Current Status of Clinical Diagnosis and Management of AdolescentEndometriosis

Endometriosis is a disorder characterized by the presence of functional endometrial tissue, including glands and stroma, outside the uterine cavity. When it occurs in adolescents, defined by the World Health Organization as individuals aged 10 to 19 years, it is referred to as adolescent endometriosis or early-onset endometriosis. It is one of the major pathological causes of dysmenorrhea and chronic pelvic pain in this population. Adolescent endometriosis is often insidious in onset and heterogeneous in clinical presentation, and may be accompanied by gastrointestinal and urinary tract symptoms, pain syndromes, as well as anxiety and depression. To date, there are no established noninvasive approaches for early diagnosis or effective strategies for disease prevention. As a result, adolescent endometriosis is frequently overlooked, leading to substantial diagnostic delay and seriously affecting physical and mental health as well as future fertility.

Adolescent; Endometriosis; Diagnosis; Management 1. Introduction Endometriosis (EMs) is a chronic gynecologic disorder characterized by the presence of functional endometrial tissue, including glands and stroma, outside the uterus, where it can proliferate, invade surrounding tissues, and undergo repeated bleeding, thereby leading to pain, inflammation, mass formation, and infertility [ 1]. It is one of the major causes of dysmenorrhea, chronic pelvic pain, and infertility. Its exact etiology and pathogenesis remain incompletely understood. The biological properties of the eutopic endometrium, retrograde menstruation, hormonal imbalance, immune and inflammatory factors, genetic susceptibility, and environmental exposures may all be involved in the development and progression of EMs [ 1]. The World Health Organization and the American College of Obstetricians and Gynecologists define adolescence as 10 to 19 years and 12 to 21 years, respectively, and EMs occurring during this period is generally referred to as adolescent endometriosis. A multicenter study showed that among individuals whose symptoms began between 9 and 19 years of age, the median delay to diagnosis was as long as 14.8 years, substantially longer than that observed in those with symptom onset in adulthood (20 to 30 years, 6.9 years; 31 to 45 years, 2.9 years) [2]. This diagnostic delay has been attributed to several factors, including nonspecific and relatively mild symptoms, the perception of menstruation as a negative event by both patients and their mothers, normalization of dysmenorrhea, limited awareness of the disease among some healthcare professionals, insufficient access to specialist care, and the

of currently available diagnostic tools. Together, these factors can profoundly impair quality of life, mental health, and long-term reproductive outcomes in adolescents with EMs [3]. Therefore, early recognition 20 Doi: 10.65140/gimn202601.18 and timely management of adolescent endometriosis deserve greater clinical attention. This review summarizes the current status of clinical diagnosis and management of adolescent endometriosis, with the aim of providing new perspectives for its early detection and treatment in adolescent females. 2. Prevalence and Risk Factors for Adolescent Endometriosis 2.1. Prevalence Reported prevalence rates of adolescent endometriosis vary considerably across studies, ranging from 19% to 73% [4]. Previous studies have shown that the disease most commonly develops after menarche, with an estimated prevalence of 4% to 17% among postmenarchal girls. Some patients may even develop related symptoms before menarche. Among adolescent females with chronic pelvic pain, the prevalence of endometriosis has been reported to range from 25% to 38% [5]. In those who undergo further laparoscopic evaluation for chronic pelvic pain or refractory dysmenorrhea, the detection rate increases substantially, reaching approximately 62% to 75% [6]. A systematic review further found that, among symptomatic adolescents undergoing laparoscopy, the detection rate of endometriosis ranged from 25% to 100% across studies, with a mean of 64%. Among cases staged according to the revised American Society for Reproductive Medicine classification, most lesions were classified as stage I or II, although some patients had already progressed to stage III or IV disease [7]. In an analysis of 50 adolescents with obstructive reproductive tract anomalies, Kapczuk et al. found that approximately half had concomitant endometriosis at the time of laparoscopy. Further stratified analysis showed marked differences in prevalence according to the site of obstruction, with the highest risk observed in patients with cervical aplasia [8]. 2.2. Risk Factors The etiology of adolescent endometriosis has not yet been fully elucidated, but available evidence suggests that its risk profile may reflect exposures occurring across the life course. Early-life intrauterine and perinatal exposures, such as low birth weight, preterm birth, in utero exposure to maternal smoking or diethylstilbestrol, and infant feeding patterns, may contribute to later susceptibility to endometriosis [9]. After the onset of puberty, with the establishment of menstruation, factors such as increased retrograde menstruation and outflow tract obstruction may further promote the development of ectopic lesions [8]. From adolescence to adulthood, early menarche before 12 years of age, short menstrual cycles, heavy menstrual bleeding, low body mass index, family history, and obstructive Müllerian anomalies have all been associated with an increased risk of endometriosis. In addition, some studies have suggested that migraine and asthma may also be associated with adolescent endometriosis [ 10]. Overall, adolescent endometriosis is likely to result from the combined effects of early-life susceptibility and puberty-specific exposures. 3. Clinical Features and Key Diagnostic Considerations in Adolescent Endometriosis 3.1. Clinical Presentation The clinical manifestations of adolescent endometriosis are nonspecific, with pain representing the predominant symptom. Among adolescents with pelvic pain, dysmenorrhea alone accounts for 9.4% of presentations, noncyclic pelvic pain alone for 28. 1%, and the coexistence of both for 62.5% [ 11 ]. In addition to pelvic pain, adolescents with endometriosis frequently present with gastrointestinal and urogenital symptoms. Studies have shown that 56% and 52% of laparoscopically confirmed cases report at least one gastrointestinal or urogenital symptom, respectively. Gastrointestinal symptoms mainly include nausea, abdominal bloating, tenesmus, diarrhea, and constipation, whereas urogenital symptoms commonly include bladder pain, dysuria, urinary frequency, urinary urgency, nocturia, and hematuria [ 12, 13]. Adolescent endometriosis is also associated with a substantial burden of comorbidity. Smorgick et al. reported that among adolescents and young women with endometriosis, 56% had concomitant pain syndromes, 48% had mood disorders, and 26% had asthma [ 14]. Miller et al. further found that migraine was significantly more common in adolescents with endometriosis than in those without the disease (69.3% vs 30.7%), and that migraine severity was linearly associated with an increased risk of endometriosis [ 15]. Collectively, these findings indicate that adolescent endometriosis is not merely a pelvic pain disorder, but rather a heterogeneous condition centered on pain and frequently 21 Doi: 10.65140/gimn202601.18 accompanied by gastrointestinal symptoms, urogenital manifestations, and chronic pain related comorbidities. Its complex and nonspecific clinical phenotype is a major contributor to difficulties in early recognition and to substantial diagnostic delay. 3.2. Imaging Findings Imaging plays an important role in the evaluation of adolescent endometriosis, but its diagnostic performance remains clearly limited, particularly for early-stage or superficial lesions. Therefore, negative imaging findings do not exclude the disease. In an ultrasonographic study of 270 symptomatic and asymptomatic adolescents, Martire et al. found that only 13.3% had at least one ultrasound feature suggestive of endometriosis, including ovarian endometrioma in 11. 0 % , adenomyosis in 5.2 % , and deep infiltrating endometriosis in 3.7%. Among patients with dysmenorrhea and dyspareunia, the rate of positive ultrasound findings increased to 21% and 33%, respectively. In those with bowel symptoms or dyspareunia, ultrasound features suggestive of deep infiltrating disease were detected in 33 % and 25 % , respectively [ 16 ]. These findings suggest that ultrasonography has greater diagnostic value in patients with specific symptom clusters, especially those at higher risk of deep lesions. Chinese expert consensus further emphasizes that ultrasound assessment should be performed in a systematic manner. For patients with suspected endometriosis, transvaginal ultrasonography should be used as the primary modality when feasible, with transrectal ultrasonography considered when necessary. In addition to identifying ovarian endometriomas, attention should be directed toward ovarian mobility, pelvic adhesions, the sliding sign in the pouch of Douglas, and deep infiltrating nodules in the anterior and posterior pelvic compartments [ 17, 18]. In cases with inconclusive ultrasound findings or suspicion of deep infiltrating lesions involving the bladder, rectosigmoid colon, bowel, or ureters, magnetic resonance imaging may be used to further assess lesion location and extent, although its sensitivity for superficial peritoneal lesions remains limited [ 19]. In addition, a retrospective analysis by Iosca et al. of 64 surgically confirmed cases showed that multidetector spiral computed tomography with colon water enema had relatively high diagnostic accuracy for intestinal and ureteral adolescent endometriosis [20]. However, because of radiation exposure, it is not suitable for routine use in adolescents. 3.3. Emerging Biomarkers At present, no single serum biomarker is available for the clinical diagnosis of adolescent endometriosis [21]. Compared with the adult literature, evidence on novel biomarkers in adolescents remains limited, although microRNAs have emerged as a particularly promising area of investigation. Vash-Margita et al. reported a distinct serum microRNA expression profile in adolescents and young women with endometriosis, including three upregulated microRNAs such as miR-501-5 p and 11 downregulated microRNAs such as miR-2116-5p [22]. These findings suggest potential utility as noninvasive biomarkers for early adolescent endometriosis. However, the evidence remains insufficient, and such markers cannot yet be applied in routine clinical diagnosis. 3.4. Laparoscopy Laparoscopy remains an important option when symptoms persist, empirical therapy fails to provide adequate relief, and the clinical suspicion of endometriosis remains high. In adolescents, laparoscopic findings are often less typical than those seen in adults. Lesions may appear as small white spots, reddish hyperemic areas, clear or polypoid changes, or vesicle-like lesions, rather than the blue-black implants and fibrotic changes more commonly described in adult disease [23]. Because these appearances can be subtle, failure to recognize them may lead to missed lesions or an underestimation of disease extent during surgery. 3.5. Early Diagnostic Considerations The diagnosis of adolescent endometriosis should be based on an integrated assessment of medical history, specialist examination, imaging findings, and response to treatment [ 18]. In adolescents with progressively worsening dysmenorrhea, noncyclic pelvic pain, or concomitant gastrointestinal and urogenital symptoms, particularly when nonsteroidal anti-inflammatory drugs or empirical hormonal therapy provide insufficient relief, clinicians should maintain a high index of suspicion for endometriosis. History taking should focus on pain characteristics, the temporal relationship between symptoms and menstruation, symptom onset, and previous 22 Doi: 10.65140/gimn202601.18 treatment response. Attention should also be paid to clues suggestive of obstructive reproductive tract anomalies, such as primary amenorrhea, cyclic pelvic masses, or impaired menstrual outflow. Ultrasonography is the first-line imaging modality, and magnetic resonance imaging may be used when necessary to further define lesion extent and deep infiltration. However, negative imaging does not rule out the disease. In patients in whom obstructive reproductive tract anomalies and other structural disorders have been excluded but clinical suspicion for endometriosis remains high, empirical treatment may be initiated first. If symptoms persist despite treatment and imaging remains nondiagnostic, laparoscopy should be further considered. Overall, the diagnosis of adolescent endometriosis relies on early recognition based on clinical suspicion, dynamic reassessment during treatment, and stratified use of different diagnostic modalities. 4. Treatment of Adolescent Endometriosis Adolescent endometriosis (EMs) lacks a universally standardized, dedicated management strategy. Current treatment principles emphasize individualized, long-term management, with the primary goals of pain control, suppression of disease progression, preservation of fertility, and reduction of recurrence risk. Given that adolescents are in a critical phase of skeletal and reproductive system development, therapeutic decision-making should comprehensively consider age, symptom burden, disease extent, as well as drug safety, tolerability, and adherence. For patients without clear surgical indications, medical therapy remains the cornerstone of management. In contrast, surgical intervention should be considered in cases complicated by obstructive reproductive tract anomalies, evident disease progression, or inadequate response to standardized medical treatment [6, 24]. 4.1. Medical treatment 4. 1.1. Nonsteroidal anti inflammatory drugs Nonsteroidal anti inflammatory drugs (NSAIDs) are first line agents for symptomatic relief of pain associated with adolescent endometriosis [26]. They exert analgesic effects mainly by inhibiting cyclooxygenase activity and reducing prostaglandin synthesis. Their role is primarily analgesic rather than disease-controlling. Although NSAIDs can reduce pain, they do not prevent progression of endometriotic lesions and therefore cannot be relied upon as the main long-term approach when suppression of disease activity is required. Current evidence is also insufficient to determine whether individual NSAIDs differ meaningfully in efficacy or safety [27,28 ]. Gastrointestinal intolerance remains a practical concern, and prolonged use warrants vigilance for gastrointestinal bleeding as well as hepatic and renal toxicity. 4. 1.2. Combined oral contraceptives Combined oral contraceptives (COCs) are commonly used in the medical management of adolescent endometriosis and are particularly relevant when pain is not adequately controlled with NSAIDs alone. In adolescents, they are generally regarded as well tolerated and suitable for long-term use, as available evidence has not shown meaningful adverse effects on short-term growth-related measures such as height, weight, or body fat indices [6, 18]. Their clinical benefit is mainly attributed to suppression of the hypothalamic-pituitary-ovarian axis, which reduces estrogenic stimulation of ectopic endometrial tissue and thereby limits lesion activity and promotes regression [26]. In practice, COCs are used primarily for the control of mild to moderate pain symptoms, including dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain, and can contribute to improved quality of life. Continuous administration may offer better symptom control than cyclic regimens, although this advantage is often offset by a higher frequency of breakthrough bleeding or irregular vaginal bleeding, which may affect adherence in some patients. The choice of regimen should therefore be individualized according to symptom severity and the patient’s ability to tolerate unscheduled bleeding [27,28]. 4. 1.3. Progestins Progestins relieve pain and suppress lesion activity by inducing decidualization and atrophy of both eutopic endometrium and ectopic lesions, while also creating a relatively hypoestrogenic state [29]. Dienogest, a newer progestin, has been shown to alleviate endometriosis related pain and reduce the size of ovarian 23 Doi: 10.65140/gimn202601.18 endometriomas [30]. It has relatively limited effects on liver function, renal function, and bone mass, and may therefore be used in the treatment of adolescent endometriosis [31]. Nevertheless, adolescence is a critical period for bone mass accrual, and prolonged progestin use may carry a risk of bone loss [32]. Its use in this population therefore requires careful balancing of clinical efficacy against skeletal safety. 4. 1.4. Gonadotropin releasing hormone agonists Gonadotropin releasing hormone agonists (GnRH agonists) suppress hypothalamic pituitary ovarian axis function and induce a hypoestrogenic state, thereby relieving symptoms and inhibiting lesion activity. They are widely regarded as among the most effective medications for endometriosis [33]. However, treatment with GnRH agonists may cause a range of hypoestrogenic adverse effects, including hot flushes, night sweats, sleep disturbance, decreased libido, and mood changes, while also increasing the risk of bone loss. Their use in adolescents should therefore be approached with caution. In clinical practice, GnRH agonists are generally considered only for patients older than 16 years, and add back therapy should be initiated from the start of treatment [34]. 4. 1.5. Traditional Chinese medicine Traditional Chinese medicine may serve as an adjunctive option for pain management in adolescent endometriosis. Available studies suggest that formulas such as Guizhi Fuling, Sanjie Zhentong, and Shaofu Zhuyu may provide analgesic benefit [35-37]. 4. 1.6. Other medications In addition to the agents commonly used in current practice, gonadotropin releasing hormone antagonists, aromatase inhibitors (AIs), selective progesterone receptor modulators (SPRMs), selective estrogen receptor modulators (SERMs), dopamine receptor 2 agonists, and statins have also been investigated for the treatment of endometriosis [38]. Among these, GnRH antagonists and aromatase inhibitors are developing relatively rapidly. The former have already entered clinical use in adults, whereas the latter are mainly reserved for refractory cases [21]. By contrast, SPRMs, SERMs, dopamine receptor 2 agonists, statins, and anti nerve growth factor antibodies remain largely exploratory. Overall, evidence regarding the efficacy and safety of these newer agents in adolescents remains insufficient, and they should not currently be recommended for routine treatment in this population. 4.2. Surgical treatment In clinical practice, treatment of adolescent endometriosis is centered primarily on nonsurgical approaches, particularly NSAIDs and hormonal therapy. The timing of initial surgical intervention must be determined with great caution. Surgery performed too early may increase the risks of loss of normal ovarian tissue, diminished ovarian reserve, and repeat operations, whereas delayed surgery may allow further disease progression, distortion of pelvic anatomy, and impairment of organ function. Both scenarios may ultimately compromise fertility in adolescent patients [39]. At present, surgery is generally considered for adolescents with endometriosis who fail to respond after 3 to 6 months of standardized medical treatment, or who present with infertility, lesions of uncertain nature with suspected malignancy, acute complications, or obstructive reproductive tract anomalies; such procedures should be undertaken by an experienced multidisciplinary team [40,41]. Laparoscopy is the preferred surgical approach because it is minimally invasive and provides excellent visualization. The goals of surgery are to remove lesions, restore normal pelvic anatomy, relieve obstruction, and preserve ovarian function and fertility to the greatest extent possible [21]. Compared with adults, adolescents are more likely to have early stage disease, and laparoscopic lesions often appear as vesicular, white punctate, or red petechial peritoneal lesions rather than the more typical pigmented lesions seen in adults [42]. As a result, the risk of intraoperative underrecognition is relatively high. Surgeons should therefore be familiar with the laparoscopic morphology of adolescent endometriotic lesions. When necessary, high definition laparoscopy with close up magnified inspection and underwater inspection after saline instillation may be used to improve lesion detection [ 10]. In addition, suspicious peritoneal lesions should preferably be excised with cold instruments rather than coagulated, so as to avoid thermal destruction of tissue that may compromise histopathologic evaluation [43 ]. For patients with ovarian endometriomas [44], meticulous cyst dissection is essential. Electrocautery should be minimized during hemostasis to reduce thermal injury to ovarian tissue, and alternative methods such as suturing or hemostatic sealants may be considered. If lesion ablation is required, plasma energy or carbon dioxide laser should be preferred. At the end of surgery, anti adhesion agents such as oxidized regenerated cellulose or hyaluronic acid carboxymethylcellulose may also be considered to reduce postoperative adhesion formation. Following surgery, adolescents with endometriosis still require long term medical management, together with psychological support and health education, in order to reduce recurrence and delay disease progression. 5. Conclusion Adolescent endometriosis is an estrogen-dependent disease with chronic inflammatory and progressive features. Although symptoms often become evident during adolescence, the processes that predispose to disease onset and progression may begin much earlier in life and may be linked to intrauterine and perinatal exposures, along with genetic background, immune dysregulation, and menstrual characteristics. Adolescents represent a distinct clinical population, and no single optimal treatment strategy has yet been defined for them. Management should be tailored to the patient’s symptoms and clinical needs, with attention to the early identification of suspected cases and, when appropriate, the timely use of empirical medical therapy. The expected benefits and potential adverse effects of different medications also need to be weighed carefully. If surgery is required, it should be performed at an appropriate time by experienced specialists, and laparoscopic procedures should be carried out as carefully as possible to preserve ovarian function. After surgery, ongoing medical treatment remains important until pregnancy is desired, with the goals of slowing disease progression, reducing recurrence, and safeguarding future fertility.

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