Vercellini Paolo, Caprara Francesca, Piccini Martina, Donati Agnese, Viganò Paola, Somigliana Edgardo, Cipriani Sonia
Department of Clinical Sciences and Community Health, Academic Center for Research on Adenomyosis and Endometriosis, Università degli Studi, Milano, Italy.
Department of Maternal and Child Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
Hum Reprod. 2025 Jun 1;40(6):1094-1109. doi: 10.1093/humrep/deaf057.
In patients with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS; population), is the presence of functional endometrium (FE) in uterine remnants (URs) (exposure), compared with the absence of FE in UR/absence of UR (comparison), associated with a higher prevalence of endometriosis (outcome)?
The aggregate prevalence of endometriosis was considerably higher in MRKHS patients with FE (MRKHSFE+) than in those without FE (MRKHSFE-).
The pathogenesis of endometriosis is not fully understood. The finding of pelvic endometriosis in patients with MRKHS is one of the main objections to the retrograde menstruation (RM) hypothesis. The recent advent of high-resolution ultrasonography and magnetic resonance imaging (MRI) allowed the reliable preoperative identification of FE concealed within UR, and histopathological examination after UR removal is no longer the only means of verifying the presence of a mucosal component. A similar prevalence of endometriosis in MRKHSFE+ and MRKHSFE- patients, as assessed by preoperative ultrasound (US) and/or MRI, would essentially rule out the RM/implantation theory, whereas a substantially higher prevalence of endometriosis in MRKHSFE+ than in MRKHSFE- patients would challenge the embryonic remnants/coelomic metaplasia hypothesis.
STUDY DESIGN, SIZE, DURATION: This systematic review was restricted to full-length, English-language articles published in peer-reviewed journals between 1 January 1980 and 1 June 2024. The electronic PubMed and Embase databases were searched in June 2024. The keyword 'endometriosis' was used in combination with 'Mayer-Rokitansky-Küster-Hauser syndrome', 'Müllerian agenesis', 'uterine agenesis', 'vaginal agenesis', 'Müllerian anomalies', and 'female genital malformations'. References from relevant publications were screened, and PubMed's 'similar articles' and 'cited by' functions were used.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Studies were selected if they reported the presence or absence of FE within UR investigated by preoperative US or MRI or histology after surgical removal, and the presence or absence of surgically confirmed endometriosis. Case series and case reports were deemed eligible for inclusion. Studies not specifically stating the intent to search for the presence of endometrium within UR, or not reporting the results of ultrasonography or MRI, or histological examinations were excluded. Two reviewers independently abstracted data. The risk of bias was assessed using a tool specifically devised to ascertain the methodological quality of case series and case reports.
A total of 102 studies (29 case series and 73 case reports), comprising 666 MRKHS patients in whom the presence or absence of FE was verified were included. Endometriosis was detected in 71 participants (10.7%; 95% CI, 8.5-13.2%), and its prevalence was 8.6% (51/593; 95% CI, 6.6-11.2%) in case series and 27.4% (20/73; 95% CI, 18.4-38.6%) in case reports (P<0.0001). When considering only the 19 case series with ≥10 participants, the proportion of MRKHS patients with endometriosis was 3.4% (41/1219; 95% CI, 2.5-4.5%). Among the 71 MRKHS patients with endometriosis, 64 had coexisting FE, and only seven had no evidence of FE within UR or did not have UR. The proportion of patients with endometriosis was 32.0% in the subgroup with FE (64/200; 95% CI, 25.9-38.8%) and 1.5% (7/466; 95% CI, 0.7-3.1%) in the subgroup without FE within UR/without UR. At meta-analysis considering case series, the overall prevalence estimates of endometriosis in patients with and without FE were, respectively, 16.8% (95% CI, 1.8-38.5%) and 0% (95% CI, 0-0%). In order to evaluate the association between FE and endometriosis we also conducted a meta-analysis that included case series reporting both FE+ and FE- patients. A significantly increased risk of endometriosis was observed in MRKHSFE+ patients compared with MRKHSFE- patients (overall odds ratio estimate was 12.0; 95% CI, 5.1-28.3%). The quality of the evidence score was higher in the case series subgroup (median score, 4 points; interquartile range, 3-5 points) than in the case reports subgroup (median score, 3 points; interquartile range, 2-4 points).
LIMITATIONS, REASON FOR CAUTION: Due to the uncontrolled and non-experimental study design, case series and case reports are associated with an increased risk of selection, performance, detection, attrition, and reporting bias. In the seven cases of endometriosis in patients purportedly without detected FE, a preoperative MRI was not systematically performed or erroneous findings were reported, the anatomical description at surgery was incomplete or inconsistent, the histopathological diagnosis of endometriosis was missing or questionable, and precise microscopic features were not always described. Whether FE (exposure) was truly absent in all these cases and/or whether all lesions diagnosed as endometriosis (outcome) were indeed true disease, seems uncertain.
Our findings should raise awareness of the importance of accurately assessing and reporting the presence or absence of FE within UR, and of systematically performing biopsies of visually diagnosed endometriosis in MRKHS patients. Considering the high risk of bias, the detection of endometriosis in MRKHS patients allegedly without FE in the few relevant case reports published in the last four decades should no longer be interpreted tout court as proof for the coelomic metaplasia/embryonic remnants theory.
STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this review. P.Ve. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and 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. E.S. is Editor-in-Chief of Human Reproduction Open; discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures; and maintains both a public and private gynaecological practice. P.Vi. is Co-Editor-in-Chief of Journal of Endometriosis and Uterine Disorders. All other authors declare they have no conflict of interest.
The study protocol was registered on PROSPERO (registration number, CRD42024512351).
在迈耶-罗基坦斯基-库斯特-豪泽综合征（MRKHS；总体人群）患者中，子宫残迹（UR）中存在功能性子宫内膜（FE）（暴露因素），与UR中无FE/无UR（对照因素）相比，是否与子宫内膜异位症的更高患病率（结果）相关？
MRKHS患者中存在FE（MRKHSFE+）的子宫内膜异位症总体患病率显著高于无FE的患者（MRKHSFE-）。
子宫内膜异位症的发病机制尚未完全明确。在MRKHS患者中发现盆腔子宫内膜异位症是逆行月经（RM）假说的主要反对依据之一。近期高分辨率超声和磁共振成像（MRI）的出现使得术前能够可靠地识别隐藏在UR中的FE，UR切除后的组织病理学检查不再是验证黏膜成分存在的唯一方法。术前超声（US）和/或MRI评估显示，MRKHSFE+和MRKHSFE-患者中子宫内膜异位症患病率相似，这将基本排除RM/植入理论，而MRKHSFE+患者中子宫内膜异位症患病率显著高于MRKHSFE-患者则会对胚胎残迹/体腔化生假说提出挑战。
研究设计、规模、持续时间：本系统评价纳入1980年1月1日至2024年6月1日期间发表在同行评审期刊上的全文英文文章。2024年6月检索了电子PubMed和Embase数据库。关键词“子宫内膜异位症”与“迈耶-罗基坦斯基-库斯特-豪泽综合征”、“苗勒管发育不全”、“子宫发育不全”、“阴道发育不全”、“苗勒管异常”和“女性生殖器畸形”联合使用。筛选相关出版物的参考文献，并使用PubMed的“相似文章”和“被引用文献”功能。
参与者/材料、环境、方法：纳入报告了术前US、MRI或手术切除后组织学检查所研究的UR中FE存在与否以及手术确诊的子宫内膜异位症存在与否的研究。病例系列和病例报告被认为符合纳入标准。未明确说明搜索UR中子宫内膜存在情况的意图、未报告超声或MRI结果或组织学检查结果的研究被排除。两名审阅者独立提取数据。使用专门设计的工具评估偏倚风险，以确定病例系列和病例报告的方法学质量。
共纳入102项研究（29项病例系列和73项病例报告），包括666例经核实FE存在与否的MRKHS患者。71名参与者（10.7%；95%CI，8.5 - 13.2%）检测到子宫内膜异位症，病例系列中的患病率为8.6%（51/593；95%CI，6.6 - 11.2%），病例报告中的患病率为27.4%（20/73；95%CI，18.4 - 38.6%）（P<0.0001）。仅考虑参与者≥10例的19项病例系列时，MRKHS患者中子宫内膜异位症的比例为3.4%（41/1219；95%CI，2.5 - 4.5%）。在71例患有子宫内膜异位症的MRKHS患者中，64例同时存在FE，只有7例在UR中没有FE证据或没有UR。FE亚组中子宫内膜异位症患者的比例为32.0%（64/200；95%CI，25.9 - 38.8%）；UR中无FE/无UR亚组中为1.5%（7/466；95%CI，0.7 - 3.1%）。在考虑病例系列的荟萃分析中，有FE和无FE患者的子宫内膜异位症总体患病率估计分别为16.8%（95%CI，1.8 - 38.5%）和0%（95%CI，0 - 0%）。为了评估FE与子宫内膜异位症之间的关联，我们还进行了一项荟萃分析，纳入了同时报告FE+和FE-患者的病例系列。与MRKHSFE-患者相比，MRKHSFE+患者中观察到子宫内膜异位症风险显著增加（总体优势比估计为12.0；95%CI，5.1 - 28.3%）。病例系列亚组的证据质量评分中位数较高（4分；四分位间距，3 - 5分），高于病例报告亚组（中位数评分，3分；四分位间距，2 - 4分）。
局限性、谨慎原因：由于研究设计为非对照和非实验性，病例系列和病例报告存在选择、实施、检测、失访和报告偏倚增加的风险。在据称未检测到FE的患者中的7例子宫内膜异位症病例中，术前MRI未系统进行或报告有错误结果，手术时的解剖描述不完整或不一致，子宫内膜异位症的组织病理学诊断缺失或存疑，且并非总是描述精确的微观特征。在所有这些病例中FE（暴露因素）是否真的不存在和/或所有诊断为子宫内膜异位症的病变（结果）是否确实为真正疾病，似乎并不确定。
我们的研究结果应提高对准确评估和报告UR中FE存在与否的重要性的认识，以及对MRKHS患者中视觉诊断的子宫内膜异位症进行系统活检的重要性的认识。考虑到高偏倚风险，在过去四十年发表的少数相关病例报告中，在据称无FE 的MRKHS患者中检测到子宫内膜异位症，不应再被一概而论地解释为体腔化生/胚胎残迹理论的证据。
研究资金/利益冲突：本综述未获得资金支持。P.Ve.是《人类生殖开放杂志》、《加拿大妇产科杂志》编辑委员会成员以及《斯堪的纳维亚产科学与妇科学杂志》国际编辑委员会成员；从Wolters Kluwer获得了关于临床决策支持资源UpToDate中子宫内膜异位症管理章节的版税；并同时拥有公共和私人妇科诊所。E.S.是《人类生殖开放杂志》主编；披露从Ferring获得研究资助以及从Merck - Serono获得讲座酬金；并同时拥有公共和私人妇科诊所。P.Vi.是《子宫内膜异位症与子宫疾病杂志》联合主编。所有其他作者声明无利益冲突。
该研究方案已在PROSPERO注册（注册号，CRD42024512351）。
