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Updated: Jul 2, 2025
Fertility Preservation in Patients with Severe Ovarian Dysfunction
Published on: March 25, 2021
Targeting Estrogen Receptor Beta Ameliorates Diminished Ovarian Reserve via Suppression of the FOXO3a/Autophagy
Fangyuan Li1, Jingwen Zhu1, Jinchen Liu2
1Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
Abstract:
Diminished ovarian reserve (DOR) refers to a decrease in the number and/or quality of oocytes, leading to infertility, poor ovarian response and adverse pregnancy outcomes. Currently, the pathogenesis of DOR is largely unknown, and the efficacy of existing therapeutic methods is limited. Therefore, in-depth exploration of the mechanism underlying DOR is highly important for identifying molecular therapeutic targets for DOR. Our study showed that estrogen receptor beta (ERβ) mRNA and protein expression was upregulated in granulosa cells (GCs) from patients with DOR and in the ovaries of DOR model mice. Mechanistically, elevated ERβ promotes forkhead transcription factor family 3a (FOXO3a) expression, which contributes to autophagic activation in GCs. Activation of FOXO3a/autophagy signalling leads to decreased cell proliferation and increased cell apoptosis and ultimately leads to DOR. In a cyclophosphamide (Cy)-induced DOR mouse model, treatment with PHTPP, a selective ERβ antagonist, rescued fertility by restoring normal sex hormone secretion, estrus cycle duration, follicle development, oocyte quality and litter size. Taken together, these findings reveal a pathological mechanism of DOR based on ERβ overexpression and identify PHTPP as a potential therapeutic agent for DOR.
Insights
Diminished ovarian reserve (DOR) is linked to increased estrogen receptor beta (ERβ) in ovarian cells. Blocking ERβ with PHTPP may restore fertility in DOR models, offering a potential therapeutic strategy.
Area of Science:
- Reproductive biology
- Endocrinology
- Cellular and molecular medicine
Background:
- Diminished ovarian reserve (DOR) significantly impacts female fertility, characterized by reduced oocyte quantity and quality.
- Current understanding of DOR pathogenesis is limited, hindering effective therapeutic development.
Purpose of the Study:
- To elucidate the underlying molecular mechanisms of DOR.
- To identify potential therapeutic targets and agents for treating DOR.
Main Methods:
- Examined estrogen receptor beta (ERβ) expression in granulosa cells (GCs) from DOR patients and DOR mouse models.
- Investigated the role of ERβ in promoting forkhead transcription factor family 3a (FOXO3a) expression and subsequent autophagic activation in GCs.
- Utilized a cyclophosphamide (Cy)-induced DOR mouse model to assess the therapeutic potential of PHTPP, a selective ERβ antagonist.
Main Results:
- ERβ mRNA and protein expression were significantly upregulated in GCs from DOR patients and in DOR mouse ovaries.
- Elevated ERβ was found to enhance FOXO3a expression, leading to autophagic activation in GCs.
- Activation of the FOXO3a/autophagy pathway resulted in decreased GC proliferation and increased apoptosis, contributing to DOR.
- PHTPP treatment in a DOR mouse model restored fertility, normal sex hormone levels, estrus cycles, follicle development, oocyte quality, and litter size.
Conclusions:
- Overexpression of ERβ plays a critical role in the pathogenesis of DOR by promoting FOXO3a-mediated autophagy in GCs.
- PHTPP emerges as a promising therapeutic agent for DOR, demonstrating efficacy in restoring reproductive function in preclinical models.
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