Current Understanding of and Future Directions for Endometriosis-Related Infertility Research with a Focus on Ferroptosis

Kobayashi, Hiroshi; Yoshimoto, Chiharu; Matsubara, Sho; Shinmoto, Hiroshi; Imanaka, Shogo

doi:10.3390/diagnostics13111926

Cited by 11 publications

(12 citation statements)

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“…Insulin resistance in GCs is a contributing factor to reproductive disorders in patients with polycystic ovary syndrome [ 19 ]. GCs are highly sensitive to ferroptosis, and the induction of ferroptosis may promote cell damage, resulting in poor oocyte quality [ 20 ]. These findings provide new clues for understanding the gene regulatory network involved in follicle development.…”

Section: Discussionmentioning

confidence: 99%

MiR-134-3p targets HMOX1 to inhibit ferroptosis in granulosa cells of sheep follicles

Abudureyimu,

Wu,

Chen

et al. 2024

J Ovarian Res

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Background The intricate interplay of gene expression within ovarian granulosa cells (GCs) is not fully understood. This study aimed to investigate the miRNA regulatory mechanisms of ferroptosis during the process of follicle development in lamb GCs. Methods Employing transcriptome sequencing, we compared differentially expressed mRNAs (DE-mRNAs) and miRNAs (DE-miRNAs) in GCs from lambs treated with follicle-stimulating hormone (FL) to untreated controls (CL). We further screened differentially expressed ferroptosis-related genes and identified potential miRNA regulatory factors. The expression patterns of HMOX1 and miRNAs in GCs were validated using qRT‒PCR and Western blotting. Additionally, we investigated the regulatory effect of oar-miR-134-3p on HMOX1 and its function in ferroptosis through cell transfection and erastin treatment. Results We identified a total of 4,184 DE-mRNAs and 304 DE-miRNAs. The DE-mRNAs were mainly enriched in ferroptosis, insulin resistance, and the cell cycle. Specifically, we focused on the differential expression of ferroptosis-related genes. Notably, the ferroptosis-related genes HMOX1 and SLC3A2, modulated by DE-miRNAs, were markedly suppressed in FLs. Experimental validation revealed that HMOX1 was significantly downregulated in FL and large follicles, while oar-miR-134-3p was significantly upregulated compared to that in the CLs. HMOX1 expression was regulated by the targeting effect of oar-miR-134-3p. Functional assays further revealed that modulation of oar-miR-134-3p influenced HMOX1 expression and altered cellular responses to ferroptosis induction by erastin. Conclusion This study suggested that oar-miR-134-3p and HMOX1 may be one of the pathways regulating ferroptosis in GCs. This finding provides new clues to understanding the development and regulatory process of follicles.

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Section: Discussionmentioning

confidence: 99%

MiR-134-3p targets HMOX1 to inhibit ferroptosis in granulosa cells of sheep follicles

Abudureyimu,

Wu,

Chen

et al. 2024

J Ovarian Res

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“…The hypothesis of an effect of ROM on the risk of endometriosis and adenomyosis maybe even more plausible if one considers not only the number of events, in terms of the mere total amount of displaced endometrial tissue and thus its probabilistic chance of survival at ectopic sites, but also the quality of such events, in terms of a possible transition from a state of acute and self-limited inflammation to a state of chronic and self-perpetuating inflammation ( Guo, 2018 , 2020 , 2023 ; Bulun et al , 2019 , 2021 ; Kobayashi, 2023 ; Kobayashi et al , 2023 ). In this context, both ovulation and menstruation can be considered as a source of acute inflammation with a risk of chronicity if relentlessy repeated ( Jarrell and Arendt-Nielsen, 2016 ; Jarrell, 2018 ).…”

Section: Ovulation and Menstruation As Inflammatory Eventsmentioning

confidence: 99%

“…Erythrocytes refluxed into the pelvis during menstruation are normally phagocytized and lysed by local macrophages ( Lousse et al , 2012 ; Donnez et al , 2016 ). However, in an oversimplified synthesis, when the capacity of pelvic macrophages to eliminate erythrocytes and haemoglobin is overwhelmed, or the homeostatic processes are defective, toxic by-products such as haem and free iron are released ( Lousse et al , 2012 ; Donnez et al , 2016 ; Kobayashi et al , 2023 ; Wyatt et al , 2023 ). The resulting Fenton reaction and generation of ROS promotes an inflammatory state, with damage to the peritoneal mesothelium, exposure of the underlying mesenchymal tissue, and the possibility of implantation of regurgitated endometrial cells ( Lousse et al , 2009 , 2012 ; Donnez et al , 2016 ; Ng et al , 2020 ; Ansariniya et al , 2022 ).…”

Section: Does Rom Contribute To the Early-onset And Progression Of En...mentioning

confidence: 99%

“…However, despite the criticisms of our view described above, it is undeniable that menstruators from Palaeolithic to pre-industrial times spent the first decade after menarche in a relatively stable hormonal environment, characterized by infrequent ovulatory menstruation, prolonged progesterone exposure and long periods of hypoestrogenism, whereas menstruators from Western, industrialized, high-income nations now experience recurrent gonadal hormone fluctuations, characterized by repetitious ovulatory menstruation, prolonged oestrogen exposure, and the absence of hypoestrogenic phases. Indeed, Renfree (2012) suggests that reiterative menstruation is an iatrogenic disorder of modern societies, potentially causing ‘ diseases of nulliparity ’, and several investigators support the notion of endometriosis and adenomyosis as disorders initiated by ROM in susceptible individuals, promoted by a mitogenic and pro-inflammatory hyper-oestrogenic local and systemic milieu, and alleviated by amenorrhoea and long-term, stable, low-oestrogen, and high-progesterone exposure ( Kruitwagen, 1993 ; D’Hooghe and Debrock, 2002 ; Lousse et al , 2009 ; Donnez et al , 2016 ; Bulun et al , 2019 , 2021 , 2023 ; Guo, 2020 , 2023 ; Maruyama et al , 2020 ; Koninckx et al , 2021c ; Bulun, 2022 ; Yovich et al , 2020; Kobayashi, 2023 ; Kobayashi et al , 2023 ; Wyatt et al , 2023 ).…”

Section: Prospectus: Preventive Interventional Endocrinology?mentioning

confidence: 99%

“…In the first part of this opinion piece, we hypothesize that endometriosis and adenomyosis may partly result from a mismatch between Darwinian genetic adaptation and global social evolution ( Thomas, 1993 ; Eaton et al , 1994 , 2002 ; Fathalla, 2019 ; Pei et al , 2022 ). As a consequence of an unprecedented increase in the number of ovulatory menstruations in the postmenarchal years, iron overload caused by repetitive bleeding episodes would act as a major trigger for chronic inflammation as well as tissue injury and repair by fibrosis, thus providing a common thread for the aetiology, pathogenesis, clinical manifestations, and potential complications of early-onset endometriosis and adenomyosis ( Lousse et al , 2012 ; Donnez et al , 2016 ; Bulun et al , 2019 , 2021 , 2023 ; Guo 2020 , 2023 ; Maruyama et al , 2020 ; Bulun, 2022 ; Kobayashi et al , 2023 ; Wyatt et al , 2023 ).…”

Section: Introduction: Connecting the Dotsmentioning

confidence: 99%

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Proposal for targeted, neo-evolutionary-oriented, secondary prevention of early-onset endometriosis and adenomyosis. Part I: pathogenic aspects

Vercellini,

Bandini,

Viganò

et al. 2023

Human Reproduction

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The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.

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Is retrograde menstruation a universal, recurrent, physiological phenomenon? A systematic review of the evidence in humans and non-human primates

Viganò,

Caprara,

Giola

et al. 2024

Human Reproduction Open

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STUDY QUESTION What are the quantitative, qualitative and temporal patterns of retrograde mentruation? SUMMARY ANSWER The extreme quantitative and qualitative heterogeneity of the available studies prevents the definitive conclusion that retrograde menstruation is a universal and consistent phenomenon during the reproductive period. WHAT IS KNOWN ALREADY Retrograde menstruation has been defined as a universal, physiological phenomenon that occurs similarly in about 90% of menstruators during the reproductive period. However, uncertainties still exists in terms of the event frequency, total amount and cellular composition of retrograde menstruation and the differences between individuals with versus those without endometriosis. STUDY DESIGN, SIZE, DURATION Two systematic reviews were performed, one for human studies and one for non-human primate studies. We retrieved studies from the PubMed and Embase databases published between January 1, 1980 and November 1, 2023. Studies published in the English language were included and identified using a combination of MeSH terms. References from relevant publications were systematically screened and further articles were identified using PubMed’s “similar articles” and “cited by” functions. PARTICIPANTS/MATERIALS, SETTING, METHODS Results were reported in accordance with the PRISMA guidelines. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included human study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE Fifteen studies were finally included in the human systematic review, mostly with limited sample sizes. The macroscopic visualization of blood in PF during menses was reported with a frequency ranging from 9% to 100%. A prevalence of endometrial cells detected in peritoneal fluid ranging from 8% to 75% was reported in the various studies. Controversial findings were reported in relation to patients with endometriosis. Retrograde menstruation has been evaluated cross-sectionally on single occasions, and no information is available on the course of the phenomenon within an entire cycle and between subsequent cycles. Two studies were included in the non-human primate systematic review; one of them showed that retrograde menstruation was observed more frequently in baboons with naturally occurring endometriosis (83%) than in those with a normal pelvis (51%). LIMITATIONS, REASONS FOR CAUTION In humans, peritoneal fluid has often been collected at different cycle phases and not systematically during menstruation. The indication for laparoscopy was not always clear for all participants. A wide variety of methods were used to detect endometrial cells, including cytological staining, cell block analysis, immunocytochemistry and various methods of cell culture. WIDER IMPLICATION OF THE FINDINGS The idea that almost all women experience retrograde menstruation regularly and similarly during their reproductive life is currently unsubstantiated. It is an academic notion accepted with criticism. Development of endometriosis may derive from differences in the frequency or severity of the event. STUDY FUNDING/COMPETING INTERESTS The review was partially funded by Italian Ministry of Health—Current Research IRCCS. PVi serves as co-editor in Chief of Journal of Endometriosis and Uterine Disorders. E.S. serves as Editor in Chief of Human Reproduction Open and discloses research grants from Ferring, Ibsa, Gedeon Richter and Theramex, and honoraria from Ibsa and Gedeon Richter. P.Ve. serves as Associate Editor for Human Reproduction Open; is a member of the Editorial Board of the Journal of Obstetrics and Gynaecology Canada, of the Italian Journal of Obstetrics and Gynaecology, and of the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate; and maintains both a public and private gynaecological practice. All other authors declare they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A

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Current Understanding of and Future Directions for Endometriosis-Related Infertility Research with a Focus on Ferroptosis

Cited by 11 publications

References 100 publications

MiR-134-3p targets HMOX1 to inhibit ferroptosis in granulosa cells of sheep follicles

MiR-134-3p targets HMOX1 to inhibit ferroptosis in granulosa cells of sheep follicles

Proposal for targeted, neo-evolutionary-oriented, secondary prevention of early-onset endometriosis and adenomyosis. Part I: pathogenic aspects

Is retrograde menstruation a universal, recurrent, physiological phenomenon? A systematic review of the evidence in humans and non-human primates

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