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. 2025 Jun 9;23(1):338.
doi: 10.1186/s12916-025-04162-3.

The impact of GnRH agonists on endometrial immune cells in patients with adenomyosis: a prospective cohort study

Anna Lena Zippl  1 , Christiana Kyvelidou  1 , Monika Frank  1 , Elisa Gapp  1 , Elisabeth Reiser  1 , Anne-Sophie Braun  1 , Katharina Feil  1 , Stefanie Schuchter  1 , Patrick Rockenschaub  2 , Bettina Toth  1 , Beata Seeber  3
Affiliations

The impact of GnRH agonists on endometrial immune cells in patients with adenomyosis: a prospective cohort study

Anna Lena Zippl et al. BMC Med. .

Abstract

Background: Adenomyosis is associated with lower implantation and higher miscarriage rates. Studies on recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) have shown that endometrial immune cell populations play a crucial role during implantation and early pregnancy. In women with adenomyosis, improved pregnancy outcomes following assisted reproductive technologies (ART) and pre-treatment with GnRH-agonists (GnRH-a) prior to frozen embryo transfer (FET) have been reported. We aimed to compare the endometrial immune cell populations of women with adenomyosis to those of women with RPL and RIF, and to characterise endometrial leucocyte subpopulations within the adenomyosis group before and after GnRH-a.

Methods: We conducted a prospective study between 2021 and 2024. Women with infertility and adenomyosis undergoing ART underwent one endometrial biopsy 6-9 days after oocyte retrieval and a second biopsy after 3 months of GnRH-a prior to FET. Women in the RPL and RIF groups underwent one endometrial biopsy in the midluteal phase. We performed flow cytometry (FC) to characterise immune cell populations and immunohistochemistry (IHC) to analyse uterine natural killer cells (uNKs) and plasma cells (PC). The Kruskal-Wallis test was used for comparisons between the study groups, and the Wilcoxon signed rank tests were used for paired samples before and after GnRH-a.

Results: Endometrial leucocyte subpopulations at baseline showed no significant differences between the adenomyosis (n = 20), the RPL (n = 40) and RIF (n = 15) group. In the adenomyosis group, following GnRH-a, we observed a significant decrease in the percentage of monocytes, from 77% (IQR 71, 82) to 71% (IQR 65, 75) (adj. p = 0.030). Baseline IHC showed elevated plasma cell concentrations (≥ 5/mm2) in 1/20 adenomyosis patients (5%), 4/40 RPL patients (10%) and 1/15 RIF patients (6.7%) while uNK cells were elevated (≥ 300/mm2) in 8/20 adenomyosis patients (40%), 11/40 RPL patients (27.5%) and 1/15 RIF patients (6.7%).

Conclusions: Women with infertility and adenomyosis showed a similar endometrial immune profile as women with RPL and RIF. The beneficial effect of GnRH-a prior to FET in women with adenomyosis may be mediated through effects on monocyte subpopulations. Based on the high prevalence of elevated uNK cells in patients with adenomyosis, we suggest testing women with adenomyosis undergoing ART before FET.

Keywords: Adenomyosis; Endometrial immune cells; GnRH-agonists; Infertility; Recurrent implantation failure; Recurrent pregnancy loss; Uterine natural killer cells.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study protocol was approved by the ethics committee of the Medical University of Innsbruck, Austria (EK Nr: 1075/2020). Oral and written informed consent was obtained by all study participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart showing the study procedures in the adenomyosis group
Fig. 2
Fig. 2
Gating strategy for viable CD45 + cells in endometrial biopsies
See this image and copyright information in PMC

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