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Decreased Endometrial Expression of Leukemia Inhibitory Factor Receptor Disrupts the STAT3 Signaling in Adenomyosis During the Implantation Window

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Abstract

Background

Adenomyosis was found to have negative impacts on embryo implantation. Leukemia inhibitory factor (LIF), proposed to be a molecular marker for endometrial receptivity, works through the LIF receptor (LIFR) on both the embryo and the endometrium. We aimed to evaluate the endometrial expression of LIF and LIFR and its subsequent signaling in patients with adenomyosis during the window of implantation (WOI).

Methods

Endometrium was obtained during the WOI from patients with adenomyosis (age <45 years) who underwent hysterectomy and from age-matched controls who had no endometriosis or adenomyosis. The LIF and LIFR expressions were measured by polymerase chain reaction for messenger RNA expression, immunohistochemistry for protein intensity and localization, and immunofluorescent staining for colocalization. The ratio of signal transducer and activator of transcription 3 (STAT3) to extracellular signal-regulated kinase (ERK) phosphorylation was measured by Western blot of both the endometrium and the isolated human endometrial stromal cells (ESCs).

Results

Patients with adenomyosis showed significantly and parallelly reduced LIF and LIFR expressions in the eutopic endometrium during WOI as compared with the control women and subsequently with remarkably reduced activation of STAT3 and ERK signaling. The significantly increased STAT3 and ERK phosphorylation induced by the LIF treatment in the cultured ESCs supported the linkage between the LIF–LIFR reaction and the signaling cascade.

Conclusion

Significant reduction in LIFR expression and the reduced activation of subsequent signaling strongly suggest a working model of how the implantation markers, LIF, may affect the endometrium of patients with adenomyosis. These molecular changes supported the declined implantation rates reported in patients with adenomyosis.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Kwei-Shan, Taoyuan, Taiwan

    Chih-Feng Yen MD, PhD & Hsin-Shih Wang MD, PhD

  2. Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taipei, Taiwan

    Chih-Feng Yen MD, PhD, Shuen-Kuei Liao PhD & Hsin-Shih Wang MD, PhD

  3. The PhD Program of Cancer Biology and Drug Discovery, Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan

    Shuen-Kuei Liao PhD

  4. Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

    S.Joseph Huang MD, PhD

  5. Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    S.Joseph Huang MD, PhD & Umit A. Kayisli PhD

  6. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

    Selcuk Tabak MD & Aydin Arici MD

  7. Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy

    Felice Arcuri PhD & Felice Petraglia MD

  8. Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan

    Chyi-Long Lee MD, PhD

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  1. Chih-Feng Yen MD, PhD
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  2. Shuen-Kuei Liao PhD
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  9. Hsin-Shih Wang MD, PhD
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  10. Umit A. Kayisli PhD
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Correspondence to Hsin-Shih Wang MD, PhD or Umit A. Kayisli PhD.

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Yen, CF., Liao, SK., Huang, S. et al. Decreased Endometrial Expression of Leukemia Inhibitory Factor Receptor Disrupts the STAT3 Signaling in Adenomyosis During the Implantation Window. Reprod. Sci. 24, 1176–1186 (2017). https://doi.org/10.1177/1933719116681515

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