Poor Endometrial Proliferation After Clomiphene is Associated With Altered Estrogen Action

Area of Science:

• Reproductive biology and endocrinology.
• Molecular and cellular aspects of infertility.

Background:

• Suboptimal endometrial thickening is a known factor contributing to lower pregnancy rates in women undergoing fertility treatments.
• Clomiphene citrate, a common ovulation induction agent, can sometimes lead to inadequate endometrial development.

Purpose of the Study:

• To investigate the cellular and molecular distinctions within the endometrium of women experiencing suboptimal versus optimal endometrial thickness after clomiphene treatment.
• To identify potential biological pathways contributing to treatment resistance.

Main Methods:

• A prospective cohort study involving women with unexplained infertility treated with clomiphene.
• Endometrial and blood samples were collected for analysis of tissue architecture, protein expression, RNA expression, and estrogen receptor binding.
• Comparison between women with optimal (≥8mm) and suboptimal (<6mm) endometrial thickness.

Main Results:

• Suboptimal endometria showed reduced glandular epithelium volume, decreased markers of proliferation (PCNA, Ki67) and angiogenesis (PECAM-1).
• Increased markers of inflammation (CD45) and altered estrogen receptor (ER) expression (decreased ERα, increased ERβ) were observed.
• RNA sequencing revealed significant differences in gene expression, pathways related to reduced proliferation, angiogenesis, and increased inflammation.

Conclusions:

• Women with suboptimal endometrial thickness following clomiphene treatment display aberrant estrogen receptor expression, architectural alterations, and modified gene/protein profiles.
• These findings suggest a biological basis involving reduced proliferation and angiogenesis, coupled with heightened inflammation, contributing to infertility.