Controlled Ovarian Stimulation Protocols Alter Endometrial Histomorphology and Gene Expression Profiles

Area of Science:

• Reproductive biology
• Endocrinology
• Molecular genetics

Background:

• Ovarian stimulation protocols for in vitro fertilization (IVF) are known to affect endometrial receptivity.
• The specific cellular and molecular mechanisms underlying these alterations remain unclear.

Purpose of the Study:

• To investigate the impact of minimal stimulation IVF (MS-IVF) using clomiphene citrate (CC) on endometrial histology and gene expression compared to conventional IVF (C-IVF).
• To elucidate the cellular mechanisms by which different ovarian stimulation protocols influence endometrial receptivity.

Main Methods:

• Endometrial biopsies were collected from 16 women undergoing either MS-IVF (n=8) or C-IVF (n=8) at oocyte retrieval.
• Histologic examination and RNA sequencing were performed to compare endometrial characteristics and gene expression profiles.
• Immunohistochemistry was used to assess protein localization and expression, focusing on Wnt signaling pathway components.

Main Results:

• Endometrial glands were significantly different: large, tortuous, and secretory in C-IVF versus small and undifferentiated in MS-IVF.
• RNA sequencing showed no significant changes in estrogen receptor or proliferation genes with MS-IVF.
• Wnt signaling was disrupted in MS-IVF endometrium, with a significant upregulation of Wnt inhibitors, specifically secreted frizzled-related protein 1 (sFRP1) and sFRP4, localized to the stroma.

Conclusions:

• MS-IVF protocols using CC do not appear to significantly alter endometrial estrogen signaling as anticipated.
• Disruption of the Wnt signaling pathway, evidenced by increased Wnt inhibitors, is a key mechanism affecting endometrial development in MS-IVF cycles.
• Wnt signaling plays a crucial role in endometrial development and receptivity during IVF procedures.