P-370 Impaired endometrial decidualization with a hyperinflammation environment is involved in poor reproductive outcomes in adenomyosis patients
Authors: Corachán A , Albert A B , Juárez-Barber E , Vidal C , Giles J , Alecsandru D , Cozzolino M , Pellicer A , Ferrero H 
Published: June 2023

Abstract

Study question
Do patients with adenomyosis have an impaired inflammatory state of the endometrium that could affect implantation and pregnancy?

Summary answer
Adenomyosis patients show increased proinflammatory cytokines expression and deregulated decidualization markers expression in eutopic endometrium which could lead to altered endometrial receptivity and impaired implantation.

What is known already
Adenomyosis is an estrogen-dependent chronic inflammatory condition, characterized by the presence of endometrial glands and stroma within the myometrium. Adenomyosis patients present altered decidualization and defective embryo-endometrium communication, resulting in implantation failure, miscarriage, and other fertility-related disorders. Although the underlying mechanisms of this infertility remain unknown, it is known that a favorable immune and inflammatory uterine environment is necessary for developmental pregnancy. It has been proposed that a uterine hyperinflammatory state could be involved in adenomyosis-related infertility. For this reason, we aim to evaluate the inflammatory and endometrial receptivity status during implantation in eutopic endometrium from adenomyosis patients.

Study design, size, duration
Sixteen endometrial samples were collected from infertile patients with and without adenomyosis undergoing hormonal replacement therapy before in vitro fertilization (IVF) at IVIRMA Valencia between January to December 2022.

Participants/materials, setting, methods
Eutopic endometrial samples were obtained at secretory phase (LH + 7) from patients diagnosed with adenomyosis (n = 8) by ultrasound or hysteroscopy and patients without gynecological diseases (control, n = 8). Total RNA extraction was performed to later determine the gene expression of the decidualization-related genes Prolactin (PRL), SPP1 and PAEP by qRT-PCR. In addition, proteins were extracted from eutopic endometrium using a lysis buffer and the relative expression levels of human cytokines were measured by Human Cytokine Array (Raybiotech).

Main results and the role of chance
Gene expression evaluation in endometrium from adenomyosis patients compared to control showed a significant downregulation of the key marker of decidualization PRL (fold change [fc] = 0.56, p = 0.0047) and a significant upregulation of SPP1 (fc = 1.75, p = 0.009) and PAEP (fc = 1.56, p = 0.0192), both involved in endometrial receptivity and in immune regulation. Regarding cytokines expression, array results showed upregulation of different interleukins (IL) involved in the mediation of the immune and inflammatory response previously described in adenomyosis. Specifically, IL1ß (12±19.63 vs. 1.37±2.77, p = 0.009) that regulates several inflammatory responses, including cell proliferation, differentiation, and apoptosis; and IL6 (584.7±121.8 vs. 488.4±57.44, p = 0.06) that acts on the inflammation and maturation of B cells, contributing to the development of autoimmune diseases. Similarly, cytokines related to the promotion of inflammation and cellular proliferation in endometriosis, IL17a (173.6±44.75 vs. 102.10±71.85, p = 0.04) and TNFβ (430.9±139.6 vs. 315.3±37.09, p = 0.04), were also upregulated in adenomyosis compared to control. There were also other cytokines upregulated with diverse functions like an anti-inflammation response, growth factors or immune modulation: IL5 (308.1±88.77 vs. 202.6±45.72, p = 0.01), IL2 (341.4±60.38 vs. 270.8±35.13, p = 0.014), TGFα (215.3±27.04 vs. 117.8±36.67, p = 0.002), IL31 (77.74±40.57 vs. 14±15.96, p = 0.0012), IL7 (739.1±147.1 vs. 511.8±103.7, p = 0.003) and IL15 (301.9±95.73 vs. 209.8±50.62, p = 0.03).

Limitations, reasons for caution
Our findings are limited by the relatively small sample size and inherent biological variability of human samples.

Wider implications of the findings
Adenomyosis patients showed impaired decidualization and a hyperinflammatory endometrial environment that could be affecting the endometrial receptivity and consequently, the embryo implantation. These findings open insight to further investigations to study the mechanism by which exaggerated inflammation affects fertility in the context of adenomyosis to define new management approaches.

Trial registration number
Not applicable