Objective: Magnetic resonance (MR) relaxometry is a diagnostic imaging method that enables non-invasive quantification of iron levels in patients with endometriosis. The aim of this study is to investigate whether cyst fluid (CF) MR relaxometry R2 values are associated with iron levels and the severity of dysmenorrhea in women with ovarian endometrioma (OMA).
Methods: A single-center prospective cohort study was conducted by collecting data from patients admitted to the Department of Gynecology, Nara Medical University Hospital, Kashihara, Japan, from February 2013 to July 2019. Fifty patients aged 21-54 years who were histologically diagnosed with OMA were enrolled. CF R2 values were measured preoperatively using MR relaxometry. The severity of dysmenorrhea was classified into four groups based on the Numeric Rating Scale (NRS-11): painless, mild, moderate, and severe. The association between clinicopathological features and CF iron levels and R2 values was analyzed.
Results: The mean (± SD) age of women was 36.58 ± 7.16 years. The mean CF R2 value was 23.83 ± 10.16 s-1. There were no significant differences among the four groups in variables regarding age at diagnosis, parity, preoperative serum CA125 and CA19-9 levels, tumor diameter, and tumor localization (unilateral or bilateral). CF iron levels were significantly correlated with the severity of dysmenorrhea (P=0.001). A significant positive correlation between preoperative CF R2 value and iron level was detected (r = 0.608, P=0.001). However, there was no significant correlation between R2 values and the severity of dysmenorrhea.
Conclusion: R2 values showed a significant positive correlation with iron levels, but were not associated with the severity of dysmenorrhea.
Endometriosis, Dysmenorrhea, Magnetic Resonance Relaxometry, R2 Value
Endometriosis is one of the most common gynecologic diseases that affects around 5% of reproductive age women . The disease is characterized by estrogen-dependent growth characterized by the presence of endometrial tissue outside the uterus . Endometriosis causes dysmenorrhea, infertility, and an elevated risk of epithelial ovarian cancer (endometriosis-associated ovarian cancer, EAOC) and is significantly associated with worse quality of life . We have previously reported that iron in endometriotic cysts is closely associated with endometriosis-related symptoms [3-5]. First, there was a positive correlation between the presence and severity of dysmenorrhea and cyst fluid (CF) iron levels (P <0.001) . Second, CF iron levels were significantly higher in infertile women compared to non-infertile women (P=0.019), and was an independent predictor of OMA patients complaining of infertility . Finally, patients with EAOC had significantly lower iron levels than benign endometriotic cyst sample (P<0.001), indicating that iron can be the preferred biomarker in clinical practice for the diagnosis of EAOC in OMA patients . The practical clinical and biological significance of iron is still unknown, but several hypotheses have been proposed [2,6]. Iron in endometriotic cysts causes oxidative stress damage and can induce redox stress. OMA is characterized by intracystic bleeding, in which hemoglobin is released from red blood cells. Hemoglobin in the cyst is converted to methemoglobin during autoxidation and releases superoxide anions . On the other hand, free iron released from hemoglobin produces hydroxyl radical through the Fenton reaction . It has been demonstrated that reactive oxygen species (ROS) such as superoxide and hydroxyl radical play a pivotal role in inflammatory pain and neuropathic pain mechanisms [7,8]. Endometriotic lesions with adhesions and deep infiltration in the pelvic organs cause diseaserelated pain. Some papers reported that OMA itself is associated with pain symptoms , while other papers reported that none of the specific features of OMA, including lesion size, are associated with the severity of dysmenorrhea . In addition to pathological abnormalities such as adhesions, humoral factors such as ROS can also cause dysmenorrhea. Oxidative stress also causes damage to sperm and oocytes and is associated with unexplained infertility [11,12]. Furthermore, there is some evidence that oxidative stress is associated with malignant transformation of endometriosis .
Since the iron measurements are limited by the need for invasive surgery, a non-invasive quantification method is desired. The iron distribution in the brain, liver and heart using MRI is provided by measuring the effective transverse relaxation rate [14,15]. In 2017, Yoshimoto et al. succeeded in non-invasive measurement of iron level in CF of OMA and ovarian cancer using MR relaxometry R2 value . The MR relaxometry-based parameter R2 value showed a significant positive correlation with the iron levels . Currently, MR relaxometry is the imaging modality that enables quantitative diagnosis of iron levels in ovarian tumors [16-18]. If iron levels correlate with the presence and severity of subjectively determined dysmenorrhea and iron levels correlate with R2 values, then R2 values may be associated with the severity of dysmenorrhea. Here, we investigate whether preoperative R2 values are associated with the presence and severity of dysmenorrhea subjectively determined by OMA patients. We are not asking an expensive radiologic study to discover a parameter that would validate or discredit a patient’s subjective report of dysmenorrhea. This study is a proof-of-concept for a non-invasive model for MR relaxometry via iron level quantification.