Courtney Coe

Background: Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in reproductive-aged women. An imbalance in hypothalamic-pituitary-ovarian axis signaling leads to symptoms such as excess androgens and ovarian dysfunction. Insulin resistance and compensatory hyperinsulinism are major factors affecting those with PCOS.¹ Current guidelines for diagnosis and management struggle to align clinical practice with the latest evidence due to variability in symptomatic presentation, but a majority of PCOS women exhibit elevated oxidative stress (OS) markers.^1,2,3 With new research linking this inflammation to abnormal follicle growth, poor oocyte quality, and infertility, the mechanisms behind utilizing exercise intervention to dampen these inflammatory pathways remain areas of active investigations to understand lifestyle impacts on PCOS progression.^2,3

Objective: In this review, we explored the molecular mechanisms by which exercise can impact the disease course of PCOS and reverse previous damage through innate inflammatory pathway inhibition.

Search Methods: An online search in the PubMed database using the search terms “Polycystic Ovary Syndrome”, “exercise”, and “inflammation” to identify research literature conducted from 2018-2024.

Results: In a recent study, researchers investigated the potential for dampening the inflammatory pathway to improve and reverse the progression of polycystic ovary syndrome (PCOS).^{4, 5} Researchers noted the increased apoptotic cells in the GC cell layer with heightened levels of proinflammatory cytokines like IL-6, IL-1b, and TNF-α, indicating an inflammatory response in the testosterone-treated PCOS mouse models. Additionally, increased NLRP3 mRNA levels suggested a connection between hyperandrogenism and inflammasome activation.⁴ Further analysis revealed enhanced expression of TLR4 and IRE1α in ovarian tissues, indicating activation of innate inflammatory pathways linked to inflammasome activation and subsequent cell death.⁵ The role of irisin, a myokine, was also found to mitigate PCOS symptoms. Exercise intervention led to a partial recovery in ovarian morphology and decreased atypical follicles in PCOS-model rats.³ Serum irisin levels, reduced in PCOS-model rats, normalized post-exercise.⁶ Pretreatment with irisin significantly improved granulosa cell viability in a hyperandrogenic environment by reducing levels of IRE1α, TXNIP, and NLRP3. Notably, irisin treatment reduced apoptotic markers, indicating its protective role against cell death induced by hyperandrogenism.³ The findings also suggest potential synergies between irisin treatment and other interventions. Combined with curcumin, exercise led to greater improvements in ovarian morphology and reduced cellular stress in PCOS-model rats.⁶ Dampening the inflammatory pathway can improve and potentially reverse PCOS progression, as demonstrated through animal models in other metabolic diseases like type 1 diabetes. In pancreatic cells of diabetic-model mice, irisin treatment lowered reactive oxygen species levels and decreased NLRP3 inflammasome and caspase-1 activity.⁷

Conclusions: Studies have found that inhibition of TXNIP and NLRP3 inflammasome activation led to reduced cystic follicle morphology and improved GC viability. Additionally, aerobic exercise has been shown to induce irisin release, lower OS markers, and increase GC viability. Consideration of exercise and irisin administration as targets could lead to effective new therapies due to their ability to interfere with inflammatory pathways.

Works Cited:

1. Hoeger KM, Dokras A, Piltonen T. Update on PCOS: Consequences, Challenges, and Guiding Treatment. J Clin Endocrinol Metab. 2021;106(3):e1071-e1083. doi:10.1210/clinem/dgaa839
2. Siddiqui S, Mateen S, Ahmad R, Moin S. A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS). J Assist Reprod Genet. 2022;39(11):2439-2473. doi:10.1007/s10815-022-02625-7
3. Weng Y, Zhang Y, Wang D, et al. Exercise-induced irisin improves follicular dysfunction by inhibiting IRE1α-TXNIP/ROS-NLRP3 pathway in PCOS. J Ovarian Res. 2023;16(1):151. Published 2023 Jul 31. doi:10.1186/s13048-023-01242-x
4. Wang D, Weng Y, Zhang Y, et al. Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice. Sci Total Environ. 2020;745:141049. doi:10.1016/j.scitotenv.2020.141049
5. Wang Y, Yang J, Wang Y, et al. Upregulation of TXNIP contributes to granulosa cell dysfunction in polycystic ovary syndrome via activation of the NLRP3 inflammasome. Mol Cell Endocrinol. 2023;561:111824. doi:10.1016/j.mce.2022.111824
6. Zhang Y, Weng Y, Wang D, et al. 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. Oxid Med Cell Longev. 2021;2021:7382900. Published 2021 Dec 26. doi:10.1155/2021/7382900
7. Li T, Yang J, Tan A, Chen H. Irisin suppresses pancreatic β cell pyroptosis in T2DM by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis. Diabetol Metab Syndr. 2023;15(1):239. Published 2023 Nov 22. doi:10.1186/s13098-023-01216-5