Unresponsive Thin Endometrium Research Articles

Role of Granulocyte Colony Stimulating Factor Effects on Unresponsive Thin Endometrium in Women Undergoing Controlled Ovarian Stimulated Intrauterine Insemination Cycles

Back Ground: It is a prospective observational study that included unexplained infertility cycles with COS –IUI protocols. Thin endometrium of less than 7mm has a negative effect on pregnancy rate. Endometrial function and receptivity factors are important in the success of implantation.
 Aim: To monitor the effects of G-CSF on thin endometrium in improving endometrium thickness and pregnancy rates in G-CSF administered COS-IUI cycles.
 Methods: This study was conducted in the Laxmi Narasimha hospital IVF center under the guidence Dr. Adaboina Anitha,Hanamkonda, warangal. Thin endometrium was defined less than 7mm on Trans vaginal ultrasound. Letrozole 5mg (2.5mg, BD) is used for ovulation induction on day 2 or day 3 of their cycle, G CSF 300units was added with significantly improved pregnancy rates in ART cycles. Trigger used was injection 10,000IU urinary hCG & 300 units G-CSF was instilled into the uterus. After 48hours ET was measured & IUI was performed under aseptic precautions. After 16 days β -hCG levels were monitored to determine whether there is a pregnancy.
 Results: In present study, we concluded that, 250 COS-IUI cycles were analysed and 50 cycles showed a thin endometrium and in them G-CSF was used. The pregnancy rate (28%) was evaluated, 14 members are positive for pregnancy.
 Conclusion: In our study we concluded that G-CSF and letrozole will improve increases endometrium thickness and conceiving rates in COS-IUI cycles.

Intrauterine Medical Therapies (i.e.: PRP Infusions, G-CSF)

Endometrial thickness is an important and crucial factor that contributed to success rate in IVF. A thin endometrium < 7 mm revealed inadequate endometrial blood flow which will affect the embryo implantation process. There are a number of intra uterine therapies currently being used to improve chances of implantation such as vaginal sildenafil, GCSF, PRP and stem cell therapy. However, despite these interventions many women with thin or damaged endometrial linings do not respond to these therapies. intrauterine autologous PRP in women with thin lining seems to show promise. Study in our group about regeneration of endometrial line using 3-D scaffold and self-endometrial cells was addressed particularly for unresponsive thin endometrium cases. Three-dimension acellular scaffolds, amnion bilayer womb patch enriched by autologous endometrial cell were attached into uterine cavity for 14 days. Endometrial sections indicated that initial biopsy before treatment had undefine histoarchitecture, while 14 days application of womb patch showed some areas had epithelial structure, although not obvious. After cell treatment, the epithelial had been formed, with high thoracal, rich with vacuoles, had cilia, and more complex with tubing system. The epithelial also expressed E-Cadherin, and the stroma cells had expressed ER, but not the PR. These had indicated patient phase secretion. This showed that 3d scaffold and self-endometrial cells look promising to improve regeneration of unresponsive thin endometrium.

Improved Pregnancy Outcomes and Endometrial Receptivity by Thawed Frozen Embryo Transfer in Mildly Stimulated Cycles with Letrozole Combined with Estrogen in Women with Unresponsive Thin Endometrium Compared to Standard Endometrial Preparation with Estrogen Alone: A Retrospective Study.

Infertile women undergoing frozen embryo transfer (FET) cycles may not show optimal endometrial growth with estrogens alone. To evaluate clinical effect of mild stimulation with letrozole and estrogens on endometrial growth in comparison to standard endometrial preparation with oral and topical estrogens in infertile women with unresponsive thin endometrium undergoing FET. Retrospective observational case-control study. Forty women unresponsive to first AC-FET cycle were given mild stimulation with letrozole and estrogens as second LE-FET cycle for endometrial preparation (LE-FET study group) and compared with 40 historical controls who had received two cycles of AC-FET (AC-FET control group). Responses were assessed by optimal endometrial thickness (≥ 7mm) and clinical pregnancy. Descriptive statistics were elaborated by mean ± SD and percentages. Results were expressed by mean ± SD, unpaired t test for difference in endometrial thickness, chi square and Fisher exact test to compare the difference in pregnancy among both groups. Mean endometrial thickness was significantly increased in LE-FET study group (6.68 ± 2.09mm) versus AC-FET control group (5.35 ± 1.90mm). Higher clinical pregnancy rate was noted in study group as compared to control group (35% versus 12.5%). This study suggests that letrozole with estradiol (LE-FET) compared to estradiol alone (AC-FET) for second cycle significantly increased endometrial thickness and improved clinical pregnancy rates in women with unresponsive thin endometrium after first AC-FET cycle with estradiol alone. Addition of letrozole to estrogen upfront for FET cycles may enhance endometrial receptivity and might improve pregnancy outcomes.

SUBENDOMETRIAL AUTOLOGOUS PLATELET RICH PLASMA INJECTION IN PATIENTS WITH UNRESPONSIVE THIN ENDOMETRIUM UNDERGOING FROZEN-THAWED EMBRYO TRANSFER

The aim of the current study was to investigate the effects of subendometrial PRP injection on endometrial thickness and pregnancy outcomes in patients with a history of unresponsive thin endometrium undergoing frozen-thawed embryo transfer (FET).

O-026 RCT of INTRA - Uterine administration of granulocyte colony-stimulating factor (G-CSF) before embryo-transfer in resistant thin endometrium in IVF-ICSI cycles

Abstract Study question Does intrauterine administration of G-CSF (granulocyte-colony-stimulating factor) prior to Embryo-Transfer in patients with resistant thin endometrium improve endometrial thickness and pregnancy rate in IVF-ICSI cycles? Summary answer Yes, Intrauterine administration of G-CSF(granulocyte colony-stimulating factor) before embryo transfer in resistant thin endometrium increases endometrial thickness and improves the pregnancy-rate in IVF-ICSI cycles. What is known already Optimal endometrial thickness reflects adequate maturation, which is a key factor for implantation. Proliferative and secretory changes at the endometrial lining are the result of a complex intrauterine environment where sex steroid hormones and local factors play important role. Lucena et al. found that the uterine-infusion of G-CSF increased endometrial thickness resulting in a successful pregnancy . Li et al. evaluated the effectiveness of G-CSF in a thin endometrium in frozen ET-cycles. The implantation and pregnancy rates were significantly higher (Scarpellini & Sbracia 2012,et al.2015), whereas did not affect endometrial thickness, implantation, or pregnancy rates (Barad et al. 2014, Li et al. 2014). Study design, size, duration 86 Infertile patients with thin endometrium below 45 years age (2018 to 2021) were included in this study, in whom traditional treatment with estradiol, sildenafil etc had been unsuccessful. Patients were randomly divided into two groups using computer generated list after proper consent .The study group received intrauterine- G-CSF and control group received placebo (saline) before Embryo Transfer in IVF-ICSI cycles. Primary Outcome Endometrial-thickness, Implantation & Pregnancy rates. Secondary-outcome Abortion-rate Participants/materials, setting, methods The study group (n = 43) received intrauterine infusion of 300 microgramme/1ml of G-CSF, and the control group (n = 43) underwent placebo-saline infusion before Embryo-Transfer. G-CSF was administered by an intrauterine catheter by slow instillation on the day of hCG administration. If the endometrium had not reached at least a 7-mm within 48 h, a second dose was administered following oocyte retrieval. Main results and the role of chance The endometrial growth was significantly different in the two groups, with an improvement in the G-CSF group. Endometrial expansion to Optimal thickness occurred within approximately 48 -72 hour after G-CSF instillation. In all subjects, at the time of administration of G-CSF, endometrial thickness was 6.43 ± 1.49 mm, and,after G-CSF administration, it increased significantly to 8.11 ± 1.42 mm. The IR and PR were statistically significantly higher in the group receiving intrauterine G-CSF (22% and 33%, respectively) as compared to the control group (08% and 14%, respectively). Abortion Rates were comparable in both the groups and difference was not significant. Endometrial instillation of G-CSF may be effective in expanding chronically unresponsive thin endometrium, resistant to conventional remedies. This treatment needs more multicentric trials to assess its potential in improving the implantation chances in IVF-ICSI cycles, thereby improving pregnancy rates. Uterine perfusion or SC injection with G-CSF represents a promising new tool for intractable problem of thin endometrium . Proliferative and secretory changes in the endometrial lining are the result of a complex intrauterine environment where sex steroid hormones and different local factors play an important role for endometrial thickening. Limitations, reasons for caution Our study is not without limitations. We did not have a large number of patients. The main strengths of study were its RCT design to evaluate the efficacy of intrauterine G-CSF administration on IVF success. Further more RCT are required to establish the best route and dose of GCSF administration in thin-endometrium. Wider implications of the findings Several methods have been proposed, to increase endometrial-thickness in women undergoing IVF-ICSI . These therapies included -tocopherol, pentoxifylline, low-dose aspirin, sildenafil citrate, estradiol administration and hCG priming.Our study using Intra-Uterine instillation of G-CSF represents a promising and cost-effective therapy for the currently most intractable problem of resistant, thin endometrium. Trial registration number not applicable

Unresponsive thin endometrium caused by Asherman syndrome treated with umbilical cord mesenchymal stem cells on collagen scaffolds: a pilot study

BackgroundUnresponsive thin endometrium caused by Asherman syndrome (AS) is the major cause of uterine infertility. However, current therapies are ineffective. This study is to evaluate the effect of transplantation with collagen scaffold/umbilical cord mesenchymal stem cells (CS/UC-MSCs) on this refractory disease.MethodsEighteen infertile women with unresponsive thin endometrium, whose frozen–thawed embryo transfers (FETs) were cancelled due to reduced endometrial thickness (ET ≤ 5.5 mm), were enrolled in this before and after self-control prospective study. Hysteroscopic examination was performed to confirm no intrauterine adhesions, then twenty million UC-MSCs loaded onto a CS were transplanted into the uterine cavity in two consecutive menstrual cycles. Then uterine cavity was assessed through hysteroscopy after two transplants. FETs were performed in the following cycle. Pregnancy outcomes were followed up. Endometrial thickness, uterine receptivity and endometrial angiogenesis, proliferation and hormone response were compared before and after treatment.ResultsSixteen patients completed the study. No treatment-related serious adverse events occurred. Three months after transplantation, the average ET increased from 4.08 ± 0.26 mm to 5.87 ± 0.77 mm (P < 0.001). Three of 15 patients after FET got pregnant, of whom 2 gave birth successfully and 1 had a miscarriage at 25 weeks’ gestation. One of 2 patients without FET had a natural pregnancy and gave birth normally after transplantation. Immunohistochemical analysis showed increased micro-vessel density, upregulated expression of Ki67, estrogen receptor alpha, and progesterone receptor, indicating an improvement in endometrial angiogenesis, proliferation, and response to hormones.ConclusionCS/UC-MSCs is a promising and potential approach for treating women with unresponsive thin endometrium caused by AS.Trial registrationClinicalTrials.gov NCT03724617. Registered on 26 October 2018—prospectively registered, https://register.clinicaltrials.gov/

Granulocyte Colony-Stimulating Factor Combined With Transcutaneous Electrical Acupoint Stimulation in Treatment of Unresponsive Thin Endometrium in Frozen Embryo Transfer Cycles.

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.

The incidence rate of unresponsive thin endometrium in frozen embryo transfer cycles: A case-series of therapy with granulocyte colony stimulating factor.

BackgroundTreatment-resistant thin endometrium (TTE) during in-vitro fertilization is a relatively uncommon and challenging problem. ObjectiveThe 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.ResultsDuring 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.ConclusionIt 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.

Comparative study of intrauterine infusion of autologous platelet rich plasma in unresponsive thin endometrium in frozen ET cycle

Aims: Study of intrauterine infusion of autologous platelet rich plasma in unresponsive thin endometrium in frozen ET cycle .Thin endometrium still remains a big challenge for clinicians, creating so much burden in the form of cycle cancellation, unplanned freezing of embryo and even need for surrogacy. Intrauterine infusion of platelet-rich plasma (PRP) is newer modality of treatment in thin endometrium, in various studies showing promising results. Material and methods: Our study was prospective randomised controlled trial done from 1 August 2018 to 31 May 2019 at a tertiary infertility centre, New Delhi, India. 30 patients undergoing frozen embryo transfer with history of thin endometriun (less than 7 mm) with normal hysteroscopic examination were enrolled. Patients with platelet count less than 1.50000/dl, uncorrected asherman syndrome, submucosal polyp, fibroid or congenital uterine anomaly and with history of systemic diseases were excluded from study. From day 2 of menses tab estradiol valerate was started in dose of 6–8 mg/day. It was increased up to 12 mg/day gradually after reviewing endometrial thickness serially. Patients with thin endometrium on day 10/11 received PRP on day 11 and repeat dose after 48 hours if endometrial thickness was less than 7 mm. Frozen embryo transfer was done in patients who achieved endometrial thickness 7 mm or more. Results: The mean pre-treatment endometrial thickness was 5.42 mm, which significantly increased to 6.64 mm, post treatment (P

Tamoxifen in recurrent thin endometrium

To evaluate the effects of tamoxifen in patients with repeated unresponsive thin endometrium (

Effect of Increased Endometrial Thickness and Implantation Rate by Granulocyte Colony-Stimulating Factor on Unresponsive Thin Endometrium in Fresh In Vitro Fertilization Cycles: A Randomized Clinical Trial.

Background The correlation between endometrial thickness and receptivity has been mentioned in various studies. This study investigated the effect of granulocyte colony-stimulating factor in treating thin endometrium of infertile women who were chosen for in vitro fertilization in our infertility clinic in 2014 and 2015. Methods In this randomized clinical trial, 28 women who were chosen for in vitro fertilization and had endometrial thickness of less than 6 mm on the day of human chorionic gonadotropin (hCG) injection were included in the study. They were randomly divided into two groups: investigation and control groups. In investigation group (n = 13) one granulocyte colony-stimulating factor vial (300 micrograms in 1 mL) was infused into the uterus within five minutes by embryo transfer catheter. In control group (n = 15) 1 mL of saline was injected into the uterus with the same catheter. Results There were significant differences between the two groups in terms of means of endometrial thickness on oocyte retrieval day (P = 0.001), embryo transfer day (P = 0.001), hCG injections (P = 0.001), and implantation rates (P = 0.001). Conclusion Granulocyte colony-stimulating factor can increase endometrial thickness in women treated with in vitro fertilization. RCT Code is 201406046063N2.

Granulocyte Colony Stimulating Factor for Treatment of Thin Endometrium in Assisted Reproduction Technology Cycles

ABSTRACTGranulocyte colony stimulating factor (G-CSF), a glycoprotein, belongs to colony stimulating factor family and mainly regulates the growth and differentiation of granulocytes. However, it also plays an important role in endometrial stromal cell decidualization, ovulation, implantation, placental metabolism, trophoblast development and endometrial regeneration. It is due to these effects, it has been used in difficult clinical scenarios, such as unresponsive thin endometrium during assisted reproductive technology treatment, repeated implantation failure and recurrent miscarriages. Most of the studies have investigated its use in thin endometrium. In this review, we have summarized the current updated evidence with regards to use of G-CSF in women with thin endometriumHow to cite this articleKamath MS, Lele P. Granulocyte Colony Stimulating Factor for Treatment of Thin Endometrium in Assisted Reproduction Technology Cycles. Int J Infertil Fetal Med 2015;6(3):97-102.

New horizon on successful management for a woman with repeated implantation failure due to unresponsive thin endometrium: Use of extended estrogen supplementation

An adequate thickness and pattern of the pre-ovulatory endometrium is considered one of the essential requirements for a successful pregnancy. Although various methods for increasing endometrial thickness have been proposed, the real value of these interventions remains controversial. Here, we present a case of successful administration of extended estrogen supplementation before conventional controlled ovarian hyperstimulation in a woman who had experienced repeated implantation failure because of an unresponsive thin endometrium. After the estrogen supplement was administrated for an extended period, the in vitro fertilization/embryo transfer in this patient led to an uneventful twin pregnancy and delivery at term.

Successful Pregnancy in Recurrent Thin Endometrium with New Uses for an Old Drug

Objective: To analyze whether the use of tamoxifen is a feasible option in repeated unresponsive thin endometrium (<6 mm) with standard treatment options. Methods: Three consecutive women undergoing Frozen Embryo Transfer (FET) who, after standard endometrial preparation, still showed thin endometrium (<6 mm). They were all given with tamoxifen treatment. Results: Successful endometrial expansion to at least 7.7 mm after tamoxifen treatment in three patients previously with thin endometrium in abandoned IVF cycles, natural cycles and extended estrogen treatment cycles with aspirin. All the three patients performed embryo-transfer, and they all conceived. One singleton stopped growing on gestational week 8. Two deliveries produced three healthy children. Conclusion: In patients of recurrent thin endometrium, regardless of whether abandoned IVF cycles, natural cycles or extended estrogen treatment cycles with aspirin, tamoxifen treatment may be a successful alternative approach.

A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies

Is thin endometrium unresponsive to standard treatments expandable by intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF)? This cohort study is supportive of the effectiveness of G-CSF in expanding chronically unresponsive endometria. In a previous small case series, we reported the successful off-label use of G-CSF in four consecutive patients, who had previously failed to expand their endometria beyond 6.9 mm with the use of standard treatments. In a prospective observational cohort pilot study over 18 months, we described 21 consecutive infertile women with endometria <7 mm on the day of hCG administration in their first IVF cycles at our center. All previous cycles using traditional treatments with estradiol, sildenafil citrate (Viagra™) and/or beta-blockers had been unsuccessful. G-CSF (Nupogen™) was administered per intrauterine catheter by slow infusion before noon on the day of hCG administration. If the endometrium had not reached at least a 7-mm within 48h, a second infusion was given following oocyte retrieval. Primary and secondary main outcomes were an increase in endometrial thickness and clinical pregnancy, respectively. Endometrial thickness was assessed by vaginal ultrasound at the most expanded area of the endometrial stripe. This study was uncontrolled, each patient serving as her own control in a prospective evaluation of endometrial thickness. The mean ± SD age of the cohort was 40.5 ± 6.6 years, gravidity was 1.8 ± 2.1 (range 0-7) and parity was 0.4 ± 1.1 (range 0-4); 76.2% of women had, based on age-specific FSH and anti-Müllerian hormone, an objective diagnosis of diminished ovarian reserve and had failed 2.0 ± 2.1 prior IVF cycles elsewhere. With 5.2 ± 1.9 days between G-CSF perfusions and embryo transfers, endometrial thickness increased from 6.4 ± 1.4 to 9.3 ± 2.1 mm (P < 0.001). The Δ in change was 2.9 ± 2.0 mm, and did not vary between conception and non-conception cycles. A 19.1% ongoing clinical pregnancy rate was observed, excluding one ectopic pregnancy. Small sample size (but a highly selected patient population) in an uncontrolled cohort study and in unselected first IVF cycles at our center. This pilot study supports the utility of G-CSF in the treatment of chronically thin endometrium and suggests that such treatment will, in very adversely affected patients, result in low but very reasonable clinical pregnancy rates. This work was supported by the Foundation for Reproductive Medicine, New York, New York, USA, a not-for-profit research foundation and intramural grants from the Center for Human Reproduction (CHR)-New York. N.G. and D.H.B. are members of the board of the Foundation for Reproductive Medicine. N.G. is owner of CHR-New York, where the study was conducted. N.G. and D.H.B. have been recipients of research awards, travel grants and speaker honoraria from various pharmaceutical and medical device companies. None of these companies was, however, in any way associated with the materials and the manuscript presented here. N.G. and D.H.B. are listed as co-inventors on a number of awarded and still pending U.S. patents, none related to the materials presented here. N.G. is on the board of a medically related company, not in any way associated with the data presented here.

Successful treatment of unresponsive thin endometrium

To assess whether inadequate, thin endometrium (<7 mm), after failure to expand with standard treatment options, will be responsive to cytokine treatment. Prospective cohort study of four patients. Two independent IVF centers in New York City. Four consecutive women undergoing IVF who, after standard endometrial preparation, still demonstrated highly inadequate endometrium. Transvaginal endometrial perfusion with granulocyte colony-stimulating factor (G-CSF). Endometrial thickness on day of ET, with pregnancy as secondary endpoint. We report successful endometrial expansion to at least minimal thickness of 7 mm after uterine perfusion with G-CSF in four patients previously resistant to treatment with estrogen and vasodilators. All four patients therefore reached ET, and all four also conceived, although one pregnancy required termination because of intramural, corneal ectopic location. Endometrial expansion to minimal thickness occurred within approximately 48 hours from infusion. Uterine perfusion with G-CSF represents a promising new tool for the currently mostly intractable problem of inadequate, thin endometrium. This treatment also deserves further investigation for its potential to improve implantation chances in association with IVF and, therefore, pregnancy rates.