Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, San Raffaele Scientific Institute.
Hum Reprod. 2014 Mar;29(3):577-83. doi: 10.1093/humrep/det466. Epub 2014 Jan 15.
Does the iron content of an endometrioma represent a potential source of toxicity for the adjacent follicles?
The presence of an endometrioma increases iron and H/L ferritin levels, and transferrin receptor (TfR1) mRNA in individual follicles proximal to the endometrioma and is accompanied by reduced oocyte retrieval.
Levels of free iron in endometriotic ovarian cysts are much higher than those in normal serum or in non-endometriotic ovarian cysts. The presence of an endometrioma exerts a detrimental effect on the surrounding healthy ovarian tissue as reflected by a reduced number of developing follicles and oocytes retrieved in IVF cycles.
STUDY DESIGN, SIZE, DURATION: This is a research study with prospective collection and evaluation of individual follicles (follicular fluid and luteinized granulosa cells) from the affected and the healthy ovaries of 13 women with unilateral endometrioma.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Individual follicular samples (145) were obtained from 13 women with endometriosis-related infertility undergoing IVF-ICSI procedures from May 2012 to March 2013. All women had unilateral endometrioma not previously treated with surgery; the contralateral ovary was free of endometriomas and previous surgery. The average ± SEM age was 35.36 ± 2.5 years with anti-Mullerian hormone levels of 2.03 ± 0.55 ng/ml. Follicles were classified as: (i) proximal follicles, in physical contact with the endometrioma; (ii) distal follicles, present in the affected ovary but not in close contact with the endometrioma and (iii) contralateral follicles, in the contralateral healthy ovary. Iron content was measured by the FerroZine method. H/L ferritin subunits were evaluated by specific enzyme-linked immunosorbant assays. Expression of H ferritin and TfR1 was examined by semi-quantitative RT-PCR. Oocyte retrieval rates and Day 3 embryo quality were analyzed.
Total iron levels were higher in endometrioma-proximal follicles compared with endometrioma-distal ones (P = 0.009) and to follicles in the healthy ovary (P = 0.02). L ferritin was higher in proximal versus distal follicles (P = 0.044) or follicles from the healthy ovary (P = 0.027). H ferritin was higher in the proximal and distal follicles compared with follicles in the healthy ovary (P = 0.042 and P = 0.0067, respectively). H ferritin transcript levels in granulosa cells were higher in proximal follicles versus follicles from healthy ovary (P = 0.02). TfR1 transcript levels were higher in proximal versus distal follicles (P = 0.03) and versus follicles from the healthy ovary (P = 0.04). The oocyte retrieval rate was lower in proximal and distal follicles than in follicles from the healthy ovary (P = 0.001 and P = 0.04, respectively).
LIMITATIONS, REASONS FOR CAUTION: This is a study on a relatively small sample size and confirmation in a larger group of patients may be required. The method used to purify luteinized granulosa cells offers the best combination of purity, viability and total number of cells recovered. However, a minor contamination by CD45(+) cells (<5%) cannot be excluded.
This study represents a further in-depth analysis of the toxic influence of the endometrioma content on the surrounding follicles. We demonstrate the presence of iron-related compounds that are potentially toxic to developing ovarian follicles adjacent to the endometrioma during IVF. Our findings provide novel information that suggests that when surgical removal of the endometrioma is not the option, follicle aspiration at sites distant from the endometrioma might increase the probability of retrieving oocytes.
STUDY FUNDING/COMPETING INTEREST(S): This project was supported by Fondazione Giorgio Pardi, Milan, Italy. The authors have no competing financial interests in relation to the content of this research paper.
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子宫内膜异位症囊肿中的铁含量是否代表了对相邻卵泡的潜在毒性来源？
子宫内膜异位症囊肿的存在会增加铁和 H/L 铁蛋白水平，并增加靠近子宫内膜异位症囊肿的单个卵泡中的转铁蛋白受体 (TfR1) mRNA，同时伴随着卵母细胞回收减少。
卵巢子宫内膜异位症囊肿中的游离铁含量远高于正常血清或非子宫内膜异位症囊肿中的游离铁含量。子宫内膜异位症囊肿的存在对周围健康卵巢组织产生有害影响，表现在体外受精 (IVF) 周期中发育卵泡和卵母细胞的数量减少。
研究设计、规模、持续时间：这是一项前瞻性收集和评估 13 名单侧子宫内膜异位症相关不孕妇女受影响和健康卵巢中单个卵泡（卵泡液和黄体化颗粒细胞）的研究。
参与者/材料、设置、方法：2012 年 5 月至 2013 年 3 月，从 13 名接受 IVF-ICSI 程序的子宫内膜异位症相关不孕妇女中获得了 145 个单个卵泡样本。所有妇女均患有单侧子宫内膜异位症囊肿，未接受过手术治疗；对侧卵巢无子宫内膜异位症囊肿和既往手术史。平均年龄 ± SEM 为 35.36 ± 2.5 岁，抗苗勒管激素水平为 2.03 ± 0.55ng/ml。卵泡分为：（i）靠近子宫内膜异位症囊肿的近端卵泡；（ii）位于受影响卵巢但与子宫内膜异位症囊肿无密切接触的远端卵泡；（iii）位于对侧健康卵巢的对侧卵泡。通过 FerroZine 法测量铁含量。通过特异性酶联免疫吸附试验评估 H/L 铁蛋白亚基。通过半定量 RT-PCR 检查 H 铁蛋白和 TfR1 的表达。分析卵母细胞回收率和第 3 天胚胎质量。
与子宫内膜异位症囊肿的远端卵泡（P = 0.02）和健康卵巢的卵泡（P = 0.02）相比，子宫内膜异位症囊肿的近端卵泡中的总铁含量更高。与远端卵泡（P = 0.044）或健康卵巢的卵泡（P = 0.027）相比，L 铁蛋白在近端卵泡中更高。与健康卵巢的卵泡相比，近端和远端卵泡中的 H 铁蛋白水平更高（P = 0.042 和 P = 0.0067）。与健康卵巢的卵泡相比，颗粒细胞中 H 铁蛋白的转录水平在近端卵泡中更高（P = 0.02）。与远端卵泡（P = 0.03）和健康卵巢的卵泡（P = 0.04）相比，TfR1 转录水平在近端卵泡中更高。与健康卵巢的卵泡相比，近端和远端卵泡的卵母细胞回收率更低（P = 0.001 和 P = 0.04）。
局限性、谨慎原因：这是一项针对相对较小样本量的研究，可能需要在更大的患者群体中进行确认。用于纯化黄体化颗粒细胞的方法提供了最佳的纯度、活力和恢复的总细胞数的组合。然而，不能排除 CD45（+）细胞（<5%）的少量污染。
本研究是对子宫内膜异位症囊肿内容物对周围卵泡的毒性影响的进一步深入分析。我们证明了在 IVF 过程中，靠近子宫内膜异位症的相邻卵泡中存在潜在毒性的铁相关化合物。我们的发现提供了新的信息，表明当手术切除子宫内膜异位症囊肿不是选择时，在远离子宫内膜异位症囊肿的部位进行卵泡抽吸可能会增加回收卵母细胞的可能性。
研究资金/利益冲突：该项目由米兰的 Giorgio Pardi 基金会资助。作者在与本研究内容相关的财务利益方面没有竞争。
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