ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Embryonic Development
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1622998
This article is part of the Research TopicCellular Micro-Environment of the Endometrium: Reproduction, Embryo Implantation, and Placentation - From Bench to Bedside and Beyond to Tissue EngineeringView all 10 articles
Excessive Progesterone Impairs Mouse Decidualization via the Kyn-AhR Pathway
Provisionally accepted
- 1South China Agricultural University, Guangzhou, China
- 2Guizhou University, Guiyang, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Progesterone (P4) is essential for pregnancy establishment and maintenance. Clinically, P4 is widely used to regulate the menstrual cycle, maintain pregnancy, and treat luteal phase deficiency. However, P4 administration protocols, particularly regarding routes, dosage, and timing remain poorly defined. Although excessive P4 impairs embryo implantation and decidualization in mice, the underlying mechanism remains unclear. Our data show that decidualization in day 8 pregnant mice and artificial decidualization in day 8 pseudopregnant mice are impaired by 4 mg or 8 mg /mouse P4. The mRNA levels of Prl8a2 and Prl3c1, markers of in vitro decidualization are significantly downregulated by 10 or 20 μM P4. The uterine fluorescent signal of indoleamine 2,3-dioxygenase 1 (IDO1) and protein levels of tryptophan 2,3-dioxygenase (TDO) are increased after ovariectomized mice are treated with excessive P4. Treatment of uterine stromal cells with excessive P4 also significantly upregulates the protein levels of IDO1 and TDO, and kynurenine (Kyn) secretion. Epacadostat (IDO1 antagonist) or RU486 (progesterone receptor antagonist) effectively block P4-induced Kyn elevation. The mRNA levels of Prl8a2 and Prl3c1 and the protein levels of BMP2 are significantly inhibited by Kyn. The high-dose of P4 activates the aryl hydrocarbon receptor (AhR) and its downstream targets CYP1A1 and CYP1B1. Under in vitro decidualization, the mRNA levels of Prl8a2 and Prl3c1 are inhibited by 2-OH-E2 and 4-OH-E2, the catalytic products of CYP1A1 and CYP1B1, respectively. CH-223191, a specific AhR antagonist, effectively counteracts the Kyn-induced effects on Cyp1a1, Cyp1b1, and Prl8a2 expression. Additionally, nucleolar size in stromal cells is increased both in vivo and in vitro following excessive P4 treatment. Our findings suggest that excessive P4 impairs mouse decidualization via the Kyn-AhR pathway.
Keywords: decidualization, Progesterone, IDO1, TDO, KYN, AhR, nucleolin
Received: 05 May 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Luo, Yang, Wang, Luo, Zhang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zeng-Ming Yang, Guizhou University, Guiyang, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.