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Metabolomics analysis of serum metabolites during endometrial transformation: association with recurrent implantation failure in hormonal replacement therapy-frozen embryo transfers cycles

  • Reproductive physiology and disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to investigate alterations in serum metabolites during endometrial transformation and possible associations with recurrent implantation failure (RIF) in hormonal replacement therapy (HRT)-frozen embryo transfer (FET) cycles.

Methods

We performed a prospective study involving 100 patients scheduled for HRT-FET cycles during January 2022 to April 2022. Blood serum samples were collected on the day of progesterone administration (dPA) and on the third day of progesterone administration (d3PA). Gas chromatography-mass spectrometry (GC-MS) analysis was performed to identify and quantify serum metabolites. A nested case-control study including 19 RIF patients and 19 matching controls was conducted to explore the predictive value of serum metabolites for RIF. Partial least squares discriminant analysis (PLS-DA) and receiver operating characteristic (ROC) curve analysis were performed to establish prediction models.

Main results

We identified 105 serum metabolites, with 76 of them exhibiting significant alterations during the initial 3 days of endometrial transformation. Metabolites involved in amino acid metabolism and tricarboxylic acid (TCA) cycle showed lower levels during endometrial transformation. In the nested case-control study, the prediction model based on the ratio of serum metabolites between d3PA and dPA showed the highest area under the ROC curve (AUC), accuracy, and R2 and Q2 values. Eight metabolites, including indol-3-propionic acid, beta-alanine, myristoleic acid, malic acid, indole, DL-isocitric acid, proline, and itaconic acid, exhibited high predictive values for RIF.

Conclusion

This study demonstrates alterations in serum metabolites during endometrial transformation, particularly in amino acid metabolism and TCA cycle. The identified metabolites, especially indol-3-propionic acid and malic acid, show potential as predictive markers for RIF. These findings contribute to a better understanding of the metabolic changes associated with endometrial receptivity and provide insights for the development of personalized approaches to improve implantation outcomes in FET cycles.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Acknowledgements

The authors express our gratitude to Yu Dai, Hongyu Liu, and Jianru Yang for collection and handling of the serum samples.

Funding

This study was supported by the National Natural Science Foundation of China (82101710), Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2022QNXM023), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0097), Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine, Ferring Pharmaceuticals and Chinese Academy of Sciences (FIRMD200502), and the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University.

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Authors and Affiliations

  1. The Center for Reproductive Medicine, Obstetrics and Gynecology Department, The Second Affiliated Hospital of Chongqing Medical University, No. 288 Tianwen Avenue, Nanan District, Chongqing, 400010, People’s Republic of China

    Jie Zheng, Ting-li Han, Chanyu Zhang & Shen Zhang

  2. Prenatal Diagnosis Center, Obstetrics and Gynecology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China

    Xianglan Tang

  3. Joint International Research Lab for Reproduction and Development of Ministry of Education of China, Chongqing Medical University, Chongqing, 400010, China

    Ting-li Han, Chanyu Zhang & Shen Zhang

  4. Mass Spectrometry Centre of Maternal-Fetal Medicine, Chongqing Medical University, Chongqing, 400010, China

    Ting-li Han

Authors
  1. Jie Zheng
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  2. Xianglan Tang
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  3. Ting-li Han
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Contributions

SZ conceived and designed the study. JZ and XT performed the experiments. JZ, XT, TH, and SZ analyzed the data and created the figures. SZ and JZ drafted and reviewed the manuscript.

Corresponding author

Correspondence to Shen Zhang.

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Ethics approval

This study was approved by the Ethics Committees of the Second Affiliated Hospital of Chongqing Medical University (2021-228). Written informed consent was obtained from all the participants.

Conflict of interest

The authors declare no competing interests.

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Supplementary information

ESM 1

Fig.S1 ROC curves for the 4 prediction models of RIF. Multivariant ROC curves for model 1 (A), model 2 (B), model 3 (C) and model 4 (D) were shown. (JPG 715 kb)

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Zheng, J., Tang, X., Han, Tl. et al. Metabolomics analysis of serum metabolites during endometrial transformation: association with recurrent implantation failure in hormonal replacement therapy-frozen embryo transfers cycles. J Assist Reprod Genet 40, 2473–2483 (2023). https://doi.org/10.1007/s10815-023-02904-x

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  • DOI: https://doi.org/10.1007/s10815-023-02904-x

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