Sigma-1 receptor is involved in diminished ovarian reserve possibly by influencing endoplasmic reticulum stress-mediated granulosa cells apoptosis.

Lile Jiang,Jinquan Cui,Wei Duo,Shaodi Zhang,Juanke Xie,Cuilian Zhang,Dongjun Fu

doi:10.18632/aging.103166

Lile Jiang, Jinquan Cui + Show 5 more

Open Access

https://doi.org/10.18632/aging.103166

Copy DOI

Abstract

Sigma non-opioid intracellular receptor 1 (sigma-1 receptor), a non-opioid transmembrane protein, is located on cellular mitochondrial membranes and endoplasmic reticulum. Current research has demonstrated that sigma-1 receptor is related to human degenerative diseases. This study is focused on the effects of sigma-1 receptor on the pathophysiological process of diminished ovarian reserve (DOR) and granulosa cells (GCs) apoptosis. Sigma-1 receptor concentration in follicular fluid (FF) and serum were negatively correlated with basal follicle-stimulating hormone (FSH) and positively correlated with anti-mullerian hormone (AMH), antral follicle count (AFC). Sigma-1 receptor reduction in GCs was accompanied by endoplasmic reticulum stress (ERS)-mediated apoptosis in women with DOR. Plasmid transfection was used to establish SIGMAR1-overexpressed and SIGMAR1-knockdown human granulosa-like tumor (KGN) cell and thapsigargin (TG) was used to induce ERS KGN cells. We found that KGN cells treated with endogenous sigma-1 receptor ligand dehydroepiandrosterone (DHEA) and sigma-1 receptor agonist PRE-084 showed similar biological effects to SIGMAR1-overexpressed KGN cells and opposite effects to SIGMAR1-knockdown KGN cells. DHEA may improve DOR patients' pregnancy outcomes by upregulating sigma-1 receptor and downregulating ERS-mediated apoptotic genes in GCs. Thus, sigma-1 receptor may be a potential ovarian reserve biomarker, and ligand-mediated sigma-1 receptor activation could be a future approach for DOR therapy.

Highlights

Infertility is a common disease and affects more than 15% of reproductive age couples [1]
The first part of our study investigated the expression of sigma-1 receptor in the follicular fluid (FF), serum and granulosa cells (GCs) of women with Diminished ovarian reserve (DOR)
We found that BIP, activating transcription factor 6 (ATF6), CHOP, and BAX were increased while the BCL-2/BAX ratio was decreased in SIGMAR1knockdown knockdown human granulosa-like tumor (KGN) cells

Summary

Introduction

Infertility is a common disease and affects more than 15% of reproductive age couples [1]. Diminished ovarian reserve (DOR) is found in approximately 10% of infertile women [2, 3]. Ovarian reserve means the number and quality of oocytes that are produced by ovaries both in the follicular phase of the natural menstrual cycle and following injection of follicle stimulating hormone (FSH) in the assisted reproductive technology (ART) protocol [2, 4, 5]. Many research groups have focused on the transcriptomes between oocytes and ovarian granulosa cells (GCs) [11,12,13,14]. They have reported that follicular atresia during the progression of DOR is primarily induced by apoptosis of GCs, so our research focus on GCs apoptosis

Methods

Results

Conclusion