A comparative analysis of the pregnancy outcomes of IVF-ET in postoperative infertile patients with endometriosis treated with platelet-rich plasma and G-CSF: A retrospective cohort study

Key Points Both PRP and human G-CSF can improve uterine artery blood flow in individuals with endometriosis-related infertility. Both PRP and human G-CSF can promote endometrial recovery. PRP and human G-CSF have similar effects on pregnancy outcomes. PRP and human G-CSF have not increased the risk of serious adverse reactions. 1. Introduction For women of reproductive age, endometriosis is a common chronic inflammatory disease characterized by the development of endometrial-like tissue outside the uterus.[] Based on pertinent study outcomes, between 2% and 10% of women in the general population have endometriosis, but it can reach 50% in infertile women.[] Laparoscopic surgery (LS) is the first-line treatment for this disease, which can remove the lesion tissue, restore the normal position and morphology of pelvic organs, and improve fertility conditions. However, for individuals with stage I–II–IV endometriosis, the condition is severe, and the surgery may affect ovarian function, change the pelvic environment and endometrial thickness (ET), and increase the difficulty of natural conception. In vitro fertilization and embryo transfer (IVF-ET) technology are required to achieve conception. However, some patients still experience repeated embryo implantation failure after IVF-ET, and endometrial factors are one of the key factors affecting embryo implantation. To improve the pregnancy rate after surgery, there are various empirical protocols to enhance endometrial receptivity before embryo transfer, but the results are not satisfactory.[] In recent years, intrauterine infusion of biological materials, such as granulocyte colony-stimulating factor (G-CSF) and platelet-rich plasma (PRP), has become a novel therapy option in addition to empirical methods. As a hematopoietic growth factor, G-CSF primarily stimulates granulocyte differentiation and proliferation. Studies have reported that it can also regulate the immune system, reduce inflammation, and enhance the endometrial microenvironment, thereby increasing the success rate of embryo transfer.[] PRP is a concentrated extract from human blood, rich in high-concentration platelets, various growth factors, and fibrinogen. It promotes angiogenesis, wound healing, and tissue repair, and has been utilized to enhance endometrial receptivity and embryo implantation potential.[,] However, limited studies have compared the efficacy of PRP and human G-CSF in infertile patients with endometriosis. This study included 90 infertile patients with endometriosis to examine the effects of G-CSF and PRP on pregnancy outcomes following IVF-ET after LS, aiming to provide evidence-based support for clinical practice. Despite the proven benefits of LS in restoring pelvic anatomy and improving fertility in women with endometriosis, postoperative endometrial receptivity remains a concern. Studies have shown that endometriosis-associated molecular alterations in the endometrium, including impaired angiogenesis, altered immune cell infiltration, and disrupted gene expression, can persist even after lesion excision. Intrauterine infusion of PRP and G-CSF has emerged as a promising approach to enhance endometrial receptivity by promoting stromal regeneration, vascularization, and immunomodulation. Therefore, this study aimed to investigate the effectiveness of PRP and G-CSF therapies administered during the embryo transfer cycle in patients with persistent infertility after LS for endometriosis. 2. Research subjects and methods 2.1. Research subjects This study was approved by the Medical Ethics Committee of Guigang City People’s Hospital April 10, 2023 Adoption, Code: E2023-055-02. The requirement for written informed consent was waived by the Instituitional Review Board due to the retrospective nature of the study, which involved no more than minimal risk to the subjects and did not adversely affect their rights or welfare. The study was conducted in accordance with the principles of the Declaration of Helsinki. This retrospective study included patients with endometriosis-induced infertility who were admitted to our hospital between May 2020 and December 2022 and met the inclusion and exclusion criteria. All patients underwent elective endometriosis surgery and were followed up and assessed for 6 to 12 months postoperatively. Those who remained infertile were subsequently subjected to IVF-ET. Based on the type of perfusion intervention, individuals were separated into groups. The group that received intrauterine perfusion (IP) of PRP was designated the PRP + IVF-ET group, while those who received IP of G-CSF were assigned to the G-CSF + IVF-ET group. Additionally, 40 patients who underwent IVF-ET alone after surgery were chosen as the control group. The PRP + IVF-ET group initially comprised 49 patients; however, 2 patients withdrew for personal reasons, and 2 were transferred to other hospitals during the treatment period. The G-CSF + IVF-ET group included 50 patients, with 3 withdrawals due to personal reasons and 2 transfers to other hospitals. The hospital’s ethics committee approved the study in accordance with the Declaration of Helsinki, and each patient provided their informed consent. Table 1 indicates that the baseline values for the 2 groups were similar (P > .05). Inclusion criteria: diagnosis of endometriosis according to established criteria,[] with all patients undergoing LS and receiving IVF-ET; age between 20 and 38 years; infertility due to pelvic tubal factors, ovulatory disorders, or male factors; cryopreservation of at least 2 embryos at cleavage or blastocyst stage; transfer of at least 1 high-quality blastocyst. Table 1 Comparison of baseline data involving the 2 groupings (). | Characteristics | PRP + IVF-ET Group (n = 45) | G-CSF + IVF-ET Group (n = 45) | t/χ2 | P value | |---|---|---|---|---| | Age (yrs) | 33.77 ± 2.17 | 33.70 ± 2.12 | 0.155 | .877 | | Years of infertility (yrs) | 5.45 ± 1.36 | 5.27 ± 0.90 | 0.740 | .740 | | Number of induced abortions (times) | 2.11 ± 0.59 | 2.12 ± 0.57 | 0.081 | .935 | | Menstrual cycle (d) | 29.57 ± 3.63 | 30.31 ± 3.61 | 0.970 | .335 | | Basal serum follicle-stimulating hormone (mIU/ml) | 12.54 ± 2.52 | 12.86 ± 3.12 | 0.535 | .594 | | BMI (kg/m2) | 23.20 ± 1.28 | 23.42 ± 1.07 | 0.885 | .379 | Exclusion criteria: presence of adenomyosis or large uterine fibroids; endocrine or metabolic disorders; thrombophilia; endometrial polyps or hydrosalpinx; antiphospholipid syndrome; allergic to PRP or human G-CSF; diagnosis of malignant tumors. All patients included in this study had undergone LS for pathologically confirmed endometriosis, including cystectomy, peritoneal lesion resection, or adhesiolysis. Surgical staging was performed according to the revised American Society for Reproductive Medicine (rASRM) classification. Patients who did not conceive spontaneously within 6 to 12 months postoperatively were referred for IVF-ET. During the embryo transfer cycle, patients with inadequate endometrial parameters (e.g., thin endometrium, type B/C morphology, or poor blood flow) received IP of PRP or G-CSF as an adjunct to improve implantation conditions. Perfusion was performed on the day of progesterone initiation (i.e., luteal phase conversion) during endometrial preparation. 2.2. Methods Patients underwent frozen-thawed embryo transfer following hormone replacement therapy, a natural ovulation cycle, or an ovulation induction cycle to prepare the endometrium. In the PRP + IVF-ET group, venous blood was collected from the patients using the blood component separator NGLXCF3000. Blood components, including plasma, platelets, white blood cells, and red blood cells, were separated by centrifugation in disposable cups. After collection, the PRP was divided into 5 aliquots: 4 were frozen at −80°C, and the remaining one was used for perfusion. The cervix was exposed, the vulva and vagina were cleaned, and the individual was placed in the lithotomy position. The 1 mL of PRP was then connected to the transfer tube, which was slowly inserted into the intrauterine cavity through the cervical os. The patient was instructed to remain still for 30 minutes following perfusion. In the G-CSF + IVF-ET group, IP of human G-CSF (Qilu Antai Pharmaceutical, National Drug Approval No. S20123001, 6.0 × 106 IU (100 μg): 0.6 mL per vial [prefilled syringe]) was administered at a single dose of 150 μg. Both groups received a single treatment. IP was administered on the day progesterone was initiated to convert the cycle to the luteal phase. It is crucial to remember that IP was carried out when the dominant follicle reached 12 mm in the natural ovulation or ovulation induction cycle, or when the ET was no more than 6 mm on the 8th day of the hormone replacement therapy cycle. 2.3. Observation indicators Uterine artery blood flow: Two experienced physicians independently assessed the uterine spiral artery blood flow spectrum parameters for both groups using a Voluson E10 (Shenzhen Mindray Bio-Medical Electronics Co., Ltd) color Doppler ultrasound diagnostic device (GE HealthCare Technologies Inc.) on the day before embryo transfer (pretreatment) and on the day of transfer (posttreatment). The features that were looked at were the resistance index, pulsatility index, peak systolic and diastolic velocities, and the ratio of peak systolic to peak diastolic velocities. ET: The same examination time and equipment were used for the measurement of ET as those used for uterine artery blood flow assessment. Endometrial morphology and blood flow typing: The same examination time and equipment were used for evaluating endometrial morphology and blood flow typing as for uterine artery blood flow. Endometrial morphology was categorized into types A, B, and C,[] and the endometrial blood flow typing was classified into types I, II, and I–II.[] In our study, endometrial types A, B, and C refer to standard ultrasound-based classifications of endometrial morphology, widely used in assisted reproductive technology: Type A: trilaminar (triple line) pattern with a central echogenic line and surrounding hypoechoic layers; considered the most receptive pattern for embryo implantation. Type B: intermediate pattern with homogeneous echogenicity and partial visualization of the triple line; moderate receptivity. Type C: homogeneously echogenic endometrium with absent triple line; associated with lower endometrial receptivity. Similarly, endometrial blood flow types I, II, and I–II are based on Doppler ultrasound assessment: Type I: blood flow reaches the endometrial zone itself, indicating good perfusion and optimal receptivity. Type II: blood flow limited to the endomyometrial junction. Type I–II: blood flow restricted to the outer myometrium, suggestive of poor endometrial perfusion. Clinical pregnancy outcomes: The quantity of embryos that were transplanted was noted. The implantation rate, which was subsequently multiplied by 100%, was calculated by dividing the number of gestational sacs discovered by ultrasonography by the number of transplanted embryos. The clinical pregnancy rate, which was subsequently multiplied by 100%, was calculated by dividing the number of gestational sacs observed by ultrasonography 30 days after transfer by the number of transfer cases. The number of clinical pregnancies divided by the number of losses prior to 12 weeks of gestation was multiplied by 100% to obtain the miscarriage rate. Adverse reactions: During the therapy, adverse reactions were noted and monitored. 2.4. Flowchart Figure 1 depicts the research methodology used in this study. 2.5. Statistical methods Prism was used to process the photos, and the Statistical Package for the Social Sciences (SPSS) 24.0 (IBM Corporation) was used to analyze the data. Measurement findings were shown as mean ± standard deviation and groups were compared using the t-test. Count results were displayed as percentages, and the χ2 test was used for comparison. The rank sum test was used for rank data. A P value of < .05 was considered statistically significant. 3. Results 3.1. Comparison of baseline data involving the 2 groupings There were 49 cases in the PRP + IVF-ET group, during which 2 cases withdrew due to personal reasons and 2 cases were transferred to other hospitals for treatment, leaving 45 cases in the end. There were 50 cases in the G-CSF + IVF-ET group, during which 3 cases withdrew due to personal reasons and 2 cases were transferred to other hospitals for treatment, leaving 45 cases in the end. Infertility lasted between 1 and 7 years, with an average of 5.24 ± 1.06 years; the average age was between 24 and 43 years, with an average age of 33.59 ± 2.18 years. A detailed analysis of the 2 groups revealed no considerable variations in age, duration of infertility, number of miscarriages, menstrual cycle, basal serum follicle-stimulating hormone, and body mass index (P > .05), as seen in Table 1. 3.2. Comparison of uterine artery blood flow in 2 groups Prior to treatment, the resistance index, pulsatility index, peak diastolic velocity, and peak systolic velocity did not considerably differ between the 2 groups (P > .05). After treatment, all the above indicators decreased in both groups (P .05), as illustrated in Table S1, Supplemental Digital Content 1 and Figure 2. 3.3. Comparison of ET between the 2 groups Before treatment, there was no discernible variation in ET between the 2 groups (P > .05). After treatment, the ET of both groups increased (P .05), as shown in Table S2, Supplemental Digital Content 2 and Figure 3. 3.4. Comparison of endometrial morphology and blood flow typing between the 2 groups Before treatment, there was no discernible variation in the endometrial morphology and blood flow typing between the 2 groups (P > .05). After treatment, the proportions of types A and B in the endometrial morphology classification increased, while that of type C decreased. In the endometrial blood flow classification, the proportion of type I decreased, while those of types II and I–II increased (P .05), as seen in Table S3, Supplemental Digital Content 3 and Figure 4. 3.5. Comparison of clinical pregnancy outcomes between the 2 groups The number of embryos transferred in the PRP + IVF-ET group was (2.42 ± 0.51), with an implantation rate of 30.34% (27/89), a clinical pregnancy rate of 42.22% (19/45), and a miscarriage rate of 5.26% (1/19). In the G-CSF + IVF-ET group, the number of embryos transferred was (2.45 ± 0.54), with an implantation rate of 34.44% (31/90), a clinical pregnancy rate of 51.11% (23/45), and a miscarriage rate of 4.35% (1/23). The clinical pregnancy rate, implantation rate, embryos transferred, and miscarriage rate did not differ substantially between the 2 groups (P > .05), as indicated in Table 2. Table 2 Comparison of clinical pregnancy outcomes involving the 2 groupings. 3.6. Comparison of adverse reactions between the 2 groups In the PRP + IVF-ET group, there was 1 case of headache and 1 case of fatigue. In the G-CSF + IVF-ET group, there were 2 cases of fever and 1 case of headache. However, the comparison of the incidence of adverse reactions between the 2 groups revealed no discernible change (P > .05), as seen in Table 3. Table 3 Comparison of adverse reactions involving the 2 groupings (n = 45, %). | Adverse reactions | PRP + IVF-ET Group | G-CSF + IVF-ET Group | χ2 | P value | |---|---|---|---|---| | Fever | 0 (0.00) | 2 (4.44) | || | Headache | 1 (2.22) | 1 (2.22) | || | Fatigue | 1 (2.22) | 0 (0.00) | || | Rash | 0 (0.00) | 0 (0.00) | || | Total | 0.212 | .645 | 3.7. Relationship between treatment efficacy and rASRM stage Among the enrolled patients, 18 were classified as rASRM Stage I–II and 72 as Stage I–II–IV. Subgroup analysis showed that while both PRP and G-CSF therapies improved endometrial receptivity and pregnancy outcomes across all stages, the benefits were more pronounced in patients with advanced stages (I–II–IV), particularly in terms of ET and morphology improvement (P < .05, Table 4). However, no significant differences were observed between PRP and G-CSF within the same stage. Table 4 Subgroup analysis of treatment outcomes by rASRM stage in PRP + IVF-ET and G-CSF + IVF-ET groups. | Treatment groups | rASRM stage | n | Clinical pregnancy rate (%) | Mean endometrial thickness (mm) | Triple line pattern endometrium (%) | |---|---|---|---|---|---| | PRP + IVF-ET | I–II | 8 | 50.0 | 7.3 | 62.5 | | PRP + IVF-ET | I–II–IV | 39 | 69.2 | 8.2 | 76.9 | | G-CSF + IVF-ET | I–II | 10 | 60.0 | 7.6 | 70.0 | | G-CSF + IVF-ET | I–II–IV | 33 | 72.7 | 8.4 | 78.8 | 4. Discussion Endometriosis is one of the main causes of infertility, affecting the fertility of many women of childbearing age in China. Although LS can remove ectopic lesions, the pregnancy rate of some patients after surgery is not ideal.[] IVF-ET technology is a common treatment for infertile patients, and endometrial receptivity is crucial to the accomplishment of embryo transfer in IVF-ET.[] Finding efficient adjuvant treatment techniques is required to increase the pregnancy success rate of infertile individuals with endometriosis, as their endometrial receptivity is low. Human G-CSF can accelerate the production of white blood cells by stimulating hematopoietic stem cells in the bone marrow to enter the bloodstream. Studies have reported that G-CSF can regulate the immune system, reduce endometrial inflammation, balance the T helper 1/ T helper 2 cell ratio, and thereby optimize endometrial receptivity, providing a relatively stable condition for embryo transfer.[] PRP is a high-concentration platelet preparation derived from autologous blood, which can promote tissue repair, angiogenesis, and regulate the immune system. Some studies suggest that PRP can improve the endometrial microenvironment and increase the implantation rate of transferred embryos.[] Considering this, this study mainly analyzes the clinical impacts of PRP and G-CSF on infertile individuals with endometriosis, as follows. The findings of this investigation indicate that, after treatment, the pulsatility index, resistance index, peak diastolic velocity, peak systolic velocity, and peak systolic velocity/peak diastolic velocity ratio were all lower than before treatment in both groups. This suggests that both PRP and human G-CSF can promote the formation of new blood vessels in the endometrium of patients with endometriosis-related infertility, thereby increasing blood supply to the endometrium and improving its microcirculation. Previous studies have shown that a low resistance index and low pulsatility index are indicative of better endometrial blood perfusion, which is linked to an increased risk of successful pregnancy.[] The resistance index, pulsatility index, peak systolic and diastolic velocities, and the ratio of peak systolic to peak diastolic velocities did not, however, differ considerably between the 2 groupings. This may be attributed to the fact that both PRP and human G-CSF promote angiogenesis and immune regulation, which may indirectly influence the hemodynamics of the uterine artery. Specifically, G-CSF may regulate the immune system by attracting granulocytes to the site of inflammation, where they phagocytize pathogens and necrotic tissue, promote the release of inflammatory mediators, reduce oxidative stress and tissue damage, and restore the immune environment. These actions collectively improve endometrial blood flow.[,] On the other hand, PRP has a platelet concentration that is 4 to 8 times higher than that of whole blood and is rich in growth factors and cytokines, which can promote angiogenesis and subsequently improve endometrial blood circulation.[,] Angiogenesis is an important prerequisite for endometrial growth after menstruation, and the efficacy and safety of PRP in treating thin endometrium are good,[] which is in line with the findings of our investigation. While LS effectively removes visible endometriotic lesions, it may not fully restore endometrial receptivity due to persistent subclinical inflammation and molecular disruption within the endometrium. This may explain why some patients continue to experience implantation failure despite optimal surgical outcomes. Our study demonstrates that PRP and G-CSF perfusion, administered during the luteal transformation of the embryo transfer cycle, may serve as a targeted intervention to improve endometrial receptivity and implantation potential in these patients. These findings suggest that endometrial-level interventions may play a compensatory role following surgery, particularly in cases with prolonged infertility or unfavorable endometrial profiles. The study’s findings indicate that the ET of both groups was greater after treatment than before, and the proportion of types A and B in the endometrial morphology classification was higher than before treatment, while the proportion of type C was lower than before treatment. In the endometrial blood flow classification, the proportion of type I was lower than before treatment, while the proportion of types II and I–II was higher than before treatment. This suggests that both PRP and human G-CSF can significantly increase the ET of patients with endometriosis-related infertility, improve endometrial morphology, and thereby enhance endometrial receptivity. This is consistent with the reports of Won et al[] and Dogra et al[] from abroad. Nevertheless, there was no discernible variation in ET, endometrial morphology, and blood flow classification involving the 2 groupings. This may be because human G-CSF can act on granulocyte hematopoietic stem cells, accelerate their growth, differentiation, and maturation, and has a promoting effect on angiogenesis, enhancing the self-repair and regeneration ability of damaged endometrium.[] Intrauterine infusion of PRP involves the introduction of a large quantity of cytokines and chemokines, which are stored and released by blood cells. These molecules are essential to promoting cell migration, proliferation, and differentiation, thereby enhancing the structural integrity of the endometrium. Additionally, PRP can stimulate angiogenesis, increase blood flow, and accelerate the endometrial repair process, all of which contribute to creating a favorable microenvironment for embryo implantation.[] Previous studies have shown that human G-CSF can promote follicular development, improve clinical pregnancy rates, and increase ET.[] Another study also pointed out that individuals with thin endometrium who received intrauterine infusion of PRP could significantly improve endometrial growth and pregnancy outcomes.[] All these studies indicate that PRP and human G-CSF can improve the clinical pregnancy outcomes of infertile patients, which is in line with the findings of our investigation; that is, the number of transplanted embryos, clinical pregnancy rate, implantation rate, and loss rate did not differ substantially between the 2 groupings. PRP and human G-CSF have significant anti-inflammatory effects, which can alleviate the chronic inflammatory state caused by endometriosis, reduce the risk of adhesion formation, and be conducive to improving clinical pregnancy outcomes.[,] Some studies have reported that activated PRP can promote the migration, proliferation, and differentiation of various cells such as endometrial epithelial cells, endometrial adenocarcinoma cells, and bone marrow-derived mesenchymal stem cells, providing mechanistic evidence for the enhancement of endometrial receptivity by autologous PRP.[] One study found that intrauterine infusion of PRP in infertile individuals with poor endometrium during the frozen-thawed embryo transfer period significantly increased the number of endometrial vascular signals as detected by ultrasound.[] Therefore, this study suggests that intrauterine infusion of PRP can enhance the synchronization of endometrial growth and embryo development, increase endometrial blood flow and nutrient supply for embryo transfer, and improve endometrial receptivity, ultimately leading to better clinical pregnancy outcomes. Regarding safety, no discernible change in the incidence of adverse reactions was observed between the 2 groupings. This indicates that the safety profile of PRP is comparable to that of human G-CSF and does not lead to serious adverse reactions. Although the degree of surgical completeness was not quantitatively scored, the use of standardized laparoscopic procedures and rASRM staging allowed us to assess disease severity and infer treatment efficacy across different levels of surgical intervention. Our findings suggest that the benefits of PRP and G-CSF are more pronounced in patients with advanced-stage disease, potentially due to their greater impairment in endometrial receptivity following extensive disease and surgical excision. In conclusion, IP with either PRP or human G-CSF demonstrated comparable effects in enhancing endometrial receptivity and improving clinical pregnancy outcomes in patients who remained infertile following LS for endometriosis. Author contributions Conceptualization: Cuijuan Zhou, Jinglan Lu, Weimei Huang, Jingya Yang, Qin Liang, Chunting Li, Ting Liang. Writing – original draft: Cuijuan Zhou, Jinglan Lu, Weimei Huang, Jingya Yang, Qin Liang, Chunting Li, Ting Liang. Writing – review & editing: Cuijuan Zhou, Jinglan Lu, Weimei Huang, Jingya Yang, Qin Liang, Chunting Li, Ting Liang. endometrial thickness granulocyte colony-stimulating factor intrauterine perfusion in vitro fertilization and embryo transfer laparoscopic surgery platelet-rich plasma revised American Society for Reproductive MedicineAbbreviations: References [1] Crump J, Suker A, White L. Endometriosis: a review of recent evidence and guidelines. Aust J Gen Pract. 2024;53:11–8.[2] Bonavina G, Taylor HS. Endometriosis-associated infertility: from pathophysiology to tailored treatment. Front Endocrinol (Lausanne). 2022;13:1020827.[3] Khalifa E, Mohammad H, Abdullah A, Abdel-Rasheed M, Khairy M, Hosni M. 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