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

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.

Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

“…Intraovarian factors have regulatory roles during the entire process of follicular growth and play crucial roles in pathological conditions of the ovary, including PCOS 39,53,60,61 . We demonstrated for the first time that ER stress pathways are activated in the granulosa cells of both a mouse model of PCOS induced by the continuous administration of androgen and in humans, and this finding has been confirmed by other groups 48,62–67 . We also found that local hyperandrogenism in the follicular microenvironment of PCOS is an activator of ER stress in human granulosa cells, 52 and this finding has been confirmed in mouse granulosa cells 63 .…”

“…39,53,60,61 We demonstrated for the first time that ER stress pathways are activated in the granulosa cells of both a mouse model of PCOS induced by the continuous administration of androgen and in humans, and this finding has been confirmed by other groups. 48,[62][63][64][65][66][67] We also found that local hyperandrogenism in the follicular microenvironment of PCOS is an activator of ER stress in human granulosa cells, 52 and this finding has been confirmed in mouse granulosa cells. 63 Other potential activators of ER stress in the follicular microenvironment of PCOS would be local inflammation and oxidative stress, which are closely connected with ER stress and form a vicious circle, and the local hyperandrogenic conditions further activate these pathways.…”

Advancements in lead therapeutic phytochemicals polycystic ovary syndrome: A review

“…In PCOS, hyperandrogenism induces ERs and activation of the UPR (to maintain ER homeostasis). Zhang et al illustrated that long-term ERs led to GC autophagy or apoptosis and caused follicle development disorders, including the accumulation of small follicles around the ovary, polycystic morphology, anovulation, and damage to follicular maturation ( Zhang et al, 2021 ). Curcumin (200 mg/kg daily for 8 weeks) combined with aerobic exercise ameliorated follicle development disorders by reducing hyperandrogen-induced ERs, inhibiting the IRE1α-XBP1 pathway in ovarian GCs, and downregulating follicular development-related genes (Ar, Cyp11α1, and Cyp19α1) ( Zhang et al, 2021 ).…”

“…Zhang et al illustrated that long-term ERs led to GC autophagy or apoptosis and caused follicle development disorders, including the accumulation of small follicles around the ovary, polycystic morphology, anovulation, and damage to follicular maturation ( Zhang et al, 2021 ). Curcumin (200 mg/kg daily for 8 weeks) combined with aerobic exercise ameliorated follicle development disorders by reducing hyperandrogen-induced ERs, inhibiting the IRE1α-XBP1 pathway in ovarian GCs, and downregulating follicular development-related genes (Ar, Cyp11α1, and Cyp19α1) ( Zhang et al, 2021 ). Heshmati et al found that in a randomized, placebo-controlled double-blind trial, curcumin (1500 mg daily for 12 weeks) significantly reduced fasting plasma glucose (FPG) and DHEA in PCOS patients.…”

Moderate Aerobic Exercise Regulates Follicular Dysfunction by Initiating Brain-Derived Neurotrophic Factor (BDNF)-Mediated Anti-Apoptotic Signaling Pathways in Polycystic Ovary Syndrome

“…Exercise can reduce androgen and insulin levels in PCOS, improve the endocrine environment of the ovary, and play an important role in promoting ovulation [ 13 , 14 ]. Our previous research has shown that aerobic exercise can alleviate hyperandrogenism-induced ER stress and reverse ovarian granulosa cells (GCs) apoptosis in PCOS-like rats [ 15 ]. In addition, exercise stimulates the release of neurotransmitters and neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4/5 in an activity-dependent manner [ 16 , 17 ].…”