Altered redox status may contribute to aberrant folliculogenesis and poor reproductive outcomes in women with polycystic ovary syndrome

Naigaonkar, Aalaap; Dadachanji, Roshan; Hinduja, Indira; Mukherjee, Srabani

doi:10.1007/s10815-021-02241-x

Cited by 22 publications

(14 citation statements)

References 45 publications

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“…Despite its prevalence in reproductive-aged women, the precise pathophysiology of PCOS remains incompletely elucidated. Ferroptosis is an iron-dependent and ROS-reliant regulated cell death, while both iron overload and increased ROS have been previously observed in PCOS patients [4,5,18,19]. In the present study, we applied an integrated bioinformatic and experimental approach to explore the unrecognized role of GC ferroptosis on PCOS development, thus providing novel biomarkers for its diagnosis, treatment, and clinical relevance with oocyte quality.…”

Section: Discussionmentioning

confidence: 97%

“…Poor oocyte quality remains one of the major obstacles encountered by PCOS patients during IVF treatment [3][4][5][6]. Gene expressions in GCs re ect the characteristics of oocytes, thus providing a noninvasive approach to assess oocyte quality [40].…”

Section: Discussionmentioning

confidence: 99%

“…The condition is characterized by a heterogeneous clustering of androgen excess, ovulatory dysfunction, polycystic ovarian morphology, as well as metabolic abnormalities including obesity and insulin resistance [2]. During in vitro fertilization (IVF) treatment, women with PCOS have typically increased oocyte yield from stimulation, while the maturation, fertilization, and implantation rates are decreased due to poor oocyte quality [3][4][5][6].…”

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confidence: 99%

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Dysregulation of ferroptosis-related genes in granulosa cells associates with impaired oocyte quality in polycystic ovary syndrome

Huang

Fan

et al. 2023

Preprint

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Background Poor oocyte quality remains one of the major challenges for polycystic ovary syndrome (PCOS) patients during in vitro fertilization (IVF) treatment. Granulosa cells (GCs) in PCOS display altered functions and could cause an unfavorable microenvironment for oocyte growth and maturation. Ferroptosis is a new form of programmed cell death, but its role in PCOS has been largely unclarified.Methods Ferroptosis-related differentially expressed genes (DEGs) in PCOS GCs were identified by bioinformatic analyses of GSE155489 and GSE168404 datasets. Functional enrichment analyses were conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Core ferroptosis-related genes were further screened by random forest, and evaluated for diagnostic value by receiver operating characteristic curve analyses. Gene expression was validated by real-time quantitative polymerase chain reaction of collected GC samples, and analyzed for association with oocyte quality. In addition, gene regulatory network was constructed based on predicted RNA interactions and transcription factors, while potential therapeutic compounds were screened through molecular docking with crystallographic protein structures.Results A total of 14 ferroptosis-related DEGs were identified. These DEGs were mainly enriched in reactive oxygen species metabolic process, mitochondrial outer membrane, antioxidant activity as well as ferroptosis and adipocytokine signaling pathways. Eight core ferroptosis-related genes (ATF3, BNIP3, DDIT4, LPIN1, NOS2, NQO1, SLC2A1 and SLC2A6) were further selected in random forest model, which showed high diagnostic performance for PCOS. Seven of them were validated in GC samples, and five were found to significantly and positively correlated with one or more oocyte quality parameters in PCOS patients, including oocyte retrieval rate, mature oocyte rate, normal fertilization rate, and good-quality embryo rate. Gene regulatory network revealed JUN and HMGA1 as two important transcription factors, while dicoumarol and flavin adenine dinucleotide were predicted as small molecules with therapeutic potential.Conclusions This is the first comprehensive report to study the differential expression of ferroptosis-related genes in GCs of PCOS and their clinical relevance with oocyte quality. Our findings could provide novel insights on the potential role of GC ferroptosis in PCOS pathogenesis, diagnosis, and targeted treatment.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dysregulation of ferroptosis-related genes in granulosa cells associates with impaired oocyte quality in polycystic ovary syndrome

Huang

Fan

et al. 2023

Preprint

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“…Oxidative stress is a common pathological mechanism of PCOS and IR. Oxidative stress can reduce glucose uptake in musculoskeletal muscle and insulin secretion in pancreatic beta cells to induce IR ( 22 , 23 ), increase androgen level ( 24 ), destroy follicular microenvironment ( 25 ), and promote the progress of PCOS and IR. Researchers found that antioxidant therapy can significantly improve the reproductive metabolic disorder of PCOS ( 26 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

The relationship between polycystic ovary syndrome and insulin resistance from 1983 to 2022: A bibliometric analysis

Chen

Fan

et al. 2022

Front. Public Health

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BackgroundPolycystic ovary syndrome (PCOS) is a common clinical disease often associated with insulin resistance (IR). The interaction between PCOS and IR will promote the progress of PCOS and the risk of related complications, harm women's physical and mental health, and increase the social and economic burden.Materials and MethodsPCOS IR-related works of literature were retrieved through the Web of Science Core Collection (WoSCC) Database and imported into VOSviewer and CiteSpace, respectively, in plain text format to conduct the literature visualization analysis of authors, countries, institutions, highly cited works of literature, and keywords, aiming to reveal the hot spots and trends of PCOS IR fields.ResultsA total of 7,244 articles were retrieved from 1900 to 2022. Among them, the United States has made the largest contribution. Diamanti-Kandarakis E was the author with the most publications, and the University of Athens was the institution with most publications. Keyword analysis showed that PCOS interacts with IR mainly through sex-hormone binding globulin, luteinizing hormone, insulin-like growth factor, oxidative stress, and other mechanisms. In addition, the complications of PCOS complicated with IR are also the focus of researchers' attention.ConclusionsThrough bibliometric analysis, this paper obtains the research hotspot and trend of PCOS IR fields, which can provide a reference for subsequent research.

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“…On the one hand, the very presence of ROS is essential for proper folliculogenesis because some of their forms are involved in signaling cascades, such as nuclear factor kappa B (NF-kB) and vascular endothelial growth factor (VEGF), which are necessary for follicle growth. On the other hand, excess ROS can lead to impaired oocyte quality due to mitochondrial dysfunction, decreased ATP production, oocyte aging, and oocyte/embryo aneuploidy [ 133 ]. Additionally, excess ROS is generated by elevated androgen levels in women with PCOS due to the high activity of the P450 enzyme.…”

Section: Adipokinesmentioning

confidence: 99%

Immunological and Metabolic Causes of Infertility in Polycystic Ovary Syndrome

Kicińska

Maksym

Zabielska-Kaczorowska

et al. 2023

Biomedicines

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Infertility has been recognized as a civilizational disease. One of the most common causes of infertility is polycystic ovary syndrome (PCOS). Closely interrelated immunometabolic mechanisms underlie the development of this complex syndrome and lead to infertility. The direct cause of infertility in PCOS is ovulation and implantation disorders caused by low-grade inflammation of ovarian tissue and endometrium which, in turn, result from immune and metabolic system disorders. The systemic immune response, in particular the inflammatory response, in conjunction with metabolic disorders, insulin resistance (IR), hyperadrenalism, insufficient secretion of progesterone, and oxidative stress lead not only to cardiovascular diseases, cancer, autoimmunity, and lipid metabolism disorders but also to infertility. Depending on the genetic and environmental conditions as well as certain cultural factors, some diseases may occur immediately, while others may become apparent years after an infertility diagnosis. Each of them alone can be a significant factor contributing to the development of PCOS and infertility. Further research will allow clinical management protocols to be established for PCOS patients experiencing infertility so that a targeted therapy approach can be applied to the factor underlying and driving the “vicious circle” alongside symptomatic treatment and ovulation stimulation. Hence, therapy of fertility for PCOS should be conducted by interdisciplinary teams of specialists as an in-depth understanding of the molecular relationships and clinical implications between the immunological and metabolic factors that trigger reproductive system disorders is necessary to restore the physiology and homeostasis of the body and, thus, fertility, among PCOS patients.

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Altered redox status may contribute to aberrant folliculogenesis and poor reproductive outcomes in women with polycystic ovary syndrome

Cited by 22 publications

References 45 publications

Dysregulation of ferroptosis-related genes in granulosa cells associates with impaired oocyte quality in polycystic ovary syndrome

Dysregulation of ferroptosis-related genes in granulosa cells associates with impaired oocyte quality in polycystic ovary syndrome

The relationship between polycystic ovary syndrome and insulin resistance from 1983 to 2022: A bibliometric analysis

Immunological and Metabolic Causes of Infertility in Polycystic Ovary Syndrome

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