Controlled Ovarian Stimulation Protocols Alter Endometrial Histomorphology and Gene Expression Profiles

John L. Wu, Patrick Keller, Mohammed Kanchwala, Chao Xing, Samir Babayev M.D., Bruce R. Carr, Orhan Bukulmez, R. Ann Word

Research output: Contribution to journalArticle


Although it is well appreciated that ovarian stimulation protocols for in vitro fertilization (IVF) alter endometrial receptivity, the precise cellular mechanisms are not known. To gain insights into potential mechanisms by which different ovarian stimulation protocols alter the endometrium, we compared histologic and gene expression profiles of endometrium from women undergoing conventional ovarian stimulation for IVF (C-IVF) with those undergoing minimal stimulation with clomiphene citrate (MS-IVF). Sixteen women undergoing MS-IVF (n = 8) or C-IVF (n = 8) were recruited for endometrial biopsy at the time of oocyte retrieval. Endometrial glands were large, tortuous, and secretory with C-IVF but small and undifferentiated with MS-IVF. Whereas RNA sequencing did not reveal changes in estrogen receptor or its co-regulators or classic proliferation associated genes in MS-IVF, together with immunohistochemistry, Wnt signaling was disrupted in endometrium from MS-IVF cycles with significant upregulation of Wnt inhibitors. Secreted frizzled-related protein 1 (sFRP1) was increased fourfold (p < 0.01), and sFRP4 was upregulated sixfold (p < 0.01) relative to C-IVF. Further these proteins were localized to subepithelial endometrial stroma. These data indicate that MS-IVF protocols with CC do not seem to impact endometrial estrogen signaling as much as would be expected from the reported antiestrogenic properties of CC. Rather, the findings of this study highlight Wnt signaling as a major factor for endometrial development during IVF cycles.

Original languageEnglish (US)
Pages (from-to)895-904
Number of pages10
JournalReproductive Sciences
Issue number3
StatePublished - Mar 1 2020


  • Clomiphene citrate
  • Endometrial gene expression
  • Minimal stimulation IVF
  • Wnt signaling
  • sFRP

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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