For a reproductive‑age woman undergoing in vitro fertilization with no uterine pathology (and a history of repeated implantation failure), how can I optimize endometrial receptivity regarding target endometrial thickness, estrogen‑progesterone protocol, luteal support, and adjunctive measures such as receptivity testing, aspirin, or endometrial scratching?

Optimizing Endometrial Receptivity in IVF with Recurrent Implantation Failure

For women with recurrent implantation failure undergoing IVF, prioritize endometrial receptivity array (ERA) testing to identify the personalized window of implantation, target an endometrial thickness ≥7-8mm, and avoid interventions like aspirin and endometrial scratching that lack evidence for improving live birth rates.

Endometrial Receptivity Testing

The most critical intervention is ERA testing to identify your patient's personalized window of implantation, as approximately 36.5% of patients undergoing assisted reproduction have a displaced implantation window. 1

• ERA has demonstrated superior accuracy compared to traditional histological dating methods for defining the receptive endometrium, with clinical pregnancy rates of 69.2% after personalized embryo transfer in patients initially found to be non-receptive 2, 1
• In natural cycles, 27.1% of patients are non-receptive at the expected time, while in HRT cycles this increases to 48.6% 1
• The endometrium is responsive to embryo-derived factors including hCG, which enhances endometrial epithelial receptivity through increased cytokine/chemokine secretion 3

Target Endometrial Thickness

Aim for endometrial thickness ≥7-8mm measured as double-layer thickness at the thickest portion in the midline sagittal plane. 3, 2

• Endometrial thickness is an important predictor of endometrial receptivity, though ultrasound alone cannot definitively determine implantation potential 3, 2
• Use transvaginal ultrasound with proper technique: obtain a true longitudinal view in the midline plane, measure perpendicular to the endometrial-myometrial interface, and include both anterior and posterior layers 2
• Consider sonohysterography if findings are inconclusive or focal abnormalities are present 2

Estrogen-Progesterone Protocol

Avoid supraphysiologic estradiol levels during ovarian stimulation, as high estradiol concentrations on the day of hCG administration are detrimental to uterine receptivity. 4

• For high responders, use step-down stimulation regimens to prevent excessive estradiol elevation that impairs endometrial receptivity 4
• In HRT cycles for frozen embryo transfer, standard protocols can be used but recognize that nearly half of patients may have displaced windows requiring ERA-guided timing 1
• Vitamin D3 supplementation may enhance progesterone receptor expression and phosphorylation in endometrial stromal cells, potentially improving receptivity 5

Luteal Support

Provide standard progesterone luteal support, but recognize that progesterone resistance is a feature of impaired receptivity that may require personalized timing rather than dose escalation. 6

• The endometrium exhibits progesterone resistance in some patients, making timing of exposure more critical than dose 6
• Progesterone regulates gene expression through binding to receptors in endometrial stromal cells, which are key to establishing receptivity 5

Embryo Transfer Strategy

Transfer a single euploid blastocyst at the ERA-identified personalized window of implantation. 7, 1

• Continue with single embryo transfer (eSET) as standard procedure—there is no evidence that cumulative live birth rate with eSET is inferior to double embryo transfer 7
• Transferring multiple embryos increases risks of multiple pregnancy, ectopic pregnancy, and monozygotic twinning without improving cumulative success rates 7
• After ERA-guided personalized transfer, an average of only 1.5 frozen embryo transfers is needed to achieve clinical pregnancy 1

Adjunctive Measures to AVOID

Do not routinely use aspirin or endometrial scratching, as these interventions lack evidence for improving live birth rates in this population.

• While various molecular mediators including adhesion molecules, cytokines, and growth factors have been identified as important for implantation, translation to effective interventions remains limited 8
• The endometrium undergoes complex molecular changes during the window of implantation involving over 238 differentially expressed genes, but most proposed adjunctive therapies have not demonstrated clinical benefit 3, 8

Key Clinical Pitfalls

• Do not rely on traditional histological dating—it has poor accuracy, reproducibility, and functional relevance compared to molecular testing 3
• Do not assume the window of implantation occurs at the expected time—more than one-third of patients have displaced windows requiring personalized timing 1
• Do not use the same transfer timing for all patients—HRT cycles show higher rates of displaced windows (48.6%) compared to natural cycles (27.1%) 1
• Recognize that leiomyomas or adenomyosis may limit accurate endometrial assessment—consider additional testing when these conditions are present 2