Curcumin in Combination with Aerobic Exercise Improves Follicular Dysfunction via Inhibition of the Hyperandrogen-Induced IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in PCOS-Like Rats

Yaling Zhang,Yong Wang,Shanmei Shen,Lihui Wang,Daojuan Wang,Yajing Weng,Hongwei Wang,Jianjun Zhou,Rong Wang,Carla Tatone

doi:10.1155/2021/7382900

Yaling Zhang, Yong Wang + Show 8 more

Open Access

https://doi.org/10.1155/2021/7382900

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Abstract

Combining diet with exercise can improve health and performance. Exercise can reduce androgen excess and insulin resistance (IR) in polycystic ovary syndrome (PCOS) patients. Curcumin is also presumed to improve the follicle development disorder. Here, we investigated the effects of a combination therapy of oral intake of curcumin and exercise on hyperandrogen-induced endoplasmic reticulum (ER) stress and ovarian granulosa cell (GC) apoptosis in rats with PCOS. We generated a PCOS model via continuous dehydroepiandrosterone subcutaneous injection into the necks of Sprague Dawley rats for 35 days. PCOS-like rats then received curcumin treatment combined with aerobic (treadmill) exercise for 8 weeks. We found that compared to control rats, the ovarian tissue and ovarian GCs of hyperandrogen-induced PCOS rats showed increased levels of ER stress-related genes and proteins. Hyperandrogen-induced ovarian GC apoptosis, which was mediated by excessive ER stress and unfolded protein response (UPR) activation, could cause follicle development disorders. Both curcumin gavage and aerobic exercise improved ovarian function via inhibiting the hyperandrogen-activated ER stress IRE1α-XBP1 pathway. Dihydrotestosterone- (DHT-) induced ER stress was mitigated by curcumin/irisin or 4μ8C (an ER stress inhibitor) in primary GC culture. In this in vitro model, the strongly expressed follicular development-related genes Ar, Cyp11α1, and Cyp19α1 were also downregulated.

Highlights

Polycystic ovary syndrome (PCOS), a common disease caused by complex endocrine and metabolic abnormalities among women of reproductive age, is characterized by hyperandrogenism, ovulatory dysfunction, and formation of polycystic ovaries
To further confirm excessive endoplasmic reticulum (ER) stress, we examined inositol-requiring protein 1α (IRE1α), p-IRE1α, X-box-binding protein 1 (XBP1), PERK, activating transcription factor 6 (ATF-6), GRP-78, and CHOP expression at both the protein and mRNA levels in granulosa cell (GC) treated with 5 μM DHT using western blotting and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) (Sup-Fig. S3E-S3G)
Appropriate ER stress is conducive to the growth and development of follicles, the corpus luteum, and embryo, whereas excessive ER stress leads to follicular atresia, luteal dysfunction, embryo development disadvantages, and implantation failure, even leading to infertility and other ovarian diseases

Summary

Introduction

Polycystic ovary syndrome (PCOS), a common disease caused by complex endocrine and metabolic abnormalities among women of reproductive age, is characterized by hyperandrogenism, ovulatory dysfunction, and formation of polycystic ovaries. Low-grade chronic inflammatory status, and insulin resistance (IR) often coexist in PCOS. The clinical manifestations and biochemical characteristics of PCOS are highly heterogeneous. The increased leutinizing/follicle-stimulating hormone (LH/ FSH) ratio, hyperandrogenemia, and hyperinsulinemia are the major endocrine characteristics of PCOS [3, 4]. Sparse or anovulation is an important feature of PCOS. Follicular development is characterized by follicular arrest, the emergence of nondominant follicles, and/or persistent nonovulation. The primary causes of ovarian dysfunction and ovulatory disruption in PCOS are incompletely clear. Most studies report that hyperandrogenism is the main cause of infertility owing to PCOS.

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