Experimental Study on the Use of Intrauterine Infusion of Autologous Platelet-rich Plasma (PRGF-IUI) in Patients With Recurrent Implantation Failure and/or Refractory Thin Endometrium

Recurrent Implantation Failure, Endometrial Receptivity Disorders, Embryo Implantation, Platelet-Rich Plasma, Platelet-rich Plasma (PRP), Infertility, Female

Endometrial receptivity, Recurrent implantation failure, Assisted reproductive technology, Platelet-rich plasma, Intrauterine infusion, Autologous biological therapy

Endometrial receptivity is a key determinant of success in assisted reproductive technology (ART). A significant proportion of patients experience repeated implantation failure despite euploid embryos and adequate laboratory conditions. Thin endometrium, often defined as ultrasound-measured thickness \<7 mm at embryo transfer, is frequently refractory to estrogen therapy and associated with low implantation and clinical pregnancy rates. Platelet-Rich Plasma (PRP), obtained from autologous blood by double centrifugation, is rich in growth factors capable of stimulating cell proliferation, angiogenesis, and tissue regeneration, suggesting potential benefits for endometrial function. Preliminary studies indicate improved endometrial thickness and reproductive outcomes following intrauterine PRP infusion, but standardized protocols and systematic data are lacking. The PMA\_PREPAIRE study is a prospective, single-center interventional clinical trial with a retrospective comparison group, conducted at the Reproductive Medicine Center of Cardinal Massaia Hospital, Asti. It aims to evaluate the efficacy of intrauterine infusion of autologous PRP in improving endometrial receptivity and reproductive outcomes in women with thin or refractory endometrium undergoing hormone replacement therapy (HRT). Eligible women will be treated with standard clinical care, with PRP infusion offered to those with insufficient response to HRT. Inclusion criteria include age 18-45, BMI 18-30 kg/m², history of ≥1 failed embryo transfer, EMT \<5 mm after ≥10 days of HRT, and normal routine lab tests. Exclusion criteria include endometrial disease, recent gynecological infection, and systemic conditions such as thrombocytopenia or coagulopathies. Procedures include standard HRT from cycle days 1-2, serial ultrasound monitoring of endometrial thickness from days 6-8, intrauterine PRP infusion if EMT ≤7 mm (up to three infusions per cycle), embryo transfer once EMT ≥7 mm, and follow-up through pregnancy testing and confirmatory ultrasound. Collected data will be analyzed with descriptive statistics, paired t-tests for pre/post PRP EMT comparison, and logistic regression to evaluate predictors of success (significance p \< 0.05). A sample size of 34 patients per arm is estimated to detect a 1.5 mm change in EMT with 90% power; with 15% dropout anticipated, 40 patients per group will be enrolled. The retrospective control group consists of 40 historical patients with refractory thin endometrium treated without PRP.

Endometrial receptivity plays a central role in the implantation process and the success of assisted reproductive technologies (ART). A receptive endometrium undergoes synchronized cellular proliferation, vascularization, stromal decidualization, and expression of specific cytokines and adhesion molecules at the time of embryo transfer. Thin endometrium, commonly defined as a transvaginal ultrasound-measured thickness of less than 7 mm, is frequently encountered in patients undergoing ART and is associated with lower implantation and clinical pregnancy rates. Refractoriness of the endometrium to standard hormone replacement therapy (HRT) represents a persistent clinical challenge. Despite optimization of estrogen administration routes and doses, a significant subset of patients fails to achieve adequate thickness and functional receptivity. These patients often experience repeated implantation failure (RIF), defined by multiple unsuccessful implantation attempts despite transfer of high-quality embryos. Platelet-Rich Plasma (PRP) is an autologous biological product obtained from peripheral blood through differential centrifugation. PRP contains a high concentration of platelets, which store a complex milieu of growth factors and cytokines, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). These bioactive molecules have mitogenic, angiogenic, and chemotactic properties that facilitate tissue repair and regeneration. The theoretical rationale for PRP application in reproductive medicine is based on its potential to augment stromal proliferation, enhance microvascular growth, and improve the structural and functional characteristics of the endometrium. Preliminary evidence from observational and interventional clinical studies suggests that intrauterine infusion of autologous PRP may be associated with increased endometrial thickness, improved uterine hemodynamics, and enhanced reproductive outcomes, including implantation and clinical pregnancy rates. In retrospective cohort analyses, patients treated with PRP showed significant improvements in endometrial parameters and pregnancy outcomes compared to conventional therapy. Although variations exist in study designs, inclusion criteria, and infusion protocols, a recurring finding is the promising therapeutic effect of PRP on endometrial receptivity. Despite these encouraging data, the current literature also highlights the lack of standardized protocols and high-quality, large-scale randomized controlled trials. Systematic reviews and meta-analyses have underscored the need for well-designed clinical trials to establish the reproducibility and clinical validity of PRP therapy in this context. Some guidelines and expert groups note that while the biological rationale is strong, PRP use cannot yet be universally recommended without further evidence from rigorously controlled studies. The PMA\_PREPAIRE study is conceived to address this critical evidence gap by systematically evaluating the effectiveness of intrauterine autologous PRP infusion in a controlled, prospective clinical setting, comparing outcomes with those of a matched retrospective control group. The trial's design allows for real-world assessment while maintaining methodological rigor, including predefined inclusion/exclusion criteria, standardized infusion techniques, and structured data collection. Outcomes of interest include changes in endometrial thickness, implantation rate, clinical pregnancy rate, and safety endpoints. By integrating clinical practice with research methodology, this study aims to contribute high-quality evidence to the field and inform future clinical guidelines on the use of PRP in patients with refractory thin endometrium.

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