The Journal of Reproduction

The endometrium: basic aspects of a complex tissue

Sergio Oehninger — 2024-08-12

This monograph reviews the orderly sequence of events that characterize the human endometrial cycle, the known key molecules and mechanisms involved during the proliferative and secretory phases, as well as the validation of the determinant processes of decidualization and the establishment of the window of implantation. A new look into old dogmas is delivered, and new challenges are posed based on contemporary and objective scientific and clinical evidence. This highly detailed narrative constitutes an in-depth academic work that presents original research, analysis, and arguments aimed to solve current dilemmas or to open the path for further analysis and debate. The understanding and development of new and robust experimental paradigms of genomics, proteomics, and transcriptomics has led to the development of novel high-throughput methodologies aimed directly at interrogating biomolecules, their cellular locations, and interactions, at previously unattainable levels. We remain enthusiastic that the information provided herein will become more and more significant not only as basic physiologic advances but importantly, critical from a clinical point of view, for improved infertility management, and perhaps with an impact on women’s health.

Non-Invasive Methodologies for Endometrial Evaluation in Medically Assisted Reproduction

Hannah E Pierson — 2024-08-12

A conceptual synopsis of the state of non-invasive image-based endometrial receptivity assessment methods utilized within in vitro fertilization (IVF) cycles is presented in narrative review format. Many methods for assessing the endometrial contribution to cycle outcome have been posited over the decades since IVF became a mainstream approach for treatment of infertility. Yet, understanding of the endometrial component remains incomplete and most methods for assessing endometrium in the context of IVF are subject to significant divides within the literature. The need for non-invasive, per-cycle approaches to assess endometrial receptivity is being addressed with innovative methods; and, incremental progress is laying a foundation for quantitative assessment of the many factors that contribute to endometrial receptivity. Non-invasive image-based assessments of the endometrium align on two key factors: 1) they make quantifiable assessments of specific endpoints; and, 2) they are conducted on a per-cycle basis which enables real-time clinical decision making. Herein we summarize endometrial thickness, endometrial pattern, uterine biophysical profiles, endometrial scoring, Doppler approaches, uterine contractility, endometrial length and volume, endometrial compaction, the ultrasound-based endometrial receptivity test, and artificial intelligence and machine learning approaches to assessment of endometrium. We also note and discuss the importance of accounting for embryo quality when making decisions focused on endometrial assessment methods since the two factors are intimately intertwined in successful establishment of pregnancy.

The impact of the microbiome in the endometrial function: is it solely influenced by the local microbiome?

M Pérez-Sánchez — 2024-08-12

The human microbiome plays an important role in the physiology of many organs and alterations in its composition can be accompanied by serious pathologies. At the reproductive level, dysbiosis of the endometrial microbiota has been related to subfertility, recurrent implantation failures (RIF), and complications during pregnancy, such as preterm birth and spontaneous abortions.

However, in recent years it has been observed that microbiome from other mucosal locations also influence women's fertility, ultimately affecting endometrial functionality.

For example, the intercommunication and colonization capacity of microorganisms present in the vagina towards the uterine cavity is well documented, evidencing the influence of the vaginal microbiome on endometrial health. Additionally, the gut microbiome also plays a critical role in regulating the female reproductive endocrine system and has a significant impact on female reproductive health and associated conditions.

This article aims to review recent findings on the influence of different microbiome locations on endometrial functionality.

Disorders affecting endometrial receptivity

Alicia Marzal — 2024-08-12

Uterine receptivity is the ability of the endometrium to allow normal embryo implantation. Abnormal uterine receptivity leads to a range of reproductive problems, from infertility or defective implantation (miscarriage) to recurrent implantation failure after IVF procedures. The best management for our couples would be to identify in advance the possible disorders that could lead to implantation failure.

Most uterine malformations and acquired abnormalities of the uterine cavity are relevant to reproductive outcomes. However, the impact of some abnormalities remains controversial, such as adenomyosis and chronic endometritis.

External factors can also affect the receptivity of the endometrium, even if they are not located inside the uterine cavity. The possible effects of endometriosis, hydrosalpinx and obesity are factors to consider when considering assisted reproductive technology.

Endometrial receptivity: The omics revolution

María Enciso — 2024-08-12

Infertility, affecting millions globally, remains a significant challenge despite advances in Assisted Reproductive Technologies (ART) over the past four decades. While the success rates have improved, many couples still face challenges in conceiving. A major contributing factor is the limited understanding of infertility causes and the inefficiency of available treatment solutions. This article delves into the intricate processes of embryonic implantation and endometrial receptivity, crucial aspects of successful pregnancy.

The emphasis is placed on the frequently overlooked endometrial environment in the context of In Vitro Fertilization (IVF) procedures. Traditional methods of assessing endometrial receptivity, such as histological examination and hormonal level monitoring, have proven insufficient.

In the last years, omics approaches have generated a vast amount of highly valuable information, contributing significantly to the comprehension of the endometrial environment necessary for successful embryonic implantation. Genomic studies have unveiled specific loci related to endometrial disorders, epigenetic regulation studies have identified distinctive signatures associated with receptivity and endometrial pathologies, proteomic analysis has revealed protein expression changes during the menstrual cycle and metabolomic signatures in endometrial fluid may offer a direct insight into tissue function. Among these methodologies, transcriptomic analysis stands out as the most advanced. Particularly, high-throughput methods have proven to be robust in assessing functional states and pathologies leading to the development of commercial tests that evaluate endometrial receptivity. Recent advancements in single-cell and spatial transcriptomics provide great potential for the advanced study of endometrial function.

Current and emerging technologies employed in the exploration of the uterine compartment exhibit significant promise for advancing diagnostic methodologies and therapies addressing infertility. Despite existing challenges, we believe that the key to optimizing ART success rates lies in advanced assessments of the endometrial environment. As technology continues to evolve, the possibilities of precision medicine and personalized approaches offer hope and new opportunities for couples pursuing parenthood.

Evaluation of the Endometrium in the XXI Century

Estefanía Moreno Luna — 2024-08-12

The endometrium is a fundamental layer of the uterus that is relevant to female reproductive function. This specialized tissue lines the inner wall of the uterus and its condition and health are essential to the process of conception and subsequent embryo implantation.

Since the early days of reproductive medicine, the maternal endometrium has been considered a passive part of the reproductive process; a "good quality embryo" was all that mattered.

This fact requires revision since the efficacy of in vitro fertilization remains low despite considerable improvements in embryology and embryo transfer technologies in recent decades. We now know that human implantation is a very complex and multifactorial process. Successful implantation requires the presence of a healthy embryo, a receptive endometrium and a synchronized molecular dialogue between the two, as well as host immune tolerance/protection.

The study of the endometrium is one of the fundamental aspects to be taken into account in assisted reproduction treatments. It is a necessary practice that is routinely performed in assisted reproduction clinics, specifically in cases of implantation failure and repeated miscarriage.

In Memoriam Ms. Tatjana Kniewald

Yona Barak — 2024-08-12

Clinical embryologists, mourns the loss of their well-known, honored colleague Ms. Tatjana Kniewald who passed away in Nasice, Croatia, on May 4th, 2024, just before her 79th birthday.

Editorial

Ricardo Héctor Asch-Schuff — 2024-08-12

This special edition on the endometrium of The Journal of Reproduction only shows some aspects of its complexity but serves to establish the direction in which the efforts of clinicians and researchers are headed in knowing, diagnosing, and above all interpreting the signals that the endometrium shows to treat the patient in a personalized and efficient way for a successful embryonic implantation and a safe pregnancy.

Advancements in Artificial Intelligence in the study of Endometrium

Jorge Suarez — 2024-08-12

Objective

Findings on the application of artificial intelligence (AI), particularly convolutional neural networks (CNNs), in enhancing diagnostic and prognostic capabilities in gynecological health were synthesized.

Design

Recent technological advancements, particularly AI and machine learning, in the study and management of endometrial conditions were reviewed.

Subjects

Various studies exploring the role of AI in diagnosing and managing endometrial conditions such as endometriosis, endometrial receptivity, and endometrial cancer were examined.

Intervention

The development and implementation of CNNs, radiomics models, and integration of omics data (proteomics, metabolomics, transcriptomics), ultrasonographic imaging, in endometrial studies were analyzed.

Main Outcomes

Diagnostic accuracy, prognostic assessments, early detection, personalized treatment, and clinical management of endometrial conditions were evaluated.

Results

It was found that AI technologies, surpassing manual methods in accuracy, enhance the classification of endometrial patterns and analysis of uterine peristalsis. The quantitative assessment of endometrial vascularization and blood supply is improved by AI, leading to better predictions for pregnancy outcomes. Traditional challenges, such as time-consuming manual measurements and significant inter-observer variability, are mitigated by AI-assisted ultrasound, which provides automated detection and measurement of follicles, reducing examination time and improving reproducibility. Diagnostic accuracy in follicular monitoring and endometrial receptivity (ER) assessment is enhanced by AI models, though challenges remain, including the need for robust AI models and validation across diverse populations. The integration of AI with transcriptomic testing and biomarkers in assisted reproductive technology (ART) shows promise in improving embryo transfer timing and personalized treatment strategies. In endometrial cancer and hyperplasia, AI models significantly enhance diagnostic accuracy, sensitivity, and specificity, improving preoperative risk classification and prognostication. Non-invasive diagnostic methods like proteomic profiling and AI models demonstrate high sensitivity and specificity for endometriosis, potentially reducing the need for invasive procedures.

Conclusions

It has been demonstrated that AI models, particularly those leveraging deep learning, show promise in enhancing diagnostic efficiency, predicting molecular subtypes, and improving clinical outcomes in gynecological cancers and reproductive health. However, challenges such as model generalization, data standardization, and interpretability need to be addressed. Future research should focus on validating these models and integrating them into clinical workflows to optimize patient care.

Tumor necrosis factor alpha and milk fat globule-epidermal growth factor 8: Novel biomarkers to predict implantation failure and pregnancy loss

Tamar Alkon-Meadows — 2024-08-12

Objective

To determinate whether implantation failure (IF) and recurrent pregnancy loss (RPL) can be predicted in serum prior to in vitro fertilization (IVF)?.

Design

Multicentric prospective controlled pilot clinical study from January 2016 to January 2020.

Material and methods

Thirty women ages 21-35 years were recruited from 3 groups: fertile controls (C), unexplained IF (following 3 failed good quality embryo transfers), and RPL (at least 2 unexplained first trimester miscarriages) in their natural cycle in which serum tumor necrosis factor (TNFα) and milk fat globule-epidermal growth factor 8 (MFG-E8) estradiol (E2) and progesterone (P4) levels were quantified in the early proliferative (cycle day 2) and secretory phases (urinary luteinizing hormone (LH)+7 days). Additionally, an endometrial biopsy was obtained on urinary LH+7 days for MFG-E8 and TNF α protein and gene expression analysis.

Results

Ten women were assigned to each group. No statistical differences were found in age, body mass index, antimullerian hormone, baseline follicle stimulating hormone and baseline antral follicle count among cohorts. Mean serum E2 and P4 levels were similar among all groups in both the proliferative and secretory phases: E2 proliferative (C 69.19±26.64 pg/ml, IF 64.19±32.56 pg/ml, RPL proliferative 57.44±38.51; p= 0.55), E2 secretory (C 164.10±52.57 pg/ml, IF 172.57±121, RPL 173.81±.97.35; p=0.25), P4 proliferative (C 0.45±0.15 ng/ml, IF 0.45±0.19 ng/ml, RPL 0.53±0.18 ng/ml; p=0.85), P4 secretory (C 7.42±4.06 ng/ml, IF 7.8±4.56 ng/ml, RPL 8.05±4.38 ng/ml; p= 0.74). Mean serum TNFα levels were significantly higher in both, the proliferative and secretory phases for the RPL group (proliferative RPL 9.98±4.47 pg/ml, IF 4.73±2.56 pg/ml, C 3.42±1.01 pg/ml; p=0.001 vs secretory RPL 8.67±4.45 pg/ml, C 3.35±0.94 pg/ml, IF 3.85±1.01 pg/ml; p= 0.03). Mean serum MFG-E8 levels were significantly higher in the IF group during the proliferative phase (IF 373±201 pg/ml, RPL 201±115 pg/ml, C 225.58±109.73pg/ml; p=0.03), but not in the secretory phase (IF 237±101 pg/ml, RPL 189±116 pg/ml, C 199.41±112.43 pg/ml; p=0.15). Endometrial MFG-E8 mRNA levels were significantly lower in the IF and RPL group compared to C (p=0.03). TNFα mRNA levels were not statistically significant among groups (p=0.12).

Conclusions

TNFα and MFG-E8 serum levels may serve as serum markers to predict IF and RPL.