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Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Guidelines".

Deadline for manuscript submissions: 20 August 2026 | Viewed by 7040

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Prof. Dr. Philippe R. Koninckx

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1. Departments of Obstetrics and Gynecology, Katholieke University Leuven, 3000 Leuven, Belgium
2. Departments of Obstetrics and Gynecology, University of Oxford, Oxford OX1 2JD, UK
3. Departments of Obstetrics and Gynecology, University Cattolica, del Sacro Cuore, 00168 Rome, Italy
Interests: endometriosis; laparoscopic surgery; reproductive medicine; endocrinology; menopause; statistics; LUF syndrome

Prof. Dr. Arnaud Wattiez

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1. Departments of Obstetrics and Gynecology, University of Strasbourg, 67081 Strasbourg, France
2. Departments of Obstetrics and Gynecology, Faculty of Medicine, Latifa Hospital, Dubai 9115, United Arab Emirates
Interests: endometriosis; gynecology; ovarian pregnancy; chronic pelvic pain; infertility

Prof. Dr. Sun-Wei Guo

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Guest Editor

1. Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
2. Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
Interests: endometriosis; adenomyosis
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Special Issue Information

Dear Colleagues,

The first goal of this Special Issue will be to explore how the evidence-based management of endometriosis [1] can be updated by collective clinical experience [2,3]. This is important since, for endometriosis, evidence is limited in the absence of a suitable animal model. Also, most clinical decisions are multivariate, which conflicts with monovariate trial evidence. This is especially important for surgery.

Therefore, all clinicians with extensive experience in managing endometriosis are invited to suggest and their plans in their specific area of their expertise in diagnosis or treatment. The collective experience of the authors will reflect the strength of the recommendations. This also permits us to discuss what should not be performed [4], or how skills and heuristics should be trained.

The second goal is to highlight new research findings that should be brought to the attention of clinicians. This is important to fill the gap between clinicians and surgeons with a large clinical load and important laboratory research. This is important since both groups, living in different information environments, can learn from each other.

This Special Issue will be the first attempt to formulate clinical guidelines based on collective expert opinion and to expose clinical needs and researchers’ opportunities.

Reference List

Becker, C.M.; Bokor, A.; Heikinheimo, O.; Horne, A.; Jansen, F.; Kiesel, L.; King, K.; Kvaskoff, M.; Nap, A.; Petersen, K.; et al. ESHRE guideline: endometriosis. Hum Reprod Open 2022, 2022, hoac009, doi:10.1093/hropen/hoac009.
Koninckx, P.R.; Ussia, A.; Stepanian, A.; Saridogan, E.; Malzoni, M.; Miller, C.E.; Keckstein, J.; Wattiez, A.; Page, G.; Bosteels, J.; et al. The Evidence-Based Medicine Management of Endometriosis Should Be Updated for the Limitations of Trial Evidence, the Multivariability of Decisions, Collective Experience, Heuristics, and Bayesian Thinking. Journal of Clinical Medicine 2025, 14, 248, doi:10.3390/jcm14010248.
Koninckx, P.R.; Ussia, A.; Miller, C.; Guo, S.-W.; Lesaffre, E.; Wattiez, A.; Adamyan, L. How to bridge the gap between evidence-based and clinical management of endometriosis. Journal of Endometriosis and Uterine Disorders 2025, 100123.
Koninckx, P.R.; Ussia, A.; Gordts, S.; Keckstein, J.; Saridogan, E.; Malzoni, M.; Stepanian, A.; Setubal, A.; Adamyan, L.; Wattiez, A. The 10 “Cardinal Sins” in the Clinical Diagnosis and Treatment of Endometriosis: A Bayesian Approach. J Clin Med 2023, 12, 4547, doi:10.3390/jcm12134547.

Prof. Dr. Philippe R. Koninckx
Prof. Dr. Arnaud Wattiez
Prof. Dr. Sun-Wei Guo
Guest Editors

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Keywords

endometriosis
guidelines
surgery
medical treatment
training
heuristics

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Published Papers (8 papers)

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Research

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16 pages, 3317 KB

Open AccessArticle

Clinical Value of Circulating Endometrial Cells in the Diagnosis and Stratified Diagnosis of Endometriosis

by Shang Wang, Buyun Li, Xue Ye, Qianchen Tai, Hongyan Cheng, Honglan Zhu, Huiping Liu, Xiaoting Wei, Jingjing Gong, Xiaohua Zhou and Xiaohong Chang

J. Clin. Med. 2026, 15(8), 3021; https://doi.org/10.3390/jcm15083021 - 15 Apr 2026

Viewed by 288

Abstract

Background/Objectives: The diagnosis of endometriosis (EM) remains challenging due to the lack of a perfect diagnostic standard and the poor concordance between clinical symptoms and lesion severity. Although laparoscopy is widely used in clinical practice, it is invasive and associated with a non-negligible false-negative rate, while serum CA125 has limited diagnostic accuracy. In our previous studies, circulating endometrial cells (CECs) were identified in the peripheral blood of patients with EM, suggesting their potential as a non-invasive biomarker. Building on this finding, the present study aimed to systematically evaluate the clinical value of CECs in the diagnosis and stratified diagnosis of EM in the absence of a perfect diagnostic reference standard. Methods: Female patients treated at the Department of Obstetrics and Gynecology, Peking University People’s Hospital, between June 2022 and June 2024 were enrolled. Participants were clinically classified according to laparoscopic evaluation into an EM group and a non-EM group. However, laparoscopy was not treated as a definitive diagnostic gold standard in the statistical analysis. Instead, given the absence of a perfect reference standard, nonparametric latent class analysis was applied to jointly estimate disease status and the diagnostic performance of CECs, CA125, and laparoscopy. Patients with EM were further stratified according to dysmenorrhea severity (mild, moderate, and severe), lesion activity status (active or dormant), and menstrual cycle phase. Peripheral blood samples were collected from all participants, and CECs were detected using subtraction enrichment combined with immunofluorescence and fluorescence in situ hybridization (SE-iFISH). Serum CA125 levels were measured concurrently. Results: A total of 302 participants were included. The primary analysis focused on 133 surgically confirmed EM patients and 146 non-EM controls. After adjustment for an imperfect diagnostic reference standard, CECs demonstrated superior diagnostic performance compared with serum CA125 in the overall cohort, with higher sensitivity (0.58 vs. 0.37) and specificity (0.81 vs. 0.75). Under laparoscopic assessment in patients with severe dysmenorrhea (VAS ≥ 7), where the sensitivity and specificity were 0.759 and 1.00, respectively, CECs demonstrated superior diagnostic performance compared with serum CA125, with higher sensitivity (0.694 vs. 0.355) and specificity (0.946 vs. 0.429). Similarly, in patients with active EM, where laparoscopy showed a sensitivity of 0.79 and a specificity of 1.00, CECs again demonstrated superior diagnostic performance compared with CA125 (sensitivity 0.73 vs. 0.35; specificity 0.96 vs. 0.31), showing high concordance with laparoscopic diagnosis. When stratified by menstrual cycle phase, CECs maintained superior diagnostic performance over CA125 during both the proliferative and menstrual phases, with higher sensitivity (0.84 vs. 0.44) and specificity (0.83 vs. 0.65). Conclusions: Circulating endometrial cells (CECs) demonstrate high diagnostic accuracy for EM, significantly outperforming serum CA125, and show high concordance with laparoscopic diagnosis across clinically relevant stratified conditions in the absence of a perfect diagnostic gold standard. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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12 pages, 7322 KB

Open AccessArticle

Clinical Efficacy of Dienogest for Symptomatic Adenomyosis

by Yejin Kwon, Ju Hee Kim, Hee Dong Chae, Sa Ra Lee and Sung Hoon Kim

J. Clin. Med. 2026, 15(7), 2763; https://doi.org/10.3390/jcm15072763 - 6 Apr 2026

Viewed by 404

Abstract

Background: This study was conducted to assess whether medical treatment with dienogest (DNG) is effective in women with symptomatic adenomyosis. Methods: This single-center, retrospective study included patients with symptomatic adenomyosis treated with oral DNG 2 mg daily. We evaluated the clinical symptoms, uterine volume, and serum CA-125 levels in these patients along with adverse events at baseline and after 3, 6, 12, 18, and 24 months of treatment, respectively. Results: A total of 102 patients were analyzed. Among women with dysmenorrhea, 79.5% reported improvement in dysmenorrhea, and the mean time to improvement in dysmenorrhea was 7.18 months. Improvement in heavy menstrual bleeding was observed in 88.3% of patients, with a mean time to improvement in heavy menstrual bleeding of 5.44 months. We could see that the uterine volume decreased significantly after 18 months of treatment. Serum CA-125 levels declined significantly from 3 months onward and remained reduced through 24 months. More than half of the patients (55.8%) continued DNG without complications, whereas 31.3% discontinued treatment or switched to alternative therapies. Conclusions: DNG effectively improved clinical symptoms and reduced uterine volume and serum CA-125 levels without serious adverse events in patients with symptomatic adenomyosis. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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25 pages, 1928 KB

Open AccessArticle

Surgically Relative Risk Factors for Lower Colorectal Anastomotic Dehiscence and Rectovaginal Fistulas in Complex Deep Endometriosis Cases: A Single-Center Retrospective–Prospective Cohort Study

by Krzysztof Nowak, Alicja Dąbrowska, Maja Mrugała and Ewa Milnerowicz-Nabzdyk

J. Clin. Med. 2026, 15(7), 2630; https://doi.org/10.3390/jcm15072630 - 30 Mar 2026

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Abstract

Background: Bowel surgery is a key component of advanced deep endometriosis management, with anastomotic leakage representing the most serious postoperative complication. This study aimed to identify risk factors for dehiscence after lower colorectal anastomosis and to determine effective preventive measures. Methods: This retrospective/prospective study included 425 consecutive patients aged 37.7 ± 6.0 years with laparoscopical bowel resection due to multiorgan complex deep endometriosis. All bowel surgeries were performed with use of indocyanine green (ICG). Many technical aspects of surgery and preventive procedures were analyzed which could impact leakage risk of surgery. Results: Endometriotic nodules were resected with segmental bowel resection (n = 294; 69.8%), discoid bowel resection (n = 84; 20.0%), and shaving procedure (n = 43; 10.2%). A total of 12 dehiscence events occurred (2.8%), including intraperitoneal leakage (n = 1; 0.2%), rectovaginal fistula (RVF) (n = 10; 2.3%), and rectoureteral fistula (n = 1; 0.2%); no rectovesical fistulas were observed. RVF developed only following segmental resections. Protective measures used during lower bowel procedures included fibrin glue (n = 375; 88.2%), omental flaps (n = 86; 20.2%), reinforcing sutures (n = 33; 7.8%), protective stomas (n = 25; 5.9%), and ghost stomas (n = 14; 3.3%). Among patients who developed RVFs, 90% had no protective stoma, and these cases were predominantly associated with low (from 6 to <8 cm; n = 4/77; 5.2%) and very low (from 5 to <6 cm; n = 4/10; 40%) anastomoses. In very low anastomoses (n = 4), 1 RVF occurred despite a protective stoma but there existed other strong risk factors, such as levator ani infiltration and vagina opening, whereas 3 others RVF developed in patients without a protective stoma. Notably, in ultra-low anastomoses (<5 cm), protective stomas prevented the anastomosis in 100%, and no fistula was observed (n = 3). The following factors were associated with the increased rate of RVF: segmental resection (p = 0.0355), low and very low anastomosis (p = 0.0010), lateral infiltration of the levator (p < 0.0001), concomitant hysterectomy or vaginal opening (p = 0.051), and prolonged operative time (p = 0.0010), Clostridioides difficile infection (p = 0.0001). Conclusions: RVFs occurred mainly after segmental resection (no other type of bowel resection), with very low anastomosis (5–6 cm from anal verge), in patients with levator ani infiltration and concomitant vaginal or uterine surgery; in such situations, discoid resection is the safer option. Despite the complexity of procedures, preventive strategies maintained a low overall RVF rate; no RVFs occurred in ultra low anastomoses (<5), indicating effective prevention with protective stomas. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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12 pages, 919 KB

Open AccessArticle

Endometriosis Is Associated with Increased Serum and Peritoneal Fluid Concentrations of Chromogranin A and Its Derivatives

by Alicja Sztokfisz-Ignasiak, Maja Owe-Larsson, Maciej Maj, Hubert Rytel, Kateryna Shevchenko, Filip Dąbrowski, Piotr Laudański, Mikołaj Pater, Izabela Róża Janiuk and Jacek Malejczyk

J. Clin. Med. 2026, 15(4), 1567; https://doi.org/10.3390/jcm15041567 - 16 Feb 2026

Viewed by 1092

Abstract

Background/Objectives: Endometriosis is a prevalent gynecological illness associated with chronic pain, inflammation, and infertility, as ectopic endometrial lesions are formed. No fully effective treatment is available, and the pathogenesis of this disease is unclear. The survival of ectopic endometrial cells is facilitated by their low susceptibility to apoptosis, an immunosuppressive environment, and local angiogenesis. Chromogranin A (CgA), a glycoprotein prohormone, modulates various processes including angiogenesis and innate immunity, and its higher levels are detected in neuroendocrine tumors and inflammatory disorders. Since endometriosis may be considered an autoinflammatory disorder, this study aimed to evaluate serum and peritoneal fluid concentrations of CgA and its derivatives, catestatin and pancreastatin, and to correlate these levels with disease severity. Methods: The study was conducted on samples of serum and peritoneal fluid (PF) obtained from 65 women diagnosed with endometriosis and from 60 control individuals who underwent surgery for other reasons. The concentrations of CgA, catestatin, and pancreastatin were assessed in the collected samples by specific enzyme-linked immunosorbent assays. Results: CgA, catestatin, and pancreastatin concentrations were significantly higher in the sera and PF of endometriosis patients compared to controls. There was a correlation between their serum and PF levels, and all tested factors were correlated with each other in both serum and PF. Serum concentrations of CgA, catestatin, and pancreastatin were also associated with disease progression. Receiver operating characteristic (ROC) analysis further confirmed that endometriosis is associated with increased circulating CgA, catestatin, and pancreastatin levels, suggesting that they may be considered markers of endometriosis. Conclusions: The upregulation of CgA and its derivatives in endometriosis may indicate their role in the disease pathogenesis and implicate them as potential diagnostic markers and/or therapeutic targets. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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14 pages, 5930 KB

Open AccessArticle

The Levonorgestrel Intrauterine System Attenuates the Expression of Angiopoietin-1, Angiopoietin-2, and Vascular Endothelial Growth Factor in Adenomyosis

by SiHyun Cho, Hyun Kyung Kim, Young Sik Choi and Joo Hyun Park

J. Clin. Med. 2025, 14(24), 8629; https://doi.org/10.3390/jcm14248629 - 5 Dec 2025

Cited by 1 | Viewed by 687

Abstract

Background/Objectives: Adenomyosis is characterized by aberrant endometrial invasion and heavy menstrual bleeding, with angiogenesis being implicated as a key mechanism of this condition. We compared vascular endothelial growth factor (VEGF), angiopoietin-1 (ANGPT-1), and angiopoietin-2 (ANGPT-2) expression in eutopic and ectopic endometria from patients with adenomyosis and evaluated whether the levonorgestrel intrauterine system (LNG-IUS) modulates these angiogenic markers. Methods: In a case–control analysis, specimens from patients with adenomyosis without an LNG-IUS (n = 20), those with adenomyosis with prior LNG-IUS insertion (n = 18), and controls (n = 12) were analyzed. Immunohistochemistry with H-scores was used to assess protein expression in eutopic and ectopic tissues. ANGPT1, ANGPT2, and VEGFA mRNA in eutopic endometrial tissue were quantified by qRT-PCR. Results: In untreated adenomyosis patients, ectopic endometria showed higher protein expression than eutopic tissue for ANGPT-1, ANGPT-2, and VEGF (all p ≤ 0.05). The LNG-IUS was associated with significantly lower expression of all three markers in both eutopic and ectopic tissue (all p < 0.01), with eutopic levels approaching those of controls. qRT-PCR findings corroborated the decrease in ANGPT1, ANGPT2, and VEGFA transcript levels after LNG-IUS insertion (all p < 0.05). Conclusions: Adenomyosis is characterized by upregulated angiogenic signaling in both eutopic and ectopic endometria. The LNG-IUS attenuates ANGPT-1, ANGPT-2, and VEGF expression at both the protein and transcript levels, suggesting that modulation of angiogenic pathways may contribute to its therapeutic benefit in abnormal uterine bleeding associated with adenomyosis. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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23 pages, 294 KB

Open AccessArticle

Psychosocial Factors and Disease Localization as Independent Predictors of Sexual Dysfunction in Women with Endometriosis

by Paula Norinho, Rosa Zulmira Vaz de Macedo, Mariana M. Martins and Hélder Ferreira

J. Clin. Med. 2025, 14(21), 7788; https://doi.org/10.3390/jcm14217788 - 2 Nov 2025

Viewed by 1115

Abstract

Background: This study examines the impact of endometriosis on sexual function, focusing on disease localization, pain severity, and psychosocial factors. It integrates the rASRM and Enzian classification systems to explore anatomical contributions to sexual dysfunction. Methods: In a cross-sectional study, 102 patients with confirmed endometriosis completed an online evaluation. Of these, 77 had surgical and histological confirmation, and 25 had no prior surgery. Thirty-five participants were using hormonal therapy. Validated instruments assessed sexual function, pain intensity (VAS), and psychosocial variables. Analyses included univariate tests and multivariate logistic regression. Results: Deep infiltrating endometriosis involving the sacrouterine ligaments, cardinal ligaments, and pelvic sidewall (Enzian B) was associated with sexual dysfunction, highlighting the anatomical utility of the Enzian system. Surprisingly, those with sexual dysfunction reported lower pain scores (p = 0.024 *). In multivariate analysis (R² = 0.281), no individual factor, including Enzian B involvement or EHP scores, remained significant. No associations were found between sexual dysfunction and anxiety, depression, stress, or relationship satisfaction, though pain was inversely correlated with anxiety (p = 0.025 *). Conclusions: Sexual dysfunction in endometriosis appears multifactorial, not solely driven by lesion burden or pain. A multidisciplinary approach is recommended, addressing anatomical, psychological, and behavioral dimensions. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

Review

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37 pages, 1703 KB

Open AccessReview

Medical Treatment for Endometriosis: One Size Does Not Fit All

by Paolo Vercellini, Noemi Salmeri, Veronica Bandini, Beatrice Conca, Paola Viganò, Edgardo Somigliana and Michele Vignali

J. Clin. Med. 2026, 15(6), 2408; https://doi.org/10.3390/jcm15062408 - 21 Mar 2026

Viewed by 828

Abstract

Endometriosis is associated with nociceptive pain, as well as peripheral and central sensitization. Evidence-based treatment suggestions for controlling endometriosis should be based on the convergence of the best scientific evidence, physicians’ clinical expertise, and the values and priorities of individual patients. In this non-systematic, comprehensive narrative review, data from available randomized controlled trials and meta-analyses on hormonal treatment for symptomatic endometriosis are interpreted through the lens of clinical experience. The role of patients in defining therapeutic trade-off balances is also taken into consideration. Most symptomatic patients benefit from hormonal therapy, including first-line (progestogens and estrogen-progestogen combinations) and second-line (GnRH agonists and antagonists) medications, to relieve nociceptive pain. To reduce the risk of venous and arterial thrombosis and avoid stimulating lesions, it is preferable to use combinations containing body-identical estrogens rather than ethinyl-estradiol. The main adverse effect of first-line medications is irregular bleeding, which adversely impacts efficacy, tolerability, and adherence. If progestogens and estrogen-progestogens do not improve health-related quality of life (HRQoL), promptly stepping up to GnRH analogues combined with add-back therapy is indicated. Add-on rather than upfront combination therapy is suggested. Separating the analogues and add-back therapy allows for choosing the compounds that best suit the characteristics of individual patients. Transdermal body-identical estradiol use is proposed in combination with both progestogens and GnRH analogues. Similar satisfactory outcomes are achieved with GnRH agonists and antagonists. Evidence on the use of neuromodulatory drugs to treat neuropathic and nociplastic pain is derived from studies of other chronic pain conditions and shows limited effectiveness. The two mainstays of hormonal therapy are (i) ovariostasis and (ii) amenorrhea. “Medical treatment failure” should not be declared unless a shift from first-line to second-line medications has been undertaken whenever these conditions are not met. For severely symptomatic adolescents and young women, secondary prevention through ovariostasis and amenorrhea should be pursued promptly to improve HRQoL, halt lesion progression, and preserve reproductive potential. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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14 pages, 1014 KB

Open AccessReview

Understanding Peritoneal Fluid Estrogen and Progesterone Concentrations Permits Individualization of Medical Treatment of Endometriosis-Associated Pain with Lower Doses, Especially in Adolescents Not Requiring Contraception

by Philippe R. Koninckx, Anastasia Ussia, Leila Adamyan, Arnaud Wattiez and Paola Vigano

J. Clin. Med. 2025, 14(20), 7196; https://doi.org/10.3390/jcm14207196 - 12 Oct 2025

Cited by 3 | Viewed by 1526

Abstract

Objectives: The aim of this study was to review the importance of peritoneal fluid steroid hormone concentrations to understand the mechanism of hormonal medical treatment of endometriosis-associated pain. Design: The study included a PubMed search and a pilot trial in 8 adolescents. Results: Oral contraceptives (OCs) were designed to inhibit ovulation in all women, and doses are much higher than the mean ovulation-inhibiting dose. Therefore, in most women, half a dose and in some women, even less is sufficient to inhibit ovulation. The inhibition of ovarian function and ovulation decreases estrogen and progesterone concentrations in plasma and peritoneal fluid. Surprisingly, the effect on peritoneal fluid steroid hormone concentrations has not been considered to explain the impact on endometriosis-associated pain. The lowering of the high estrogen concentrations in peritoneal fluid is sufficient to explain the pain decrease in superficial and ovarian endometriosis. A direct progesterone effect is unlikely, given the high progesterone concentrations in the peritoneal fluid of ovulatory women. In 8 adolescents, half an OC dose resulted in an apparently similar pain relief as a full dose (personal observation). Conclusions: The decrease in ovarian and superficial pelvic endometriosis-associated pain with OCs can be explained by lowering the intra-ovarian and the high estrogen concentrations in peritoneal fluid after ovulation. A direct progesterone effect is unlikely. Since OCs are severely overdosed in most women, half a dose is sufficient in most with fewer side effects, permitting individualization of therapy in women not requiring contraception. Understanding peritoneal fluid also explains that hormone replacement therapy is not contraindicated in most women with a history of endometriosis. Since the mechanisms of medical therapy of endometriosis-associated pain and the prevention of progression might be different, the growth of lesions must be monitored during treatment. Full article

(This article belongs to the Special Issue Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research)

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Management of Endometriosis: Evidence-Based Updated by Collective Clinical Experience and New Perspectives from Research

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