Recurrent Implantation Failure: A Molecular Perspective and the Role of Endoret® PRGF

In assisted reproductive treatment (ART), few challenges are as emotionally and clinically complex as Recurrent Implantation Failure (RIF). It is a diagnosis that not only frustrates patients and clinicians but also raises important questions about the subtleties of embryo-endometrial interaction. Despite advances in embryo selection and laboratory techniques, many high-quality embryos fail to implant—suggesting that endometrial receptivity may be a limiting factor in a significant number of IVF cycles. 

This article explores the evolving science behind RIF, its multifactorial causes, and how regenerative biologics like Endoret® PRGF are being integrated into treatment protocols to restore endometrial functionality at the molecular and cellular level. 

Defining Recurrent Implantation Failure 

RIF is generally defined as the failure to achieve clinical pregnancy after the transfer of three or more good-quality embryos across multiple IVF cycles. However, a purely numerical definition can overlook the biological complexity at play. Many patients may not meet this strict threshold yet still experience unexplained implantation failure, while others present underlying uterine factors that only become apparent after multiple unsuccessful attempts. 

In this light, RIF is increasingly viewed not merely as an IVF failure, but as an endometrial dysfunction syndrome, in which the endometrium fails to transition into a receptive, synchronised, and immunologically tolerant state during the window of implantation. 

The Endometrium: Structure vs Function 

A receptive endometrium is not defined solely by morphology or thickness. While a trilaminar pattern and a lining ≥7mm are considered favourable, these do not guarantee successful implantation. Rather, the focus has shifted to functional receptivity—which depends on a dynamic interplay of cellular proliferation, angiogenesis, immune tolerance, and molecular signalling. 

Aberrations in these mechanisms—whether through chronic inflammation, defective angiogenesis, altered cytokine expression, or suboptimal stromal transformation—can lead to a non-receptive environment, even in the presence of high-quality embryos. 

Immunological and Inflammatory Contributions 

In many cases of RIF, immunological dysregulation is a silent but significant contributor. Chronic endometritis, elevated uterine Natural Killer (uNK) cell activity, abnormal expression of adhesion molecules (e.g., integrins), or altered T-helper (Th1/Th2) cytokine ratios can impair endometrial receptivity. These alterations may remain undetected on ultrasound or hysteroscopy, making molecular diagnostics and personalised therapies increasingly necessary. 

Standard treatments such as corticosteroids, antibiotics, or low-dose aspirin may offer benefit, but lack precision in targeting tissue-level dysfunction. This has prompted the use of more biologically tailored approaches—most notably, regenerative strategies using platelet-rich plasma (PRP). 

Endoret® PRGF: Reprogramming the Endometrial Microenvironment 

Endoret® PRGF, developed by BTI, represents a clinically optimised, second-generation PRP system engineered for regenerative medicine—including gynaecological applications. Unlike generic PRP preparations, Endoret® is leukocyte-free, reducing the risk of introducing inflammatory mediators into the uterine cavity. It is also activated with calcium chloride, promoting a gradual and physiological release of growth factors. 

Key to its effect in RIF patients is the modulation of angiogenesis, immune signalling, and cellular proliferation—factors often disrupted in non-receptive endometria. 

• VEGF promotes new capillary formation, enhancing tissue perfusion and oxygenation. 

• EGF supports epithelial repair and luminal development. 

• TGF-β1 acts to balance fibrotic processes and reduce chronic inflammation. 

• IGF-1 improves metabolic support for stromal cells during decidualisation. 

• PDGF supports fibroblast migration and collagen remodelling. 

Through this complex biochemical cascade, Endoret® helps the endometrium achieve a functionally receptive state—characterised by improved vascular supply, reduced inflammatory cytokines, and enhanced stromal readiness for embryo implantation. 

Clinical Integration and Timing 

The administration of Endoret® PRGF is typically timed to the mid-luteal phase of the cycle preceding embryo transfer or during a frozen embryo transfer (FET) cycle. It is usually performed intrauterinely via catheter, with the protocol adjusted based on individual history, endometrial metrics, or molecular findings (e.g. ERA, ALICE/EMMA testing). 

Studies have reported encouraging outcomes in RIF patients using intrauterine PRGF, showing improved implantation rates, higher clinical pregnancy rates, and enhanced endometrial vascularisation on Doppler imaging. 

Towards Precision Medicine in RIF 

The future of RIF management lies not in escalating hormone dosages or repeated embryo transfers, but in addressing the biological competence of the endometrium. Endometrium-targeted regenerative therapies—particularly those grounded in molecular science and clinical validation—offer a promising frontier. 

Endoret® PRGF fits into this paradigm by offering a reproducible, safe, and tissue-specific regenerative tool. Its ability to recondition the endometrial microenvironment—without inducing inflammation or hormonal disruption—makes it especially suitable for patients with thin lining, persistent inflammation, or prior unexplained transfer failures. 

As personalised medicine becomes more integrated into reproductive care, clinicians are empowered to move beyond trial-and-error approaches and towards interventions that are molecularly informed, clinically targeted, and biologically restorative.