{"paper_id":"1e108969-6e6b-481c-9f66-c36c7466ed89","body_text":"Vol.:(0123456789)1 3\nhttps://doi.or\ng/10.1007/s13669-021-00320-5\nUTERINE FIBROIDS AND ENDOMETRIAL LESIONS (T. TULANDI, SECTION EDITOR)\nClassifications of Adenomyosis and Correlation of Phenotypes \nin Imaging and Histopathology to Clinical Outcomes: a Review\nTina Tellum1  · Malcolm G. Munro2 \nAccepted: 10 December 2021 \n© The Author(s) 2022\nAbstract\nPurpose of Review  To pro\nvide an update on published classification and reporting systems for adenomyosis. There is an \nurgent need to standardize reporting of various phenotypes of adenomyosis into a validated and globally recognized sys-\ntem. This can be used to examine the nature and severity of adenomyosis symptoms and inform the design, evaluation, and \nimplementation of appropriate treatment options.\nRecent Findings\n In recent \nyears, several new proposals for adenomyosis classification have emerged. Most are MRI-based \nand include features such as uterine size, junctional zone thickness, size and location of the lesions, and distribution patterns. \nTo date, none of those proposals has been validated. Only one recent classification based on transvaginal ultrasound was \nvalidated for interobserver congruence and correlated to clinical findings. However, the differentiation of diffuse and focal \nadenomyosis still lacks consensus. In addition, only a few authors advocated imaging-based definitions.\nSummary\n There is a need for one or a combination of a classification and r\neporting system for adenomyosis. To date, there \nis no widely accepted and validated system.\nKeywords Adenomy\nosis · Classifications · Imaging · Histopathology · Pathophysiology\nIntroduction\nIn medicine, several disorders and conditions are poorly \nor incompletely understood. They might have a variety of \nimaging, molecular or other clinical features. Such circum-\nstances beg for creating systems of categorization, or “clas-\nsification,” that support clinical care, patient and trainee \neducation, and the performance of basic, translational, clini-\ncal, and epidemiological research. At a scientific level, a \nclassification system can serve to identify categories of a \ndisorder that allows for the comparison of outcomes between \ndifferent investigators by facilitating systematic review and \nmeta-analysis. From a clinical perspective, classification or \ncategorization can aid diagnosis, prognosis, or inform the \nselection of management options ranging from expectant to a \nspectrum of medical and procedural options. Classifications \ncan be based on phenotypical traits including imaging, his-\ntopathology, genetic markers, or molecular characteristics.\nDespite the first published description of adenomyosis in \n1860 [1], understanding of pathogenesis, prevalence, clini-\ncal relevance, ideal diagnostic techniques, and appropriate \nand effective management of adenomyosis remain unclear. \nHistorically, adenomyosis is diagnosed by histopathology \nof hysterectomy specimen. Diagnosing adenomyosis by \nmyometrial biopsy is impractical and suboptimal. Today, \nimaging techniques are relatively accurate for the detection \nof adenomyosis. Yet, there is a lack of standardization [2–4]. \nWhile there are several proposed systems, none has been \nuniversally adopted—a circumstance that is problematic for \nboth clinicians and investigators and the patients [2, 5].\nSonographic features of adenomyosis have been reported \nin about 21–34% of women attending gynecology clinics \n[6\n••, 7]. The clinical relevance of the disorder has been \nlimited to the two best-known symptoms, which are heavy \nmenstrual bleeding (HMB) and dysmenorrhea [8 ]. Recent \nThis article is part of the Topical Collection on Uterine Fibroids \nand Endometrial Lesions\n * Tina Tellum \n tina.tellum@gmail.com\n1 Department of Gynecology, Oslo University Hospital Trust, \nOslo, N\norway\n2 Department of Obstetrics & Gynecology, David Geffen \nSchool of Medicine, UCL\nA/Kaiser Permanente Los Angeles \nMedical Center, Los Angeles, CA, USA\n/ Published online: 7 February 2022\nCurrent Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nstudies suggest that adenomyosis may be associated with \nadverse effects on fertility and might contribute to obstetrical \ncomplications, such as preterm labor, fetal growth restric-\ntion, and preeclampsia [9–11].\nThe purpose of our review was to identify and compare \nstudies evaluating adenomyosis features and their clinical \nrelevance, as well as describe classification systems for \nadenomyosis, based on one or a combination of clinical, \nphenotypical, histological, molecular, or genetic features. \nFurthermore, we evaluated studies that assess adenomyosis \nfeatures and those that correlate a classification or individual \ncharacteristics to clinical outcomes.\nDiagnostic Classifications\nWe identified 10 manuscripts describing a histological diag-\nnostic classification system. Six are based on the diagnosis \non the depth of myometrial involvement [12–17], two on the \nproportion of myometrium involvement [18, 19], and two \nothers use other features [20, 21]. For ultrasound a system \nof terminology for categorizing and describing sonographic \nfeatures associated with adenomyosis was presented by \nexperts in the so-called Morphological Uterus Sonographic \nAssessment (MUSA) statement [22\n••]. This system is cur -\nrently the most recognized and widely used ultrasound clas-\nsification of adenomyosis. For magnetic resonance imaging \n(MRI), several diagnostic accuracy studies were published; \nhowever, the consensus is still lacking [23].\nDisease Classifications\nHistopathology\nIdentified histology-based classifications are shown in \nTable  1 [ 13–17, 19, 21, 24–26]. They focus primarily on dis-\nease location or extent. While phenotypical features such as \nmuscular hypertrophy or hyperplasia were described, these \nwere not used as markers in these classifications.\nMRI‑Based Systems\nTable  2 shows the MRI-based systems using a spectrum of \ncriteria [2, 5, 27•, 28–30]. An early proposal from Kishi et al. \ndistinguished four subtypes of adenomyosis based on the \nmyometrial region involved: subtype I—intrinsic (inner myo-\nmetrium), subtype II—extrinsic (outer myometrium), subtype \nIII—intramural (surrounded by normal outer myometrium), \nand subtype IV—indeterminate (not fit into any of the other \ntypes) [27\n•]. The authors concluded that the pathogenesis \nof these different phenotypes might vary from the concept \nof myometrial invasion of heterotopic endometrium. Yet, it \ndoes not explain the mechanism of subtypes II and III. This \nclassification has since been adapted and modified by many \nauthors. A similar layered concept has been included in the \nBazot system [30], which further distinguishes anterior from \nposterior involvement as well as disease volume and patterns \n(Table  2).\nWhile all other systems are purely based upon MRI char-\nacteristics, Grimbizis et al. added endometrial finding of \na polypoid adenomyoma confirmed by histopathology [5].\nSeveral authors postulated that adenomyosis in the out-\nermost aspect of the myometrium (“extrinsic” type) may \noriginate from endometriosis involving the myometrium \nby “invasion” through the serosa [29,  31–34]. However the \nextrinsic type is frequently found in women without endo-\nmetriosis [29]. Since it is difficult to reliably determine the \norigin of the findings at least by imaging we conclude that \n“extrinsic” adenomyosis should not be classified as a sub-\ntype of endometriosis.\nUltrasound‑Based Systems\nWe identified two studies describing classifications based \non transvaginal ultrasound (Table  2) [34–36]. In a consen -\nsus work, the MUSA statement [22\n••] was later modified to \nallow the description of findings stratified by anterior and \nposterior location and by involvement with one or more of \nthree arbitrarily defined myometrial layers [35].\nLazeri et al. proposed a system combining the pattern \n(diffuse adenomyosis, focal adenomyosis, or adenomyoma) \nwith location based on a more “anatomic” two-layer myo-\nmetrium (inner or outer myometrium) and a grade of disease \n(severity score 1–4) (Table 2) [36]. The inter-rater reproduc-\nibility of this system has been internally validated and found \nto be suitable for clinical use. In a second publication, this \nsystem was correlated with clinical symptoms [34].\nOthers\nGordts et al. proposed an imaging-based classification that \ncould be used with either MRI or ultrasound [37]. The \nauthors proposed identifying the affected myometrial layer \n(inner or outer myometrium), the location (anterior, poste-\nrior, or fundus), the pattern (diffuse or focal, if focal speci-\nfied as muscular or cystic), and disease volume.\nAdenomyosis Imaging Features \nand Correlation to Clinical Outcomes\nStudy characteristics and detailed results of the included \nstudies are shown in Table  3.\n2 Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nDisease Distribution: Diffuse vs. Focal\nThree studies found that women with diffuse adenomyo-\nsis were older [7, 8, 34] and suffered more frequently from \nHMB [34] than those with focal disease. There was no asso-\nciation of the diffuse type with dysmenorrhea in one study \n[34], while such a relationship was found in another [8 ]. \nPinzauti et al. showed that diffuse adenomyosis was associ-\nated with a higher average symptom burden than women \nwithout adenomyosis. However, in this population, no focal \ntype adenomyosis was described [7].\nWomen with focal findings had a higher risk of infertility \nand miscarriage in one study [34]. This relationship was also \nfound in a study published by Bourdon et al. [38]. Tamura \net al. reported no elevated risk of miscarriage [39].\nDisease Location: Inner, Middle Outer Myometrium\nThe terms “inner adenomyosis,” “intrinsic adenomyosis,” \nor “JZ disease” are often interchangeably used. Kishi et al. \nfound no difference in pain scores (dysmenorrhea, dys-\npareunia, or CPP) or HMB based on the location within the \nmyometrium [27\n•]. Naftalin et al. showed that an irregular \nJZ was significantly associated with higher pain scores for \ndysmenorrhea [40].\nIwasawa et al. showed that the location of the adenomy -\notic lesion did not affect the clinical pregnancy rate in a \ncohort undergoing embryo transfer [41]. Still, the extrinsic \ngroup had fewer pregnancy losses [41]. In a retrospective \nstudy, Bourdon showed that infertility was related to focal \nfindings in the outer myometrium but not to diffuse internal \nTable 1  Histopathological adenomyosis classification systems\nAuthor, year Category Pattern\nName Depth Name Foci\nSampson [21] Group 1 Invasion from within N/A N/A\nGroup 2 Invasion from without N/A N/A\nGroup 3 Adenomyoma (intramyometrial) N/A N/A\nBird et al. [13] Grade I Sub-endometrial basalis Mild 1–3 foci/LPF\nGrade II Mid-myometrium Moderate 4–9\nGrade III Outer myometrium Severe  ≥  10\nNishida e\nt al. [24] Type 1 Continuous from endometrium N/A Islands/section\nType 2 Continuous from serosa N/A Glands/section\nMcCausland [25] Superficial  ≤  1 mm \ndepth N/A N/A\nDeep  > 1 mm \ndepth N/A N/A\nSiegler et al. [19] Grade 1 Inner 1/3 Mild 1–3 foci/LPF\nGrade 2 2/3 Moderate 4–9\nGrade 3 Entire myometrium Severe  ≥  10\nLe\nvgur et al. [14] Superficial  < 40% N/A\nFoci/LPF\nIntermediate 40–80% N/A N/A\nDeep  > 80% N/A\nN/A\nSammour et al. [15] N/A  < 25% N/A\nFoci/slide\nN/A 26–50% N/A N/A\nN/A 51–75% N/A N/A\nN/A  > 75% N/A\nN/A\nHulka et al. [16] Mild Inner 1/3 (or microscopic foci) N/A N/A\nFocal Adenomyoma N/A N/A\nSevere/diffuse Outer 2/3 (include entire myometrium) N/A N/A\nVercellini et al. [3] Mild Up to 1/3 Grade 1 1–3 islets\nModerate 1/3 to 2/3 Grade 2 4–10 islets\nSevere  > 2/3 Gr\nade 3  > 10 \nislets\nRasmussen et al. [26] Intrinsic  ≥  2 mm my\nometrial invasion without contact to the basal \nendometrium\nSerrated junctional zone  > 3 mm my\nometrial invasion with contact to the basal endo-\nmetrium (precursor of adenomyosis)\nLinear junctional zone: No or marginal myometrial invasion  ≤  3 mm with cont\nact to \nthe basal endometrium\n3Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nTable 2  Imaging-based adenomy osis classification and grading systems. MRI magnetic resonance imaging. JZ junctional zone\nAuthor, year Criteria Classification\nMRI-based systems\nGordts et al. [2] T2 -JZ ≥  8 mm;  < 12 JZ Hyper\nplasia\nAge ≤  35 y\nears\nPartial or diffuse\nJZ\n ≥  12 mm A\ndenomyosis\nT2 high-intensity foci\nInvolvement of outer myometrium\n < 1/3; < 2/3; > 2/3\nMy\nometrial mass, indistinct margins, low signal intensity Adenomyoma\nRetrocervical, retrovaginal, fallopian tube, bladder\nKishi et al. [27 •] Only contiguous with inner myometrium Subtype I (intrinsic)\nNormal JZ and myometrium between Subtype II (extrinsic)\nNormal JZ and surrounding myometrium Subtype III (intramural)\nDoesn't fit the other definitions Subtype IV (All others)\nGrimbizis et al. [5] 1. Diffuse adenomyosis Diffuse\n2. Focal adenomyosis Focal\n    a. Adenomyoma\n    b. Cystic adenomyosis (single adenomyotic cyst)\n3. Polypoid adenomyomas (endometrial masses) Polypoid\n    a. Typical\n    b. Atypical\n4. Other forms Other\n    a. Endocervical\n    b. Retroperitoneal\nDashottar et al. [28] Diffuse consistent (“even”) JZ thickening\n ≥  14 mm thr\noughout uterus Diffuse even\nDiffuse JZ variable (“uneven”) thickening ≥  14 mm thr\noughout uterus Diffuse uneven\nFocal widening of the JZ ≥  14 mm Focal\nChapr\non et al. [29] Three subtypes according to location: outer, middle, and inner myometrium Focal\nJZmax of at least 12 mm and wallthicknes/JZ ratiomax  > 40% Diffuse\nBazot e\nt al. [30] A. Focal or multifocal Internal\nB. Superficial asymmetric\nC. Superficial symmetric\nD. Diffuse asymmetric\nE. Diffuse symmetric\nF. Solid adenomyoma Adenomyoma\nG. Cystic adenomyoma\nH. Submucous adenomyoma\nI. Subserosal adenomyoma\nJ. External posterior External\nK. External anterior\nTransvaginal ultrasound–based systems\nVan den Bosch et al. [35] Presence of diagnostic signs\nLocation: anterior posterior lateral left lateral right fundal Location\ndiffuse, focal (>\n 25% surr\nounded by normal myometrium), mixed, adenomyoma Differentiation\nMeasurable, size of the largest lesion Cystic-non-cystic\nInner: Type 1 Layer\nMiddle (inner to vascular arcade): Type 2\nOuter: (vascular arcade to serosa): Type 3\nMulti-layer: (type 1–2, 2–3, or 1 to 3)\n4 Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nadenomyosis. They defined adenomyosis as a JZ 12 mm or \nmore in thickness and involving at least 40% of the total \nmyometrial thickness [38]. These findings appear to be in \ncontrast to a prospective study from Maubon et al. that \ndemonstrated that embryo transfer failure was more com-\nmon when the mean JZ thickness was more significant than \n7 mm and the maximum thickness more than 10 mm [42].\nDisease Pattern: Cystic vs. Hypertrophic\nRole of disease patterns in clinical manifestations is \nunclear. Naftalin et al. found that the presence of myome-\ntrial cysts was not explicitly associated with a higher dys-\nmenorrhea score [43]. Hemorrhagic lesions that can be dis-\ncriminated from cysts without hemorrhage in T1-weighted \nMRI were more frequently found in intrinsic or extrinsic \nadenomyosis when compared to isolated adenomyosis in \nthe middle myometrium [ 27\n•]. Yet, the number of cases \nwas relatively small and involved a selected group of \nwomen. Bourdon et al. found no association between infer -\ntility and the presence of bright spots on T2 [38].\nSeveral investigators have correlated MRI-based sig-\nnal intensity (T2 hyperintense foci or T1 lesion signal) to \nthe success of high-intensity focused ultrasound (HIFU) \ntherapy [44– 47]. These studies suggest that the relative \namounts of glands and stroma in the adenomyotic mass \ncan impact the results of hyperthermic treatment—at least \nbased on the imaging outcomes.\nVolumetric Relationships: Lesion Size and Disease \nExtent\nBird et al. studied the association between depth of adeno-\nmyosis involvement and symptoms. They found no relation-\nship with recorded bleeding symptoms, but they demon-\nstrated that the number of “islets” of adenomyotic glandular \ntissue per low powered field was proportional to the subjec-\ntively determined volume of menses [13]. Similar findings \nwere described by Sammour et al. and Rasmussen et al., who \nalso reported no relationship between depth of myometrial \ninvolvement and the symptom of HMB [15, 26]. However, \nRasmusen et al. reported that symptom improvement after \nTable 2  (continued)\nAuthor, year Criteria Classification\nMild: < 25% Extent\nModer\nate: 25–50%\nSevere: > 50%\nF\nocal: plane of largest diameter of largest lesion Size\nDiffuse: myometrial thickness\nExacoustos et al. [34] Score 1: single myometrial wall involvement with thickness ≤  20 mm Diffuse outer\nScore 2: double m\nyometrial wall involvement with thickness ≥  20 mm or\nSingle m\nyometrial wall involvement with thickness ≥  20– ≤  30 mm\nScore 3: sing\nle myometrial wall involvement with thickness ≥  30 mm or\ndouble my\nometrial wall involvement with thickness ≥  20– ≤  30 mm\nScore 4: Double m\nyometrial wall involvement with thickness ≥  30 mm or whole uterus \nin\nvolved with global enlargement\nDiffuse inner\nScore 1: JZmax ≥  6- ≤  8 mm or diffuse infiltration of t\nhe JZ ≤  20 mm in length\nScor\ne 2: JZmax ≥  8 mm or diffuse infiltration of t\nhe JZ ≤  20 mm in length or  ≤  50% of the \nuter\nus\nScore 3: diffuse infiltration of the JZ ≥  50% ≤  80% of the uter\nus\nScore 4: diffuse infiltration of the JZ ≥  80% of the uter\nus\nScore 1: One focal intramyometrial lesion < 10 mm Focal outer\nScor\ne 2: ≥  2 intram\nyometrial lesions < 10 mm or one focal intr\namyometrial lesion of \n10–20 mm\nScore 3: ≥  2 intram\nyometrial lesions 10–20 mm or one focal intramyometrial lesion \nof > 20 mm\nScor\ne 4: ≥  2 intram\nyometrial lesions > 20 mm or  ≥  3 focal intr\namyometrial lesions\nScore 1: One focal lesion in JZ or cystic areas ≤  10 mm Focal inner\nScor\ne 2: ≥  2 focal lesions of t\nhe JZ ≤  10 mm or one focal intr\namyometrial lesion of 10–20 mm\nScore 3: ≥  2 focal lesions of t\nhe JZ 10–20 mm or one focal lesion of the JZ of  > 20 mm\nScore 4: ≥  2 focal lesions of t\nhe JZ > 20 mm or  ≥  3 focal lesions of t\nhe JZ\n5Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nTable 3  Studies correlating adenomyosis features to clinical outcomes. MRI, magnetic resonance imaging; TVUS, transvaginal ultrasound; 2D, two dimensional; 3D, three dimensional; GnRHa, \ngonado\ntropin releasing hormone agonist; HMB, heavy menstrual bleeding; JZ, junctional zone; CPP, chronic pelvic pain\nFirst author, year Study design N, population  \ncharacteristics\nMode of diagnosis Classification feature Clinical outcomes Limitations\nIwasawa et al. [41] Retrospective cohort 136 embryo transfers in  \n52 infertile women with  \nadenomyosis, undergoing \nin vitro fertilization (fresh and \nfrozen)\nMRI\n + T\nVUS • Advanced (invades the full \nthickness of the uterine \nmyometrium)\n• Extrinsic (localized on the \nserosal side)\n• intrinsic (localized on the \nendometrial side)\n• Adenomyoma (not present in \nthis population)\n• Fertility outcomes\n• Pregnancy  \ncomplications\n• Obstetric outcomes\nRetrospective, endometriosis \nas confounder, phenotype \ngroups unevenly distributed, \nsome received GnRHa-\ntreatment\nBourdon et al. [49] Same as Bourdon 2020 Same as Bourdon 2020 MRI • Internal vs. external  \nadenomyosis\n• JZ thickness\n• HMB\n• Dysmenorrhea\n• Non-cyclic CPP\n• Dyspareunia\nBourdon et al. [38] Retrospective observational, \ncross-sectional cohort\n248 women with adenomyosis \nout of nonpregnant women\nbetween 18 and 42 years of age \nwho underwent surgery for \nbenign gynecological  \npathologies\nMRI • Focal: localized,  \nill-defined, low  \nsignal intensity mass,  \ninhomogeneous  \ncircumscribed area located \nin the outer shell of the \nuterus, with indistinct  \nmargins separated from \nthe JZ\n• Lesion size\n• Location (anterior/ \nposterior)\n• Infertility (none/ pri-\nmary/secondary)\nRetrospective design; Single \ntimepoint; Male factor as \nconfounder not assessed\nExacoustos et al. \n[34]\nProspective cohort 108, premenopausal  \nwomen referred for  \npelvic pain assessment\nTVUS (2D/3D) • Adenomyosis severity  \nscore\n• Diffuse vs focal vs  \nadenomyoma\n• HMB\n• Dysmenorrhea\n• Dyspareunia\n• Infertility\n• Miscarriage\n• Endometriosis\nRelatively low n, selection \nbias (pelvic pain)\nTamura et al. [39] Retrospective, multicenter, \nquestionnaire-based \ncohort\n262 pregnant women with \nadenomyosis, without fibroids/\nendometriosis\nMRI and/or TVUS • Focal/diffuse, lesion  \nsize, location (anterior/\nposterior)\n• Pregnancy and  \nobstetric complications\nRecall bias, selection bias\nLi et al. [50] Prospective case–control; \nconsecutive cohort\n578\n(298 with adenomyosis,  \n280 matched controls)\nMRI or TVUS • Uterine size • Lower urinary tract \nsymptoms\nOrazov et al. [52] Prospective translational 90 (60 adenomyosis\n +  \npain; 30 adenomy\nosis without \npain but  \nHMB)\nTVUS\n + MRI + His\ntology • VEGF expression in  \nadenomyosis and eutopic \ntissues\n• Dysmenorrhea No adjustment for confounders\n6 Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nTable 3  (continued)\nFirst author, year Study design N, population  \ncharacteristics\nMode of diagnosis Classification feature Clinical outcomes Limitations\nNaftalin et al. [40] Prospective observational \nconsecutive cohort\n718 premenopausal women, 157 \nwith adenomyosis\nTVUS (2D, 3D) • Asymmetrical myometrial \nthickening\n• Parallel shadowing\n• Linear striations\n• Myometrial cysts  \nHyperechoic islands  \nAdenomyomas\n• Irregular endometrial–  \nmyometrial junction\n• Dysmenorrhea\nPinzauti et al. [7] Prospective observational \nconsecutive cohort\n156 women, 18 and 30 years, \nregular menstrual cycle, nul-\nligravid, no endometriosis or \nfibroids\nTVUS (2D, 3D) • MUSA criteria\n• Diffuse vs focal  \nadenomyosis (focal not \npresent in population)\n• Dysmenorrhea\n• HMB\n• Dyspareunia\n• CPP\nOnly diffuse adenomyosis \nfound in this cohort\nWang et al. [51] Prospective translational 80; (40 adenomyosis\n + dy\nsmen-\norrhea; 20 no adeno dysmen-\norrhea, 20 controls)\nTVUS\n + his\ntology/hyster-\nectomy\n• CD65 expression in  \nadenomyosis tissue\n• Dysmenorrhea Hysterectomy specimen\nLi et al. [8] Retrospective cohort; con-\nsecutive\n734 with adenomyosis (97% \npremenopausal)\nHistology/Hysterectomy \nspecimen\n• Uterine size (TVUS based)\n• Diffuse/focal (histology \ndiagnosis)\n• HMB\n• Dysmenorrhea\n• Metrorrhagia\n• Time from symptom \nonset to diagnosis\n• CPP\nRetrospective, hysterectomy\nNaftalin et al. [48] Prospective observational \nconsecutive cohort\n714 premenopausal women, 100 \nwith adenomyosis\nTVUS (2D, 3D) • Number of TVUS features \nfor adenomyosis found\n• Menstrual blood loss Different blood loss  \nassessment measures in \nsame cohort\nKishi et al. [27 •] Retrospective cohort 152, surgical treatment for \nadenomyosis (hysterectomy or \nadenomyomectomy)\nMRI • Location:\n• Type I: intrinsic\n• Type II: extrinsic\n• Type III: middle only\n• Type IV: does not fit other \ncategory\n• T2/T1 high intensity spots\n• Dysmenorrhea\n• HMB\n• CPP\nRetrospective, surgical \ncohort with expected high \nsymptom scores\nLevgur et al. [14] Retrospective cohort 111\n(17 with adenomyosis alone, 19 \nwith adenomyosis with leio-\nmyomas, 39 with leiomyomas \nalone, and 36 with neither)\nHistology/Hysterectomy \nspecimen\n• Invasion:\n• Deep (above 80%),  \nintermediate (40–80%),  \nand superficial (under  \n40%),\n• Number of adenomyotic \nfoci\n• Dysmenorrhea\n• HMB\nUterus weight under\n ≤  280 g,\nclinical dat\na were collected \nretrospectively from \npatient records, possibly \nunderpowered\n7Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\ntranscervical endometrium resection was greater with mini-\nmal depth of involvement of the myometrium [26].\nThe outlier in this group of studies is the report by Levgur \net al., where the symptom of HMB was 36.8% in women with \ndeep foci and 13.3% in those with “intermediate” depth foci \n[14]. Sammour et al., who evaluated dyspareunia and “other \npain” found a poor correlation with depth, but again, there was \na correlation with the number of foci identified histopathologi-\ncally. A few authors reported a correlation between depth of \nadenomyosis involvement as well as the number or volume of \nfoci of glandular tissue and dysmenorrhea [13, 14,  24].\nNaftalin et al. and Pinzauti et al. reported a linear rela-\ntionship between ultrasound diagnosis of adenomyosis and \ndysmenorrhea and HMB symptom severity [7, 40, 48].\nVolumetric Relationships\nLesion Volume\nEstimated adenomyosis volume and clinical manifestations have \nbeen examined by Exacoustos et al. who showed that symp-\ntom severity was associated with disease severity mainly based \non lesion size and %-involvement of the myometrium [34]. \nHowever, it seems that the size of an adenomyoma, defined as \na subgroup of focal adenomyosis surrounded by hypertrophic \nmyometrium, is not associated with more pain, as demonstrated \nin two studies [34, 48]. There have been early evaluations of \nthe volume of adenomyosis findings and pregnancy outcomes. \nTamura et al. found the rates of miscarriage and cervical insuf-\nficiency were higher in the group with large lesions [39].\nUterine Volume\nAnother feature associated with adenomyosis, and indirectly, \nwith disease volume, is uterine volume. Li et al. showed that \nlarge uterine size was independently associated with both-\nersome lower urinary tract symptoms (LUTS) and HMB, \nbut not dysmenorrhea or chronic pelvic pain (CPP) [50]. \nAnother group showed that smaller uteri were associated \nwith more CPP (8). Disease duration and age were also \npositively associated with the uterine size, supporting the \nprogressive nature of adenomyosis.\nMolecular Markers\nAn evolving approach to evaluating the potential impact \nof adenomyosis is using molecular markers, not only for \ndiagnosis but also as instruments to monitor response to \ntherapeutic interventions. Wang showed that CD65 expres-\nsion was higher in women with dysmenorrhea than those \nwithout dysmenorrhea and controls [51]. The same associa-\ntion was also found for VEGF expression and dysmenorrhea \n[52]. VEGF was found in hypertrophic muscular bundles \n[52]. Bourdon et al. correlated MRI findings with serum \ncytokine profiles. They found that in women with both focal \nand diffuse adenomyosis, the levels of IL-23, IL-25, IL-31, \nand IL-33 were lower than in controls. The levels of IL-17F \nlevels were lower in women with focal adenomyosis than \nin controls. TNFα levels were lower in women with focal \ndisease compared to those with diffuse adenomyosis [53].\nDiscussion\nAdenomyosis is a disorder of increasing interest, in part because \nof its newfound high prevalence on ultrasonic and magnetic \nresonance imaging and in part because of its variable impact on \nclinical outcomes such as infertility, pelvic pain, abnormal uterine \nbleeding, and pregnancy-related disorders. It is still unclear how \nimaging features of adenomyosis correlate to symptoms or other \nadverse outcomes such as infertility or pregnancy loss. There \nexists an urgent need, at least for a standardized reporting system \nto harmonize the design and interpretation of basic science and \nclinical investigation as well as education and clinical care.\nIn this review, we found various reporting or classifica-\ntion systems based on histopathological, MRI, or TVUS \nfeatures. While most systems are designed to include the \nlocation, the extent, and the distribution pattern of adeno-\nmyosis features (focal or diffuse), few describe more specific \nphenotypical patterns such as the presence, size, or types \nof cysts, or the location and extent of findings suggesting \nthe presence of muscular hyperplasia. We identified studies \nthat correlated clinical findings with phenotypical traits of \nadenomyosis, suggesting that a variety of features could be \nrelevant in the design of a reporting or classification system.\nThere have been conflicting results regarding the clini-\ncal significance of the disease pattern (diffuse, focal, and \nadenomyoma). The differences in patient populations, the \nlow number of participants in some studies, and the differ -\nent definitions of those groups are likely the reason for these \nincongruencies. Also, as those traits are assessed by subjec-\ntive pattern recognition, a high inter-rater variation is likely \nan important reason for these conflicting results.\nThe clinical significance of myometrial cysts (with and with-\nout hemorrhage) and muscular hyperplasia remains unclear. In a \nstudy investigating treatment response of high-intensity focused \nultrasound (HIFU) in different phenotypes, the absence of T2 \nhyperintense spots in MRI was associated with an increased \nchance of nonperfusion and thus treatment response [45].\nAs a result of these considerations, it would seem prudent \nto include disease patterns in a reporting system. Such an \napproach would allow investigators to evaluate further the \nrelationship of such findings to clinical manifestations of \nadenomyosis and characterize responses to various types of \nmedical, ablative, and surgical therapy.\nWe found that the disease extent is likely to be linked \nto symptom severity. This was consistently shown in \n8 Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\nhistopathological, MRI-based, and ultrasound-based stud-\nies. Furthermore, it was demonstrated that treatment effi -\ncacy depended on disease extent, which is not surprising \n[26,  44]. These observations, along with the spectrum of \ndisorder phenotypes, beg for evidence-based information to \nassist patients and clinicians in informed decision-making.\nWhile the need for a uniform system for reporting should \nlead to a valuable classification of adenomyosis, it is equally \napparent that such a system does not yet exist. We suggest \nthat the research needed to obtain such information requires \nan accurate diagnosis and methods by which some composite \nof disease phenotype and molecular expressions are identi-\nfied and documented. Categorizing the phenotype in a stand-\nardized fashion would allow for meaningful comparison of \nsymptoms and clinical outcomes of medical and procedural \ninterventions in patients with similar disease characteristics. It \nmight lead to a better understanding of adenomyosis in a fash-\nion sufficient to inform more tailored therapeutic approaches.\nImaging modalities are now widely accepted to be reli-\nable tools and the first choice in diagnosing adenomyosis. \nHistopathology, while once the “gold standard” for diagnos-\ning adenomyosis, requires extensive sections throughout the \nwhole uterus to be reliable, which is not given in standard \nclinical practice [13, 54]. Furthermore, using a hysterectomy \nspecimen introduces a selection bias that does not allow to \ndraw conclusions on, for example, symptoms [55\n•].\nTherefore, a classification and reporting system needs to \nbe based on imaging. Previous reviews suggest that both \nMRI and ultrasound, as currently used, may have similar \nsensitivity and specificity for diagnosing adenomyosis [23]. \nAs MRI potentially provides greater accuracy in determining \ndisease volume, distribution, location, and pattern, it seems \nto be best suited to develop a classification system. However, \nas TVUS is widely available and either the only or the first-\nline tool in diagnosing adenomyosis, a universally useful \nclassification needs to be applicable for ultrasound.\nAssessment of molecular and genetic expressions, be \nthey from serum, endometrial aspirates, or endometrial or \nmyometrial biopsy specimens, may be necessary for deter -\nmining the impact of adenomyosis in a given patient: a cir -\ncumstance that may have particular importance in women \nwith reproductive failure or who are planning to undergo \nembryo transfer. The place for such variables should be con-\nsidered in the design of any system.\nConclusions\nIn summary, there is a need for a harmonized reporting sys-\ntem for both ultrasound and MRI that would allow performing \nresearch, which could be used to develop a disease classifica-\ntion system. In both reporting and classification systems, imag-\ning modalities should take into account the histopathological \nfeatures of the disorder. Fortunately, initiatives involving the \ninternational radiological and gynecological communities are \nunderway. They are designed to achieve this goal so that clini-\ncians, investigators, and especially patients will benefit from \nan increased understanding of this disorder.\nAuthor Contribution  The authors contr ibuted equally to this \nmanuscript.\nFunding Open access funding pro\nvided by University of Oslo (incl \nOslo University Hospital).\nAvailability of Data and Material (Data Transparency)\n All data is included\n \nin the manuscript.\nCode Availability\n No\nt applicable.\nCompliance with Ethical Standards \nEthics Approval Ethical appr oval was not necessary due to the nature \nof this work.\nConsent to Participate No\nt applicable.\nConflict of Interest  Dr. T\nellum reports grants from South Eastern \nNorwegian Health Authority, personal fees from GE Healthcare, and \npersonal fees from Medtronic, outside the submitted work. Dr Munro \nreports personal fees from Hologic, AbbVie, and Myovant as well as \noptions held with Gynesonics Inc.\nHuman and Animal Rights and Informed Consent\n This article does no\nt \ncontain any studies with human or animal subjects performed by any \nof the authors.\nOpen Access This article is licensed under a Cr\neative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article's Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article's Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a \ncopy of this licence, visit http://\n cr\neat iv\neco mmons. or\ng/ licen ses/ b\ny/4. 0/\n.\nReferences\nPapers of particular interest, published recently, have \nbeen highlighted as:  \n• Of importance  \n•• Of major importance\n 1. von Rokitansky C. Über Uterusdrüsen‐N eubildung. Z Gesellschaft Aer-\nzte (Wien). 1860;16:577–81.\n9Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\n 2. Gordts S, Brosens JJ, Fusi L, Benagiano G, Brosens I. Uterine \nadenom\nyosis: a need for uniform terminology and consensus \nclassification. Reprod Biomed Online. 2008;17(2):244–8.\n 3. Ver\ncellini P, Vigano P, Somigliana E, Daguati R. Abbiati A. Fedele \nL Adenomyosis: epidemiological factors. 2006;20(4):465–77.\n 4. Benagiano G, Brosens I, Habiba M. S\ntructural and molecular \nfeatures of the endomyometrium in endometriosis and adeno-\nmyosis. Hum Reprod Update. 2014;20(3):386–402.\n 5. Grimbizis GF\n, Mikos T, Tarlatzis B. Uterus-sparing operative \ntreatment for adenomyosis. Fertil Steril. 2014;101(2):472–87.\n 6.\n•• Naf\ntalin J, Hoo W, Pateman K, Mavrelos D, Holland T, Jurkovic \nD. How common is adenomyosis? A prospective study of prev-\nalence using transvaginal ultrasound in a gynaecology clinic. \nHum Reprod (Oxford, England). 2012;27(12):3432–9.\n 7. Pinzauti S, Lazzeri L, T\nosti C, Centini G, Orlandini C, Luisi S, \net al. Transvaginal sonographic features of diffuse adenomyosis \nin 18–30-year-old nulligravid women without endometriosis: \nassociation with symptoms. Ultrasound in obstetrics & gyne-\ncology\n : the official jour\nnal of the International Society of Ultra-\nsound in Obstetrics and Gynecology. 2015;46(6):730–6.\n 8. Li X\n, Liu X, Guo SW. Clinical profiles of 710 premenopausal \nwomen with adenomyosis who underwent hysterectomy. J Obstet \nGynaecol Res. 2014;40(2):485–94.\n 9. Younes G, T\nulandi T. Effects of adenomyosis on in vitro fer -\ntilization treatment outcomes: a meta-analysis. Fertil Steril. \n2017;108(3):483-90.e3.\n 10\n. Hort\non J, Sterrenburg M, Lane S, Maheshwari A, Li TC, Cheong \nY. Reproductive, obstetric, and perinatal outcomes of women \nwith adenomyosis and endometriosis: a systematic review and \nmeta-analysis. Hum Reprod Update. 2019;25(5):592–632.\n 11\n. Harada T\n, Taniguchi F, Amano H, Kurozawa Y, Ideno Y, Hayashi \nK, et al. Adverse obstetrical outcomes for women with endome-\ntriosis and adenomyosis: a large cohort of the Japan Environ-\nment and Children's Study. PLoS One. 2019;14(8):e0220256.\n 12\n. Sandberg EC, Cohn F\n. Adenomyosis in the gravid uterus at term. \nAm J Obstet Gynecol. 1962;84:1457–65.\n 13\n. Bird CC, McElin T\nW, Manalo-Estrella P. The elusive adenomyosis \nof the uterus–revisited. Am J Obstet Gynecol. 1972;112(5):583–93.\n 14\n. Lev\ngur M, Abadi MA, Tucker A. Adenomyosis: symptoms, histology, \nand pregnancy terminations. Obstet Gynecol. 2000;95(5):688–91.\n 15\n. Sammour A, Pir\nwany I, Usubutun A, Arseneau J, Tulandi T. \nCorrelations between extent and spread of adenomyosis and \nclinical symptoms. Gynecol Obstet Invest. 2002;54(4):213–6.\n 16\n. Hulka C\nA, Hall DA, McCarthy K, Simeone J. Sonographic \nfindings in patients with adenomyosis: can sonography assist in \npredicting extent of disease? 2002;179(2):379–83.\n 17\n. Ver\ncellini P, Trespidi L, Panazza S, Bramante T, Mauro F, \nCrosignani PG. Laparoscopic uterine biopsy for diagnosing \ndiffuse adenomyosis. The J Reprod Med. 1996;41(4):220–4.\n 18\n. Fer\nenczy A. Pathophysiology of adenomyosis. Hum Reprod \nUpdate. 1998;4(4):312–22.\n 19\n. Siegler AM, Camilien L. A\ndenomyosis. J Reprod Med. \n1994;39(11):841–53.\n 20\n. Uduwela AS, P\nerera MA, Aiqing L, Fraser IS. Endometrial-\nmyometrial interface: relationship to adenomyosis and changes \nin pregnancy. Obstet Gynecol Surv. 2000;55(6):390–400.\n 21\n. Sampson J\nA. Perforating hemorrhagic (choclate) cysts of \nthe ovary: Their importance and especially their relation to \npelvic adenomas of endometrial type (\"Adenomyoma\" of \nthe uterus, rectovaginal septum, sigmoid, etc.). Arch Surg. \n1921;3(2):245–323.\n 22\n.•• Van den Bosc\nh T, Dueholm M, Leone FP, Valentin L, Rasmussen \nCK, Votino A, et al. Terms, definitions and measurements to describe \nsonographic features of myometrium and uterine masses: a consen-\nsus opinion from the Morphological Uterus Sonographic Assessment \n(MUSA) group. Ultrasound Obstet Gynecol. 2015;46(3):284–98.\n 23 . Tellum T , Nygaard S, Lieng M. Noninvasive diagnosis of aden-\nomyosis: a structured review and meta-analysis of diagnostic \naccuracy in imaging. J Minim Invasive Gynecol. 2019.\n 24\n. Nishida M. Relationship be\ntween the onset of dysmenorrhea \nand histologic findings in adenomyosis. Am J Obstet Gynecol. \n1991;165(1):229–31.\n 25\n. Mc\nCausland AM. Hysteroscopic myometrial biopsy: its use in \ndiagnosing adenomyosis and its clinical application. Am J Obstet \nGynecol. 1992;166(6 Pt 1):1619–26; discussion 26–8.\n 26\n. Rasmussen C\nK, Hansen ES, Al-Mashadi Dahl S, Ernst E, Dueholm \nM. The effect of transcervical endometrial resection on clinical \nsymptoms related to intrinsic adenomyosis and junctional zone \nchanges. Eur J Obstet Gynecol Reprod Biol X. 2019;3:100029.\n 27\n.• Kishi Y, Suginami H, K\nuramori R, Yabuta M, Suginami R, \nTaniguchi F. Four subtypes of adenomyosis assessed by mag-\nnetic resonance imaging and their specification. Am J Obstet \nGynecol. 2012;207(2):114.e1–7.\n 28\n. Dashott\nar S, Singh AK, Debnath J, Muralidharan CG, Singh RK, \nKumar S. Comparative analysis of changes in MR imaging of \npre and post intrauterine progesterone implants in adenomyosis \ncases. Med J Armed Forces India. 2015;71(2):145–51.\n 29\n. Chapron C, T\nosti C, Marcellin L, Bourdon M, Lafay-Pillet MC, \nMillischer AE, et al. Relationship between the magnetic reso -\nnance imaging appearance of adenomyosis and endometriosis \nphenotypes. Hum Reprod. 2017;32(7):1393–401.\n 30\n. Bazot M, Dar\nai E. Role of transvaginal sonography and magnetic \nresonance imaging in the diagnosis of uterine adenomyosis. Fer-\ntil Steril. 2018;109(3):389–97.\n 31\n. Koninc\nkx PR, Ussia A, Adamyan L, Wattiez A, Donnez J. \nDeep endometriosis: definition, diagnosis, and treatment. \n2012;98(3):564–71.\n 32\n. Ma\nrcellin L, Santulli P, Bortolato S, Morin C, Millischer AE, \nBorghese B, et al. Anterior focal adenomyosis and bladder deep \ninfiltrating endometriosis: is there a link? 2018;25(5):896–901.\n 33\n. Gordts S, K\noninckx P, Brosens I. Pathogenesis of deep endome-\ntriosis. Fertil Steril. 2017;108(6):872-85.e1.\n 34. Exacous\ntos C, Morosetti G, Conway F, Camilli S, Martire FG, \nLazzeri L, et al. New sonographic classification of adenomyo-\nsis: do type and degree of adenomyosis correlate to severity of \nsymptoms? J Minim Invasive Gynecol. 2019.\n 35\n. Van den Bosc\nh T, de Bruijn AM, de Leeuw RA, Dueholm M, \nExacoustos C, Valentin L, et al. Sonographic classification \nand reporting system for diagnosing adenomyosis. Ultrasound \nin obstetrics & gynecology\n : the official jour\nnal of the Inter -\nnational Society of Ultrasound in Obstetrics and Gynecology. \n2019;53(5):576–82.\n 36\n. Lazzeri L, Mor\nosetti G, Centini G, Monti G, Zupi E, Piccione \nE, et al. A sonographic classification of adenomyosis: interob-\nserver reproducibility in the evaluation of type and degree of the \nmyometrial involvement. 2018;110(6):1154-61.e3.\n 37. Gordts S, Gr\nimbizis G, Campo R. Symptoms and classification \nof uterine adenomyosis, including the place of hysteroscopy in \ndiagnosis. Fertil Steril. 2018;109(3):380-8.e1.\n 38\n. Bourdon M, Santulli P\n, Oliveira J, Marcellin L, Maignien C, \nMelka L, et al. Focal adenomyosis is associated with primary \ninfertility. Fertil Steril. 2020.\n 39\n. Ta\nmura H, Kishi H, Kitade M, Asai-Sato M, Tanaka A, \nMurakami T, et al. Clinical outcomes of infertility treatment \nfor women with adenomyosis in Japan. Reprod Med Biol. \n2017;16(3):276–82.\n 40\n. Naf\ntalin J, Hoo W, Nunes N, Holland T, Mavrelos D, Jurkovic D. \nAssociation between ultrasound features of adenomyosis and severity \nof menstrual pain. Ultrasound Obstet Gynecol. 2016;47(6):779–83.\n 41\n. Iwasa\nwa T, Takahashi T, Maeda E, Ishiyama K, Takahashi S, \nSuganuma R, et al. Effects of localisation of uterine adenomyo-\nsis on outcome of in vitro fertilisation/intracytoplasmic sperm \n10 Current Obstetrics and Gynecology Reports (2022) 11:1–11\n\n1 3\ninjection fresh and frozen-thawed embryo transfer cycles: a mul-\nticentre retrospective cohort study. Reproductive biology and \nendocrinology\n : RB&E. \n2021;19(1):84.\n 42\n. Maubon A, F\naury A, Kapella M, Pouquet M, Piver P. Uterine \njunctional zone at magnetic resonance imaging: a predictor of \nin vitro fertilization implantation failure. J Obstet Gynaecol Res. \n2010;36(3):611–8.\n 43. Naf\ntalin J, Hoo W, Nunes N, Holland T, Mavrelos D, Jurkovic \nD. The association between ultrasound features of adenomyo-\nsis and severity of menstrual pain. Ultrasound in obstetrics & \ngynecology : the official journal of the International Society of \nUltrasound in Obstetrics and Gynecology. 2015.\n 44. Gong C, Yang B, Shi Y\n, Liu Z, Wan L, Zhang H, et al. Factors \ninfluencing the ablative efficiency of high intensity focused ultra-\nsound (HIFU) treatment for adenomyosis: a retrospective study. \n2016;32(5):496–503.\n 45\n. Gong C, Setzen R, Liu Z, Liu Y\n, Xie B, Aili A, et al. High inten-\nsity focused ultrasound treatment of adenomyosis: the relation-\nship between the features of magnetic resonance imaging on \nT2 weighted images and the therapeutic efficacy. Eur J Radiol. \n2017;89:117–22.\n 46. Keser\nci B, Duc NM. The role of T1 perfusion-based classifica-\ntion in predicting the outcome of magnetic resonance-guided \nhigh-intensity focused ultrasound treatment of adenomyosis. \n2018;34(3):306–14.\n 47\n. Keser\nci B, Duc NM. Magnetic resonance imaging features influ-\nencing high-intensity focused ultrasound ablation of adenomyo-\nsis with a nonperfused volume ratio of >/=90% as a measure of \nclinical treatment success: retrospective multivariate analysis. \n2018;35(1):626–36.\n 48\n. Naf\ntalin J, Hoo W, Pateman K, Mavrelos D, Foo X, Jurkovic D. \nIs adenomyosis associated with menorrhagia? 2014;29(3):473–9.\n 49 . Bourdon M, Oliv eira J, Marcellin L, Santulli P, Bordonne C, \nMaitrot Mantelet L, et al. Adenomyosis of the inner and outer \nmyometrium are associated with different clinical profiles. Hum \nReprod (Oxford, England). 2021;36(2):349–57.\n 50\n. Li T, X\nu XX, Dai Y, Zhang JJ, Lang JH, Leng JH. Menorrha-\ngia and uterine volume associated with lower urinary tract \nsymptoms in patients with adenomyosis. Chin Med J (Engl). \n2017;130(13):1552–6.\n 51\n. Wa\nng F, Shi X, Qin X, Wen Z, Zhao X, Li C. Expression of \nCD56 in patients with adenomyosis and its correlation with dys-\nmenorrhea. Eur J Obstet Gynecol Reprod Biol. 2015;194:101–5.\n 52\n. Orazo\nv MR, Nosenko EN, Radzinsky VE, Khamoshina MB, \nLebedeva MG, Sounov MA. Proangiogenic features in chronic \npelvic pain caused by adenomyosis. Gynecological endocrinol-\nogy\n : the official jour\nnal of the International Society of Gyneco-\nlogical Endocrinology. 2016;32(sup2):7–10.\n 53\n. Bour\ndon M, Santulli P, Jeljeli M, Vannuccini S, Marcellin L, Doridot \nL, et al. Immunological changes associated with adenomyosis: a \nsystematic review. Hum Reprod Update. 2021;27(1):108–29.\n 54\n. Seidman JD, Kjerulff KH. P\nathologic findings from the Mary -\nland Women’s Health Study: practice patterns in the diagnosis of \nadenomyosis. International journal of gynecological pathology\n : \no\nfficial journal of the International Society of Gynecological \nPathologists. 1996;15(3):217–21.\n 55\n.• Upson K, Missmer S\nA. Epidemiology of adenomyosis. Seminars \nin reproductive medicine. 2020;38(2–03):89–107.\nPublisher's Note  Spring\ner Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.\n11Current Obstetrics and Gynecology Reports (2022) 11:1–11","source_license":"CC0","license_restricted":false}