Effect of the cyst fluid concentration of iron on infertility in patients with ovarian endometrioma

Nagayasu, Mika; Imanaka, Shogo; Kimura, Mai; Maruyama, Sachiyo; Kawahara, Naoki; Kobayashi, Hiroshi

doi:10.3892/wasj.2020.66

Cited by 6 publications

(10 citation statements)

References 24 publications

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“…The iron content of ovarian endometriomas is well studied, with 11 papers reporting on the iron concentrations in this tissue ( Takahashi et al , 1996 ; Iizuka et al , 1998 ; Yamaguchi et al , 2008 ; Singh et al , 2013 ; Sanchez et al , 2014 ; Benaglia et al , 2015 ; Guo et al , 2015 ; Yoshimoto et al , 2015 ; Nagayasu et al , 2020 ; Imanaka et al , 2021a , b ). The findings of Benaglia et al (2015) , Sanchez et al (2014) , Nagayasu et al (2020) , and Singh et al (2013) are summarized elsewhere in this review.…”

Section: Resultsmentioning

confidence: 99%

“…Eight studies examined the association between iron levels and infertility in women with endometriosis ( Arumugam, 1994 ; Singh et al , 2013 ; Sanchez et al , 2014 ; Benaglia et al , 2015 ; Hayashi et al , 2020 ; Li et al , 2020a ; Nagayasu et al , 2020 ; Chen et al , 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Iron exposure significantly impaired murine embryo development in vitro , with rates of both apoptosis and ferroptosis positively associated with iron concentration ( Chen et al , 2021 ). Women with endometriosis-associated infertility had significantly higher levels of iron within their endometriomas ( Nagayasu et al , 2020 ) than women with no signs of infertility, suggesting a role of iron in endometriosis-associated infertility. The infertile group in this study was significantly younger, and thus, this observational study may have demonstrated age-related iron levels in endometriomas as opposed to a true association with infertility.…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative stress has also been implicated in endometriosis-associated subfertility by several high-quality studies ( Singh et al , 2013 ; Hayashi et al , 2020 ; Li et al , 2020a ). Ovarian follicles with iron-rich environments demonstrated lower-quality immature embryos, and animal models confirmed fewer viable foetuses ( Hayashi et al , 2020 ; Li et al , 2020a ; Nagayasu et al , 2020 ). Furthermore, there was evidence of reversibility, since oocyte maturation rates were significantly improved with the introduction of transferrin to bind and stabilize free iron ( Li et al , 2020a ).…”

Section: Discussionmentioning

confidence: 99%

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The role of iron in the pathogenesis of endometriosis: a systematic review

Wyatt

Fernando

Powell

et al. 2023

Human Reproduction Open

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STUDY QUESTION What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory microenvironment and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity and malignant transformation. WHAT IS KNOWN ALREADY Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarise our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN, SIZE, DURATION This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms (‘Iron’ and ‘Endometriosis’) and free-text search terms (‘Iron’, ‘Ferric’, ‘Ferrous’, ‘Endometriosis’, ‘Endometrioma’). PARTICIPANTS/MATERIALS, SETTING, METHODS This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies which did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3,556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity and, possibly, malignant transformation. LIMITATIONS, REASONS FOR CAUTION A minority of the included studies were of objectively low quality with a high-risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterise the included patients by known confounding variables such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localised hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTEREST(S) J.W and S.P are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818)

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The role of iron in the pathogenesis of endometriosis: a systematic review

Wyatt

Fernando

Powell

et al. 2023

Human Reproduction Open

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“…Nagayasu et al reported that iron levels in the cyst can predict endometriosisrelated infertility [18]. High levels of iron (>326.6 mg/L) in the cyst increase the frequency of infertility [18]. On the other hand, decrease in iron levels (<64.8 mg/L) suggests malignant Table 3.…”

Section: Discussionmentioning

confidence: 99%

Validation of magnetic resonance relaxometry R2 value and cyst fluid iron level for diagnosis of ovarian endometrioma

et al. 2021

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Objectives: Magnetic resonance (MR) R2 relaxometry is a safe, noninvasive diagnostic modality for the evaluation of iron levels in the contents of ovarian cysts. The study aims to investigate the sensitivity and specificity of the two methods, R2 value and iron level, in diagnosing OMA patients in the validation set. Methods: A prospective cohort study was conducted from 2013 to 2019. We investigated how R2 value was affected by iron-related compounds, antioxidants and bioelements in the cysts. Results: The sensitivity and specificity of CF iron-based diagnosis of OMA was 96.6% and 95.4%, respectively. The sensitivity and specificity for R2 value in diagnosing OMA were 86.2% and 70.7%, respectively. The outcomes of the two tests were highly correlated (r = 0.758; P <0.001). The R2 value was positively correlated with CF levels of iron-related compounds and antioxidants. The R2 value was affected not only by iron ions but also by calcium ions. Conclusion: Preoperative MR relaxometry may provide a noninvasive alternative to CF iron test in diagnosing OMA. The presence of paramagnetic cations in the cyst may be associated with reduced specificity.

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