Zippl Anna Lena, Kyvelidou Christiana, Frank Monika, Gapp Elisa, Reiser Elisabeth, Braun Anne-Sophie, Feil Katharina, Schuchter Stefanie, Rockenschaub Patrick, Toth Bettina, Seeber Beata
Department of Gynaecologic Endocrinology and Reproductive Medicine, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Clinical Epidemiology, Medical Statistics and Informatics, Medical University of Innsbruck, Public Health, Health Economics, Innsbruck, Austria.
BMC Med. 2025 Jun 9;23(1):338. doi: 10.1186/s12916-025-04162-3.
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.
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.
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/mm) in 1/20 adenomyosis patients (5%), 4/40 RPL patients (10%) and 1/15 RIF patients (6.7%) while uNK cells were elevated (≥ 300/mm) in 8/20 adenomyosis patients (40%), 11/40 RPL patients (27.5%) and 1/15 RIF patients (6.7%).
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.
子宫腺肌病与较低的着床率和较高的流产率相关。关于复发性流产（RPL）和反复种植失败（RIF）的研究表明，子宫内膜免疫细胞群体在着床和早期妊娠期间起着至关重要的作用。据报道，在子宫腺肌病女性中，辅助生殖技术（ART）后妊娠结局得到改善，以及在冻融胚胎移植（FET）前用促性腺激素释放激素激动剂（GnRH-a）进行预处理后妊娠结局也得到改善。我们旨在比较子宫腺肌病女性与RPL和RIF女性的子宫内膜免疫细胞群体，并对GnRH-a治疗前后子宫腺肌病组内的子宫内膜白细胞亚群进行特征分析。
我们在2021年至2024年期间进行了一项前瞻性研究。接受ART治疗的子宫腺肌病不孕女性在取卵后6 - 9天进行一次子宫内膜活检，并在FET前3个月进行GnRH-a治疗后进行第二次活检。RPL和RIF组的女性在黄体中期进行一次子宫内膜活检。我们进行流式细胞术（FC）以表征免疫细胞群体，并进行免疫组织化学（IHC）以分析子宫自然杀伤细胞（uNKs）和浆细胞（PC）。Kruskal-Wallis检验用于研究组之间的比较，Wilcoxon符号秩检验用于GnRH-a治疗前后的配对样本。
基线时，子宫腺肌病组（n = 20）、RPL组（n = 40）和RIF组（n = 15）之间的子宫内膜白细胞亚群无显著差异。在子宫腺肌病组中，GnRH-a治疗后，我们观察到单核细胞百分比显著下降，从77%（四分位间距71, 82）降至71%（四分位间距65, 75）（校正p = 0.030）。基线IHC显示，1/20例子宫腺肌病患者（5%）、4/40例RPL患者（10%）和1/15例RIF患者（6.7%）的浆细胞浓度升高（≥5/mm），而8/20例子宫腺肌病患者（40%）、11/40例RPL患者（27.5%）和1/15例RIF患者（6.7%）的uNK细胞升高（≥300/mm）。
子宫腺肌病不孕女性的子宫内膜免疫特征与RPL和RIF女性相似。GnRH-a在FET前对子宫腺肌病女性的有益作用可能是通过对单核细胞亚群的影响介导的。基于子宫腺肌病患者中uNK细胞升高的高患病率，我们建议对接受ART治疗且患有子宫腺肌病的女性在FET前进行检测。
