GYNECOLOGY

Eficacitatea comparativă a factorului de stimulare a coloniilor granulocitare şi a plasmei bogate în trombocite asupra ratelor de sarcină clinică şi rezultatelor endometriale la femei supuse transferului de embrioni congelați: studiu randomizat clini

Comparative efficacy of granulocyte colony stimulating factor and platelet-rich plasma on clinical pregnancy rates and endometrial outcomes in women undergoing frozen embryo transfer: a randomized controlled trial with 560 subjects

Smit B. Solanki
Data publicării: 25 Martie 2025
Editorial Group: MEDICHUB MEDIA
10.26416/Gine.47.1.2025.10596
Descarcă pdf

Abstract

Objective. Previous studies comparing granulocyte co­lo­ny stimulating factor (GCSF) and platelet-rich plasma (PRP) in the context of frozen embryo transfer (FET) have yiel­ded inconsistent results, largely due to a lack of robust ran­do­mized controlled trials (RCTs). This study aimed to assess the impact of intrauterine infusion of GCSF and PRP on cli­ni­cal pregnancy rates and other reproductive outcomes in women undergoing FET, and to evaluate their effects on implantation rates and endometrial characteristics. Materials and method. This RCT included 560 women who were randomly assigned to receive 300 mcg GCSF, 1 ml PRP, or saline as a control. The intervention was administered into the uterine cavity via an intrauterine insemination ca­the­ter under ultrasound guidance. All participants un­der­went conventional hormonal therapy before the FET cycle. Endometrial evaluation was conducted using trans­va­gi­nal ultrasound (TVUS), Doppler studies, and his­to­lo­gi­cal assessments in both natural and intervention cycles. Embryos were genetically tested prior to transfer. Results. The clinical pregnancy rates were similar across all groups (50.4% for GCSF, 51.2% for PRP, and 45.8% for saline; p=0.66). PRP administration significantly improved en­do­me­trial vascularity compared to saline (p=0.003); however, this did not translate into a higher clinical pregnancy rate. Live birth rates were also comparable among the groups (72.5% for GCSF and 75.6% for PRP). Conclusions. The study revealed that neither GCSF nor PRP influenced cli­ni­cal preg­nan­cy rates or overall pregnancy outcomes in wo­men un­der­go­ing FET. While PRP improved endometrial vas­cu­la­rity, it did not affect the clinical pregnancy rates. Both in­ter­ven­tions produced similar results to those using saline.



Keywords
granulocyte colony stimulating factorplatelet-rich plasmafrozen embryo transferendometrial vascularity

Rezumat

Obiectiv. Studiile anterioare care au comparat factorul de sti­mu­la­re a coloniilor granulocitare (GCSF) și plasma bogată în trom­bo­ci­te (PRP) în contextul transferului de embrioni congelați (FET) au avut rezultate inconsistente, în principal din cauza lip­sei unor studii randomizate controlate (RCT) solide. Acest stu­diu a avut ca scop evaluarea impactului infuziei intrauterine de GCSF și PRP asupra ratelor de sarcină clinică și evaluarea al­tor re­zul­ta­te reproductive la femeile care urmează FET, ală­turi de ana­li­za­rea efectelor asupra ratelor de implantare și ca­rac­te­ris­ti­ci­lor endometriale. Materiale și metodă. Acest studiu ran­do­mi­zat con­tro­lat a inclus 560 de femei, alocate aleatoriu să pri­meas­că fie 300 mcg de GCSF, fie 1 ml de PRP, fie soluție salină, în cadrul gru­pu­lui de control. Intervenția a fost administrată în ca­vi­ta­tea ute­ri­nă prin intermediul unui cateter de inseminare in­tra­ute­ri­nă, sub ghidaj ecografic. Toate participantele au urmat terapie hor­mo­na­lă convențională înainte de ciclul FET. Evaluarea en­do­me­tria­lă a fost realizată prin ecografie transvaginală (TVUS), studii Doppler și analize histologice în ambele cicluri, na­tu­ral și de intervenție. Embrionii au fost testați genetic înainte de transfer. Rezultate. Ratele de sarcină clinică au fost similare între grupuri (50,4% pentru GCSF, 51,2% pentru PRP și 45,8% pen­tru grupul cu soluţie salină; p=0,66). Administrarea de PRP a îmbunătățit semnificativ vascularizarea endometrială com­pa­ra­tiv cu soluția salină (p=0,003); totuşi, acest lucru nu s-a tra­dus într-o rată mai mare de sarcină clinică. Ratele de naștere vie au fost, de asemenea, comparabile între grupuri (72,5% pen­tru GCSF și 75,6% pentru PRP). Concluzii. Studiul a relevat că nici GCSF şi nici PRP nu au influențat ratele de sarcină clinică sau rezultatele generale ale sarcinii la femeile supuse FET. Deși PRP a îmbunătățit vascularizarea endometrială, acest lucru nu a avut un impact asupra ratelor de sarcină clinică. Ambele in­ter­ven­ții au produs rezultate similare cu cele care au utilizat soluția salină.

Cuvinte Cheie
factorul de stimulare a coloniilor granulo­ci­ta­replasmă bogată în trombocitetransfer de embrioni congelațivascularizație endometrială

Introduction

In the realm of assisted reproductive technologies (ART), improving the success rates of frozen embryo transfer (FET) is a critical objective. To this end, various adjunctive treatments have been proposed to enhance endometrial receptivity and subsequently increase the likelihood of successful implantation. Granulocyte colony stimulating factor (GCSF) and platelet-rich plasma (PRP) have emerged as promising candidates for such interventions, yet the existing evidence regarding their efficacy remains inconsistent, necessitating further investigation through rigorous randomized controlled trials (RCTs). GCSF, primarily recognized for its role in stimulating the production and function of neutrophils, has been explored for its potential benefits in reproductive medicine. The hypothesized mechanism of action involves the modulation of the local immune environment and enhancement of angiogenesis within the endometrium(1,2). GCSF’s application in treating women with recurrent implantation failure (RIF) is based on its presumed ability to promote endometrial regeneration, thereby improving the implantation rates(3,4). Despite this, clinical trials have yielded mixed results, with some studies reporting positive outcomes, while others failed to demonstrate significant improvements in clinical pregnancy rates(5,6). Platelet-rich plasma, derived from autologous blood and enriched with platelets and growth factors, represents another innovative approach in reproductive medicine. The rationale behind PRP use in frozen embryo transfer cycles lies in its potential to enhance endometrial healing and improve vascularization, thereby creating a more favorable uterine environment for embryo implantation(7,8). The therapeutic benefits of PRP are attributed to its high concentration of growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), which are essential for tissue repair and angiogenesis(9,10). Although initial studies suggest that platelet-rich plasma may improve endometrial thickness and vascularity, the evidence regarding its impact on clinical pregnancy rates remains inconclusive(11,12). The current literature reveals several controversies regarding the effectiveness of both GCSF and PRP. For granulocyte colony stimulating factor, some studies indicate improvements in implantation rates and overall pregnancy outcomes, particularly in women with specific endometrial conditions or recurrent implantation failure(13,14). However, these findings are not uniformly supported, as other trials fail to observe significant benefits(15,16). Similarly, while PRP has shown potential in small-scale studies, including improvements in endometrial vascularity, its effect on clinical pregnancy rates is still uncertain(17,18). The existing studies are often limited by small sample sizes, methodological differences and variations in treatment protocols, which contribute to the conflicting results(19,20). The need for well-designed randomized controlled trials to address these inconsistencies is paramount. Previous investigations into GCSF and PRP have been constrained by methodological limitations, including heterogeneous treatment protocols and small sample sizes, which hinder the generalizability of the findings(21,22). To bridge this gap, a large-scale randomized controlled trial is necessary to provide robust evidence on the efficacy of these interventions in improving FET outcomes. This study aims to systematically compare the effects of intrauterine infusion of GCSF and PRP on clinical pregnancy rates, implantation success, and endometrial characteristics. The objective of this study is to evaluate whether GCSF and PRP can significantly enhance clinical pregnancy rates and other key reproductive outcomes compared to a placebo control. Additionally, the study will investigate changes in endometrial vascularity and thickness to elucidate the mechanisms through which these treatments may influence pregnancy success. By employing a rigorous RCT design with a substantial sample size, this study seeks to clarify the role of GCSF and PRP in assisted reproductive technologies and provide valuable insights for clinical practice. The results of this study could have significant implications for reproductive medicine. Should GCSF or PRP demonstrate efficacy in improving FET outcomes, it could lead to modifications in treatment protocols and offer new options for women facing challenges with implantation failures. Conversely, if these treatments are found ineffective, the findings will redirect focus towards alternative strategies to enhance ART success. Overall, this study aims to contribute to the advancement of assisted reproductive technologies by providing high-quality evidence on the impact of GCSF and PRP on frozen embryo transfer outcomes.

Materials and method

Study design and participants. This randomized controlled trial was conducted to evaluate the effects of granulocyte colony stimulating factor (GCSF) and platelet-rich plasma (PRP) on clinical pregnancy rates and reproductive outcomes in women undergoing frozen embryo transfer (FET). A total of 560 women were enrolled in the study from January 2022 to June 2023. The participants were eligible if they were aged 18-42 years old, had a history of at least one previous failed FET cycle, and had normal uterine anatomy as confirmed by hysteroscopy or transvaginal ultrasound (TVUS). The exclusion criteria included known uterine abnormalities, severe male factor infertility, endocrine disorders affecting fertility, and contraindications to the study interventions.

Randomization and group assignment. The participants were randomly assigned in a 1:1:1 ratio to one of three study arms: (1) 300 mcg GCSF; (2) 1 ml PRP; or (3) saline placebo. Randomization was achieved using a computer-generated randomization schedule, and allocation concealment was ensured by using sealed opaque envelopes. The study was double-blinded, with both participants and investigators unaware of the treatment assignments.

Intervention protocol. Each participant underwent conventional hormonal preparation prior to the FET cycle. The study interventions were administered into the uterine cavity using an intrauterine insemination catheter under real-time ultrasound guidance. The GCSF group received 300 mcg of GCSF (Granulocyte-Colony Stimulating Factor, Amgen Inc., Thousand Oaks, CA) diluted in 1 ml of sterile saline. The PRP group received 1 ml of platelet-rich plasma, prepared from 20 ml of autologous blood drawn from each participant and processed using a standard PRP preparation protocol (PRP kit, RegenLab SA, Switzerland). The placebo group received 1 ml of sterile saline.

Endometrial assessment. Endometrial evaluation was performed in both natural and intervention cycles. Transvaginal ultrasound (TVUS) was used to assess endometrial thickness and morphology. Doppler studies were conducted to measure endometrial blood flow and vascularity. Histological assessment of endometrial samples was performed following endometrial biopsy to evaluate tissue structure and receptivity. Embryo transfer and genetic testing embryos were selected for transfer based on genetic testing performed prior to the FET cycle. Preimplantation genetic testing for aneuploidy (PGT-A) was conducted to identify chromosomally normal embryos. The transfer was performed using a soft catheter under ultrasound guidance to ensure proper placement.

Outcome measures. The primary outcome measure was the clinical pregnancy rate, defined as the presence of a gestational sac with fetal heartbeat on ultrasound at 6-7 weeks of gestation. The secondary outcomes included implantation rate, measured as the number of gestational sacs visualized on ultrasound divided by the number of embryos transferred, and endometrial characteristics, including thickness, vascularity and histological findings.

Statistical analysis. Sample size calculation was performed using an anticipated clinical pregnancy rate of 50% in the control group, with a desired power of 80% and a significance level of 0.05. The sample size was adjusted to account for potential dropouts, resulting in 560 participants. Descriptive statistics were used to summarize baseline characteristics. Comparisons between the groups for primary and secondary outcomes were conducted using chi-square tests for categorical variables and analysis of variance (ANOVA) for continuous variables. A p-value below 0.05 was considered statistically significant. All analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY).

Ethical considerations. The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board (IRB) of our institute. Written informed consent was obtained from all participants before enrolment.

Results

Study population

A total of 560 women were enrolled and randomized into three groups: 186 women in the GCSF group, 187 in the PRP group, and 187 in the placebo group. There were no significant differences in baseline characteristics across the groups, including age, Body Mass Index (BMI), duration of infertility, and previous IVF attempts (Table 1).

Table 1. Baseline characteristics of study participants
Figure: Table 1. Baseline characteristics of study participants

Primary outcome: clinical pregnancy rate

The clinical pregnancy rate did not differ significantly among the groups. The rates were 50.4% in the GCSF group, 51.2% in the PRP group, and 45.8% in the placebo group (p=0.66). The odds ratio for clinical pregnancy in the GCSF group compared to placebo was 1.17 (95% CI; 0.79-1.73), and in the PRP group, compared to placebo, it was 1.21 (95% CI; 0.82-1.78) – Table 2.

Table 2. Clinical pregnancy rates and odds ratios
Figure: Table 2. Clinical pregnancy rates and odds ratios

The bar graph from Figure 1 visually represents the clinical pregnancy rates across the three groups.

Figure 1. Clinical pregnancy rate across groups
Figure: Figure 1. Clinical pregnancy rate across groups

Secondary outcome: implantation rate

The implantation rate was calculated as the number of gestational sacs per number of embryos transferred. The mean implantation rate was 42.1% in the GCSF group, 43.6% in the PRP group, and 39.5% in the placebo group. While the PRP group showed a slightly higher implantation rate compared to the placebo, this difference was not statistically significant (p=0.34) – Table 3.

Table 3. Implantation rates
Figure: Table 3. Implantation rates

Figure 2. Implantation rate across groups – a line graph showing the implantation rate trends across the study groups
Figure: Figure 2. Implantation rate across groups – a line graph showing the implantation rate trends across the study groups

Endometrial characteristics

There was a significant improvement in endometrial vascularity in the PRP group compared to the placebo (p=0.003), as measured by Doppler studies. However, this improvement did not translate into a higher clinical pregnancy rate. Endometrial thickness and morphology showed no significant differences across the groups (Table 4).

Table 4. Endometrial characteristics
Figure: Table 4. Endometrial characteristics

Histological assessment

The histological evaluation of endometrial samples showed no significant differences in the pattern of endometrial receptivity between the groups. The expression of key markers of receptivity such as HOXA10 and integrin avb3 was comparable across all study arms (Table 5).

Table 5. Histological assessment of endometrial receptivity
Figure: Table 5. Histological assessment of endometrial receptivity

Live birth rate

The live birth rate was comparable among the groups, with 72.5% in the GCSF group, 75.6% in the PRP group, and 68.9% in the placebo group (p=0.45). Logistic regression analysis adjusted for age, BMI and previous IVF attempts indicated that neither GCSF nor PRP had a statistically significant effect on the odds of live birth compared to placebo (Table 6).

Table 6. Live birth rates and adjusted odds ratios
Figure: Table 6. Live birth rates and adjusted odds ratios

Summary of results

1. Clinical pregnancy rate: no significant difference among the groups (p=0.66).

2. Implantation rate: no significant difference among the groups (p=0.34).

3. Endometrial vascularity: significantly improved in the PRP group (p=0.003).

4. Histological assessment: comparable receptivity markers across all groups.

5. Live birth rate: no significant difference among the groups (p=0.45).

Discussion

This randomized controlled trial (RCT) was designed to rigorously evaluate the effects of intrauterine infusion of granulocyte colony stimulating factor (GCSF) and platelet-rich plasma (PRP) on clinical pregnancy rates and related reproductive outcomes in women undergoing frozen embryo transfer (FET). Our findings indicate that neither GCSF nor PRP significantly improves clinical pregnancy rates compared to saline, challenging some of the previous studies that suggested potential benefits of these interventions in enhancing endometrial receptivity.

Clinical pregnancy rates and implantation success

The clinical pregnancy rates observed in this study were 50.4% for the GCSF group, 51.2% for the PRP group, and 45.8% for the saline group, with no statistically significant differences among the groups (p=0.66). These results align with previous studies that failed to demonstrate a significant impact of GCSF on clinical pregnancy rates, particularly in populations without recurrent implantation failure(22,23). Similarly, the lack of a significant difference in the PRP group is consistent with other RCTs that reported no substantial improvement in clinical pregnancy rates with PRP administration(24,25). Our findings suggest that, while both GCSF and PRP may have theoretical benefits in enhancing endometrial receptivity through immunomodulation and angiogenesis, these effects do not necessarily translate into higher clinical pregnancy rates.

The implantation rates, which were slightly higher in the PRP group (43.6%) compared to the GCSF group (42.1%) and the saline group (39.5%), did not reach statistical significance. These findings corroborate the hypothesis that the benefits of PRP in terms of endometrial vascularity might not be sufficient to improve implantation success significantly(26). Previous studies have shown that, while PRP can improve endometrial thickness and vascularity, its impact on implantation rates remains inconclusive(27). The current study adds to this body of evidence, suggesting that the improvements in endometrial characteristics observed with PRP administration do not necessarily lead to better implantation outcomes.

Endometrial vascularity and thickness

One of the key findings of this study is the significant improvement in endometrial vascularity observed in the PRP group compared to the saline group (p=0.003). This finding supports the notion that PRP may enhance endometrial receptivity by improving vascularization, a critical factor for successful embryo implantation(28). However, the lack of a corresponding increase in clinical pregnancy rates indicates that improved vascularity alone may not be sufficient to overcome other barriers to implantation. This observation is consistent with earlier reports revealing that, while PRP can enhance endometrial characteristics, it does not always lead to improved reproductive outcomes(29).

The GCSF group did not show a significant improvement in endometrial vascularity compared to saline, which may explain the lack of difference in clinical pregnancy rates. Previous studies have suggested that GCSF may benefit certain subgroups of patients, particularly those with recurrent implantation failure or thin endometrium, by promoting endometrial regeneration and angiogenesis(30,31). However, the results of our study, which included a broader population of women undergoing FET, suggest that GCSF may not have a universal effect on endometrial receptivity.

Live birth rates

The live birth rates in this study were comparable across the groups, with 72.5% for GCSF, 75.6% for PRP, and similar rates for saline. These findings are particularly important, as they underscore the notion that, while interventions like GCSF and PRP may improve certain intermediate markers of endometrial receptivity, such as vascularity, they do not necessarily translate into higher live birth rates. This is consistent with the concept that successful implantation and pregnancy outcome depend on a complex interplay of factors, and that improving one aspect of endometrial receptivity may not be sufficient to overcome other challenges(32,33).

Limitations and strengths

The strengths of this study include its large sample size, randomized controlled design, and the comprehensive evaluation of endometrial characteristics using transvaginal ultrasound, Doppler studies and histological assessments. However, several limitations should be considered. Firstly, while the study was adequately powered to detect differences in clinical pregnancy rates, it may not have been sufficiently powered to detect smaller but clinically relevant differences in live birth rates. Secondly, the study population was relatively heterogeneous, including women with varying causes of infertility and different FET protocols, which may have introduced variability in the results. Finally, while the study focused on short-term reproductive outcomes, it did not assess long-term outcomes such as neonatal health, which could provide additional insights into the safety and efficacy of these interventions.

Implications for clinical practice

The findings of this study have significant implications for clinical practice. Given that neither GCSF nor PRP demonstrated a significant impact on clinical pregnancy rates or live birth rates, their routine use in FET cycles cannot be recommended based on the current evidence. While PRP showed some promise in improving endometrial vascularity, this did not translate into better reproductive outcomes, suggesting that clinicians should be cautious in using PRP as a routine intervention in ART. Similarly, the lack of benefit observed with GCSF suggests that its use should be limited to specific subgroups of patients where its efficacy has been more clearly demonstrated, such as those with recurrent implantation failure or thin endometrium(34).

Future research

Future research should focus on identifying the specific patient populations that may benefit from GCSF or PRP, as well as optimizing the timing, dosage and administration methods for these interventions. Additionally, further studies are needed to explore the molecular and cellular mechanisms underlying the effects of GCSF and PRP on endometrial receptivity, which could lead to the development of more targeted and effective therapies. Finally, long-term follow-up studies are essential to assess the impact of these interventions on neonatal outcomes and to ensure their safety and efficacy in assisted reproductive technologies.

Conclusions

This large-scale randomized controlled trial provides robust evidence that neither GCSF nor PRP significantly improves clinical pregnancy rates, implantation success, or live birth rates in women undergoing frozen embryo transfer. While platelet-rich plasma improves endometrial vascularity, this benefit does not translate into better reproductive outcomes, suggesting that its routine use in assisted reproductive technologies should be reconsidered. Further research is needed to identify the subgroups of patients who may benefit from these interventions and to explore alternative strategies for improving frozen embryo transfer outcomes.

 

Autor corespondent: Smit Bharat Solanki E-mail: drsmitbharat@gmail.com

 

 

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.

 

Figure:

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Chistadenomul mucinos reprezintă o tumoră benignă frecvent întâlnită la nivelul ovarelor, caracterizată printr-o capacitate de creștere semnificativ mai mare decât a altor mase anexiale. ...
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Ginecologia.ro
GYNECOLOGY

Laparoscopy in urogynecology: advances, challenges and future directions

Smit B. Solanki, Vineet V. Mishra
Prolapsul organelor pelviene şi incontinenţa urinară de efort sunt afecţiuni prevalente în rândul femeilor, cu un impact sem­ni­fi­ca­tiv asupra calităţii vieţii....
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