Uterine receptivity as a cause of sterility

By (gynecologist), BSc, MSc (embryologist), MD (gynecologist), MD, PhD, MSc (gynecologist), BSc, MSc (embryologist) and (invitra staff).
Last Update: 01/10/2020

Endometrial or uterine receptivity is defined as the ability of the uterus to allow an embryo to implant and begin gestation.

Thanks to advances in assisted reproduction and, above all, in vitro fertilization (IVF) treatment, it has been possible to study in greater depth the role of the endometrium and its implication in reproductive success.

Alterations in endometrial receptivity, therefore, are a cause of female sterility, since they lead to suffering the so-called repeated implementation failures.

What is endometrial receptivity?

The endometrium is the internal tissue of the uterus, whose main function is the interaction with the embryo to achieve its implantation and consequently an evolutionary gestation.

This tissue is highly dynamic and undergoes multiple changes throughout the menstrual cycle, from preparing for implantation to evacuating through menstruation when pregnancy has not occurred, through hormonal regulation and adopting an immune function.

Within this context, uterine receptivity refers to a specific state of the endometrium in which its conditions are optimal for embryo implantation to occur.

It should be noted that the endometrium is only receptive to certain days of the menstrual cycle, exactly 6-7 days after ovulation. This is what is known as implantation window.

Endometrial receptivity involves a series of molecular, structural and vascular changes in the inner layer of the uterus that will allow the nesting of the developing embryo.

The importance of endometrial thickness

The classic way to assess uterine receptivity is by measuring endometrial thickness.

An optimal endometrium for implantation must measure between 8-12 mm and have a trilaminar aspect. Endometrios with a thickness inferior to 7 mm and superior to 13 mm have demonstrated to have a smaller rate of gestation.

For all these reasons, ultrasound is an essential test to determine whether the uterus is ready for embryo implantation, something that must always be proven in any assisted reproduction treatment.

Low endometrial receptivity

Sometimes, when the endometrium is analyzed with ultrasound, it is verified that it does not have the adequate thickness or, even if it has the correct aspect and good quality embryos, the patient does not manage to get pregnant.

This is when the specialist must begin to pay attention to the receptivity of the uterus, as there are several causes that may be affecting it and, depending on each case, additional diagnostic tests may be indicated.

Causes

The causes of low endometrial receptivity are many and varied, with the involvement of various pathophysiological mechanisms:

  • Abnormalities in the uterine cavity: polyps, partitions, myomas, synechiae, etc.
  • Infectious or inflammatory processes: endometritis, hydrosalpinx.
  • Deficit in endometrial proliferation: thin endometrium without sufficient thickness for embryo implantation. This is known as refractory endometrium.
  • Alterations of the coagulation system (thrombophilias).
  • Displacement of the implantation window.
  • Chromosomal Alterations
  • Systemic immunological diseases.
  • Local immunological processes: in the endometrium there must be an environment of immune tolerance so that the embryo is not rejected by the mother, which is conditioned by genetic, epigenetic and environmental factors.
  • Microbiota alterations: microorganisms such as bacteria, fungi, and/or viruses that establish a "biofilm" inside the uterus.
  • Incompatibility of "dialogue" between embryo and endometrium: implies morphological and functional changes (genomic and/or molecular in the endometrium before the arrival of the embryo).

Occasionally, several factors cause low uterine receptivity or the cause may not yet be known, leading to the diagnosis unexplained infertility.

Endometrial testing

As we have already mentioned, the classical endometrial evaluation has been carried out by ultrasound and also hysteroscopy, histology and immunology analysis. However, today there are newer and more specific techniques that allow a more advanced study of the endometrium. That’s what’s known as genomic testingas they study the receptivity of the endometrium at the level of genes and their expression.

One of the most important tests for analyzing endometrial receptivity is the Endometrial Receptivity Array (ERA) test. This is a molecular test that studies the expression of 248 genes associated with the receptive state of the endometrium. This makes it possible to determine whether the endometrium is receptive at a specific time in the menstrual cycle or whether the implantation window is displaced.

Molecular biology, through RNA and transcriptomics and secretomics, has allowed us to deepen the endometrial receptivity and the adjustment of the embryo implantation window.

On the other hand, there are also analyses of the endometrial microbiota with the aim of getting to know the intrauterine microflora in greater depth and treating its imbalances prior to the treatments. They're called EMMA test and ALICE test.

The endometrium still hides great discoveries for scientists, and maximizing their knowledge will allow us to achieve better results in assisted reproduction techniques.

How to get pregnant?

Once uterine receptivity has been analyzed and, depending on whether it has been possible to identify the exact cause of having a nonreceptive endometrium, various strategies can be carried out to try to achieve gestation. We will discuss them below:

  • If you have a displaced implantation window identified by the ERA test, you should schedule the embryo transfer at another point in the menstrual cycle where the endometrium is shown to be receptive.
  • If the patient suffers from endometritis or any other infection in the reproductive tract, she must carry out a specific treatment with antibiotics before attempting a new pregnancy. The EMMA and ALICE tests identify the microorganisms responsible for the infection and determine which antibiotic is adequate to combat them.
  • Treatment with aspirin and/or heparin in case of diagnosis of thrombophilia.
  • Treatment with corticoids or immunoglobulins in case of immune rejection of the embryo.
  • In the case of a refractory endometrium incapable of proliferating with estrogens and progesterone, drugs that favour blood supply to the endometrium, such as sildenafil, pentoxifylline, vitamin A, vitamin E, etc., may be indicated.
  • Evaluating endometrial scratching. This is a small surgical procedure to damage the endometrium and cause it to regenerate.

In short, in a case of repetitive implantation failure and an endometrium with little receptivity, it is very important to carry out an exhaustive study and to carry out all the necessary tests to approach an exact diagnosis that allows to establish the reproductive strategy.

Finally, it should be remembered that maintaining healthy lifestyle habits together with a healthy and balanced diet will always help to improve overall health and facilitate the onset of pregnancy.

FAQs from users

Why doesn't my endometrium grow yet on estrogen and progesterone?

By Dr. Paloma de la Fuente Vaquero MD, PhD, MSc (gynecologist).

We know that correct endometrial perfusion is key to the growth of the endometrium and therefore to correct embryo implantation. If there is no correct blood supply to the endometrium, even if we administer exogenous hormones, they will never reach it properly. This is the reason why we administer drugs that promote the arrival of blood to the endometrium (sildenafil, pentoxifylline, vitamin A, vitamin E ...) when we are faced with refractory endometrios to treatment with estrogens and progesterone (those that do not grow despite the correct hormone intake).

When does the endometrium become receptive?

By Dr. José Luis Gómez Palomares (gynecologist).

The endometrium is receptive when the embryo can adhere to the endometrial cells and then be introduced into their thickness. Classically, this process was said to occur between days 20 and 24 of a normal 28-day cycle.
Read more

Do natural killer cells provoke implantation failures?

By Zaira Salvador BSc, MSc (embryologist).

Yes, recent studies have shown that women with repeated implantation failure have a higher number of NK cells and this increase is more significant in the endometrium than in the woman's blood.

Is it true that Viagra can help thicken the endometrium?

By Zaira Salvador BSc, MSc (embryologist).

The mechanism of action of viagra is to dilate blood vessels to increase blood flow to the penis. Studies have shown that viagra also serves as a vasodilator to increase blood flow to the uterus and improve endometrial growth.

Although it is not very common, some specialists prescribe vaginal ova with the active principle of viagra to encourage endometrial thickening.

Is a thickened endometrium receptive?

By Zaira Salvador BSc, MSc (embryologist).

Not necessarily. A receptive endometrium is one that has a thickness between 8-12 mm and a trilaminar aspect. An endometrial thickness greater than 13 mm is associated with a low implantation rate.

In addition, for an endometrium to be receptive it must have undergone several structural changes that can only be visualised after a biopsy and observation of the endometrial tissue under the microscope: presence of pinopods, endometrial glands, greater number of cells, etc.

Suggested for you

As we have said throughout the article, low uterine receptivity can lead the patient to suffer repeated implantation failures, something that takes a toll on her physical, emotional and economic state in fertility treatment. If you want to read more about this, we recommend you read on here: Repeated embryo implantation failures: Reasons why embryos don't implant.

On the other hand, there are some recommendations that women can follow in order to improve the state of their endometrium and encourage implantation. You can read them in the next post: 6 effective ways to increase endometrial thickness naturally.

Our editors have made great efforts to create this content for you. By sharing this post, you are helping us to keep ourselves motivated to work even harder.

References

Casper RF. It's time to pay attention to the endometrium. Fertil Steril. 2011 Sep;96(3):519-21.

D'Ippolito S, Di Nicuolo F, Pontecorvi A, Gratta M, Scambia G, Di Simone N. Endometrial microbes and microbiome: Recent insights on the inflammatory and immune "players" of the human endometrium. Am J Reprod Immunol. 2018 Dec;80(6):e13065.

Kliman, H. J., & Frankfurter, D. (2019). Clinical approach to recurrent implantation failure: evidence-based evaluation of the endometrium. Fertility and Sterility, 111(4), 618–628.

Lessey, B. A., & Young, S. L. (2019). What exactly is endometrial receptivity? Fertility and Sterility, 111(4), 611–617.

Mariani G, Bellver J. Strategies to improve endometrial receptivity. Rev. Iberoam. Fert Rep Hum, 2017; 34; 9-20

Sociedad Española de Fertilidad. Guía 9. Bruna I, Morraja J, Collado O. Estudio del fallo repetido de implantación y sus posibles alternativas terapéuticas. (ver)

Speroff, L., & Fritz, M. A. (2005). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins.

FAQs from users: 'Why doesn't my endometrium grow yet on estrogen and progesterone?', 'When does the endometrium become receptive?', 'Do natural killer cells provoke implantation failures?', 'Is it true that Viagra can help thicken the endometrium?' and 'Is a thickened endometrium receptive?'.

Read more

Authors and contributors

Dr. José Luis Gómez Palomares
Dr. José Luis Gómez Palomares
Gynecologist
Degree in Medicine from the University of Valencia, specialized in Obstetrics and Gynecology at the Son Dureta Hospital in Palma de Mallorca. He has an extensive career as a gynecologist specializing in assisted reproduction and is also a scientific disseminator through the Youtube channel Feliztividad: hábitos de éxito y diferentes podcast. More information about Dr. José Luis Gómez Palomares
Licence number: 280705568
 Laura Garrido
Laura Garrido
BSc, MSc
Embryologist
Bachelor's Degree in Biotechnology from the Pablo de Olavide University (UPO) of Seville, Spain. Master's Degree in Biotechnology of Human Assisted Reproduction from the University of Valencia (UV) and the Valencian Infertility Institute (IVI). Experience at IVF, andrology, and general analysis laboratories. Embryologist specialized in Assisted Reproduction. More information about Laura Garrido
 Óscar Oviedo Moreno
Óscar Oviedo Moreno
MD
Gynecologist
Bachelor's Degree in Medicine & Surgery from the University of Caldas (Colombia). Specialist in Internal Medicine by the Pontificia Universidad Javeriana of Bogotá. Degree standardized in Spain in 2003. Specialist in Gynecology & Obstetrics from the Complutense University of Madrid, with residence at Hospital Clínico Universitario San Carlos de Madrid. Expert in Reproductive Medicine and Certification in Obstetric-Gynecologic Ultrasound (levels I, II and III). More information about Óscar Oviedo Moreno
License: 282858310
Dr. Paloma de la Fuente Vaquero
Dr. Paloma de la Fuente Vaquero
MD, PhD, MSc
Gynecologist
Bachelor's Degree in Medicine from the Complutense University of Madrid, with a Master's Degree in Human Reproduction and a Doctorate in Medicine and Surgery from the University of Seville. Member of the Spanish Fertility Society (SEF) and the Spanish Society of Gynecology and Obstetrics (SEGO), she performs as a gynecologist specializing in assisted reproduction in the clinic YES! Reproducción. More information about Dr. Paloma de la Fuente Vaquero
License: 4117294
 Zaira Salvador
Zaira Salvador
BSc, MSc
Embryologist
Bachelor's Degree in Biotechnology from the Technical University of Valencia (UPV). Biotechnology Degree from the National University of Ireland en Galway (NUIG) and embryologist specializing in Assisted Reproduction, with a Master's Degree in Biotechnology of Human Reproduction from the University of Valencia (UV) and the Valencian Infertility Institute (IVI) More information about Zaira Salvador
License: 3185-CV
Adapted into english by:
 Romina Packan
Romina Packan
inviTRA Staff
Editor and translator for the English and German edition of inviTRA. More information about Romina Packan

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