Excessive progesterone impairs mouse decidualization via the Kyn-AhR pathway

Area of Science:

• Reproductive Biology
• Endocrinology
• Molecular Biology

Background:

• Progesterone (P4) is crucial for pregnancy establishment and maintenance, with clinical applications in reproductive health.
• Optimal P4 administration protocols regarding dosage, route, and timing are not well-defined.
• Excessive P4 is known to impair embryo implantation and decidualization, but the underlying mechanisms are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which excessive progesterone impairs decidualization in mice.
• To investigate the role of the kynurenine-aryl hydrocarbon receptor (AhR) pathway in progesterone-induced decidualization defects.

Main Methods:

• Decidualization was assessed in vivo (pregnant and pseudopregnant mice) and in vitro using uterine stromal cells treated with varying P4 concentrations.
• Gene and protein expression of decidualization markers (Prl8a2, Prl3c1), enzymes (IDO1, TDO), and signaling molecules (BMP2) were analyzed.
• Pharmacological inhibitors (Epacadostat, RU486, CH-223191) and specific P4 metabolites were used to probe pathway activation.

Main Results:

• High-dose P4 (4-8 mg/mouse) impaired decidualization in vivo and downregulated key decidualization markers in vitro.
• Excessive P4 upregulated indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), increasing kynurenine (Kyn) secretion.
• The Kyn-AhR pathway, including downstream targets CYP1A1 and CYP1B1, was activated by high-dose P4, leading to inhibition of decidualization markers and BMP2.

Conclusions:

• Excessive progesterone impairs mouse decidualization through the activation of the Kyn-AhR pathway.
• This pathway involves increased Kyn production and subsequent inhibition of decidualization markers and BMP2.
• Findings highlight a novel mechanism by which supra-physiological P4 levels can disrupt reproductive processes.