hou
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Fangjie Jiang
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Jie Yang
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Yang Liu
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Hao Zha
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Xiaoling Yang
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Jia Bie
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
| | - Yushi Meng
- grid.415444.4Department of Reproductive Medicine, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming, 650101 Yunnan Province China
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Song L, Zhang Q, Zhu S, Shan X. Granulocyte Colony-Stimulating Factor Combined With Transcutaneous Electrical Acupoint Stimulation in Treatment of Unresponsive Thin Endometrium in Frozen Embryo Transfer Cycles. FRONTIERS IN REPRODUCTIVE HEALTH 2021; 3:647336. [PMID: 36304049 PMCID: PMC9580712 DOI: 10.3389/frph.2021.647336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 06/14/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: This trial was designed to assess the treatment effects of granulocyte colony-stimulating factor (G-CSF) and transcutaneous electrical acupoint stimulation (TEAS) on thin endometrium in frozen-thawed embryo transfer (FET) cycles. Methods: Ninety-nine patients with previous cancellations of embryo transfer were included, 56 of whom were prospectively treated with intrauterine perfusion of G-CSF in subsequent FET cycles. The selected patients were randomized into the G-CSF perfusion only group and the G-CSF perfusion combined with TEAS group. The other 43 patients were retrospectively included as controls. Results: Compared to previous cycles, endometrial thickness was statistically significantly increased in the two treatment groups (5.97 ± 0.60, 7.52 ± 0.56, 6.14 ± 0.52, and 7.66 ± 0.44; P = 0.00 and 0.00, respectively). The increases in endometrial thickness suggested that no statistically significant difference was found between the two treatment groups. The G-CSF with TEAS group suggested a higher embryo implantation rate than the G-CSF perfusion only and control groups (33.33 and 29.1% and 33.33 and 17.39%; P = 0.412 and 0.091, respectively). The G-CSF combined with TEAS group demonstrated nominally higher clinical and ongoing pregnancy rates than the G-CSF perfusion-only group and controls, though, the difference was not statistically significant. Conclusion: G-CSF has a potential role in improving endometrium thickness in patients with thin unresponsive endometrium in FET treatment cycles. In addition, when combined with TEAS, G-CSF perfusion treatment also improves the embryo implantation rate; however, randomized controlled trials are highly demanded to provide high-grade evidence regarding clinical pregnancy rate after G-CSF perfusion treatment.
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Işık G, Oktem M, Guler I, Oktem E, Ozogul C, Saribas S, Erdem A, Erdem M. The impact of granulocyte colony-stimulating factor (G-CSF) on thin endometrium of an animal model with rats. Gynecol Endocrinol 2021; 37:438-445. [PMID: 32611261 DOI: 10.1080/09513590.2020.1786508] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 05/09/2020] [Accepted: 06/19/2020] [Indexed: 12/13/2022] Open
Abstract
MATERIALS AND METHODS After forming of the thin endometrium by uterine injection of 0.2 ml 96% ethyl alcohol to the rats, five days of subcutaneous injections of 40 μg/kg G-CSF or saline were given. Endometrial thickness, immunohistochemically expression of vascular endothelial growth factor receptor-2 (VEGF-R2), proliferative cell nuclear antigen (PCNA) and fibronectin apoptosis with TUNEL method were compared in specimens among four groups of post-model rats. RESULTS Endometrial thickness was significantly improved in thin but not in normal endometrium group with GCSF when compared to saline injection. Stromal and glandular epithelial expression of PCNA and pericapillary VEGF-R2 was significantly increased, and apoptosis was significantly decreased with G-CSF. Although fibronectin was also increased with G-CSF in the thin endometrium, the difference was non-significant. In further, G-CSF decreased apoptotic cells and increased expression of PCNA when compared to saline injection in normal endometrium. CONCLUSIONS G-CSF improves endometrial thickness, proliferation, angiogenesis and DNA fragmentation in thin endometrium.
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Affiliation(s)
- G Işık
- Department of Obstetrics and Gynecology, Gazi University School of Medicine, Besevler, Ankara, Turkey
| | - M Oktem
- Department of Obstetrics and Gynecology, Gazi University School of Medicine, Besevler, Ankara, Turkey
| | - I Guler
- Department of Obstetrics and Gynecology, Gazi University School of Medicine, Besevler, Ankara, Turkey
| | - E Oktem
- Department of Obstetrics and Gynecology, Gazi University School of Medicine, Besevler, Ankara, Turkey
| | - C Ozogul
- Department of Histology and Embryology, Gazi University School of Medicine, Besevler, Ankara, Turkey
| | - S Saribas
- Department of Histology and Embryology, Ahi Evran University School of Medicine, Bagbasi, Kirsehir, Turkey
| | - A Erdem
- Department of Obstetrics and Gynecology, Gazi University School of Medicine, Besevler, Ankara, Turkey
| | - M Erdem
- Department of Obstetrics and Gynecology, Gazi University School of Medicine, Besevler, Ankara, Turkey
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Abraham S, Sanjay G, Majiyd NA, Chinnaiah A. Encapsulated VEGF 121-PLA microparticles promote angiogenesis in human endometrium stromal cells. J Genet Eng Biotechnol 2021; 19:23. [PMID: 33523322 PMCID: PMC7851192 DOI: 10.1186/s43141-021-00118-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022]
Abstract
Background In this study, Vascular Endothelial Growth Factor 121 expressed abundantly in endometrial stromal cells is encapsulated with poly-l-lactide and characterized the properties for endometrial angiogenesis. We studied the migration, proliferation and the protein levels of human immortalized endometrium stromal cells after treating the cells with recombinant Vascular Endothelial Growth Factor (200 and 500 nanogram), and poly-l-lactide loaded Vascular Endothelial Growth Factor 121 (day 1, 20 and 30). The present study explains endometrium angiogenesis because endometrium plays an important role in pregnancy. Results Migration and proliferation studies in endometrium cells proved the efficiency of Vascular Endothelial Growth Factor and poly-l-lactide loaded Vascular Endothelial Growth Factor 121. This proliferated and increased the migration of the cells in vitro and also activated the Protein kinase B, Phosphatidylinositol-4, 5-Bisphosphate 3-Kinase Catalytic Subunit Beta, α-Smooth muscle actin and vascular endothelial growth factor receptor 2 pathways. Western blot analysis showed the increased expression levels of kinases, smooth muscle actin and vascular endothelial growth factor receptor 2 after the treatment with Vascular Endothelial Growth Factor and poly-l-lactide loaded Vascular Endothelial Growth Factor 121 particles in comparison to the control group. The elevated levels of α-Smooth muscle actin in endometrium cells with Vascular Endothelial Growth Factor prove the regulation of angiogenesis in vitro. Conclusion Endometrium thickness is one of the important factors during implantation of embryo and pregnancy. Slow release of VEGF from PLA encapsulated microparticle further controls the endothelial cell proliferation and migration and helps in the promotion of angiogenesis. The combined effect studied in vitro could be used as a pro-angiogenic drug on further in vivo confirmation.
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Affiliation(s)
- Sunil Abraham
- Department of Animal Behavior & Physiology, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, India
| | - Geetha Sanjay
- Innov4Sight Health and Biomedical Systems Pvt. Ltd. Biologics Lab- # EGF11, Bangalore Bioinnovation Centre, Bangalore Helix Biotech Park, Electronics City Phase 1, Bangalore, Karnataka, 560100, India
| | - Noushin Abdul Majiyd
- CRAFT Hospital and Research Centre, Centre for Excellence in Infertility Treatment, Kodungalur P O, Thrissur, Kerala, 680664, India
| | - Amutha Chinnaiah
- Department of Animal Behavior & Physiology, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, India.
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Ding J, Yang C, Zhang Y, Wang J, Zhang S, Guo D, Yin T, Yang J. M2 macrophage-derived G-CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy. J Cell Mol Med 2021; 25:2136-2147. [PMID: 33393205 PMCID: PMC7882967 DOI: 10.1111/jcmm.16191] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 11/10/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
Trophoblasts are important parts of the placenta and exert vital roles in the maternal-foetal crosstalk, and sufficient trophoblasts migration and invasion is critical for embryo implantation and normal pregnancy. Macrophages, as the major components of decidual microenvironment at maternal-foetal interface, can interact with trophoblasts to participate in the regulation of normal pregnancy. Previously, our group have demonstrated that trophoblasts could induce macrophages polarization to M2 subtype by secreting interleukin-6 (IL-6); however, the understanding of macrophages regulating the migration and invasion of trophoblasts is limited. In the present study, we used the co-cultured model to further investigate the effects of macrophages on trophoblasts migration and invasion. Our results showed that co-culture with macrophages promoted epithelial-to-mesenchymal transition (EMT) of trophoblasts, thereby enhancing their migrative and invasive abilities. Further experiments revealed that M2 macrophage-derived G-CSF was a key factor, which promoted the EMT, migration and invasion of trophoblasts via activating PI3K/Akt/Erk1/2 signalling pathway. Clinically, G-CSF was highly expressed in placental villous tissues of normal pregnancy patients compared to patients with recurrent spontaneous abortion, and its expression level was significantly correlation with EMT markers. Taken together, these findings indicate the important role of M2 macrophages in regulating trophoblasts EMT, migration and invasion, contributing to a new insight in concerning the crosstalk between macrophages and trophoblasts in the establishment and maintenance of normal pregnancy.
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Affiliation(s)
- Jinli Ding
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Jiayu Wang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Sainan Zhang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Duanying Guo
- Department of Gynecology, Longgang District People's Hospital of Shenzhen, Shenzhen, China
| | - Tailang Yin
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Jing Yang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
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Jiang L, Xu X, Cao Z, Yang N, Wang S, Wang L, Xu X, Li Q, Shi B, Hao G. Comparison of Frozen Embryo Transfer Outcomes Between Uterine Infusion of Granulocyte Colony-Stimulating Factor and Growth Hormone Application in Patients With Thin Endometrium: A Retrospective Study. Front Endocrinol (Lausanne) 2021; 12:725202. [PMID: 35027908 PMCID: PMC8750567 DOI: 10.3389/fendo.2021.725202] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE To investigate the effect of two treatments on the outcome of freeze-thaw embryo transfer for pregnancy assistance in thin endometrium. METHODS A retrospective study was conducted on 66 patients who failed in the first cycle treated in the reproductive medicine center of the Second Hospital of Hebei Medical University from January 2018 to December 2019. Granulocyte colony stimulating factor (G-CSF) was used through cavity infusion in one group (n=25, and growth hormone (GH) was subcutaneously injected in the group (n=41). The clinical data of the two groups were compared, including morphology and thickness of the endometrium, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, miscarriage rate, and live birth rate in each period of the hormone replacement cycle. RESULTS There was no significant difference in age, BMI, AMH, FSH, LH, E2, infertility years, number of transferred embryos, basal endometrium, and thickness of endometrium on the day of P administration before and after treatment (P> 0.05). After treatment, compared to the GH group, the G-CSF group presented higher biochemical pregnancy rate (56% versus 48.8%; P=0.569), clinical pregnancy rate (52% versus 46.3%; P=0.655), implantation rate (34.8% versus 27.5%; P=0.391), and live birth rate (40% versus 31.7%; P=0.493), but the differences were not statistically significant (P > 0.05). On the 5th day of treatment, the endometrial thickness in the G-CSF group was thinner than that in the GH group (4.83 ± 0.85 versus 5.75 ± 1.27; P< 0.05), but it had no correlation with pregnancy outcome (P > 0.05). There was no significant difference in endometrial thickness between the two groups on the 7th, 9th day of treatment and the day of P administration (P > 0.05). On the 5th day of treatment, the proportion of endometrial type A morphology in the GH group was significantly higher than that in the G-CSF group (P < 0.05), while the type B morphology in the G-CSF group was significantly higher than that in the GH group (P< 0.05). CONCLUSION Although G-CSF and GH may not have a role in increasing endometrium, both of them can improve the pregnancy outcomes of patients with thin endometrium in the FET cycle. And the effects of the two treatments were similar.
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Affiliation(s)
- Lei Jiang
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xin Xu
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ziyu Cao
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ni Yang
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shaoqing Wang
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Luning Wang
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiuhua Xu
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
- Cardiovascular Platform, Institute of Health and Disease, Hebei Medical University, Shijiazhuang, China
| | - Qian Li
- Cardiovascular Platform, Institute of Health and Disease, Hebei Medical University, Shijiazhuang, China
| | - Baojun Shi
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guimin Hao
- Department of Reproductive Medicine, Second Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Guimin Hao,
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Hooker AB, de Leeuw RA, Twisk JWR, Brölmann HAM, Huirne JAF. Reproductive performance of women with and without intrauterine adhesions following recurrent dilatation and curettage for miscarriage: long-term follow-up of a randomized controlled trial. Hum Reprod 2021; 36:70-81. [PMID: 33320197 PMCID: PMC7801791 DOI: 10.1093/humrep/deaa289] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 08/04/2020] [Indexed: 01/22/2023] Open
Abstract
STUDY QUESTION Are the long-term reproductive outcomes following recurrent dilatation and curettage (D&C) for miscarriage in women with identified and treated intrauterine adhesions (IUAs) comparable to women without IUAs. SUMMARY ANSWER Reproductive outcomes in women with identified and treated IUAs following recurrent D&C for miscarriage are impaired compared to women without IUAs; fewer ongoing pregnancies and live births are achieved with a prolonged time to a live birth. WHAT IS KNOWN ALREADY The Prevention of Adhesions Post Abortion (PAPA) study showed that application of auto-crosslinked hyaluronic acid (ACP) gel, an absorbable barrier in women undergoing recurrent D&C for miscarriage resulted in a lower rate of IUAs, 13% versus 31% (relative risk 0.43, 95% CI 0.22 to 0.83), lower mean adhesion score and significant less moderate to severe IUAs. It is unclear what the impact is of IUAs on long-term reproductive performance. STUDY DESIGN, SIZE, DURATION This was a follow-up of the PAPA study, a multicenter randomized controlled trial evaluating the application of ACP gel in women undergoing recurrent D&C for miscarriage. All included women received a diagnostic hysteroscopy 8-12 weeks after randomization to evaluate the uterine cavity and for adhesiolysis if IUAs were present. Here, we present the reproductive outcomes in women with identified and treated IUAs versus women without IUAs, 46 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS Between December 2011 and July 2015, 152 women with a first-trimester miscarriage with at least one previous D&C, were randomized for D&C alone or D&C with immediate intrauterine application of ACP gel. Participants were approached at least 30 months after randomization to evaluate reproductive performance, obstetric and neonatal outcomes and cycle characteristics. Additionally, the medical files of all participants were reviewed. Main outcome was ongoing pregnancy. Outcomes of subsequent pregnancies, time to conception and time to live birth were also recorded. MAIN RESULTS AND THE ROLE OF CHANCE In women pursuing a pregnancy, 14/24 (58%) ongoing pregnancies were recorded in women with identified and treated IUAs versus 80/89 (90%) ongoing pregnancies in women without IUAs odds ratio (OR) 0.18 (95% CI 0.06 to 0.50, P-value <0.001). Documented live birth was also lower in women with IUAs; 13/24 (54%) with versus 75/89 (84%) without IUAs, OR 0.22 (95% CI: 0.08 to-0.59, P-value 0.004). The median time to conception was 7 months in women with identified and treated IUAs versus 5 months in women without IUAs (hazard ratio (HR) 0.84 (95% CI 0.54 to 1.33)) and time to conception leading to a live birth 15 months versus 5.0 months (HR 0.54 (95% CI: 0.30 to 0.97)). In women with identified and treated IUAs, premature deliveries were recorded in 3/16 (19%) versus 4/88 (5%) in women without IUAs, P-value 0.01. Complications were recorded in respectively 12/16 (75%) versus 26/88 (30%), P-value 0.001. No differences were recorded in mean birth weight between the groups. LIMITATIONS, REASONS FOR CAUTION In the original PAPA study, randomization was applied for ACP gel application. Comparing women with and without IUAs is not in line with the randomization and therefore confounding of the results cannot be excluded. IUAs, if visible during routine hysteroscopy after randomization were removed as part of the study protocol; the influence of IUAs on reproductive outcome may therefore be underestimated. Women undergoing a recurrent D&C for miscarriage were included, a specific group likely to generate clinically significant adhesions. The findings should therefore not be generalized to all women undergoing D&C for miscarriage. WIDER IMPLICATIONS OF THE FINDINGS As IUAs have an impact on reproductive performance, even after hysteroscopic adhesiolysis, primary prevention is essential. Expectative and medical management should therefore be considered as serious alternatives for D&C in women with a miscarriage. In case D&C is necessary, application of ACP gel should be considered. STUDY FUNDING/COMPETING INTEREST(S) The original PAPA study (NTR 3120) was an investigator initiated study that was funded by the Foundation for scientific investigation in Obstetrics and Gynaecology of the Saint Lucas Andreas Hospital (currently renamed OLVG Oost), SWOGA. The syringes containing ACP gel were received from Anika Therapeutics, the manufacturer of Hyalobarrier® Gel Endo. The current follow-up study was also an investigator-initiated study without funding. The funder and sponsor had no role in the design of this follow-up study, data collection, data analysis, data interpretation, trial design, patient recruitment, writing of the report or any aspect pertinent to the study. ABH, RAL, JAFH and JWRT have no conflict to declare. HAMB reports being a member of safety board research Womed. TRIAL REGISTRATION NUMBER Netherlands Trial Register NTR 3120.
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Affiliation(s)
- Angelo B Hooker
- Department of Obstetrics and Gynecology, Zaans Medical Center, Zaandam, the Netherlands
- Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands
| | - Robert A de Leeuw
- Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands
| | - Jos W R Twisk
- Department of Epidemiology and Biostatistics, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands
| | - Hans A M Brölmann
- Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands
| | - Judith A F Huirne
- Department of Obstetrics and Gynecology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands
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Mierzejewski K, Paukszto Ł, Kurzyńska A, Kunicka Z, Jastrzębski JP, Bogacka I. Transcriptome analysis of porcine endometrium after LPS-induced inflammation: effects of the PPAR-gamma ligands in vitro†. Biol Reprod 2020; 104:130-143. [PMID: 33112378 DOI: 10.1093/biolre/ioaa200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/29/2020] [Accepted: 10/23/2019] [Indexed: 12/25/2022] Open
Abstract
Female fertility depends greatly on the capacity of the uterus to recognize and eliminate microbial infections, a major reason of inflammation in the endometrium in many species. This study aimed to determine the in vitro effect of peroxisome proliferator-activated receptor gamma (PPARγ) ligands on the transcriptome genes expression and alternative splicing in the porcine endometrium in the mid-luteal phase of the estrous cycle during LPS-stimulated inflammation using RNA-seq technology. The endometrial slices were incubated in vitro in the presence of LPS and PPARγ agonists-PGJ2 or pioglitazone and antagonist-T0070907. We identified 222, 3, 4, and 62 differentially expressed genes after LPS, PGJ2, pioglitazone, or T0070907 treatment, respectively. In addition, we detected differentially alternative spliced events: after treatment with LPS-78, PGJ2-60, pioglitazone-52, or T0070907-134. These results should become a basis for further studies explaining the mechanism of PPARγ action in the reproductive system in pigs.
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Affiliation(s)
- Karol Mierzejewski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Łukasz Paukszto
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Aleksandra Kurzyńska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Zuzanna Kunicka
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Jan Paweł Jastrzębski
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Iwona Bogacka
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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Rocha MNDC, Florêncio RDS, Alves RRF. The role played by granulocyte colony stimulating factor (G-CSF) on women submitted to in vitro fertilization associated with thin endometrium: systematic review. JBRA Assist Reprod 2020; 24:278-282. [PMID: 32293824 PMCID: PMC7365529 DOI: 10.5935/1518-0557.20200025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Objective: To provide evidence available in the literature on the role of granulocyte colony stimulating factor (G-CSF) in women submitted to in vitro fertilization, with repeated implantation failure associated with thin endometrium. Methods: Systematic review of the use of G-CSF, as part of assisted reproduction techniques in women with repeated embryo implantation failures associated with thin endometrium. The study was carried out in the PubMed, BIREME and Elsevier databases from 2008 to 2018, in English, Spanish and Portuguese. Results: We included all the studies, which used intrauterine G-CSF. We found an increase in endometrial thickness in eight of the 10 studies included. Of these, the implantation rate improved significantly in two studies, but the gestation rate increased in only one. We found the highest rates of implantation (32%) and pregnancy (48%) in a non-randomized clinical trial. On the other hand, two other studies did not demonstrate an increase in endometrial thickness and in pregnancy rates in patients with thin endometrium submitted to the assisted reproduction in frozen embryo transfer cycles. Conclusion: Studies published so far point to a positive influence on the use of G-CSF in relation to the improvement in endometrial receptivity and pregnancy rates. Therefore, there is a need for further studies to determine whether to use it, as well as the period, route of administration, dosage and duration of treatment.
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Chalova L, Lokshin V, Orazov M, Rybina A, Kim T, Kinzhibayev A. MODERN METHODS OF DIAGNOSIS AND TREATMENT OF CHRONIC ENDOMETRITIS, IN PREPARING PATIENTS FOR ASSISTED REPRODUCTIVE TREATMENT TECHNOLOGIES (LIT ERATURE REVIEW). REPORTS 2020. [DOI: 10.32014/10.32014/2020.2518-1483.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Since the chronic endometritis often leads to impaired reproductive function causing infertility, failed IVF attempts, miscarriage, and complicated pregnancy and childbirth, it has become not only medically relevant but also socially significant. For successful embryo implantation, the thickness of the endometrium should be at least 7 cm. Even though there is always a chance for embryo implantation, despite the endometrial hypoplasia, the attachment may be fragile, and such pregnancy may cease its development further on. Recently, in connection with an increase in the rate of developing allergic reactions, dysbacteriosis, and the emergence of drug-resistant strains of microorganisms, a search for new treatment methods to avoid these complications has begun. One of such methods in treating chronic endometritis, satisfying several requirements (efficiency, comfort, accessibility, safety), is the ultrasonic cavitation of the uterine cavity.
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Affiliation(s)
- L. Chalova
- reproductive medicine and fertility specialist, obstetrician and gynaecologist, Director of LLP Health and Science Сenter "М1", Nur-Sultan, Kazakhstan, , https://orcid.org/0000-0003-3040-3751
| | - V. Lokshin
- PhD, professor, Director of ICCR "PERSONA", Almaty, Kazakhstan; ; https://orcid.org/0000-0002-4792-5380
| | - M. Orazov
- MD, Professor at the Department of obstetrics and gynecology with course of Perinatology of the PFUR, Moscow, Russia; . https://orcid.org/0000-0002-1767-5536
| | - A. Rybina
- reproductive medicine and fertility specialist, obstetrician and gynaecologist of ICCR "PERSONA", Almaty, Kazakhstan; ; https://orcid.org/0000-0002-9368-6683
| | - T. Kim
- PhD, reproductive medicine and fertility specialist, obstetrician and gynaecologist of LLP Health and Science Сenter "M1", Nur-Sultan, Kazakhstan, , https://orcid.org/0000-0001-9964-9042
| | - A. Kinzhibayev
- clinical embryologist of LLP Health and Science Сenter "M1", Nur-Sultan, Kazakhstan; ; https://orcid.org/0000-0002-1752-0964
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Lian R, Wang X, Lin R, Zeng H, Zeng Y, Liu S. Evaluation of granulocyte colony-stimulating factor on the treatment of thin endometrium during frozen-thawed embryo transfer cycles: a retrospective cohort study. Gynecol Endocrinol 2020; 36:370-374. [PMID: 31464150 DOI: 10.1080/09513590.2019.1658187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The aim of this study was to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on thin endometrium (≤7 mm) in women undergoing frozen-thawed embryo transfer (FET). This retrospective cohort study includes 271 infertile patients with thin endometrium. 117 patients who received intrauterine perfusion of G-CSF before the day of administration of progesterone were defined as G-CSF group, whereas 154 patients who refused to use G-CSF treatment were defined as control group. In the G-CSF group, significantly higher endometrial thickness was observed after G-CSF perfusion (p < .001). When we divided the G-CSF group into two subgroups according to whether they conceived, the endometrial thickness increased from 6.02 ± 0.92 mm to 6.98 ± 1.20 mm in the conception group (p < .001) and from 6.21 ± 0.96 mm to 6.87 ± 1.16 mm in the non-conception group (p < .001). However, there were no significant differences between the two subgroups in respect to the endometrial thickness both before and after G-CSF perfusion. The implantation rate, hCG positive rate and clinical pregnancy rate were similar between G-CSF group and control group. Thus, our study fails to demonstrate that G-CSF has the potential to improve pregnancy outcome but has the potential to increase endometrial thickness of the women with thin endometrium in FET cycles.
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Affiliation(s)
- Ruochun Lian
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Xiaohui Wang
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Rong Lin
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Huimin Zeng
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Yong Zeng
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Su Liu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
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Kamath MS, Kirubakaran R, Sunkara SK. Granulocyte-colony stimulating factor administration for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev 2020; 1:CD013226. [PMID: 31978254 PMCID: PMC6984624 DOI: 10.1002/14651858.cd013226.pub2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in the process of embryo implantation and continuation of pregnancy. It has been used during in vitro fertilisation (IVF) treatment for subfertile women with chronically thin endometrium and those with previous multiple IVF failures. It is currently unknown whether G-CSF is effective in improving results following assisted reproductive technology (ART). OBJECTIVES To evaluate the effectiveness and safety of G-CSF in women undergoing ART. SEARCH METHODS We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform in February 2019. We searched reference lists of relevant articles and handsearched relevant conference proceedings. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing G-CSF administration versus no treatment or placebo in subfertile women undergoing IVF treatment. DATA COLLECTION AND ANALYSIS Two review authors independently screened studies, extracted data, and assessed risk of bias. The primary outcomes were live-birth rate and miscarriage rate following G-CSF administration. We have reported ongoing pregnancy rate in cases where studies did not report live birth but reported ongoing pregnancy. Secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, adverse events, ectopic pregnancy rate, small for gestational age at birth, abnormally adherent placenta, and congenital anomaly rate. We analysed data using risk ratio (RR), Peto odds ratio and a fixed-effect model. We assessed the quality of the evidence using the GRADE criteria. MAIN RESULTS We included 15 trials involving 622 women who received G-CSF and 631 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 15 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate. We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.42, 95% confidence interval (CI) 0.83 to 2.42; 2 RCTs; participants = 263; I² = 0%; very low-quality evidence). For a typical clinic with 14% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 12% and 35%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.55, 95% CI 0.17 to 1.83; 3 RCTs; participants = 391; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART. We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.63, 95% CI 1.32 to 2.01; 14 RCTs; participants = 1253; I² = 13%; very low-quality evidence). For a typical clinic with 17% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 35%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.11, 95% CI 0.77 to 1.60; 3 RCTs; participants = 404; I² = 0%; low-quality evidence). G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.11, 95% CI 1.56 to 2.85; 7 RCTs; participants = 643; I² = 0%; low-quality evidence). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment. AUTHORS' CONCLUSIONS In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.
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Affiliation(s)
- Mohan S Kamath
- Christian Medical College, Department of Reproductive Medicine, Ida Scudder Road, Vellore, Tamil Nadu, India, 632004
| | - Richard Kirubakaran
- Christian Medical College, Cochrane South Asia, Prof. BV Moses Centre for Evidence-Informed Healthcare and Health Policy, Carman Block II Floor, CMC Campus, Bagayam, Vellore, India, 632002
| | - Sesh Kamal Sunkara
- King's College London, Division of Women's Health, Faculty of Life Sciences & Medicine, Strand, London, UK, WC2R 2LS
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Miralaei S, Ashrafi M, Arabipoor A, Zolfaghari Z, Taghvaei S. The incidence rate of unresponsive thin endometrium in frozen embryo transfer cycles: A case-series of therapy with granulocyte colony stimulating factor. Int J Reprod Biomed 2019; 17:923-928. [PMID: 31970314 PMCID: PMC6943793 DOI: 10.18502/ijrm.v17i12.5797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 06/03/2019] [Accepted: 08/14/2019] [Indexed: 12/15/2022] Open
Abstract
Background Treatment-resistant thin endometrium (TTE) during in-vitro fertilization is a relatively uncommon and challenging problem.
Objective The primary aim of the study was to assess the TTE rate during frozen embryo transfer (FET) cycles and the secondary aim was to evaluate the effect of intrauterine instillation of granulocyte colony stimulating factor (G-CSF) in these cases. Materials and Methods In this cross-sectional study, all of the women who underwent FET cycles with hormonal endometrial preparation in Royan Institute from June 2015 to March 2018 were evaluated and all of the cases with TTE diagnosis (endometrial thickness < 7 mm after using high doses of estradiol) were included. In the eligible cases, 300 μgr of G-CSF was infused intrauterine. If the endometrium had not reached at least a 7-mm, a second infusion was prescribed within 48 hr later. Results During the study, 8,363 of FET cycles were evaluated and a total of 30 infertile patients (0.35%) with TTE diagnosis were detected. Finally, 20 eligible patients were included. The changes of endometrial thickness after G-CSF therapy were significant (p < 0.001); however, the endometrial thickness did not reach 7 mm in nine patients (45%) and the embryo transfer was canceled. Conclusion It was found that the rate of TTE during the FET cycle is very low and intrauterine perfusion of G-CSF has a potential effect to increase the endometrial thickness in these patients; however, the rate of cancellation was still high and poor pregnancy outcomes were observed.
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Affiliation(s)
- Shokouhosadat Miralaei
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mahnaz Ashrafi
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,Department of Obstetrics and Gynecology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran.,Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Science (IUMS), Tehran, Iran
| | - Arezoo Arabipoor
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Zahra Zolfaghari
- Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Saeideh Taghvaei
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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Embryo transfer strategy and therapeutic options in infertile patients with thin endometrium: a systematic review. J Assist Reprod Genet 2019; 36:2217-2231. [PMID: 31502111 DOI: 10.1007/s10815-019-01576-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 08/28/2019] [Indexed: 10/26/2022] Open
Abstract
Human endometrium has a key role in implantation process. The measurement of endometrial thickness is the most commonly used in clinical practice. Managing patients with thin endometrium still represents a major challenge for clinicians. The objective of this systematic review was to investigate all available interventions to improve endometrial thickness (EMT) in women with history of thin endometrium undergoing fresh or frozen-thawed embryo transfers (ET). We performed a comprehensive search of relevant studies from January 1978 to February 2018. The different strategies were categorized as hormonal, vascular, and growth factor approaches and specifically analyzed according to the type of ET. Thirty-one studies were included. Overall, quality of the evidence ranged from very low to moderate, with only few randomized controlled trials that support the use of either GnRH analogues in fresh ET or sildenafil in frozen ET for enhancing endometrial growth. Besides, intensified estradiol administration is a common approach that might improve EMT in frozen ET. The present review evidences the paucity of reliable data regarding the efficiency of different interventions aiming at increasing EMT before fresh or frozen-thawed ET. Robust and high-quality randomized controlled trials are still needed before guidelines can be established.
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Zeyneloglu HB, Tohma YA, Onalan G, Moran U. Granulocyte colony-stimulating factor for intracytoplasmic sperm injection patients with repeated implantation failure: which route is best?†. J OBSTET GYNAECOL 2019; 40:526-530. [PMID: 31496328 DOI: 10.1080/01443615.2019.1631772] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The aim of this study was to assess whether the dual administration of granulocyte colony-stimulating factor (G-CSF) increases the effect of only systemic administration in patients with RIF. This retrospective study included 111 infertile normoresponder cases with two or more unsuccessful in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatments, despite the transfer of good quality embryos. Patients were divided into three groups according to using G-CSF and administration route; Group 1 included patients who received subcutaneous (SC) G-CSF only (n = 38), Group 2 comprised patients who received both intrauterine (IU) and SC G-CSF (n = 39), the control group included patients who did not receive G-CSF who were matched by age (n = 34). The IU route of G-CSF was employed on ovulation triggering day. G-CSF was administered via an IU insemination catheter. SC injection was started on the day of oocyte retrieval and administered for 15 days at 100,000 IU/kg. Foetal cardiac activity (clinical pregnancy) was present in 50 patients (46.2%) after embryo transfer, with 20 patients included in SC group (Group 1) (52.6%), 25 in SC + IU group (Group 2) (64.1%) and 8 (23.5%) in control group and significant difference was observed between groups (p: .001). Pregnancy resulted in live birth in 43 patients (39.8%), with 13 patients belonging in Group 1 (34.2%), 25 in Group 2 (61.5%) and 8 (23.5%) in control group; significant differences were observed between groups (p: .001). In conclusion, our results showed that dual administration of G-CSF was significantly more effective that the SC only method.Impact statementWhat is already known on this subject? A number of studies reported the possible benefits of granulocyte colony-stimulating factor (G-CSF) administration in recurrent implantation failure (RIF) and recurrent pregnancy loss patients; however, it is unclear which administration route is better.What do the results of this study add? Our results showed that G-CSF is a promising and safe agent for increasing live birth rates in patients with RIF. Additionally, dual administration is considered the better method than SC only administration.What are the implications of these findings for clinical practice and/or further research? Clinicians should consider a combination of IU use before ovulation triggering with SC administration starting from the day of oocyte collection for using G-CSF for the treatment of recurrent implantation failure. Additionally, our data show the need for research in the field of administration route of G-CSF for RIF. We suggest that further studies be performed in this field.
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Affiliation(s)
| | - Yusuf Aytac Tohma
- Department of Obstetrics and Gynecology, Baskent University School of Medicine, Ankara, Turkey
| | - Gogsen Onalan
- Department of Obstetrics and Gynecology, Baskent University School of Medicine, Ankara, Turkey
| | - Utkun Moran
- Department of Obstetrics and Gynecology, Baskent University School of Medicine, Ankara, Turkey
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Robert CA, Abbas MK, Zaidi ARZ, Thiha S, Malik BH. Mediator in the Embryo-endometrium Cross-talk: Granulocyte Colony-stimulating Factor in Infertility. Cureus 2019; 11:e5390. [PMID: 31428551 PMCID: PMC6695290 DOI: 10.7759/cureus.5390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Successful implantation requires a receptive endometrium and a good quality egg. The challenges a physician encounters with regard to this in assisted reproductive technology are obtaining good quality embryo, achieving optimal endometrial thickness (EMT), and subsequently implantation, which is denotive of a receptive endometrium. Granulocyte colony-stimulating factor (G-CSF) has been observed to be a biomarker of oocyte quality and has been shown to enhance EMT and implantation because of its immunological effects. A systematic search for all relevant articles on G-CSF in follicular fluid and its therapeutic benefit in thin endometrium and recurrent implantation failure was performed, and peer-reviewed, full-text articles related to humans were included in the study. As a tool to determine the potentiality of oocyte, G-CSF shows promise with its predictability increasing in combination with morphological embryo scoring or interleukin 15. For the thin endometrium, G-CSF is especially useful in patients who are refractory to other treatment modalities. In recurrent implantation failure (RIF), G-CSF showed potential in a subset of patients with immunological deficiency lacking killer cell immunoglobulin-like receptor genes. This review highlights the various forms of usage of G-CSF and the effectiveness of G-CSF in infertility. G-CSF equips embryologists with a tool to determine the potentiality of oocyte and physicians with therapy for thin endometrium and RIF, especially since the available treatment options are ineffective.
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Affiliation(s)
- Chris A Robert
- Obstetrics & Gynecology, California Institute of Behavioral Neurosciences and Psychology, California, USA
| | - Mohammed K Abbas
- Internal Medicine, California Instititute of Behavioral Neurosciences and Psychology, California, USA
| | - Abdul Rehman Z Zaidi
- Research, California Institute of Behavioral Neurosciences and Psychology, California, USA
| | - Suyeewin Thiha
- Internal Medicine, California Institute of Behavioural Neurosciences and Psychology, California, USA
| | - Bilal Haider Malik
- Medicine, California Institute of Behavioral Neurosciences and Psychology, California, USA
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Liu KE, Hartman M, Hartman A. Management of thin endometrium in assisted reproduction: a clinical practice guideline from the Canadian Fertility and Andrology Society. Reprod Biomed Online 2019; 39:49-62. [PMID: 31029557 DOI: 10.1016/j.rbmo.2019.02.013] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 02/12/2019] [Indexed: 02/03/2023]
Abstract
The impact and management of thin endometrium is a common challenge for patients undergoing assisted reproduction. The objective of this Canadian Fertility and Andrology Society (CFAS) guideline is to provide evidence-based recommendations using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework on the assessment, impact and management of thin endometrium in assisted reproduction. The effect of endometrial thickness on pregnancy and live birth outcomes in ovarian stimulation and IVF (fresh and frozen cycles) is addressed. In addition, recommendations on the use of adjuvants to improve endometrial thickness and pregnancy outcomes are provided.
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Affiliation(s)
- Kimberly E Liu
- Mount Sinai Fertility, 250 Dundas St. W, Suite 700, Dept of Obstetrics and Gynecology, Mount Sinai Hospital, 600 University Ave., University of Toronto, Toronto ON, M5T 2Z5, Canada.
| | - Michael Hartman
- Trio Fertility, 655 Bay St., Suite 1101, Toronto ON, M5G 2K4, Canada
| | - Alex Hartman
- True North Imaging, 7330 Yonge St., Suite 120, Thornhill ON, L4J 7Y7, Canada
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Effect of Ligustrazine on Endometrium Injury of Thin Endometrium Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:7161906. [PMID: 31308854 PMCID: PMC6594312 DOI: 10.1155/2019/7161906] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 04/30/2019] [Indexed: 01/14/2023]
Abstract
The purpose of this experiment is to establish a rat model of thin endometrium and to explore the effect of ligustrazine on the thin endometrium of rats. The thin endometrium model was made by using infusing absolute ethyl alcohol into the uterine cavity. The thickness of endometrium was measured. Hematoxylin-Eosin (HE) staining was used to observe the histopathological changes of endometrium. The mRNA levels of VEGF, VEGFR-2, PI3K, and AKT were detected by RT-PCR. Western blotting was used to detect the levels of VEGF, VEGFR-2, PI3K, and AKT in endometrial tissue. The thickness of endometrium in the model group was significantly thinner than that in the control group. Compared with the model group, the thickness of endometrium in ligustrazine group was increased. HE staining shown that ligustrazine restored the histopathological changes of endometrium. RT-PCR and Western Blotting results showed that the mRNA and protein levels of VEGF, VEGFR-2, PI3K, and AKT in the model group were significantly decreased compared with the control group, while ligustrazine restored the changes. Ligustrazine can improve the morphology of endometrium, can promote the growth of endometrium, and has obvious therapeutic effect. Its mechanism is related to the activation of PI3K/Akt signaling pathway through upregulation of VEGF and VEGFR-2 expression to induce the repair of thin endometrium in rats.
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Deans R, Vancaillie T, Ledger W, Liu J, Abbott JA. Live birth rate and obstetric complications following the hysteroscopic management of intrauterine adhesions including Asherman syndrome. Hum Reprod 2019; 33:1847-1853. [PMID: 30239778 DOI: 10.1093/humrep/dey237] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION What are the live birth rate and risks of obstetric complications following the surgical management of intrauterine adhesions (IUA) such as Asherman syndrome (AS)? SUMMARY ANSWER The live birth rate is 63.7%, and obstetric complications including placentation issues, prematurity and postpartum hysterectomy require that pregnancies in women after treatment for IUA should be considered moderate to high risk. WHAT IS KNOWN ALREADY Studies reviewing short-term surgical, menstrual and fertility outcomes following hysteroscopic management are reassuring, with success correlated to the severity of IUA. There are limited data reporting live birth, neonatal and maternal complications. STUDY DESIGN, SIZE, DURATION This retrospective study included all women treated for IUA by hysteroscopic synechiolysis under fluoroscopic guidance in two tertiary University-affiliated hospitals. All women reported at least one pre-treatment symptom including menstrual dysfunction, subfertility or pelvic pain and intended to become pregnant post-treatment. Survival curve analysis was performed for time to pregnancy, and obstetric data were collated from a National Obstetric Database for delivery and neonatal outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 154 women were included in the study. Surgical intervention involved hysteroscopic synechiolysis under fluoroscopic guidance until cavity restoration was confirmed. Questionnaires regarding fertility and its outcomes were sent to all women undergoing surgery, with analysis of menstrual, fertility rates and outcomes of those pregnancies including risks and complications to the woman and the offspring. MAIN RESULTS AND THE ROLE OF CHANCE Women were followed up for a minimum of 1 year (range: 1-14 years) from index surgery. The chance of pregnancy was 98/124 (79.0% CI: 63.6, 83.1%) in women wishing to conceive and the chance of a live birth was 79/124 (63.7% CI: 51.3, 70.7%). The chance of a miscarriage was 29/124 (23.4% CI: 18.8, 37.1%). There were 93 live births in 79 women following surgery, with detailed obstetric data available for 85 of these births. They were complicated by abnormal placentation in 15/85 (17.6% CI: 13.0, 30.2%), postpartum hysterectomy in 4/85 (4.7% CI: -0.4, 7.0%), and prematurity in 25/85 (29.4% CI: 17.0, 35.3%) women. LIMITATIONS, REASONS FOR CAUTION The retrospective nature of the study and extended follow-up time may cause selection and recall bias, however, pregnancy and its outcomes-particularly in women with problems of subfertility-are frequently key milestones, with birthdates readily recalled. Menstrual outcomes are more likely to be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS Our surgical data are similar to the published literature with reassuring short-term outcomes for menstruation and cavity reconstruction following surgery for IUA. Long-term outcomes including pregnancy rates were higher than published data, however, the obstetric and neonatal complication rates were increased, indicating a continuation of risk beyond infertility and into pregnancy. An altered biochemical or vascular environment is a possible explanation for impaired implantation resulting in poorer reproductive obstetric and neonatal outcomes. The relative rarity of IUA-particularly severe disease-makes prospective data collection difficult. Our data suggest that women with IUA should be treated as moderate-high risk obstetric patients in subsequent pregnancy and counselled appropriately. STUDY FUNDING/COMPETING INTEREST(S) No funding and no competing interests.
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Affiliation(s)
- Rebecca Deans
- School of Women's and Children's Health, University of New South Wales, Barker St, Randwick, NSW, Australia.,Royal Hospital for Women, Barker, St Randwick, NSW, Australia.,Genea Ltd., 321 Kent St, Sydney, NSW, Australia
| | - Thierry Vancaillie
- School of Women's and Children's Health, University of New South Wales, Barker St, Randwick, NSW, Australia.,Royal Hospital for Women, Barker, St Randwick, NSW, Australia
| | - William Ledger
- School of Women's and Children's Health, University of New South Wales, Barker St, Randwick, NSW, Australia.,Royal Hospital for Women, Barker, St Randwick, NSW, Australia
| | - Jinzhu Liu
- School of Women's and Children's Health, University of New South Wales, Barker St, Randwick, NSW, Australia
| | - Jason A Abbott
- School of Women's and Children's Health, University of New South Wales, Barker St, Randwick, NSW, Australia.,Royal Hospital for Women, Barker, St Randwick, NSW, Australia
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Santamaria X, Mas A, Cervelló I, Taylor H, Simon C. Uterine stem cells: from basic research to advanced cell therapies. Hum Reprod Update 2019; 24:673-693. [PMID: 30239705 DOI: 10.1093/humupd/dmy028] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/04/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells. OBJECTIVE AND RATIONALE In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others. SEARCH METHODS A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus. OUTCOMES The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation. WIDER IMPLICATIONS More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
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Affiliation(s)
- Xavier Santamaria
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Reproductive Medicine Department, IVI Barcelona, Barcelona, Spain.,Department of Obstetrics and Gynecology, Biomedical Research Group in Gynecology, Vall Hebron Institut de Recerca, Barcelona, Spain
| | - Aymara Mas
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Obstetrics and Gynecology, Reproductive Medicine Research Group, La Fe Health Research Institute, Valencia, Spain
| | - Irene Cervelló
- Department of Obstetrics and Gynecology, Fundación Instituto Valenciano de Infertilidad (FIVI), and Instituto Universitario IVI/INCLIVA, Valencia, Spain
| | - Hugh Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Carlos Simon
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Pediatrics, Obstetrics, and Gynecology, Valencia University and INCLIVA, Valencia, Spain.,Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
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Bos-Mikich A, Ferreira MO, de Oliveira R, Frantz N. Platelet-rich plasma or blood-derived products to improve endometrial receptivity? J Assist Reprod Genet 2019; 36:613-620. [PMID: 30610660 PMCID: PMC6504981 DOI: 10.1007/s10815-018-1386-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
The use of platelet-rich plasma (PRP) to improve endometrial receptivity is gaining increasing attention in assisted reproduction technologies. The authors report that autologous PRP intrauterine administration improves pregnancy and birth rates, particularly in cases of patients presenting poor endometrial growth. Different groups of scientists proposed a similar approach years ago using whole blood-derived products also to improve endometrial receptivity. The important role played by cytokines and growth factors during embryo implantation has been well-known for a long time. These signaling molecules are present and released by blood cells during physiological, normal endometrial growth and implantation. Similar blood mediators are released from platelet granules upon a blood vessel injury. Methods described for PRP preparation for intrauterine administration are not precise, and they seem to be similar to those used to prepare peripheral blood-derived products. Thus, it is possible that when preparing PRP from whole blood, the final plasma product used as "PRP" contains platelets in addition to the important cytokines and growth factors released by the peripheral blood mononuclear cells present in the whole blood. Precise knowledge of the identity, concentration, and effects of the individual blood factors, their origin, whether platelets or blood mononuclear cells, will greatly contribute to improve and to make results obtained in fertility treatments more repeatable.
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Affiliation(s)
- Adriana Bos-Mikich
- Department of Morphological Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
| | | | | | - Nilo Frantz
- nilo.frantz Medicina Reprodutiva, Porto Alegre, RS, Brazil
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Eapen A, Joing M, Kwon P, Tong J, Maneta E, De Santo C, Mussai F, Lissauer D, Carter D. Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial. Hum Reprod 2019; 34:424-432. [PMID: 30776296 PMCID: PMC6389865 DOI: 10.1093/humrep/dey393] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/31/2018] [Indexed: 12/04/2022] Open
Abstract
STUDY QUESTION Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93). LIMITATIONS, REASONS FOR CAUTION This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy. STUDY FUNDING/COMPETING INTEREST(S) This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported. TRIAL REGISTRATION NUMBER EUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063. TRIAL REGISTRATION DATE 31 Mar 2014. DATE OF FIRST PATIENT’S ENROLMENT 23 Jun 2014.
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Affiliation(s)
- A Eapen
- Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK
- University of Iowa Hospitals and Clinics, Carver college of Medicine, IA, USA
| | - M Joing
- Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA, USA
| | - P Kwon
- Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA, USA
| | - J Tong
- Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA, USA
| | - E Maneta
- Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK
| | - C De Santo
- Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK
| | - F Mussai
- Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK
| | - D Lissauer
- Tommy’s National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK
| | - D Carter
- Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA, USA
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Chang Y, Li J, Wei LN, Pang J, Chen J, Liang X. Autologous platelet-rich plasma infusion improves clinical pregnancy rate in frozen embryo transfer cycles for women with thin endometrium. Medicine (Baltimore) 2019; 98:e14062. [PMID: 30653117 PMCID: PMC6370111 DOI: 10.1097/md.0000000000014062] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Adequate thickness of the endometrium has been well recognized as a critical factor for embryo implantation. This was a prospective cohort study to investigate the benefits of platelet-rich plasma (PRP) for women with thin endometrium who received frozen embryo transfer (FET) program in a larger number of patients and explore the underlying mechanism. METHODS In this study, we investigated the effects of PRP in women with thin endometrium in FET program. 64 patients with thin endometrium (<7 mm) were recruited. PRP intrauterine infusion was given in PRP group during hormone replacement therapy (HRT) cycle in FET cycles. RESULTS After PRP infusion, the endometrium thickness in PRP group was 7.65 ± 0.22 mm, which was significantly thicker than that in control group (6.52 ± 0.31 mm) (P <.05). Furthermore, PRP group had lower cycle cancellation rate when compared to control group (19.05% vs. 41.18%, P <.01). The implantation rate and clinical pregnancy rate in PRP group were significantly higher than those in control group (27.94% vs 11.67%, P <.05; 44.12% vs 20%, P <.05, respectively). PRP blood contained 4 folds higher platelets and significantly greater amounts of growth factors including platelet-derived growth factor (PDGF)-AB, PDGF-BB, and transforming growth factor (TGF)-β than peripheral blood (P <.01). CONCLUSIONS PRP plays a positive role in promoting endometrium proliferation, improving embryo implantation rate and clinical pregnancy rate for women with thin endometrium in FET cycles.
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Kamath MS, Kirubakaran R, Sunkara SK. Granulocyte‐colony stimulating factor administration for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev 2018; 2018:CD013226. [PMCID: PMC6517183 DOI: 10.1002/14651858.cd013226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2024]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the effectiveness and safety of granulocyte‐colony stimulating factor in women undergoing ART.
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Affiliation(s)
- Mohan S Kamath
- Christian Medical College and HospitalReproductive Medicine UnitIda Scudder RoadVelloreIndia632004
| | - Richard Kirubakaran
- Christian Medical CollegeCochrane South Asia, Prof. BV Moses Centre for Evidence‐Informed Healthcare and Health PolicyCarman Block II FloorCMC Campus, BagayamVelloreIndia632002
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Farimani M, Mehrabi N, Pirdehghan A, Bahmanzadeh M. The Effects of Subcutaneous Administration of Granulocyte Colony-Stimulating Factor on Pregnancy Outcome After Assisted Reproductive Technology: Clinical Trial. AVICENNA JOURNAL OF MEDICAL BIOCHEMISTRY 2018. [DOI: 10.15171/ajmb.2018.08] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background: Granulocyte-colony stimulating factor (G-CSF) is an innovative therapy in reproductive medicine. Although its mechanisms of action have remained unknown, G-CSF seems to be effective in the case of recurrent abortion or implantation failure and thin endometrium. Objectives: This study was conducted to investigate whether subcutaneous administration of G-CSF has any effect on pregnancy outcome after assisted reproductive technology (ART). Methods: Fifty women with male infertility factors undergoing ART treatment were enrolled and stimulated with the standard long protocol. The G-CSF group of women received one dose of subcutaneous G-CSF (Filgrastim, 300 µg/1 mL) on the day of embryo transfer and again two days later while the placebo group received normal saline. Results: Seventeen patients had a positive β-human chorionic gonadotropin concentration after embryo transfer (8 and 9 in G-CSF and placebo groups, respectively) although the difference was not statistically significant. In addition, spontaneous abortion occurred in three patients (1 patient in the G-CSF group vs. 2 patients in the placebo group). Conclusion: Overall, although G-CSF failed to affect the endometrial thickness, as well as implantation, or clinical pregnancy rates, a lower prevalence of abortion in G-CSF group may be due to the positive effect of G-CSF administration on the endometrium as compared to the placebo group.
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Affiliation(s)
- Marzie Farimani
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Narges Mehrabi
- Department of Obstetrics & Gynecology, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Azar Pirdehghan
- Department of Community and Preventive Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Maryam Bahmanzadeh
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Anatomical Sciences, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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