{"paper_id":"6a0bc3ac-0d80-42a5-9140-a39f96fb2329","body_text":"2023/2024 \n \n \n \n \n \nInês Tomás Jerónimo Oliveira \nNon-invasive diagnosis of endometriosis in adolescents:  \na systematic review \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nFevereiro, 2024 \n  \n\n \n \n \n \n \n \nInês Tomás Jerónimo Oliveira   \nNon-invasive diagnosis of endometriosis in adolescents:  \na systematic review \n \n \nMestrado Integrado em Medicina \n \n \nÁrea: Ginecologia/Obstetrícia \nTipologia: Dissertação \n \n \nTrabalho efetuado sob a Orientação de: \nDoutor Pedro Viana Pinto  \nE sob a Coorientação de: \nProfessor Doutor João Bernardes \n \nTrabalho organizado de acordo com as normas da revista: \nJournal of Pediatric and Adolescent Gynecology \n \n \n \n \nFevereiro, 2024 \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nUC Dissertação - DECLARAÇÃO DE INTEGRIDADE \n \n \n \n \nEu, Inês Tomás Jerónimo Oliveira,  abaixo assinado, nº mecanográfico  201910435, estudante  do 6º \nano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Port o, \ndeclaro ter a ctuado com absoluta integr idade na elaboração do meu trabalho de Dissertação ou \nMonografia.  \nNeste sentido, confirmo que NÃO incorri em plágio (acto pelo qual um indivíduo, mesmo por omissão, \nassume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as \nfrases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou \nredigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica. \n \nFaculdade de Medicina da Universidade do Porto, 05/02/2024 \n \nAssinatura conforme cartão de identificação: \n \n ________________________________________________ \n \n\n\nUC Dissertação – DECLARAÇÃO DE REPRODUÇÃO \n \n \nNOME \nInês Tomás Jerónimo Oliveira \n \nNÚMERO DE ESTUDANTE     E-MAIL \n201910435 inesjeronimo.oliveira@gmail.com \n \nDESIGNAÇÃO DA ÁREA DO PROJECTO \nMedicina clínica - Obstetrícia e Ginecologia  \n \nTÍTULO DISSERTAÇÃO \nNon-invasive diagnosis of endometriosis in adolescents: a systematic review \n \nORIENTADOR  \nDoutor Pedro Viana Pinto \n \nCOORIENTADOR  \nProfessor Doutor João Bernardes \n \nASSINALE APENAS UMA DAS OPÇÕES: \nÉ AUTORIZADA A REPRODUÇÃO INTEGRAL DESTE TRABALHO APENAS PARA EFEITOS DE INVESTIGAÇÃO, \nMEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE. \n \nÉ AUTORIZADA A REPRODUÇÃO PARCIAL DESTE TRABALHO (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº \nMÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE \nDECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE. \n \nDE ACORDO COM A LEGISLAÇÃO EM VIGOR, (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, \nILUSTRAÇÕES, GRÁFICOS, ETC.) NÃO É PERMITIDA A REPRODUÇÃO DE QUALQUER PARTE DESTE TRABALHO. \n \n \nFaculdade de Medicina da Universidade do Porto, 05/02/2024 \n \n \nAssinatura conforme cartão de identificação: ______________________________________________ \n\n\nUC Dissertação - DECLARAÇÃO DE TRANSPARÊNCIA RELATIVAMENTE \nÀ UTILIZAÇÃO DE FERRAMENTAS DE CHATBOT GENERATIVO BASEADAS \nEM LARGE LANGUAGE MODELS \n \n \n \n \nEu, Inês Tomás Jeró nimo Oliveira, abaixo assinado, nº mecanográfico  201910435, estudante  do 6º \nano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Port o, \ndeclaro que: \n \n Não procedi à utilização de ferramentas de chatbox generativo baseadas em large language models \npara nenhuma das tarefas no contexto do meu trabalho de Dissertação ou Monografia \n Procedi à utilização de ferramentas de chatbox generativo baseadas em large language models no \ncontexto do meu trabalho de Dissertação ou Monografia, encontrando -se todas as interacções \n(prompts e respostas) transcritas em anexo bem como a indicação das aplicações utilizadas.  \n  \nNeste sentido, confirmo que a eventual utilização de ferramentas de chatbox generativo baseadas em \nlarge language models no contexto do meu trabalho de Dissertação ou Monografia foi exclusivamente \ndescrita na sequência de prompts e respostas transcritos em anexo e nas aplicações indicadas. \n \nFaculdade de Medicina da Universidade do Porto, 12/02/2024 \n \nAssinatura conforme cartão de identificação:  \n \n________________________________________________ \n \n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nAo meu orientador, Dr. Pedro  Viana Pinto, por ter aceitado este desafio e sobretudo pela \ndisponibilidade. Aos amigos que Medicina me deu, por todos os momentos e partilhas. À família \nde Aveiro , pelo amor para a vida toda.  À minha irmã, pela paciência no momento das \nindecisões. Ao Ivo, por todo o  apoio, sem ele não seria possível. Ao meu namorado, por me \ninspirar. \n \nEm especial, ao meu grande pilar.  \nAs minhas conquistas são também as tuas, minha mãe. \n\n1 \n \n \n \nNon-invasive diagnosis of endometriosis in adolescents:  \na systematic review \nInês TJ Oliveira1, Pedro V Pinto2,3,4, João FMAL Bernardes3,4 \n \n1- Mestrado Integrado em Medicina, Faculdade de Medicina da Universidade do \nPorto, Portugal \n2- Serviço de Anatomia, Faculdade de Medicina da Universidade do Porto \n3- Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da \nUniversidade do Porto \n4- Serviço de Ginecologia, Centro Hospitalar e Universitário de São João \n5-  Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS@RISE), \nFaculdade de Medicina da Universidade do Porto, Portugal \n \nThe study has taken place at Porto, Portugal – University of Porto  \nNo source of funding.  \nDisclosure: The authors declared no potential conflicts of interest or financial support \nconcerning the research, authorship, and/or publication of this article \n \nCorresponding author: \nInês Tomás Jerónimo Oliveira \nFaculty of Medicine, University of Porto \nAlameda Professor Hernâni Monteiro, 4200-319 Porto – Portugal \nEmail: inesjeronimo.oliveira@gmail.com \n \nAbstract: 261 words \nMain text: 4311 words \n5 tables/figures \n\n2 \n \nABSTRACT  \nStudy Objectives: Our aim was to review the evidence concerning the non-invasive diagnosis of \nendometriosis in adolescents. \nMethods: A systematic review was written following the SWiM reporting guidelines. The study \nresearch was made across three databases (MEDLINE/PubMed, Scopus, and Web of Science) to \nidentify articles about the adolescent population and the diagnosis of endometriosis through \nnon-invasive methods. The search included the keywords \"endometriosis,\" \"adolescents,\" \n\"diagnosis,\" \"ultrasound,\" and \"MRI.\" Only English language articles were considered and those \npublished prior to 2000 were excluded. The established outcomes focused on clinical symptoms, \nultrasound (US), and magnetic resonance imaging (MRI) findings suggestive of endometriosis. \nResults: We included 26 articles, mostly comprising case series and cross-sectional studies. The \npooled analysis involved 2,299 female adolescents (age range 8 -25 years old) with clinically \nsuspected, imaged, and/or surgically confirmed endometriosis. The most frequently reported \nsymptom was dys menorrhea, followed by chronic pelvic pain. Among adolescents clinically \nsuspected of endometriosis undergoing ultrasound (US), 32.8% exhibited at least one sign of \nendometriosis. Of the 167 patients with ultrasound -diagnosed endometriosis, 48.5% had deep \ninfiltrating endometriosis (DIE), and 45.5% had an endometrioma detected. Three studies \nassessed MRI findings, revealing that 49.8% presented with signs of endometriosis. \nConclusions:  Dysmenorrhea and chronic pelvic pain stand out as key symptoms of adolescent \nendometriosis. Although their diagnostic accuracy varies, both US  and MRI have emerged as \nvaluable tools for diagnosing the disease. While the US may have limitations, especially in \ndetecting subtle lesions, MRI shows promise, even in cases with normal previous ultrasounds. \nEarly recognition and proactive diagnosis are crucial for improving the management of \nendometriosis in adolescents. \n\n3 \n \nKEYWORDS: Endometriosis, adolescent, diagnosis, ultrasound, US, magnetic resonance imaging, \nMRI. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n4 \n \n1. INTRODUCTION \nEndometriosis is a common gynaecological disorder thought to affect around 64% of adolescents \nwith pelvic pain undergoing gynaecological investigation1.  It was first described in adolescents \nas early as the 1940s 2. Although more than 4 million reproductive-age women have been \ndiagnosed with the disease, population-based studies show that an estimated 6 of 10 cases are \nundiagnosed3.  \nThis chronic inflammatory disease  is defined by endometrium -like tissue outside the uterus , \nmost commonly on the ovary, peritoneum, and adjacent organs like the bladder or rectum4. Even \nthough a benign disease,  ectopic endometrial tissue may implant and develop an inflammatory \nreaction responsive  to estrogens , leading to dysmenorrhea, dyspareunia, chronic pain, and \ninfertility5. Although several theories have been developed over the years, t he exact cause  \nbehind this disease  remains unknown 6. The natural course of the disease is unclear, and \nquestions persist about the potential progression of superficial endometriosis to other subtypes, \nspontaneous regression, or implications for infertility, especially in the absence of treatment.  \nThe American Society for Reproductive Medicine (ASRM) categorises endometriosis into four \nstages (minimal, mild, moderate, and severe), determined by the location, depth, and site of \nlesions and adhesion s7. Despite being the most widely used system, multiple revisio ns of the \nASRM classification have not notably enhanced its predictive accuracy for pain, dyspareunia, or \ninfertility 8, 9.  \nEndometriosis is remarkably responsible for a decrease in women’s quality of life (QOL), not only \ndue to the physical discomfort it causes but also because of the mental and emotional burden \ninvolved 10, both in adults and adolescents. It has been shown that dysmenorrhea occurs in 16% \nto possibly as high as 93% of teen girls and is the leading cause of recurrent short-term school \nabsence in this age group 11. A survey analysis demonstrated that women with endometriosis \n\n5 \n \noften begin to report symptoms in their adolescence, with 70% of the patients reporting before \nage 20 and nearly 40% before 1512. \nDiagnosis of endometriosis remains a challenge worldwide , especially in women who first \nexperience symptoms at a young age. Recent evidence points out that it takes around 8 years to \ndiagnose this disorder 13 and the median delay in diagnosis increases if the symptoms are present \nin adolescence 13, 14. The lack of pathognomonic features or biomarkers 15, the absence of an \naccurate and sufficient non-invasive diagnostic test 16, 17, and the variability in symptom patterns \nover time 18 illustrate the difficulty imposed on clinicians, especially general practitioners, in the \ndiagnosis of this disease. Furthermore, the disease in its earlier stages may be associated with \ndifferent imaging and laparoscopical signals. To worsen the scenario, it is also known that the \nawareness of endometriosis in adolescents among medical professionals is low 19.  \nSince symptoms of endometriosis usually begin in adolescence 20, 21 and the huge future medical \nand social consequences associated, an approach in this age group  becomes even more \nimportant. Furthermore, it is recognized that early lesions, although smaller and subtler may be \nassociated with more severe symptoms than bigger and more fibrotic lesions, that are less \nmetabolically active and inflammatory 6. Treating the disease before central sensitization occurs \nmay be key to guaranteeing a better quality of life for these patients. Furthermore, the need for \na laparoscopy to make a diagnosis of this disease is, nowadays, not adequate for adult women \nand maybe even less for adolescents. \nThis systematic  review aims to gat her evidence concerning the  accuracy of  non-invasive \ndiagnosis of endometriosis in adolescent patients. This contribution seeks to  enhance our \nunderstanding of the appropriate approach in this specific population. \n \n \n \n\n6 \n \n2. METHODS  \nThis systematic review was conducted according to  Synthesis without meta -analysis (SWiM) \nreporting guideline , 22 used as an extension to PRISMA 23. The systematic review protocol is \nregistered in the international PROSPERO database as No. CRD42023457516. Considering that \nthis study was a systematic review, an Institutional Review Board was not required. \n2.1 Search strategy \nWe aimed to assess how is endometriosis diagnosed in adolescent females, more specifically  \nwhich non -invasive diagnostic procedures are being applied in adolescents with suspected  \nendometriosis to achieve an early diagnosis. We took into consideration a variety of studies from \n2000 onward in this analysis . Randomized controlled trials (RCTs), prospective cohort studies, \ncase–control studies, retrospective cohort studies, and case series were screened. \nWe searched three databases: MEDLINE /Pubmed, Scopus , and Web of Science. The search \nstrategy used was the query (\"adolescent\" OR \"adolescence\"  OR \"adolescents\" OR \"pediatric\" \nAND \"endometriosis” AND (\"diagnosis\" OR \"ultrasound”  OR \"MRI\"), on 24 August 2023. The \nsearch was limited to publications in the English language and articles published earlier than \n2000 were excluded. The reference list of the included studies and relevant reviews on the \nmatter were analysed to identify other studies for potential inclusion in this article. \n2.2 Inclusion and exclusion criteria and study selection \nAll records identified using our search strategy were independently screened by two authors \nbased on the titles and abstracts, applying predetermined inclusion and exclusion criteria. Any \ndiscrepancies were resolved by consensus, and different interpretations were resolved by a third \nauthor. The second selection stage was based on reviewing the full text of potentially relevant \narticles. The same independent reviewers read relevant full-text articles for inclusion. \nArticles were included if the following inclusion criteria were  met: a) adolescent population \ndefined as patients between 10 and 24 years old, as defined by Sawyer et al. 24, or patients that \n\n7 \n \nwere referred as “adolescent” or “teenager”; b) patients who either have clinically suspected \nendometriosis or have received a diagnosis of endometriosis ; c) the outcome refers to the \ndiagnosis of endometriosis using non -invasive methods (clinical symptoms and/or imaging) or \nwhere the invasive diagnosis is compared with the non-invasive methods; and d) observational \nstudies or interventional studies.  \nWe excluded non -original studies classified as guidelines, reviews, conference abstracts, \neditorials, opinion articles, or protocols, as well as case reports and articles where the full -text \nmanuscript was not available, after efforts contacting authors. Articles were excluded if they \nfocused solely on adult women aged 18 or older and did not conduct a cluster analysis based on \nage, making it impossible to extract data specifically for the desired adolescent population.  \nFor the process of study selection, EndNote was used to exclude duplicated studies, and online \nRayyan software was used to help in the organization and selection of eligible studies. \n2.3 Quality assessment \nQuality assessment of cohort and cross -sectional studies was conducted using the Newcastle-\nOttawa Scale (NOS)  25. For the cross -sectional studies, an adapted NOS  was used 26 and t o \nevaluate the methodological quality of the case series and  address potential biases in their \nconduct we used the JBI (Joanna Briggs Institute) Critical Appraisal tool 27.  \n2.4 Data extraction \nThe following data was independently extracted from each of the studies to a spreadsheet: \nauthors, publication year, country, study design, study period, studied population, number of \nparticipants either with clinically suspected  and/or with the confirmed diagnosis of \nendometriosis by imaging and/or laparoscopically. Other items included were the non-invasive \ndiagnosis imaging modality mentioned/used, outcomes of interest , and the aim of the study.  \nStudy outcomes on the clinical presentation of endometriosi s, ultrasound (US), and Magnetic \n\n8 \n \nresonance imaging (MRI) findings of endometriosis, and rASRM classification data from patients \nthat have undergone laparoscopy/laparotomy were extracted too. A standardized table was \ncreated for each outcome after the data from the included studies were extracted. The studies \nwere categorized based on the outcomes that were classified by the non-diagnostic tools used, \nsuch as clinical diagnosis, US findings, and MRI findings. This was thought to be the most \ntransparent method of reporting the results. \nEvery study's results were combined, and since this condition significantly affects quality of life \nand none of the studies indicated a high risk of bias, none of the results were chosen for \nprioritization. \n3. RESULTS \nOur search identified a total of 1197 articles and 281 duplicates were excluded. After a review of \n916 titles and abstracts, we retained 84 full -text articles for eligibility. Among them, 26 articles \nwere included: 2 cohort, 1 case -control, 4 cross -sectional, and 19 case series studies. A flow \ndiagram was created, using a PRISMA flowchart to describe this search method (Figure I) and \nthe main study characteristics are displayed in Table I.  \nOverall, the analysis included a total of 2 167 female adolescents with clinical and/or \nimagiological suspected diagnosis of endometriosis and 1124 ( 51.9%) female adolescents who \nunderwent laparoscopy for a definitive diagnosis of endometriosis. The term ‘adolescents’ was \ndefined differently in each study, with some authors sticking to the World Health Organization \ndefinition (up to 19 years old), while others defined it until 25 years old. The age range of the \npopulation studied was from 8 to 25 years old and the weighted mean of ages was 18,2 years \nold, calculated with the findings presented in 21 articles; 5 articles were excluded for this \ncalculation due to lack of reports of individual patient ages. This systematic review covered cases \nfrom several continents. \n \n\n9 \n \nAmong 19 case series studies assessed using the JBI Critical Appraisal Checklist, 16 were deemed \nto have a \"low\" risk of bias, while 3 were categorized as having a \"moderate\" risk. Cross-sectional \nstudies, evaluated through the NOS, scored between 5 and 7 points out of 10, with notable \nweaknesses in the selection process . The case-control study, with a NOS score of 5 out of 9 \npoints, demonstrated bias in the representativeness of cases, selection of controls, and \ncomparability. Cohort studies, despite the highest risk of selection bias,  were considered of high \nquality. Bias assessment evaluation is demonstrated in Supplementary Table S1.  \n \n1. Clinical characteristics of endometriosis in adolescents \nThe clinical symptoms and physical examination findings of endometriosis in adolescent patients \nwere assessed in 23 articles (Supplementary Table S2). \nThe typically reported symptoms of endometriosis such as dysmenorrhea and chronic pelvic pain \nwere encompassed by less typical symptoms, such as vague abdominal pain, and gastrointestinal \nand genitourinary symptoms.  Of the total of 1426 endometriosis patients included in this \nanalysis, dysmenorrhea was the predominant symptom, reported by 82.9% of adolescent girls \n(1182 patients). Furthermore, 43% reported having chronic, acute, or acyclic pelvic discomfort, \n18% abnormal uterine bleeding and 19% gastrointestinal symptoms. Dyspareunia was reported \nby 13.7% and urinary complaints were scarcely reported (6.6% of patients). Infertility was also a \nrare complaint (2.1%) since a great proportion of women were not sexually activ e or actually \nlooking to conceive.  \nKhashchenko et al.  28 revealed moderate-severe dysmenorrhea in 97.8%   (95.6% persistent to \nNSAIDs) of adolescents with laparoscopically confirmed peritoneal endometriosis  (PE). High-\nintensity pain (7.5 ± 2.1 vs. 2.5 ± 2.3 in the control group, VAS points, p < 0.001) that most often \nbegan 1 day before menses and lasted 3 days into menses  was reported; the majority (63.3%, \n57/90) referred the symptoms since menarche and approximately 15.6% experienced pain daily. \n\n10 \n \nDiVasta et al. 18, reported endometriosis symptoms starting at 13 years old on average; Martire \net al. 29 found more painful symptoms in adolescents with US signs of endometriosis.  \nAl-Jefout's study 30 found a significant association  (p=0.039) between endometriosis and cold \nintolerance, particularly in those with generalized anxiety disorder. \nThe majority of cases described (74.2%) had mild to moderate disease according to the ASRM \n(Table II), with studies, such as Marsh  et al.  31 and Unger  et al.  32 with no cases of severe \nendometriosis (stage III and IV).  \n2. US Findings  \nOverall, only 7 studies reported US findings in patients with endometriosis (Table IIIA).  \nAmong the 509 adolescents who underwent US testing and were clinically suspected of having \nendometriosis, 32.8% exhibited at least one ultrasound marker indicative of the disease. Out of \nthe 167 patients with ultrasound -confirmed endometriosis, 45.5% presented with \nendometrioma, 48.5% had deep infiltrative endometriosis ( DIE), 40.1% showed signs of \nadenomyosis, and 13.7% displayed adhesions. \nMartire et al.  29, included in their study adolescents with ultrasound for different clinical \nindications; from this population, 36 women had at least one sign of endometriosis; DIE was \ndetected in 10 adolescents . The symptom that exhibited the strongest correlation with \nultrasound findings of endometriosis was dysmenorrhea, reported in 86.1% of the patients . In \ntheir study in 2023 16, there was a statistically significant difference in the number of cases \nbetween early adolescents (12-16 years – 27/39 with normal ultrasound) and young women (21–\n25 years – 90/211 with normal ultrasound); the majority of patients with US signs had posterior \nDIE (53.4%, the majority in the uterosacral ligaments) and an endometrioma (41.2%). Only one \ncase of anterior DIE was identified in both studies. \nIn the articles with a laparoscopic diagnosis of endometriosis, the majority described a pelvic \n\n11 \n \nmass in the US, but not specifically endometrioma . Interestingly, in the study by Yang et al.  33, \nadolescents with genital tract malformations had mainly ovarian endometriosis (14/15), while \nadolescents with a normal genital tract had both, DIE (26/48) and ovarian endometriosis (41/48).  \nTable IIIB summarizes the results of the data analysis, for the detection of endometriotic lesions \nin the ultrasound, compared with the gold standard, laparoscopy. In the study by Yang et al. 33, \nof 63 patients with endometriosis, a pelvic mass was found in 87.3%. In the  Audebert et al. \nstudy34, 36.4% of the findings in the US correspond to an endometrioma  and DIE  after \nhistological confirmation. Ragab et al.  35, from the 56 patients who had severe dysmenorrhea \nrefractory to medical therapy and positive ultrasound picture of endometriosis, only 34 accepted \nlaparoscopy, with a confirmed diagnosis in 79.4% of the cases. In the Khashchenko et al. study28, \necografic signs of PE were found in only 3,3% of the patients. \n \n3. Pelvic MRI Findings \nTable IV represents the 3 studies that included MRI findings of adolescent patients with  \nsuspected or confirmed endometriosis.  \nAmong 22 patients in the study by Ragab et al. with severe dysmenorrhea and positive \nultrasound for endometriosis who declined laparoscopy, an MRI had findings consistent with \nendometriosis in  77.3% (n=17) 35.  \nOf the 308 adolescent girls included in Millischer et al. 36,  39.3% presented with endometriosis \nsigns at MRI, the majority (88.9%) with DIE; 11,4% had also signs of adenomyosis. The majority \nof ovarian endometriomas occurred in those aged ≥ 18 years, while retrocervical lesions were \nobserved from a young age (< 15 years). Rectosigmoid lesions were rare (3.3%), with all the \nintestinal lesions diagnosed after the age of 17 years. Ureteral or bladder involvement was \nabsent. Interestingly, 107 adolescents with endometriosis suspected in the MRI had a previous \n\n12 \n \nultrasound without suspicion of the disease.  \nIn Khashchenko et al.  28 study, 78.9% of pediatric patients showed  MRI signs of PE, mainly in \nuterosacral ligaments (39.4%), parametrium (38.0%), pouch of Douglas (25.4%), and peritoneum \nof the ovarian fossae (29.6%).  \n4. DISCUSSION \nDespite being widely researched in adult women, endometriosis presents a variety of difficulties \nfor clinicians particularly when it comes to adolescents. Given the limited literature surrounding \ndiagnostic characteristics in this population, the management approach often relies on \nextrapolated data gathered in adults. This study collected data to enhance our understanding of \nthis disease in adolescents and the efficacy of the non-invasive tools at our disposal to achieve \nan early diagnosis, showing that dysmenorrhea and chronic pelvic p ain are the most common \nsymptoms of the disease in adolescents and that ultrasound and MRI may have an important \nrole for its diagnosis. A ll the subtypes of endometriosis were diagnosed, going through \nperitoneal lesions, ovarian endometriosis and DIE.  \n1. Clinical characteristics of endometriosis in adolescents \nOverall, adolescents with endometriosis commonly experience severe dysmenorrhea resistant \nto conventional treatments such as contraceptive pills, NSAIDs, or antispasmodics.  The second \nmost frequently reported symptom was pelvic pain, which, when coupled with persistent \ndysmenorrhea despite pharmacological treatments, strongly correlates with the presence of \nendometriosis. Nongynecologic symptoms may also occur frequently in adolescents with \nendometriosis, such as  gastrointestinal manifestations and other vague abdominal symptoms. \nAttention should be given to the potential bias that may be implicit when addressing \ndyspareunia. In early adolescence, a higher number of pre-sexually active girls results in a lower \npercentage of dyspareunia being reported, as shown in Martire et al. 29, however, sexually active \nteenagers appear to have more severe dyspareunia than do older women 37.   \n\n13 \n \nMartire’s 2020 and 2023 results 16, 29 reveal that although dysmenorrhea was considered an  \nindication for US examination in 10.4% of cases, the symptom was self -reported by 54.4% of  \npatients when interviewed, making it the most common symptom. The 2023 study further found \nthat patients reported severe dysmenorrhea only when specifically questioned about pelvic pain \nand asked to score their symptoms using the Visual Analogue Scale (VAS). These findings suggest \nnot only an underestimation of endometriosis symptoms by adolescents, who  may perceive \ndysmenorrhea as a natural aspect of menstruation but also by general practitioners. Both articles \nunderscore dysmenorrhea as a reliable indicator of endometriosis,  emphasizing the need to \nrecognize it in adolescents as a warning sign. The studies highlight the  crucial need for actively \ninquiring about this symptom to ensure accurate diagnosis and appropriate management. \nThe results demonstrated by Al-Jefout et al.  30 suggest a potential link between chronic pain \nconditions, such as endometriosis, and a higher likelihood of anxiety -related symptoms, \nincluding cold intolerance.  \nWhile symptoms may align closely with the existence of endometriosis, they do not necessarily \ncorrespond to the stage or severity of the disease. The proposition that has been put forward \nsuggests that endometriosis may be characterized as a \"progressive\" condition, as proposed by \nBrosens et al. 21, 38. Prior studies addressing non-invasive endometriosis diagnosis in adolescents \n39 revealed that the majority of adolescents are diagnosed with Stage I endometriosis. Our study \nreinforces these observations, with most laparoscopically confirmed cases in the lower  ASRM \nstages. \nStochino's findings 40 suggest an age-related increase in endometriosis severity, with adolescents \n(<20 years) having a mean disease stage of II. Furthermore, in the studies by DiVasta and Martire \net al . 16, 18, 29 , no cases of advanced disease were diagnosed by laparoscopy or ultrasound, \nrespectively, corroborating previous results mentioned. This is consistent with published data in \nregards to staging of endometriosis 41, 42, 43, 44, 45. \n\n14 \n \nAn exception is observed in 5 studies 33, 46, 47, 48, 49 , which report a large proportion of patients \nwith endometriosis Stage III and IV. This advanced-stage prevalence may be attributed to \ncomplex cases treated in tertiary centres, delayed healthcare seeking, traditional medicine use, \nand the acceptance of surgery only when pelvic masses are evident . Fong’s findings 49 suggest \nthat older age (82.3% of women aged 21-25 years), higher prevalence of ovarian endometriomas \n(a marker of extensive disease),  and selection bias (retrospective nature of the  study) \ncontributed to advanced -stage overrepresentation. Importantly, the majority of cases with \nhigher ASRM stages in adolescents are due to ovarian endometriomas (compared with extensive \nperitoneal or adhesive disease).  Lee et al. 48 reported only cases of Stage III and IV since the \npopulation included were adolescent females who underwent surgery for endometrioma, a \nlesion frequently associated with advanced endometriosis, a condition that often requires \nsurgical intervention. \nEndometriosis in its early stages may be associated with more metabolically active lesions, \npossibly associated with more painful symptoms, as opposed to larger more fibrotic lesions. \nWuest et al. 37 observed in their study that women younger than 24 years old with endometriosis \nhad higher visual analogue scale scores for dysmenorrhea and non-cyclic pelvic pain than women \nolder than 24 . Tandoi et al. 47 pointed out that young age represents a determinant for the \nrecurrence of the disease, speculating that the younger the age of onset, the more aggressive \nform of endometriosis. Also, Smorgick et al. 50 demonstrated that the occurrence of daily pelvic \npain was found to be more common among women with early-stage endometriosis.  \n2. US findings \nGirls undergoing US had an average age of 17.3 years, reflecting late adolescence. This aligns \nwith increased sexual activity, contraception -seeking behaviour, and gynaecological \nconsultations. Notably, only 7 of 26 articles provided detailed US findings, even though the \nmajority of articles mentioned its use.  \n\n15 \n \nOnly 32.8% of the adolescents evaluated by ultrasound without laparoscopy showed signs of \nendometriosis, possibly due to challenges in detecting small lesions in young patients. Some \nexaminations were performed with a transrectal probe, which may have a lower sensibility for \nthis disease. However, it should be reinforced that even with normal US findings in adolescents, \nthe disease should be taken into consideratio n. Ex perienced sonographers in accurately \ndiagnosing endometriosis in this age group should be involved in the diagnosis.  \nDysmenorrhea (86.1%) and dyspareunia (22.2%) were the most frequently reported symptoms \nby Martire et al. (16) that were linked to ultrasound findings for endometriosis . In the younger \nage group (12 to 16 years old), there was a lower prevalence of posterior DIE, endometrioma, \nand adenomyosis compared with the oldest group (17 to 20 years old). Martire's studies highlight \nthe prevalence of posterior compartment involvement in adolescent patients  with \nendometriosis, contrasting with minimal reports in the anterior compartment, where only one \nlesion was reported. These results are consistent with the ones found by Ozyer 51 and Millischer \n36. This anatomical distribution supports the retrograde menstruation theory in this population, \nexplaining the preference for lesions in Douglas's pouch 52.  \nGenital tract malformations were identified as a feature associated with endometriosis , with \nadolescents with genital malformations 33 having an  earlier diagnosis and mainly \nendometriomas53.  This can be attributed to the correlation between obstructive tract anomalies \nand increased retrograde menstruation, both risk factors for severe pelvic pain and \nendometriosis 54.  Studies vary greatly in how sensitive the US is for diagnosing endometriosis. \nThe study design and the population recruitment strategy (adolescents with a laparoscopic \ndiagnosis of endometriosis) limited the calculation of the true negative and false positive rates, \nand consequently the specificity of the US. \nOur results suggest a complex landscape regarding the accuracy of ultrasound in diagnosing \nendometriosis in young females. The heterogeneity in methodologies, such as the requirement \n\n16 \n \nfor laparoscopic confirmation and retrospective data collection, contributes to varying true \npositive rates across studies. \n3. MRI findings \nIn the studies included, MRI seems to be a promising  diagnostic tool even in patients who \npreviously had normal ultrasounds. Results should be interpreted carefully, as we are not aware \nof how the previous US was performed (transvaginal/transabdominal approach, experienced \nsonographers...) and one study focused on PE. MRI provides accurate insights into various forms \nof endometriosis and proves informative in assessing the extent of organ involvement, the \npresence of lesions away from the transvaginal ultrasound field , and the severity of adhesive \nprocesses. Khashckenko et al . 28 corroborate the superior diagnostic accuracy of MRI over \nultrasound (US) for detecting PE in adolescents.  \nMillischer et al.  36 revealed an age -dependent increase in the prevalence of MRI -visible \nendometriosis, particularly among adolescents with severe dysmenorrhea, confirming that \nendometrioma and/or DIE can be observed in a large number of adolescents. Caution is \nwarranted due to the potential overestimation of DIE lesions, given the recognized rate of false \npositives in MRI, even when administered by trained radiologists. \nLimitations \nThis systematic review notes some limitations: English-only searches, a small sample size (n=26), \nand varied 'adolescent' definitions, leading to population heterogeneity. Scarce publications on \nultrasound and MRI limit understanding of their role in diagnosing  endometriosis. Also, t he \nliterature mainly comprises case series, offering low-grade evidence. Laparoscopic challenges in \ndiagnosing subtle atypical lesions such as those that are clear, white, or red being more common \nare more prone to being missed duri ng surgery even by experienced surgeons adding \ncomplexities. This means that even in reports with laparoscopically confirmed endometriosis, \nthe population might be truly underrepresented.  Selection bias comes from predominantly \n\n17 \n \nincluding adolescents with prior diagnoses. The suitability of ASRM classification is uncertain in \nthis population and data heterogeneity prevents the performance of a meta-analysis.  \nStrengths \nWhile an increasing number of papers have addressed endometriosis in adolescence in recent \nyears, this systematic review represents the first comprehensive systematic review focused on \nnon-invasive diagnostic methods for endometriosis in this specific population, with a high \nnumber of adolescents included  from many different countries. The study's strength lies in its \nmeticulous methodological design, with a registered a priori protocol, guarding against selective \nreporting and substantial deviations from t he original plan. Despite variations in age groups, \noutcome measures, and follow-up moments in the published literature, the study provides the \nmost precise overview of the current knowledge on diagnosing endometriosis in the adolescent \npopulation. Promisingly, the majority of studies in this review were classified as low risk of bias, \ncontributing to the robustness of the findings.  \nFuture research \nFuture research should not only concentrate on identifying disease markers and expanding the \nrole of MRI but also on enhancing endometriosis awareness by patients, general practitioners, \nand paediatricians for further diagnosis, emphasizing predictive algorithms for the disease stage \nsuch as questionnaires assessing women’s medical, obstetric and family history, along with the \npattern of symptoms. Continued validation and wider implementation of these algorithms may \nhelp cut down on pointless surgeries, particularly in cases where patients with severe symptoms \nand advanced disease who are not responding to current treatments might benefit  more from \nsurgery. Research on imaging methods for diagnosing endometriosis in adolescents is vital for  \nimproving diagnostic accuracy. Advances in transvaginal ultrasound criteria and additional  \ntechniques show promise. \n \n \n\n18 \n \n5. CONCLUSION  \nThis systematic review has successfully identified patterns that can offer valuable insights for \nclinicians when assessing adolescent patients with pelvic pain. Dysmenorrhea and persistent \npelvic pain were the most frequently reported symptoms while US and MRI appear to offer \nvaluable information for the disease's diagnosis when performed by qualified radiologists and \nsonographers. Posterior DIE is also identified in this  population and anterior compartment DIE \nseems rare. Furthermore, adolescents seem to experience severe pain more frequently than \nolder women. The great number of different pain symptoms and low-stage lesions, based on the \nASRM classification, reported in adolescents aligns with the hypothesis that endometriosis is a \nprogressive disease.  The review underscores the importance of non -invasive endometriosis \ndiagnosis in  adolescents, advocating for careful consideration of surgical interventions when \nimaging is normal. This represents an important step forward in understanding and managing  \nendometriosis in adolescents. \nFunding  \nThe authors declared no financial support. \nAuthor Contributions  \nAll authors contributed to the design of this review. IO and PP developed the search strategy \nwith the help of JB. After the final search, IO was the first reviewer for article screening. PP and \nJB were the independent second and third reviewers for article screening. IO and PP contributed \nto data analysis, interpretation and writing. JB contributed to data interpretation, reviewing the \narticle and approving the final version.  \nDisclosure/Conflict of Interest Statement \nThe authors declare that they have no known competing financial interests or personal \nrelationships that could have appeared to influence the work reported in this paper.  \n\n19 \n \n6. REFERENCES \n1. Hirsch M, Dhillon-Smith R, Cutner AS, Yap M, Creighton SM. The Prevalence of \nEndometriosis in Adolescents with Pelvic Pain: A Systematic Review. J Pediatr Adolesc Gynecol. \n2020;33(6):623-30. \n2. Fallon J. Endometriosis in youth. J Am Med Assoc. 1946;131:1405. \n3. Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Missmer SA, et al. Clinical \ndiagnosis of endometriosis: a call to action. Am J Obstet Gynecol. 2019;220(4):354 e1- e12. \n4. Kennedy S, Bergqvist A, Chapron C, D'Hooghe T, Dunselman G, Greb R, et al. ESHRE \nguideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20(10):2698-\n704. \n5. Schneider MP , Vitonis AF, Fadayomi AB, Charlton BM, Missmer SA, DiVasta AD. Quality of \nLife in Adolescent and Young Adult Women With Dyspareunia and Endometriosis. J Adolesc \nHealth. 2020;67(4):557-61. \n6. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244-56. \n7. Capezzuoli TC, S; Sorbi, F; Campana, D; Vannuccini, S. Classification/staging systems for \nendometriosis: the state of the art. GREM 2020. 2020;1:14-22. \n8. Stratton P , Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the \nrelationship and implications. Hum Reprod Update. 2011;17(3):327-46. \n9. Johnson NP , Hummelshoj L, Adamson GD, Keckstein J, Taylor HS, Abrao MS, et al. World \nEndometriosis Society consensus on the classification of endometriosis. Hum Reprod. \n2017;32(2):315-24. \n10. Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, et al. The social and \npsychological impact of endometriosis on women's lives: a critical narrative review. Hum \nReprod Update. 2013;19(6):625-39. \n11. Dun EC, Kho KA, Morozov VV, Kearney S, Zurawin JL, Nezhat CH. Endometriosis in \nadolescents. JSLS. 2015;19(2). \n\n20 \n \n12. Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P . High rates of autoimmune and \nendocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among \nwomen with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-24. \n13. Ghai V, Jan H, Shakir F, Haines P , Kent A. Diagnostic delay for superficial and deep \nendometriosis in the United Kingdom. J Obstet Gynaecol. 2020;40(1):83-9. \n14. Arruda MS, Petta CA, Abrao MS, Benetti-Pinto CL. Time elapsed from onset of symptoms to \ndiagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003;18(4):756-\n9. \n15. Gupta D, Hull ML, Fraser I, Miller L, Bossuyt PM, Johnson N, et al. Endometrial biomarkers \nfor the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev. 2016;4(4): \nCD012165. \n16. Martire FG, Russo C, Selntigia A, Nocita E, Soreca G, Lazzeri L, et al. Early noninvasive \ndiagnosis of endometriosis: dysmenorrhea and specific ultrasound findings are important \nindicators in young women. Fertil Steril. 2023;119(3):455-64. \n17. Wrobel M, Wielgos M, Laudanski P . Diagnostic delay of endometriosis in adults and \nadolescence-current stage of knowledge. Adv Med Sci. 2022;67(1):148-53. \n18. DiVasta AD, Vitonis AF, Laufer MR, Missmer SA. Spectrum of symptoms in women diagnosed \nwith endometriosis during adolescence vs adulthood. Am J Obstet Gynecol. 2018;218(3):324 \ne1- e11. \n19. Simpson CN, Lomiguen CM, Chin J. Combating Diagnostic Delay of Endometriosis in \nAdolescents via Educational Awareness: A Systematic Review. Cureus. 2021;13(5):e15143. \n20. Vercellini P , Vigano P , Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. \nNat Rev Endocrinol. 2014;10(5):261-75. \n21. Brosens I, Gordts S, Benagiano G. Endometriosis in adolescents is a hidden, progressive and \nsevere disease that deserves attention, not just compassion. Hum Reprod. 2013;28(8):2026-31. \n\n21 \n \n22. Campbell M MJ, Sowden A, Katikireddi SV, Brennan SE, Ellis S, Hartmann-Boyce J, Ryan R, \nShepperd S, Thomas J, Welch V, Thomson H. Synthesis without meta-analysis (SWiM) in \nsystematic reviews: reporting guideline. BMJ 2020;368:l6890. \n23. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA \n2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. \n24. Sawyer SM, Azzopardi PS, Wickremarathne D, Patton GC. The age of adolescence. Lancet \nChild Adolesc Health. 2018;2(3):223-8. \n25. Wells GA SB, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale \n(NOS) for assessing the quality of nonrandomised studies in meta-analyses \nhttps://www.ohri.ca/programs/clinical_epidemiology/oxford.asp: Ottawa Hospital Research \nInstitute; 2000  \n26. Herzog R, Alvarez-Pasquin MJ, Diaz C, Del Barrio JL, Estrada JM, Gil A. Are healthcare \nworkers' intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic \nreview. BMC Public Health. 2013;13:154. \n27. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality \nof case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. \n2020;18(10):2127-33. \n28. Khashchenko EP , Uvarova EV, Fatkhudinov TK, Chuprynin VD, Asaturova AV, Kulabukhova EA, \net al. Endometriosis in Adolescents: Diagnostics, Clinical and Laparoscopic Features. J Clin Med. \n2023;12(4). \n29. Martire FG, Lazzeri L, Conway F, Siciliano T, Pietropolli A, Piccione E, et al. Adolescence and \nendometriosis: symptoms, ultrasound signs and early diagnosis. Fertil Steril. 2020;114(5):1049-\n57. \n30. Al-Jefout M, Alnawaiseh N, Yaghi S, Alqaisi A. Prevalence of Endometriosis and Its Symptoms \namong Young Jordanian Women with Chronic Pelvic Pain Refractory to Conventional Therapy. J \nObstet Gynaecol Can. 2018;40(2):165-70. \n\n22 \n \n31. Marsh EE, Laufer MR. Endometriosis in premenarcheal girls who do not have an associated \nobstructive anomaly. Fertil Steril. 2005;83(3):758-60. \n32. Unger CA, Laufer MR. Progression of endometriosis in non-medically managed adolescents: \na case series. J Pediatr Adolesc Gynecol. 2011;24(2):e21-3. \n33. Yang Y , Wang Y , Yang J, Wang S, Lang J. Adolescent endometriosis in China: a retrospective \nanalysis of 63 cases. J Pediatr Adolesc Gynecol. 2012;25(5):295-9. \n34. Audebert A, Lecointre L, Afors K, Koch A, Wattiez A, Akladios C. Adolescent Endometriosis: \nReport of a Series of 55 Cases With a Focus on Clinical Presentation and Long-term Issues. J \nMinim Invasive Gynecol. 2015;22(5):834-40. \n35. Ragab A, Shams M, Badawy A, Alsammani MA. Prevalence of endometriosis among \nadolescent school girls with severe dysmenorrhea: A cross-sectional prospective study. Int J \nHealth Sci (Qassim). 2015;9(3):273-81. \n36. Millischer AE, Santulli P , Da Costa S, Bordonne C, Cazaubon E, Marcellin L, et al. Adolescent \nendometriosis: prevalence increases with age on magnetic resonance imaging scan. Fertil \nSteril. 2023;119(4):626-33. \n37. Wuest A, Limacher JM, Dingeldein I, Siegenthaler F, Vaineau C, Wilhelm I, et al. Pain Levels \nof Women Diagnosed with Endometriosis: Is There a Difference in Younger Women? J Pediatr \nAdolesc Gynecol. 2023;36(2):140-7. \n38. Brosens IA. Evolution of endometriotic lesions: is endometriosis a progressive disease? Prog \nClin Biol Res. 1990;323:151-6. \n39. Yeung P GS, Gieg S. Endometriosis in Adolescents: A Systematic Review. J Endometr Pelvic \nPain Disord. 2017;9(1):17-29. \n40. Stochino-Loi E, Millochau JC, Angioni S, Touleimat S, Abo C, Chanavaz-Lacheray I, et al. \nRelationship between Patient Age and Disease Features in a Prospective Cohort of 1560 \nWomen Affected by Endometriosis. J Minim Invasive Gynecol. 2020;27(5):1158-66. \n\n23 \n \n41. Vercellini P , Fedele L, Arcaini L, Bianchi S, Rognoni MT, Candiani GB. Laparoscopy in the \ndiagnosis of chronic pelvic pain in adolescent women. J Reprod Med. 1989;34(10):827-30. \n42. Laufer MR, Goitein L, Bush M, Cramer DW, Emans SJ. Prevalence of endometriosis in \nadolescent girls with chronic pelvic pain not responding to conventional therapy. J Pediatr \nAdolesc Gynecol. 1997;10(4):199-202. \n43. Emmert C, Romann D, Riedel HH. Endometriosis diagnosed by laparoscopy in adolescent \ngirls. Arch Gynecol Obstet. 1998;261(2):89-93. \n44. Goldstein DP , De Cholnoky C, Emans SJ. Adolescent endometriosis. J Adolesc Health Care. \n1980;1(1):37-41. \n45. Stavroulis AI, Saridogan E, Creighton SM, Cutner AS. Laparoscopic treatment of \nendometriosis in teenagers. Eur J Obstet Gynecol Reprod Biol. 2006;125(2):248-50. \n46. Vicino M, Parazzini F, Cipriani S, Frontino G. Endometriosis in young women: the experience \nof GISE. J Pediatr Adolesc Gynecol. 2010;23(4):223-5. \n47. Tandoi I, Somigliana E, Riparini J, Ronzoni S, Vigano P , Candiani M. High rate of \nendometriosis recurrence in young women. J Pediatr Adolesc Gynecol. 2011;24(6):376-9. \n48. Lee DY , Kim HJ, Yoon BK, Choi D. Clinical characteristics of adolescent endometrioma. J \nPediatr Adolesc Gynecol. 2013;26(2):117-9. \n49. Fong YF, Hon SK, Low LL, Lim Mei Xian K. The clinical profile of young and adolescent \nwomen with laparoscopically diagnosed endometriosis in a Singapore tertiary hospital. Taiwan \nJ Obstet Gynecol. 2017;56(2):181-3. \n50. Smorgick N, As-Sanie S, Marsh CA, Smith YR, Quint EH. Advanced stage endometriosis in \nadolescents and young women. J Pediatr Adolesc Gynecol. 2014;27(6):320-3. \n51. Ozyer S, Uzunlar O, Ozcan N, Yesilyurt H, Karayalcin R, Sargin A, et al. Endometriomas in \nadolescents and young women. J Pediatr Adolesc Gynecol. 2013;26(3):176-9. \n52. Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J \nReprod Med. 2014;2014:179515. \n\n24 \n \n53. Kapczuk K, Zajaczkowska W , Madziar K, Kedzia W. Endometriosis in Adolescents with \nObstructive Anomalies of the Reproductive Tract. J Clin Med. 2023;12(5). \n54. ACOG Committee Opinion No. 760: Dysmenorrhea and Endometriosis in the Adolescent. \nObstet Gynecol. 2018;132(6):e249-e58. \n55. Bai SW , Cho HJ, Kim JY , Jeong KA, Kim SK, Cho DJ, et al. Endometriosis in an adolescent \npopulation: the severance hospital in Korean experience. Yonsei Med J. 2002;43(1):48-52. \n56. Roman JD. Adolescent endometriosis in the Waikato region of New Zealand--a comparative \ncohort study with a mean follow-up time of 2.6 years. Aust N Z J Obstet Gynaecol. \n2010;50(2):179-83. \n57. Yeung P , Jr., Sinervo K, Winer W, Albee RB, Jr. Complete laparoscopic excision of \nendometriosis in teenagers: is postoperative hormonal suppression necessary? Fertil Steril. \n2011;95(6):1909-12, 12 e1. \n58. Andres Mde P , Podgaec S, Carreiro KB, Baracat EC. Endometriosis is an important cause of \npelvic pain in adolescence. Rev Assoc Med Bras (1992). 2014;60(6):560-4. \n59. Timur EI, Adnan & Camuzcuoglu, Aysun & Hilali, Nese & Camuzcuoglu, Hakan & Vural, \nMehmet. . Adnexal Mass Requiring Surgical Intervention in Adolescent Girls. Electron J Gen \nMed. 2015;12. \n60. Matalliotakis M, Goulielmos GN, Matalliotaki C, Trivli A, Matalliotakis I, Arici A. \nEndometriosis in Adolescent and Young Girls: Report on a Series of 55 Cases. J Pediatr Adolesc \nGynecol. 2017;30(5):568-70. \n \n \n \n \n \n\n25 \n \nFigure Legend \nFigure 1. PRISMA flowchart 23 showcasing the search method. \nN – Number \n \nTable Legends \nTable I. Characteristics of included studies in our systematic review.  \nN.Par - number of participants with clinically and/or imagistically suspected and/or confirmed diagnosis of \nendometriosis; NID - Non-invasive diagnosis method used; US - ultrasound imaging; MRI - magnetic resonance \nimaging; rASRM - revised American Society of Reproductive Medicine classification; CPP= chronic pelvic pain \n*weighted mean age \nTABLE II. Studies where endometriosis adolescent patients underwent laparoscopy/laparotomy \nand the Revised American Society for Reproductive Medicine classification of endometriosis was \nutilized (rASRM).  \nTABLE III. A - US findings in patients with clinically suspected endometriosis and US findings in \npatients laparoscopically diagnosed with endometriosis. B - Diagnostic accuracy of US findings \nin adolescent patients with clinically suspected endometriosis who underwent US and \nlaparoscopic surgery to confirm the diagnosis of endometriosis. \nNR - not reported; DIE - deep infiltrating endometriosis ; US - ultrasound; PE - peritoneal endometriosis; NR – not \nreported \n*24.1% of the adolescent population were referred to the US unit for a routine scan in the absence of any symptoms \nor clinical suspicions (270x24.1% = 65; 270 - 65 = 205). Since no asymptomatic teenager had endometrial s igns in \nultrasound, 65 adolescents were excluded from the analyses. \n**18.1% of the teenagers had routine examination referrals for the US, meaning that endometriosis was not suspected \nby the clinician in these cases.  67 teenagers were excluded from our  analyses since all endometriotic abnormalities \nhad been identified in symptomatic patients. \n***60.7% accepted laparoscopic surgery.  \n\n26 \n \nTABLE IV. Pelvic MRI findings in patients with clinically and/or imagological suspected signs of \nendometriosis  \nNR - not reported; OMA - ovarian endometrioma; DIE - deep infiltrating endometriosis; PE - peritoneal \nendometriosis  \nSupplementary Table S1. A. Bias appraisal in case-series studies included in the systematic \nreview. B. Bias appraisal in the cross-sectional studies included in the systematic review. C. Bias \nappraisal in the case-control study included in the systematic review. D. Risk of bias from the \nNOS tool for the cohort studies included in our systematic review. \nNA – not applicable; UN – unclear.  \nSupplementary Table S 2. Studies evaluating the clinical symptoms and physical examination \nfindings of endometriosis in adolescent patients with suspected or confirmed diagnosis of \nendometriosis by laparoscopy.  \nGI - gastrointestinal; GU - genitourinary; VAS - visual analogue scale; MRI - magnetic resonance imaging; NSAIDs - \nnon-steroidal anti-inflammatory drugs. \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nRecords identified from: \nMEDLINE (n = 147) \nWeb of Science (n = 191) \nSCOPUS (n=859) \nRecords removed before screening: \nDuplicate records removed  \n(n = 281) \nRecords screened \n(n = 916) \nRecords excluded (n =822) \n Not the pathology of interest (n=257) \n Not the outcome of interest (n=227) \n Different study design  (n=267) \n Not the population of interest (n=47) \n Abstract not available (n=23) \n Duplicate (n=1) \n Written in French (n=1) \n \nReports sought for retrieval \n(n = 93) Reports not retrieved (n = 9) \nIdentification of studies via databases and registers \nIdentification \nScreening \n \nReports excluded (n=58): \nNot the outcome of interest (n = 8) \nNot the population of interest (n = 12) \nNot organized in clusters by age, \ninability to extract data from the \npopulation of interest (n =37) \nData about endometriosis included in a \ncluster of non-neoplastic pathologies \n(n=1) \nReports assessed for eligibility \n(n = 84) \nStudies included in review (n = 26) \nRetrospective Cohort (n=2)  \nCase-control (n=1) \nCross-sectional (n=4) \nCase series (n=19) \nIncluded \n\nTable I. Characteristics of included studies in our systematic review. \n \nAuthor, year Country Study design Study \nperiod Population of the study* N. \nPar. \nMean \nage \nNID \nimage  Outcomes of interest Aim of the study \n \nBai, S et al \n2002 55 \nKorea \nRetrospective \nanalysis; \nCase series \n1990-\n1999 \nAdolescent girls aged 14 to 21 years \nold, who had undergone a \nlaparotomy or laparoscopy and \nwere diagnosed with \nendometriosis. \n39 20,1 - \nChief symptoms leading to the \ndiagnosis, clinical stage, age \ndistribution, and treatment modality. \nEvaluate the age distribution, diagnosis, clinical \nstage, and treatment for endometriosis in \nadolescents in Korea. \nMarsh, E et \nal, 2005 31 USA Case-series - \nPremenarcheal girls, aged 8 to 13 \nyears old, with chronic pelvic pain \nof unclear origin who underwent \nUS and laparoscopic excision of \nendometriotic lesions. \n5 - US \n \nVisual presence of endometriosis and \ndecrease in pelvic pain after destruction \nof lesions. \nIdentify endometriosis as a cause of chronic \npelvic pain in premenarcheal girls without an \nobstructive anomaly of the reproductive tract. \nRoman, J et \nal, 2010 56 \nNew \nZealand \nComparative \nCohort \n2003-\n2009 \nFemale patients aged 14 to 19 \nyears old, who underwent \noperative laparoscopy at Braemar \nHospital with the presumptive \ndiagnosis of endometriosis. \n20 17.4 US; \nMRI \nChief complaint at the initial \nconsultation; gynaecological \nexamination findings; VAS for \nendometriosis-related symptoms; \nsurgical findings. \nDescribe their experience \nwith laparoscopic excision of endometriosis in \nan adolescent  population and to compare it \nwith a non-adolescent population \ntreated during the same period.  \nVicino, M et \nal, 2010 46 Italy \nProspective \nanalysis; \nCase-series \n2005-\n2006 \nFemales aged ≤21 years who had a \nfirst surgically confirmed diagnosis \nof endometriosis. \n38 18.6 - \nAge at diagnosis, symptoms at \npresentation, and stage of disease \naccording to rASRM classification. \nAnalyze the clinical manifestations \nof endometriosis in adolescents. \nTandoi, I. et \nal, 2011 47 Italy \nRetrospective \nanalysis; \ncase series \n2000 - \n2005 \nFemale aged 16 to 21 years old \nwith a surgically and histologically \nconfirmed first diagnosis \nof endometriosis by laparoscopy or \nlapa- \n-rotomy. \n57 19 US \nRecurrence of endometriosis after \nconservative surgery for endometriosis \nbased on clinical symptoms, physical \nexamination, and US findings. \nDetermine a profile of women with a \nconsistently higher risk of recurrence who may \nbenefit from specific management strategies. \n \nUnger, C et al, \n2011 32 \nUSA \n \nCase-series \n \n- \nPatients aged 13 to 16 years old, \nwith complaints of severe pelvic \npain, and diagnosed with stage 1 \nendometriosis at the time of \nlaparoscopy. \n3 14 - \n \nClinical presentation. \n \n \nDescribe 3 cases of endometriosis progression in \nadolescents who did not maintain medical \nregimen postoperatively. \nYeung, P et \nal, 2011 57 \n USA Prospective \nanalysis; \n1999-\n2007 \nTeenagers aged 12 to 19 years old, \nwith symptoms suspicious for 17 - -  Determine long-term outcomes after complete \nlaparoscopic excision in a teenage population. \n\ncase series endometriosis who underwent \nlaparoscopic excision. \nRate of recurrent (or persistent) \nendometriosis. \nYang, Y et al, \n2012 33 \nChina \nRetrospective \nanalysis; \ncase series \n1992-\n2010 \nPatients aged 12 to 20 years of \nage who underwent surgery and \nhad a pathologically \nconfirmed diagnosis of \nendometriosis \n63 18,4 US \nClinical symptoms, \npreoperative ultrasound findings, \nsurgical procedures, and findings, and \npost-operation management \n(recurrence). \nPresent the \nexperience in diagnosis, management, and \nfollow-up of endometriosis in a Chinese \nadolescent population. \nLee, D. et al, \n2013 48 \nKorea Cross-\nsectional \n2003-\n2010 \nAdolescent females  \n≤ 20 years old who underwent \nlaparoscopic surgery for the \ntreatment of endometrioma \n35 19.2 - \nClinical characteristics include \ndemographic factors, menstrual \npatterns, and characteristics of \nendometriosis. \nEvaluate the clinical characteristics of \nendometrioma in adolescent women compared \nto women of other age groups. \nÖzyer et al, \n2013 51 \nTurkey \nRetrospective \nanalysis; case \nseries \n2007-\n2011 \nAdolescent females and young \nwomen, aged 17 to 24 years old \nwho underwent laparoscopic \nsurgery for ovarian endometrioma \n63 22 US \nSymptoms on admission; endometriosis \ncharacteristics during surgery; Adnexal \nadhesions according to rASRM \nclassification. \nEvaluate clinical aspects of endometriomas \nencountered in late adolescent females and \nyoung women and to review the issues \nspecifically related to the disease in this age \ngroup. \nAndres, M et \nal, 2014 58 \nBrazil \nRetrospective \nanalysis; \ncase series \n2008-\n2013 \nPatients, aged 13 to 20 years old, \nundergoing surgery with a \nhistological diagnosis of \nendometriosis \n21 17,9 \nUS; \nMRI \nThe clinical condition of adolescents \nwith \nEndometriosis. \nReport the clinical characteristics \nof adolescent patients with endometriosis. \nSmorgick, N \net al, 2014 50 \nUSA \nRetrospective \nanalysis; case \nseries \n2000-\n2011 \nAdolescents and young women \nwho underwent surgery for \nsuspected/confirmed \nendometriosis and were  ≤22 years \nold at the time of surgery \n86 19,9 - \nPain symptoms; indication for surgery; \nendometriosis stage reported according \nto the revised AFS classification. \nDescribe the prevalence and characteristics of \nadvanced-stage endometriosis in adolescents \nand young women. \n \nTimur, E et al, \n2015 59 \n \nTurkey \nRetrospective \nanalysis; case \nseries \n \n2008-\n2012 \nPatients < 18 years who underwent \nan operation for an adnexal mass 41 14,5 US; \nMRI \nComplaints during admission, images of \nthe masses that were detected with \ndifferent modalities, laboratory \nfindings, applied surgical procedures, \nand pathology findings. \nEvaluate preoperative findings, surgical \nprocedures, and histopathologic findings of the \nadolescent patients who had surgery for adnexal \nmass. \nDun, E et al, \n2015 11 \nUSA \nRetrospective \nanalysis; case \nseries \n2001-\n2009 \nAdolescent females, aged 10 to 21 \nyears old with endometriosis \ndiagnosed during laparoscopy for \npelvic pain \n25 17,2 - \nSymptoms, time from onset of \nsymptoms to correct diagnosis, \nnumber, and type of medical \nprofessionals seen, diagnosis, \ntreatment, and postoperative \noutcomes. \nDescribe the \nexperience of adolescents who underwent \nlaparoscopy \nfor pelvic pain and were diagnosed with \nendometriosis. \n\nRagab, A. et \nal 2015 35 \nEgypt Cross-\nsectional  \n2012-\n2014 \nAdolescent school girls from 3 \ndifferent schools covering rural and \nurban areas in Egypt, with \nsymptoms and signs suggestive of \nendometriosis \n56 15.2 US; \nMRI \nSymptoms of endometriosis, the \naccuracy of abdominal US, MRI, and \nlaparoscopic findings. \nDetermine the prevalence of endometriosis \namong adolescent school girls with severe \ndysmenorrhea. \nAudebert, A \net al, 2015 34 \nFrance \n \nRetrospective \nanalysis; \ncase series \n \n1998-\n2013 \nAdolescents, aged 12 to 19 years \nold who underwent surgical \ntreatment \nfor endometriosis. \n55 17,8 US; \nMRI \nThe main indications for surgery, \nare preoperatively ultrasound findings, \nmedical history, family history of \nendometriosis, operative findings, \nclinical symptoms, and MRI findings at \nfollow-up. \nIllustrate \nthe different clinical presentations of these \ncases while providing accurate follow-up data, \nwith a focus on the recurrence of symptoms, \ndisease, and fertility outcomes. \nFong, Y et al, \n2017 49 \nSingapor\ne \nRetrospective \nanalysis; \ncase series \n2000-\n2007 \nPatients aged 14 to 25 years old \nwho had laparoscopy for suspected \nendometriosis, with histological. \n45 - US Presenting symptoms, \nInvestigation findings (preoperative US). \n \nDescribe the disease pattern in a group of young \nAsian women with a histological diagnosis of \nendometriosis. \n \nMatalliotakis, \n2017 60 \nGreece \nRetrospective \nanalysis; case \nseries \n1996-\n2016 \nPatients aged 13 to 21 years old \nwho underwent surgical treatment \nfor endometriosis using \nlaparoscopy or laparotomy \n55 18,3 - \nPresenting symptoms, age at menarche, \nhistory of asthma, obstetric outcome, \nfamily history, and congenital \nmalformations. \nEvaluate endometriosis in adolescents and \nyoung girls; review the menstrual, reproductive \ncharacteristics, and risk factors. \nAl-Jefout, M \net al, 2018 30 Canada \nProspective \nanalysis, case \nseries \n2010-\n2014 \nFemale patients, aged 15 to 21 \nyears old, who had CPP refractory \nto conventional medical therapy \n28 18.4 US \nPresence and stage of endometriosis at \nlaparoscopy, the presence of cold \nintolerance, and the severity and \nduration of pain symptoms. \nExplore the prevalence and clinical \nmanifestations of endometriosis in young \nwomen with CPP refractory to conventional \nmedical therapy. \nDiVasta, A et \nal, 2018 18 USA Cross-\nsectional  \n2012-\n2016 \nAdolescents (diagnosed at ≤18 \nyears old) with surgically confirmed \nendometriosis. \n295  16  - \nClinical presentation - self-reported \npain, dysmenorrhea, urinary \nor bowel movement habit changes, \ninfertility. \nElucidate the symptom presentation of \nadolescents as compared with adults to \ndetermine \nwhether differences existed, based on age at \nsurgical diagnosis that \ncould impact time to diagnosis. \nStochino-Loi, \nE et al, 2020 \n40 \nFrance, \nSwitzerl\nand, \nDenmar\nk \nRetrospective \nanalysis; \ncase series \n2009-\n2014 \nAdolescent patients, aged < 20 \nyears old, who underwent surgical \nmanagement of symptomatic \nendometriosis. \n32 - - Main baseline painful symptoms \ncompared between groups of age. \nAssess the relationship between age, location of \nthe disease, and surgical procedures performed \nin patients undergoing surgical management of \nendometriosis. \n\nMartire, F et \nal, 2020 29 \nItaly \nRetrospective \nanalysis; \ncase series \n2014-\n2019 \nAdolescent patients aged 12 to 20 \nyears, who received a pelvic US \nexamination with a transvaginal \n(TVS) or transrectal (TRS) probe. \n205 18 US \nLocations of endometriosis were \nrecorded using a dedicated ultrasound \nmapping sheet and the severity of \npainful symptoms. \nEvaluate the ultrasonographic presence of \ndifferent forms of endometriosis and the \nassociated clinical symptoms in adolescent \nwomen. \nKhashchenko, \nE. P et at, \n2023 28 \nRussia Case-control \nstudy \n2020-\n2022 \nCases: Girls from menarche to 17 \nyears old with a laparoscopically \nconfirmed diagnosis of peritoneal \nendometriosis (PE); \nControls: healthy adolescent girls of \nthe same age with regular periods \nand no gynaecological and \nendocrine pathologies. \n \n90 \n(case\ns) \n \n16 \n \nUS; \nMRI. \nClinical symptoms, diagnostic accuracy \nof VAS score; \n US for the pelvic organs; \nMRI findings - frequency of suspected \nPE, location of endometriotic foci, and \naccuracy of signs in the prediction of \nlaparoscopic confirmation of PE. \nCompare the clinical features, instrumental \ndiagnostics, and surgical and histological \npeculiarities in adolescent patients with \nperitoneal endometriosis. \nMartire, F et \nal, 2023 16 \n  Italy \nRetrospective \nanalysis; \ncase series \n2016-\n2021 \nWomen aged 12–25 years were \nreferred to a gynaecological \nultrasound (US) Unit with severe \ndysmenorrhea.  \n304 20,8 US \nLocations of endometriosis using the \nUS; Painful symptoms correlated to the \ndifferent endometriosis forms. \nDiagnose endometriosis in young patients ≤ 25 \nwith severe dysmenorrhea through US findings \nand correlate the symptoms to its different \nforms. \nMillischer, A \net al, 2023 36 \nFrance \nProspective \nanalysis; \ncross-\nsectional \n2019-\n2020 \nAdolescents aged 12-20 years who \nunderwent MRI for severe \ndysmenorrhea \n345 17,4 MRI \nData on the endometriosis phenotypes \n(OMA and/or DIE) and distribution of \nanatomical lesions; \nThe severity of painful symptoms. \nEvaluate the prevalence of MRI of ovarian \nendometrioma (OMA) and deep infiltrating \nendometriosis (DIE) in adolescents presenting \nwith severe dysmenorrhea. \nWüest, 2023 \n37 \nSwitzerl\nand \nRetrospective \ncohort study \n2017-\n2020 \nPatients, aged 15 to 24 years old, \nwith a diagnosis of endometriosis \n(either clinically suspected, \ndiagnosed by examination and \nimaging, or confirmed by surgery). \n144 - US; \nMRI \nThe difference in the severity of the \nsymptoms between 2 age groups, with \nand without hormonal treatment.  \nAnalyze the clinical characteristics and severity \nof symptoms in adolescent patients with \nendometriosis compared with older patients. \nTotal 2167 18,2*  \nN.Par - number of participants with clinically and/or imagistically suspected and/or confirmed diagnosis of endometriosis; NID - Non-invasive diagnosis method used; US - ultrasound imaging; \nMRI - magnetic resonance imaging; rASRM - revised American Society of Reproductive Medicine classification; CPP= chronic pelvic pain \n*weighted mean  \n \n \n \n \n \n \n \n \n \n\nTABLE II. Studies where endometriosis adolescent patients underwent laparoscopy/laparotomy \nand the Revised American Society for Reproductive Medicine classification of endometriosis \nwas utilized (rASRM).  \n \n \nAuthor \nNo \npat. \nrASRM classification of endometriosis  \nI II III IV \nBai, et al. 55 39 4 (10%) 17 (44%) 11 (28%) 7 (18%) \nMarsh, et al. 31 5 5 (100%)    \nRoman, et al. 56 20 8 (40%) 9 (45%) 1 (5%) 2 (10%) \nVicino, et al. 46 38 7 (18.4%) 5 (13.2%) 13 (34.2%) 13 (34.2%) \nTandoi, et al. 47 57 14 (24.6%) 43 (75.4%) \nUnger, et al. 32 3 3 (100%) 0 0 0 \nYeung, et al. 57 17 5 (29.4%) 11 (64.7%) 1 (5.9%) 0 \nYang, et al. 33 63 5 (7.9%) 2 (3.2%) 33 (52.4%) 23 (36.5%) \nLee, et al. 48 35   17(49) 18(51) \nÖzyer, et al. 51 63 55 (87%) 8 (13%) \nSmorgick, et al. 50 86 58 (67%) 8(9%) 7(8%) 13(15%) \nDun, et al. 11 25 17 (68%) 5 (20%) 3 (12%) 0 \nRagab, et al. 35 27 12 (44.4%) 7 (26%) 8 (29.6%) 0 \nAudebert, et al. 34 55 33 (60%) 22 (40%) \nFong, et al. 49 45 5 (11.1%) 8 (17.8%) 19 (42.2%) 13 (28.9%) \nMatalliotakis, et al. 60 55 25 (45.4%) 20 (36.4%) 8 (14.5%) 2 (3.7%) \nAl-Jefout, et al. 30 20 9 (45%) 8 (40%) 2 (10%) 1 (5%) \nDiVasta, et al. 18 295 295   \nKhashchenko, et al. 28 90 58 (64.4%) 25 (27.8%) 7 (7.8%) 0 \nWüest, et al. 37 34 21 (61.8%) 5 (14.7%) 6 (17.6%) 2 (5.9%) \nTotal 744 552 (74.2%) 192 (25.8%) \n\nTABLE III. A - US findings in patients with clinically suspected endometriosis and US findings in \npatients laparoscopically diagnosed with endometriosis. B - Diagnostic accuracy of US findings \nin adolescent patients with clinically suspected endometriosis who underwent US and \nlaparoscopic surgery to confirm the diagnosis of endometriosis \nUS findings in patients with clinically suspected endometriosis \nAuthor, year No. \npatient \nAge \nrange   US method/device US findings (no patients, % ) \nRagab, 201535 220 NR Transabdominal probe Positive US findings (56, 25.4%) \nMartire, 202029 205* 12-20 \nVoluson E6 or E8 device \nwith \ntransvaginal/transrectal \nprobe \n≥ 1 US sign of endometriosis (36, 17.6%): \nNegative posterior sliding sign (18, \n6.7%) \nAdnexal adhesions (18, 6.7%) \nDIE (10, 3.7%)  \nEndometrioma (22, 8,1%) \nMartire, 202316 304** 12-25 \nVoluson E6 or E8 or E10 \ndevice with \ntransvaginal/transrectal \nprobe \n≥ 1 typical US sign of pelvic \nendometriosis or adenomyosis (131, \n43.1%) \nPosterior DIE (70, 18.9%) \nAnterior DIE (1, 0.3%) \nEndometrioma (54, 14.5%) \nAdenomyosis (67, 18.1%) \nAdhesions (15, 13.7%) \nTotal of patients \nwith clinically \nsuspected \nendometriosis \n729 12-25 - \n167 (32.8%) ≥ 1 sign of endometriosis in \nUS \nDIE (81/167, 48,5%) \nEndometrioma (76/167, 45.5%) \nAdenomyosis (67/167, 40.1%) \nAdhesions (33, 19.8%) \nUS findings in patients laparoscopically diagnosed with endometriosis \nYang, 2012 33 63 12-20 NR Pelvic mass (55, 87.30%) \nGenital tract malformations (15, 23.8%)  \nAudebert, 2015 34 55 12-19 NR Pelvic mass (23, 41.8%) \nMullerian abnormality (4, 7.3%) \nFong, 2017 49 42 14-25 NR Bilateral ovarian cysts (18, 42.9%) \nUnilateral ovarian cyst (23, 54.8%) \nAl-Jefout, 2018 30 20 15-21 NR Ovarian mass (8, 40%) \nEndometrioma (3, 15%) \nKhashchenko, \n2023 28 90 15-17 \nVivid-q, GE HEALTHCARE, \nwith transabdominal \nprobe \nSigns of peritoneal endometriosis (3, \n3.3%): thicker uterine walls, thicker \nendometrium, similar ovarian \nmorphologies. \nTotal of patients \nwith \nlaparoscopically \ndiagnosis of \nendometriosis  \n270 12-25 - Pelvic mass/cyst: 127 (47%) \nEndometrioma: 3 (1.1%) \n. \n \n \n \n\n \nB.  \n \nNR - not reported; DIE - deep infiltrating endometriosis ; US - ultrasound; PE - peritoneal endometriosis; NR – not \nreported \n*24.1% of the adolescent population were referred to the US unit for a routine scan in the absence of any symptoms \nor clinical suspicions (270x24.1% = 65; 270 - 65 = 205). Since no asymptomatic teenager had endometrial s igns in \nultrasound, 65 adolescents were excluded from the analyses. \n**18.1% of the teenagers had routine examination referrals for the US, meaning that endometriosis was not suspected \nby the clinician in these cases.  67 teenagers were excluded from our  analyses since all endometriotic abnormalities \nhad been identified in symptomatic patients. \n***60.7% accepted laparoscopic surgery.  \n \nAuthor US  \nFINDING \nNO \nPATIENTS \nTP (%) FP (%) FN (%) TN (%) \nYang, et al. 33 Pelvic mass 63 87.3 - 12.7 - \nAudebert, et al. 34 Pelvic mass 55 36.4 - 63.6 - \nRagab, et al. 35 NR 34*** 79.4 20.6 0 100 \nFong, et al. 49 Ovarian cyst 42 97.6 - 2.4 - \nKhashchenko, et al. 28 PE 90 3,3 - 96.7 - \n\nTABLE IV. Pelvic MRI findings in patients with clinically and/or imagological suspected signs of \nendometriosis. \nAuthor, \nyear \nNo. \nPat. \nAge \n(years)  Protocol MRI machine MRI findings (no patients, % ) \nRagab, \n201535 22 \n15.2 \n(mean \nage) \nClinical and \nsonographic \nsuspicion of \nendometriosis. \nAfter refusing \nlaparoscopy. \n- Findings of endometriosis (17, 77.3%) \nMillischer, \n202336 308 12-20 \nAfter a recorded \nclinical history \nwhere severe \ndysmenorrhea \nwas reported \n1.5T MRI \nmachine \n(Sonata; \nSiemens, \nErlangen, \nGermany)   \nFindings of endometriosis (121, 39.3%): \nIsolated OMA (14, 11.6%) \nIsolated DIE (96, 79.3%) \nDIE and OMA (11, 9.1%) \nNo visible lesion (187, 60.7%) \n \nType of endometriosis among 121 \npatients: \nOMA (25, 20.7%) \nRetrocervical lesions (106, 87.6%) \n \n \n \n \n \n \nRectosigmoid lesions (4, 3.3%) \nAssociated adenomyosis (21, 17.4%) \nUterine contractions (39, 32.2%) \nKhashchenko, \n202328 90 15-17 \nAfter clinical \nhistory and US \nimaging \nrecorded in \npatients with \nlaparoscopically \ndiagnosis of PE \nGE Signa \nExcite 1.5T \nand GE \nSigna \nArchitect \n3.0T MRI \nsystems \nPeritoneal endometriosis (71, 78.9%): \nUterosacral ligament (39.4%) \nParametrial tissue (38%) \nAlong the ovarian capsule (35.2%) \nParaovarian tissue (29.6%) \nPeritoneum and tissue of the Douglas \npouch (25,4%) \nPosterior leaf of broad ligament \n(18.3%) \nParacervical tissue (5.6%) \nTotal 420 12-20   209 (49.8%) \nNR - not reported; OMA - ovarian endometrioma; DIE - deep infiltrating endometriosis; PE - peritoneal \nendometriosis  \n \n \n\nSupplementary Table S1. A. Bias appraisal in case-series studies included in the systematic \nreview. B. Bias appraisal in the cross-sectional studies included in the systematic review. C. Bias \nappraisal in the case-control study included in the systematic review. D. Risk of bias from the \nNOS tool for the cohort studies included in our systematic review \n \nNA – not applicable; UN – unclear.  \nA. Case series studies \nJBI checklist questions/ \nAuthor, year 1 2 3 4 5 6 7 8 9 10 % \nBai, 2002 55 no yes yes no no yes no yes yes NA 50 \nMarsh, 2005 31 no yes yes no no yes yes yes yes NA 60 \nVicino, 2010 46 yes yes yes no no yes yes yes yes NA 70 \nTandoi, 2011 47 yes yes yes no no yes yes yes yes yes 80 \nUnger, 2011 32 no yes yes no no yes yes yes no NA 50 \nYeung, 2011 57 no yes yes yes no yes yes yes yes yes 80 \nYang, 2012 33 no yes yes no no yes yes yes yes yes 70 \nÖzyer,2013 51 yes yes yes no no yes yes yes yes yes 80 \nAndres, 2014 58 yes yes yes yes yes yes yes yes yes NA 90 \nSmorgick, 2014 50 yes yes yes yes no yes yes yes yes yes 90 \nTimur, 2015 59 yes yes yes no no yes no yes yes yes 70 \nDun, 2015 11 yes yes yes yes no yes yes yes yes yes 90 \nAudebert, 2015 34 no yes yes yes yes yes yes yes yes NA 80 \nFong, 2017 49 yes yes yes yes yes yes yes yes yes UN 90 \nMatalliotakis, 2017 60 yes yes yes no yes yes yes yes yes yes 90 \nAl-Jefout, 2018 30 yes yes yes yes yes yes yes yes yes yes 100 \nStochino, 2020 40 yes yes yes no UN yes yes yes yes yes 80 \nMartire, 2020 29 yes yes yes yes yes yes yes yes yes yes 100 \nMartire, 2023 16 yes yes yes yes yes yes yes yes yes yes 100 \nB. Cross-sectional studies  \nAuthor, year Selection Comparability Outcome Total \n 1 2 3 4 1 1 2  \nLee, 2013 48 *   *  ** * 5 \nRagab, 2015 35 * *  *  * * 5 \nDiVasta, 2018 18 * *   * ** * 6 \nMillischer, 2023 36 * *  * * ** * 7 \nC. Case-control study \nStudy Selection Comparability Outcome Total \n 1 2 3 4 1 1 2 3  \nKhashchenko, 2023 28 *   * * * *  5 \nD. Cohort study  \n  1  2  3  4  1  1  2  3  Total  \nRoman, 2010 56 *  *  *  -  **  *  *  -  7 (Good quality)  \nWüest, 2023 37 *  *  *  -  *  *  *  *  7 (Good quality)   \n\nSupplementary Table S 2. Studies evaluating the clinical symptoms and physical examination \nfindings of endometriosis in adolescent patients with suspected or confirmed diagnosis of \nendometriosis by laparoscopy.  \nAuthor, \nyear \nNo. \npat. \nAge \n(years) \nMethod of final \ndiagnosis \nClinical presentation \n(no, % of patients) \nCase series \n   Bai, 2002 \n55 39 14-21 Laparoscopy/ \nlaparotomy \nChronic pelvic pain (11, 27%) \nAcute pelvic pain (8, 21%) \nPalpable pelvic mass (8, 21%) \nDysmenorrhea (7, 18%) \nInfertility (1, 3%) \nVicino, \n2010 46 38 ≤ 21 Laparoscopy Pelvic pain (38, 100%) \nTandoi, \n2011 47 57 16-21 Laparoscopy/ \nlaparotomy \nDysmenorrhea (43, 75%) \nChronic pelvic pain (21, 37%) \nDyspareunia (13, 23%) \nDyschezia (3, 5.3%) \nMenometrorrhagia (1, 1.7%) \nUnger, \n2011 32 3 13-16 Laparoscopy Severe pelvic pain (3, 100%) \nYeung, \n2011 57 17 12-19 Laparoscopy \nDysmenorrhea (14, 82.4%) \nDyschezia (13, 76.5%) \nChronic Pelvic pain (13, 76.5%) \nPainful exercise (12, 70.6%) \nIntestinal cramping (10, 58.8%) \nBladder pain and tender exam (9, 52.9%) \nConstipation (7, 41.2%) \nDyspareunia (3, 17.6%) \nYang, 2012 \n33 63 12-20 \nLaparoscopy/ \nlaparotomy \n \nCyclic pelvic pain (45, 71.4%) \nAcute abdominal pain (19, 30.1%) \nGastrointestinal dysfunction (19, 30.1%) \nChronic pelvic pain (13, 20.6%) \nIrregular menses (5, 7.9%) \nDyspareunia (1, 1.6%) \nLee, 2013 \n48 35 ≤ 20 Laparoscopy Pelvic pain (27,77%) \nIncidentally (8, 23%) \nOzyer, \n2013 51 63 17-24 Laparoscopy \nChronic pelvic pain (28, 44%) \nInfertility (15, 24%) \nIncidentally (8, 13%) \nDysmenorrhea (11, 8%) \nAndres, \n2014 58 21 13-20 Laparoscopy \nDysmenorrhea (17, 80.9%) \nIncapacitating dysmenorrhea (7, 33.3%) \nChronic pelvic pain (7, 33.3%) \nDeep dyspareunia (7, 33.3%) \nCyclic bowel symptoms (3, 14.2%) \nInfertility (1, 4.7%) \nSmorgick, \n2014 50 86 ≤ 22 Laparoscopy/ \nlaparotomy \nPelvic pain (70, 81.4%) \nDyspareunia (46, 53.5%) \nGI symptoms (15, 17.4%) \nGU symptoms (10, 11.6%) \nInfertility (2, 2.3%) \nDun, 2015 \n11 25 10-21 Laparoscopy \nDysmenorrhea (16, 64%) \nAbnormal/irregular uterine bleeding (15, 60%) \nGI symptoms (14, 56%) \nGU symptoms (13, 52%) \n\nMenorrhagia (11, 44%) \nAudebert, \n2015 34 55 12-19 Laparoscopy \nDysmenorrhea (53, 96.4%) \nChronic pelvic pain, dyspareunia, acute pain, \nand/or dyschezia (47, 85.4%) \nInfertility (5, 9%) \nFong, 2017 \n49 45 14-25 Laparoscopy \nMild dysmenorrhea (20, 44.5%) \nSevere dysmenorrhea (18, 40%) \nNoncyclical pain (2, 4.4%) \nMenorrhagia (2, 4.4%) \nMatalliota\nkis, 2017 60 55 13-21 Laparoscopy \nDysmenorrhea (45, 81%) \nPelvic pain (40, 72%) \nInfertility (6, 11%) \nAl-Jefout, \n2018 30 20 15-21 Laparoscopy \nChronic pelvic pain (CPP) refractory to NSAIDs \nand hormonal therapy (20, 100%) \nCold intolerance (14, 75%) \nSevere CPP with VAS ≥ 7 (14, 70%) \nAbnormal uterine bleeding (7, 35%) \n \nStochino, \n2020 40 \n32 < 20 Laparoscopy \nDysmenorrhea (30, 93.7%) \nDeep dyspareunia (19, 76%) \nChronic pelvic pain (23, 71.9%) \nDefecation pain (10, 31.2%) \nConstipation (9, 28.1%) \nDiarrhea (8, 25%) \nMartire, \n2020 29 36 12-20 US \nDysmenorrhea (31, 86.1%) \nHeavy menstrual bleeding (20, 55.5%) \nDyspareunia (8, 22.2%) \nChronic pelvic pain (5, 13.9%) \nDyschezia (5, 13.9%) \nFunctional bowel symptoms (4, 11.1%) \nDysuria (3, 8.3%) \nMartire, \n2023 16 131 12-25 US \nDysmenorrhea (131, 100%) \nHeavy menstrual bleeding (80, 61.1%) \nDyspareunia (71, 54.2%) \nDischezia and/or bowel functional symptoms \n(58, 44.3%) \nDysuria (13, 9.9%) \nCross-sectional study \nRagab, \n2015 35 56 \n15.2 \n(mean \nage) \nUS, MRI \nSevere dysmenorrhea refractory to NSAIDs and \nhormonal therapy (56, 100%) \nGI symptoms (27, 48.2%) \nGU symptoms (15, 26.8%) \nDiVasta, \n2018 18 295 8-18 Laparoscopy \nNausea associated with pain (130, 69.5%) \nGeneral acyclic pelvic pain (194, 65.8%) \nSevere dysmenorrhea (186, 63.1%) \nModerate dysmenorrhea (86, 29.2%) \nVomiting associated with pain (45, 24.6%) \nMild dysmenorrhea (20, 6.8%) \nCase-control study \nKhashchen\nko, 2023 28 90 15-17 Laparoscopy \nDysmenorrhea moderate-severe (88, 97.8%) \nDysmenorrhea persistent to NSAIDs (86, 95.6%) \nDysmenorrhea at menarche (57, 63.3%) \nGI symptoms (35, 38.9%) \nHeavy menstrual bleeding (31, 34.4%) \n\nGI - gastrointestinal; GU - genitourinary; VAS - visual analogue scale; MRI - magnetic resonance imaging; NSAIDs - \nnon-steroidal anti-inflammatory drugs. \n \n \nGU symptoms (22, 22.4%) \nCohort study \nRoman, \n2010 56 20 14-19 Laparoscopy \nDysmenorrhea (16, 80%) \nNon-menstrual pelvic pain (4, 20%) \nWuest, \n2023 37 144 15-24 \nClinically \nconfirmed \ndiagnosis \nDysmenorrhea (133, 92.4% ) \nDyspareunia \nNon-cyclic pain \nDysuria, dyschezia \nTotal 1426 8-25 - \nDysmenorrhea (1182, 82.9%) \nPelvic pain (527/1227, 43%) \nGastrointestinal symptoms (233/1227, 19%) \nAbnormal menstrual bleeding (257, 18%) \nDyspareunia (168/1227, 13.7%) \nGenito-urinary symptoms (85/1282, 6.6%) \n\nPRISMA 2009 Checklist \nSection/topic  # Checklist item  Reported on page and paragraph/ table #  \nTITLE   \nTitle  1 Identify the report as a systematic review, meta-analysis, or both. Page 1: “Non-invasive diagnosis of endometriosis in adolescents:  \na systematic review”. \nABSTRACT   \nStructured summary  2 Provide a structured summary including, as applicable: background; objectives; \ndata sources; study eligibility criteria, participants, and interventions; study \nappraisal and synthesis methods; results; limitations; conclusions and \nimplications of key findings; systematic review registration number.  \n \nPage 2 and 3 (Abstract): “Study Objectives: Our aim was to review \n(…) management of endometriosis in adolescents.” \n \nINTRODUCTION   \nRationale  3 Describe the rationale for the review in the context of what is already known.  Page 4 (paragraph 3): “Endometriosis is remarkably responsible \nfor a decrease in women’s quality of life (QOL)…” \nPage 5: “Diagnosis of endometriosis remains a challenge \nworldwide (…) not adequate for adult women and maybe even \nless for adolescents.” \nObjectives  4 Provide an explicit statement of questions being addressed with reference to \nparticipants, interventions, comparisons, outcomes, and study design (PICOS).  \nPage 5 (paragraph 3): “This systematic review aims (…) specific \npopulation”. \nMETHODS   \nProtocol and \nregistration  \n5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web \naddress), and, if available, provide registration information including registration \nnumber. \nPage 6 (paragraph 1): “The systematic review protocol is \nregistered in the international PROSPERO database as No. \nCRD42023457516”. \nEligibility criteria  6 Specify study characteristics (e.g., PICOS, length of follow-up) and report \ncharacteristics (e.g., years considered, language, publication status) used as \ncriteria for eligibility, giving rationale.  \nPage 6 (paragraph 2): “We aimed to assess how is endometriosis \ndiagnosed in adolescent females, more specifically which non -\ninvasive diagnostic procedures are being applied in adolescents \nwith suspected endometriosis to achieve an early diagnosis. We \ntook into consideration a variety of studies from 2000 onward in \nthis analysis. Randomized controlled trials (RCTs), prospective \ncohort studies, case–control studies, retrospective cohort studies, \nand case series were screened.” \nInformation sources  7 Describe all information sources (e.g., databases with dates of coverage, \ncontact with study authors to identify additional studies) in the search and date \nlast searched. \nPage 6 (paragraph 3): “We searched three databases: \nMEDLINE/Pubmed, Scopus, and Web of Science (…) on 24 \nAugust 2023 (…) The reference list of the included studies and \nrelevant reviews on the matter were analysed to identify other \nstudies for potential inclusion in this article.” \nSearch  8 Present full electronic search strategy for at least one database, including any \nlimits used, such that it could be repeated.  \nPage 6: “The search strategy used was the query (\"adolescent\" \nOR \"adolescence\" OR \"adolescents\" OR \"pediatric\" AND \n\"endometriosis” AND (\"diagnosis\" OR \"ultrasound” OR \"MRI\") (…) \nThe search was limited to publications in the English language \nand articles published earlier than 2000 were excluded.” \n\nPRISMA 2009 Checklist \nStudy selection  9 State the process for selecting studies (i.e., screening, eligibility, included in \nsystematic review, and, if applicable, included in the meta-analysis). \n \nPage 6 and 7 (Inclusion and exclusion criteria and study \nselection): “All records identified using our search strategy were \nindependently screened by two authors based on the titles and \nabstracts, applying predetermined inclusion and exclusion criteria. \nAny discrepancies were resolved by consensus, and different \ninterpretations were resolved by a third author. The second \nselection stage was based on reviewing the full text of potentially \nrelevant articles. The same independent reviewers read relevant \nfull-text articles for inclusion.” \nData collection \nprocess  \n10 Describe method of data extraction from reports (e.g., piloted forms, \nindependently, in duplicate) and any processes for obtaining and confirming \ndata from investigators.  \nPage 7 and 8 (Data extraction): “The following data was \nindependently extracted from each of the studies to a \nspreadsheet” \nData items  11 List and define all variables for which data were sought (e.g., PICOS, funding \nsources) and any assumptions and simplifications made.  \n \nPage 7 and 8: “(…) extracted from each of the studies to a \nspreadsheet: authors, publication year, country, study design, \nstudy period, studied population, number of participants either with \nclinically suspected and/or with the confirmed diagnosis of \nendometriosis by imaging and/or laparoscopically. Other items \nincluded were the non-invasive diagnosis imaging modality \nmentioned/used, outcomes of interest, and the aim of the study. \nStudy outcomes on the clinical presentation of endometriosis, \nultrasound (US), and Magnetic resonance imaging (MRI) findings \nof endometriosis, and rASRM classification data from patients that \nhave undergone laparoscopy/laparotomy were extracted too.” \nRisk of bias in \nindividual studies / \nRisk of bias across \nstudies \n12/ \n15 \nDescribe methods used for assessing risk of bias of individual studies (including \nspecification of whether this was done at the study or outcome level), and how \nthis information is to be used in any data synthesis. \n \nPage 7 (Quality assessment): “(…) of cohort and cross-sectional \nstudies was conducted using the Newcastle-Ottawa Scale (NOS). \nFor the cross-sectional studies, an adapted NOS was used and to \nevaluate the methodological quality of the case series and \naddress potential biases in their conduct we used the JBI”  \nSummary measures  13 State the principal summary measures (e.g., risk ratio, difference in means).   \nSynthesis of results  14 Describe the methods of handling data and combining results of studies, if \ndone, including measures of consistency (e.g., I2) for each meta-analysis.  \n \nAdditional analyses  16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, \nmeta-regression), if done, indicating which were pre-specified.  \n \nRESULTS   \nStudy selection  17 Give numbers of studies screened, assessed for eligibility, and included in the \nreview, with reasons for exclusions at each stage, ideally with a flow diagram.  \nFigure I \nStudy characteristics  18 For each study, present characteristics for which data were extracted (e.g., \nstudy size, PICOS, follow-up period) and provide the citations.  \nTable I \nRisk of bias within \nand across studies  \n19/ \n22 \nPresent data on risk of bias of each study and, if available, any outcome level \nassessment (see item 12).  \nPage 9 (paragraph 1): “Among 19 case series studies assessed \nusing the JBI Critical Appraisal Checklist (…) Bias assessment \nevaluation is demonstrated in Supplementary Table S1” \n\nPRISMA 2009 Checklist \nResults of individual \nstudies  \n20 For all outcomes considered (benefits or harms), present, for each study: (a) \nsimple summary data for each intervention group (b) effect estimates and \nconfidence intervals, ideally with a forest plot.  \n \nSynthesis of results  21 Present results of each meta-analysis done, including confidence intervals and \nmeasures of consistency.  \n \nAdditional analysis  23 Give results of additional analyses, if done (e.g., sensitivity or subgroup \nanalyses, meta-regression [see Item 16]).  \n \nDISCUSSION   \nSummary of \nevidence  \n24 Summarize the main findings including the strength of evidence for each main \noutcome; consider their relevance to key groups (e.g., healthcare providers, \nusers, and policy makers). \nPage 12 , 1 3, 14, 1 5, 16 : “adolescents with endometriosis \ncommonly experience severe dysmenorrhea resistant to \nconventional treatments (…) Caution is warranted due to \nthe potential overestimation of DIE lesions, given the \nrecognized rate of false positives in MRI, even when \nadministered by trained radiologists.” \nPage 17 (strengths):“first comprehensive systematic review \nfocused on non -invasive diagnostic methods for \nendometriosis in this specific population, with a high \nnumber of adolescents included from many different \ncountries. The study's strength lies in its meticulous \nmethodological design, with a registered a priori protocol.” \nLimitations  25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-\nlevel (e.g., incomplete retrieval of identified research, reporting bias).  \nPage 16 and 17 (Limitations): “This systematic review notes \nsome limitations” \nConclusions  26 Provide a general interpretation of the results in the context of other evidence, \nand implications for future research.  \nPage 18: “This systematic review has successfully \nidentified patterns that can offer valuable insights for \nclinicians”; “Future research should not only concentrate on \nidentifying disease markers”. \nFUNDING   \nFunding  27 Describe sources of funding for the systematic review and other support (e.g., \nsupply of data); role of funders for the systematic review.  \nPage 18: “The authors declared no financial support.” \n \nFrom:  Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta -Analyses: The PRISMA Statement. PLoS Med 6(7 ): e1000097. \ndoi:10.1371/journal.pmed1000097  \nFor more information, visit: www.prisma-statement.org.  \nPage 2 of 2","source_license":"CC0","license_restricted":false}