What is the contribution of embryo-endometrial asynchrony to implantation failure?

Abstract

Purpose: The synchronized development of a viable embryo and a receptive endometrium is critical for successful implantation to take place. The aim of this paper is to review current thinking about the importance of embryo-endometrial synchrony in in vitro fertilization (IVF).

Methods: Detailed review of the literature on embryo-endometrial synchrony.

Results: By convention, the time when the blastocyst first attaches and starts to invade into the endometrium has been defined as the 'window of implantation'. The term window of implantation can be misleading when it is used to imply that there is a single critical window in time that determines whether implantation will be successful or not. Embryo maturation and endometrial development are two independent continuous processes. Implantation occurs when the two tissues fuse and pregnancy is established. A key concept in understanding this event is developmental 'synchrony', defined as when the early embryo and the uterus are both developing at the same rate such that they will be ready to commence and successfully continue implantation at the same time. Many different events, including controlled ovarian hyperstimulation as routinely used in IVF, can potentially disrupt embryo-endometrial synchrony. There is some evidence in humans that implantation rates are significantly reduced when embryo-endometrial development asynchrony is greater than 3 days (±1.5 days).

Conclusions: Embryo-endometrial synchrony is critical for successful implantation. There is an unmet need for improved precision in the evaluation of endometrial development to permit better synchronization of the embryo and the endometrium prior to implantation.

Keywords: Embryo; Endometrium; Implantation; Synchrony; Uterine receptivity.

Conflict of interest statement

Compliance with ethical standards Conflicts of interest The authors declare that they have no conflict of interest. Funding Wan-Tinn Teh received National Health and Medical Research Council Medical Postgraduate Scholarship (No. 1055814) for her PhD study.

Figures

Fig. 1

a A functional embryo, a receptive endometrium and a synchrony between the embryo and the endometrium are the three pre-requisites for successful implantation. This figure demonstrates the developmental synchrony between the endometrium and the embryo within a ‘cycle’. The main causes of implantation failure have been noted: (1) Embryo developmental defects, e.g. chromosomal anomalies. (2) Endometrial developmental defects, e.g. luteal phase deficiency, reduced endometrial receptivity. (3) Embryo-endometrial developmental asynchrony. b Human implantation rates reduce as asynchrony between the embryo and the endometrium increases. Evidence suggests that the human embryo implantation rate is significantly reduced when asynchrony between the embryo and the endometrium is greater than ±1.5 days

Fig. 2

Controlled ovarian hyperstimulation (COH) has a detrimental effect on uterine receptivity. Various modalities have been demonstrated in this figure for assessing uterine receptivity in an IVF cycle with COH. Potential modalities that can be used to predict uterine receptivity prior to embryo transfer include ultrasound assessment of endometrium, serum progesterone levels and genomic or proteomic assessment of uterine cells/fluid. Other assessments of uterine receptivity that can be offered in a cycle prior to an embryo transfer cycle include traditional histology dating and endometrial gene expression assays

Fig. 3

Controlled ovarian hyperstimulation in IVF cycles leads to suboptimal endometrial function. Supra-physiological serum concentrations of sex hormones during ovarian hyperstimulation can negatively influence uterine receptivity by disrupting embryo-endometrial synchrony. This figure demonstrated the concept of advanced endometrial development, leading to increased embryo-endometrial asynchrony in ovarian hyperstimulation and resulting in implantation failure