Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Selective Estrogen Receptor Modulators (SERMs) inhibit cumulus-oocyte complex adhesion and affect cumulus cell and granulosa cell viability (#440)

Takashi Okada 1 , Tim McPhee 1 , Tasman Daish 1 , Rebecca Robker 1 , Darryl Russell 1
  1. Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, Australia

Aims: SERMs act on the estrogen receptor (ER) as agonists or antagonists. For example, the antagonistic effects of clomiphene citrate increase gonadotropin levels and induce ovulation. Clomiphene citrate has been used for ovulation induction in fertility clinics worldwide for decades(1). However, considerable evidence suggests that clomiphene therapy is associated with defective oocyte maturation(2), inhibition of implantation(3), and reduced fertility(4). The underlying mechanisms of these adverse effects are largely unknown, and how other SERMs influence reproductive cells needs further elucidation. Therefore, we aim to investigate the effects of SERMs on reproductive cells using a murine model.

Methods: The effect of SERM treatment on cell adhesion ability in cumulus-oocyte complexes (COCs) was investigated using xCELLigence(5). Granulosa cell (GC) response to SERMs was analysed by time-course imaging for cell viability and morphology. Cytotoxicity was investigated using SytoxTM Green staining and lactate dehydrogenase assays.

Results: SERM treatment rapidly and significantly decreased COC adhesion levels by inhibiting cumulus cell migration and affecting cell viability. SERM treatment induced necrotic cell death in GCs within 4 hours in a dose-dependent manner. These effects were not associated with ER signalling pathways, as estradiol did not replicate nor reverse the SERM effects, suggesting a non-estrogenic function of SERMs. Cytotoxicity of SERMs in COCs was detectable with 10μM SERM treatment after 6 hours, while lower doses did not induce cell death but still decreased COC adhesion levels. These indicate cell death does occur but is not the direct cause of very rapid (within minutes) and sensitive (~1μM) COC adhesion inhibition. Morphological observations of dose-dependently increased cell circularity and solidity and decreased cell size and perimeter match cell fragmentation and detachment traits, suggesting SERMs effect cell adhesion molecules.

Conclusion: SERMs inhibit COC adhesion and induce necrotic cell death in cumulus cells and GCs through a pathway not associated with classical ER

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  5. Akison LK, Alvino ER, Dunning KR, Robker RL, Russell DL (2012) Transient invasive migration in mouse cumulus oocyte complexes induced at ovulation by luteinizing hormone. Biol Reprod 86:125