PLATELET-RICH PLASMA PRP AND STEM CELLS NOVELTİES IN ART: FACTS OR FADS?

Abstract

The integration of platelet-rich plasma (PRP) and stem cells novelties into assisted reproductive technology (ART) has sparked considerable interest due to their potential to enhance reproductive outcomes, especially in challenging cases such as diminished ovarian reserve (DOR), recurrent implantation failure (RIF), and thin endometrium. These regenerative therapies have been posited as innovative strategies to rejuvenate ovarian function, improve endometrial receptivity, and boost implantation success rates. While preclinical studies have shown encouraging biological effects, the translation of these therapies into routine clinical practice remains contentious.

Platelet-rich plasma effectiveness was explored in a 2023 systematic review and network meta-analysis in women with RIF. Results indicated significantly improved clinical pregnancy rates (CPR) and live birth rates (LBR) after PRP infusion compared to placebo or no intervention. The most recent Cochrane review (2024) evaluated twelve parallel-group randomized controlled trials (RCTs) involving 1,069 women with RIF. The review concluded that intrauterine PRP infusion increased live births by 2.38-fold (95% CI: 1.16 to 4.86) compared to controls. However, PRP was also associated with a higher risk of preterm delivery. The main limitations across the studies included lack of standardization in PRP preparation, absence of uniform placebo control, and the fact that most studies were conducted in a single country with a narrow patient population. This highlights the need for multi-centered trials with standardized protocols to establish PRP's therapeutic reliability in RIF management.

The use of PRP in women with DOR has shown limited promising preliminary results. A 2024 systematic review and meta-analysis of 38 observational studies encompassing 2,256 women reported that PRP ovarian injections led to a monthly rise in AMH serum levels and antral follicle count (AFC), in addition to an increase in oocytes retrieved and embryo counts. Despite these encouraging outcomes, a contrasting Cochrane review of a single RCT involving 73 women with poor ovarian response found no significant improvement in ongoing and clinical pregnancy rates following intra-ovarian PRP injections. This discrepancy in findings underscores the variability in study protocols, patient selection criteria, and PRP preparation techniques, which complicate conclusive clinical recommendations.

Stem cell therapies, particularly mesenchymal stem cells (MSCs), have garnered attention for their regenerative potential in both ovarian and endometrial tissues. MSCs, derived from sources such as bone marrow and adipose tissue, exhibit immunomodulatory properties and secrete bioactive factors that promote tissue repair. However, misconceptions persist about MSCs ability to differentiate into oocytes. A recent clinical trial using bone marrow-derived MSCs (BM-MSCs) for women with poor ovarian response demonstrated promising results. After mobilization using granulocyte colony-stimulating factor (G-CSF), stem cells were delivered intra-arterially, leading to embryo generation in 67.8% of initiated cycles and a pregnancy rate of 33.3%. Another trial exploring umbilical cord MSCs (UC-MSCs) for women with incipient ovarian failure reported improved follicular growth, especially in patients with shorter durations of amenorrhea. Despite these promising early-phase trials, the high costs, potential for tumorigenesis, and ethical concerns surrounding stem cell therapies temper their widespread clinical adoption. Additionally, concerns regarding immunogenicity and the long-term safety of stem cell transplantation necessitate ongoing research.

MSC-derived extracellular vesicles (MSC-EVs), nano-sized transporters that mediate MSCs paracrine effects, represent a novel therapeutic avenue. Studies on animal models with induced premature ovarian insufficiency (POI) have shown that MSC-EV therapy significantly enhances AMH production and restores endometrial thickness. These results suggest that MSC-EVs could serve as a more targeted, less invasive alternative to whole-cell transplantation, potentially mitigating the risks associated with live cell therapies. However, clinical studies on MSC-EVs in human reproductive health are still in their infancy.

Induced pluripotent stem cells (iPSCs) have gained attention for their potential to circumvent ethical concerns surrounding embryonic stem cells (ESCs) and their capacity for indefinite propagation. A 2023 study on mouse granulosa cell-derived iPSCs (mGriPSCs) demonstrated the cells ability to differentiate into ovarian cell types in vitro, leading to de novo oocyte formation and follicular development. Orthotopic injection of these differentiated cells into subfertile mice resulted in pregnancies and sizeable litters. Although still in the preclinical phase, iPSCs may offer a patient-specific, autologous stem cell model for future fertility treatments.

While the application of PRP and stem cells in ART presents exciting opportunities, their clinical integration must proceed with caution. Although preliminary studies highlight their potential for improving ovarian function and endometrial receptivity, the current evidence base remains insufficient for their widespread adoption. Well-designed, large-scale RCTs are essential to validate the safety, efficacy, and cost-effectiveness of these therapies. Until then, clinicians must balance innovation with evidence-based practice, ensuring patients are informed about the experimental nature of these treatments and the risks they may carry.