The Link Between Endometrial Receptivity and IVF Success

What Is Endometrium?

The endometrium is a layer of tissue in the uterine space. The lining consists of two layers: the stratum basalis, located adjacent to the smooth muscle layer, which persists through the menstrual cycle without shedding, and the stratum functionals, which thicken and drop during menstruation. Estrogen and progesterone control the growth of the endometrium. The hormones help increase the endometrial layers to prepare the womb for embryo implantation.

What Is Endometrial Receptivity?

Endometrial receptivity is a complex process that offers the embryo the chance to attach, invade, and grow, culminating in a new individual and continuation of the species. In most typical women, the period of implantation extends three to six days within the secretory phase. In certain inflammatory or structural conditions, this period is narrowed or shifted to prevent normal implantation, leading to infertility or pregnancy loss. Of the elements that hinder normal implantation and pregnancy, embryo and endometrial quality share responsibility.

How Do Hormones Affect Endometrial Receptivity During IVF?

To establish an endometrium capable of offering the blastocyst (cluster of cells of future embryos) a site for attachment and nourishment, it has to undergo certain proliferative changes. Changes to the endometrium occur as a response to hormonal signals.

During natural periods, these signals are rendered by estradiol and progesterone. Still, in assisted phases, these hormones are substituted by controlled ovarian hyperstimulation (COH), using gonadotropins in various strategies to induce multiple follicular growth. This may lead to differing hormone levels for those in natural cycles and may alter endometrial development and receptivity. Moreover, it was shown by other authors that different stimulation protocols used for COH severely affected the ART (assisted reproductive technology) outcome of conception rates.

These pharmacological treatments impact endometrial quality, which may be one reason for decreased implantation rates. Following COH, in IVF, estradiol levels rise during the follicular phase, and consecutively, multiple corpora lutea produce estradiol and progesterone levels. In addition, changes in estrogen-to-progesterone ratio, growth factor concentrations, and cell adhesion molecule profiles may affect endometrial receptivity.

Abnormally high estradiol levels during the early luteal period cause irregular endometrial patterns. In addition, changes in the estrogen-to-progesterone balance, growth factor concentrations, and cell adhesion molecule profiles may impact endometrial receptivity. Due to COH, a time shift in the implantation period occurs.

What Is Endometrial Receptivity Analysis?

Endometrial receptivity analysis (ERA) measures the thickness of the uterine covering and genetic changes to determine whether the endometrium is sufficiently ripe for embryo implantation. ERA can determine the optimal timing for progesterone administration before an embryo transfer to improve the success of embryo implantation, pregnancy, and live delivery since successful implantation can only happen during the acceptance window.

How Is Endometrial Receptivity Tested?

Endometrial receptivity testing involves taking a sample of the endometrial lining of the uterus and analyzing the tissue to see which genes are activated. Combined with a computational predictor, these results show when the endometrium may be most receptive to an embryo embedding. The endometrium will be classified as either receptive, pre-receptive, or post-receptive. In subsequent treatment cycles, the woman will then have what is called a ‘personalized embryo transfer,’ occurring at the ideal time for her specific window of implantation. This would theoretically boost the chances of the embryo embedding successfully and the woman having a baby.

Methods for assessing endometrial sensitivity include the following:

• Transvaginal Ultrasound Imaging (TVUS) - TVUS is a widely available instrument that can be used to assess endometrial sensitivity. TVUS can be used to measure the endometrial thickness, volume, and configuration.

• Histologic Evaluation by Endometrial Biopsy - Histologic evaluation of endometrial receptivity requires endometrial sampling. Luteal phase deficiency (LPD) is described as an abnormal luteal phase with a duration of less than or equal to ten days and was one of the first known descriptions of endometrial receptivity. Biopsies for endometrial receptivity were traditionally conducted within three days of the anticipated onset of menses and evaluated based on histologic standards. Histologic sampling does not provide an accurate or reliable assessment of endometrial receptivity and is not currently used to assess endometrial receptivity in clinical practice.

• Endometrial Receptivity Array (ERA) - The ERA is a molecular diagnostic tool used to identify a receptive endometrium via a specific transcriptomic pattern in natural and hormone replacement therapy cycles. The technology has been applied clinically to identify a patient-specific window of implantation, which is then used to guide a customized timing of embryo transfer for patients with recurrent implantation failure. This is done by taking an endometrial biopsy at specific times during the mid-luteal phase. The ERA results are then used to guide shifts in the timing of progesterone administration before embryo transfer in a future cycle.

• ReceptivaDx Assay (BCL6) - The ReceptivaDx test determines endometrial receptivity defects due to progesterone resistance. The BCL6 (B cell lymphoma 6) protein is increased in women with endometriosis (tissue of uterine lining growing outside of uterus), resulting in lower clinical pregnancy rates in women undergoing IVF. The ReceptivaDx test's ability to improve IVF outcomes has still not been proven.

When Should Women Undergo Endometrial Receptivity Testing During IVF?

ERA is helpful for women with a record of recurrent implantation failures or multiple unsuccessful IVF rounds. ERA allows the assessment of 236-gene array indicators to pinpoint the optimal receptivity window for embryo implantation. The precise timing improves the likelihood of a successful pregnancy, with the ideal period falling between the 19th and 23rd day of her cycle in 80 percent of women; however, the remaining 20 percent may have an earlier or later window of receptivity. Determining whether the receptivity window is open or closed is important before embryo transfer in IVF therapy.

What Are the Procedural Steps of ERA?

• Take the recommended oral or self-injected medications to stimulate the development of the uterine covering and monitor with transvaginal scans and blood tests for the reaction.

• The doctor performs an endometrial biopsy to determine the gene expression profile of a group of genes.

• Based on the biopsy result, the doctor will evaluate whether the endometrium is receptive or non-receptive for embryo implantation.

• In the event of non-receptivity, the doctor will postpone the embryo transfer to the next cycle and adjust the progesterone amounts to increase the chance of a successful pregnancy.

Conclusion:

A multitude of factors play a significant role in successful implantation and gestation, nonetheless, in cycles of assisted reproduction. The embryo’s quality and endometrial receptivity are crucial for a successful pregnancy. As the embryo’s quality could be determined by preimplantation genetic analysis, endometrial receptivity is considered the final barrier. It is known that the endometrium is a crucial element during the so-called implantation window, a brief period of optimal endometrial receptivity to blastocyst cues during which the human embryo approaches the endometrium in the secretory phase to attach and penetrate. This embryo-maternal interaction is crucial for the establishment of a healthy pregnancy.