Advances in Metabolic Syndrome and Endometriosis: Emerging Insights and Therapeutic Horizons

Metabolic syndrome and endometriosis are two complex conditions that can significantly impact a woman’s quality of life. Research suggests that there may be a link between metabolic syndrome and endometriosis, with some studies indicating that women with endometriosis are more likely to develop metabolic syndrome. The exact mechanisms underlying this association are not yet fully understood. Methods: A selection of articles from Google Scholar, PubMed, and CrossRef, along with a review of recent articles from the literature, was conducted with the aim of providing a comprehensive overview of the current understanding of the interplay between metabolic syndrome and endometriosis. The following topics will be explored: underlying mechanisms, clinical implications, emerging therapeutic strategies for managing metabolic syndrome and endometriosis, and non-invasive methods for diagnosing endometriosis. Results: Women with endometriosis are at a higher risk of developing metabolic syndrome. Screening for metabolic syndrome and its components (e.g., high triglycerides, hypertension, insulin resistance) is recommended to prevent long-term health complications. Lifestyle interventions (diet, exercise) may help reduce metabolic syndrome risk in women with endometriosis. Addressing both conditions can improve fertility outcomes and overall health for infertile women. Conclusions: Healthcare providers should consider a comprehensive approach to managing endometriosis, including screening and treatment for metabolic syndrome. Early intervention and lifestyle modifications can potentially improve health outcomes for women with endometriosis and metabolic syndrome.

- chronic inflammation - hormonal imbalances - insulin resistance - biomarkers - metabolic syndrome 1. Introduction Metabolic syndrome (MetS) and endometriosis are two complex, multifactorial conditions that significantly impact women’s health across the globe. MetS is defined as a cluster of interrelated metabolic abnormalities – including central obesity, insulin resistance, hypertension, hyperglycemia, and dyslipidemia – that substantially increase the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease [1]. Endometriosis, on the other hand, is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, resulting in inflammation, pelvic pain, infertility, and impaired quality of life [2]. Although historically studied in isolation, recent research suggests that these conditions may be interconnected, with metabolic dysregulation influencing endometriosis development and progression, and endometriosis conferring a heightened risk for cardiometabolic disorders [3]. This chapter examines the prevalence, mechanisms, interplay, clinical implications, and therapeutic strategies of MetS and endometriosis, with an emphasis on reproductive health and emerging treatment horizons. 2. Prevalence of metabolic syndrome and endometriosis 2.1 Endometriosis prevalence Endometriosis affects approximately 10% of women and girls of reproductive age worldwide, equating to around 190 million individuals [4]. Despite this high prevalence, diagnostic delays of 7–10 years are common, often due to the normalization of menstrual pain and the lack of non-invasive diagnostic tools [2]. 2.2 Metabolic syndrome prevalence The prevalence of MetS varies depending on the diagnostic criteria used. The National Cholesterol Education Program’s Adult Treatment Panel III (ATP III), the International Diabetes Federation (IDF), and the Joint Interim Statement (JIS) offer slightly differing cut-offs for waist circumference, glucose, and lipid abnormalities [5]. Global estimates suggest that between 12.5% and 31.4% of adults meet the criteria for MetS, with prevalence increasing in parallel with rising obesity and sedentary lifestyles [1]. 2.3 Comorbidity between mets and endometriosis Recent epidemiological studies, including analyses of the U.S. National Health and Nutrition Examination Survey (NHANES), demonstrate that women with endometriosis have 1.5-fold higher odds of developing MetS compared to those without [3]. This association highlights the need for integrated care approaches and early metabolic screening in women diagnosed with endometriosis. 3. Pathophysiological mechanisms 3.1 Mechanisms in metabolic syndrome MetS is driven by insulin resistance, visceral obesity, and adipose tissue dysfunction, leading to elevated free fatty acids, chronic low-grade inflammation, and dysregulated adipokine secretion [6]. This inflammatory milieu exacerbates vascular dysfunction and accelerates atherosclerosis. 3.2 Mechanisms in endometriosis Endometriosis is fueled by estrogen dominance, chronic peritoneal inflammation, angiogenesis, and impaired immune surveillance [7]. Reactive oxygen species and iron overload in lesions further perpetuate oxidative stress and tissue injury [8]. 3.3 Shared mechanisms Key shared pathways between MetS and endometriosis include chronic inflammation (TNF-α, IL-6), hormonal imbalance (estrogen dominance, insulin signaling), oxidative stress, and genetic predisposition with polymorphisms linked to immune and metabolic regulation [9]. These shared mechanisms are illustrated in Figure 1, which highlights the overlapping inflammatory, hormonal, and oxidative stress pathways linking metabolic syndrome and endometriosis. The diagnotic frameworks and core features of both metabolic syndrome and endometriosis are summarized in Figure 2. 4. Interplay between metabolic syndrome and endometriosis The relationship between MetS and endometriosis is bidirectional. Metabolic disturbances may exacerbate endometriosis lesion growth via hyperinsulinemia, dyslipidemia, and inflammation [10]. Conversely, endometriosis has been prospectively linked to hypertension, hypercholesterolemia, and increased cardiovascular risk, suggesting systemic metabolic consequences [11]. 5. Impact on reproductive health Both MetS and endometriosis profoundly impair reproductive health. Endometriosis accounts for up to 50% of infertility in women with subfertility due to anatomical distortion, poor oocyte quality, and altered endometrial receptivity [12]. MetS impairs ovulation and pregnancy outcomes through insulin resistance and obesity [13]. When combined, these conditions increase the risk of infertility, miscarriage, gestational diabetes, preeclampsia, preterm birth, and placenta previa [14, 15]. Mental health burdens are also heightened, with women experiencing increased depression, anxiety, and a diminished quality of life [16]. 6. Clinical implications From a clinical perspective, women with endometriosis should be screened for MetS and vice versa. Integrated diagnostic models, incorporating both gynecological and metabolic assessments, are needed. Prognostically, co-occurrence worsens reproductive outcomes, elevates cardiovascular risk, and complicates treatment decisions [17]. Therapeutically, hormonal treatments for endometriosis may aggravate metabolic dysfunction, while insulin sensitizers such as metformin may improve both conditions [13]. Multidisciplinary management is essential, involving gynecologists, endocrinologists, cardiologists, and mental health professionals [18]. 7. Therapeutic horizons and emerging strategies Emerging therapeutic strategies targeting shared molecular and metabolic pathways are outlined in Figure 3. Emerging therapies target shared disease pathways: metabolic modulators (metformin, glycolytic inhibitors, mitochondrial-targeted drugs) [19, 20], ferroptosis inducers (preclinical) [21], hormonal refinements (oral GnRH antagonists, aromatase inhibitors) [22, 23], regenerative medicine (stem cell/exosome-based) [24, 25], microbiome interventions [26], and precision medicine using biomarkers/genomics [9]. 8. Management of reproductive health and infertility A comprehensive clinical algorithm for fertility management in women with co-existing metabolic syndrome and endometriosis is illustrated in Figure 4. 8.1 Evaluation Women should undergo a complete fertility assessment [27] alongside a metabolic evaluation [5]. EFI (endometriosis fertility Index) scoring assists in prognosis for endometriosis [28]. The EFI is a clinical tool and validated scoring system that predicts non-assisted reproductive technologies pregnancy following surgical evaluation when the patient has functional gametes and uterus used. The following are the parameters considered in the EFI scoring[28]: Historical factors (50%): This includes: Age: 2 points for ≤ 35 years, 1 point for 36–39 years, and 0 points for ≥ 40 years. Years of infertility: 2 points for ≤ 3 years and 0 points for > 3 years. Prior pregnancy: 1 point for yes and 0 points for no. Surgical findings (30%): This assesses the extent of endometriosis and adhesions, with scores ranging from 0 to 5 points based on the severity of the condition and damage to the tubes. rAFS scores (20%): The revised American Fertility Society (rAFS) staging system evaluates the extent of endometriosis. The EFI score ranges from 0 to 10 and correlates with estimated pregnancy rates at 1 and 3 years. For instance: EFI score 9–10: 67% pregnant at 1 year and 75% at 3 years. EFI score 7–8: 39% pregnant at 1 year and 66% at 3 years. EFI score 0–3: 10% pregnant at 1 and 3 years. 8.2 Preconception care Optimization of cardiometabolic health through lifestyle modification and metabolic control is essential before conception [29]. 8.3 ART Intrauterine Insemination (IUI) may be attempted in minimal-to-mild disease, while In Vitro Fertilization (IVF) is the preferred option in advanced endometriosis [30]. In MetS, ART success is improved by prior weight and metabolic optimization [31]. 8.4 Pregnancy management Women face heightened risks of gestational diabetes mellitus (GDM), hypertensive disorders, preterm birth, and adverse neonatal outcomes [15]. Multidisciplinary antenatal monitoring is mandatory. 9. Mental health impacts and quality of life Both conditions, independently and collectively, impair quality of life, causing high levels of depression, anxiety, and social dysfunction [32, 33]. Chronic pain, infertility, and obesity-related stigma exacerbate psychological burdens [34]. Interventions include CBT, mindfulness, lifestyle modification, and patient-centered care [35]. 10. Emerging therapeutic strategies Therapeutic horizons include metabolic modulators, ferroptosis inducers, stem cell therapies, microbiome-targeted interventions, and biomarker-driven personalized medicine. Integration of these approaches into clinical practice requires robust clinical trial validation [20, 36]. 11. Management of reproductive health in co-occurrence Women with both MetS and endometriosis require tailored fertility management. Assisted reproductive technology (ART) strategies should be chosen according to the disease stage and metabolic status, with an emphasis on preconception optimization [18]. Surgery may aid fertility in select cases but carries the risk of ovarian reserve depletion [37]. 12. Diagnosis of endometriosis There are various methods proposed for the diagnosis of endometriosis, including clinical history and physical examination, radiological diagnostic imaging, surgical visualization with histopathological confirmation, and blood-based biomarkers (ongoing research) [38, 39]. Table 1 summarizes strengths, limitations, and diagnostic accuracy. | Diagnostic method | Advantages/benefits | Limitations | Sensitivity (Sn) | Specificity (Sp) | Notes | |---|---|---|---|---|---| | Clinical history and physical exam | Non-invasive; inexpensive; useful for initial suspicion and directing work-up | Non-specific symptoms; low reliability for staging or mapping disease | 76–98% (history); 18–88% (exam) | 20–58% (history); 76–100% (exam) | Suggests presence; advanced disease may be detected on exam | | Ultrasound (transvaginal/abdominal) | Widely available; anatomic mapping; high accuracy for ovarian endometrioma; dynamic assessment (sliding sign) | Operator-dependent; limited for superficial peritoneal disease; exam may be uncomfortable | OE: ~ 93%; DE: ~ 79%; SE: 65–79% | OE: ~ 96%; DE: ~ 94%; SE: 91–95% | Principal pelvic imaging modality; excellent for cystic disease and DIE mapping with expertise | | MRI | High-resolution, reproducible images; excellent for deep endometriosis and extrapelvic sites; preoperative mapping | Static assessment; protocol variability; bowel depth assessment imperfect; higher cost and limited access | 76–95% (overall; subtype-dependent) | 87–98% (overall; subtype-dependent) | Useful for severe disease and extrapelvic involvement; complements ultrasound | | CT/plain radiography | CT helpful for alternative diagnoses in acute abdomen; plain films rarely contributory | Not preferred for endometriosis; nonspecific findings for endometriomas; radiation exposure (CT) | – | – | Use selectively to rule out other conditions; not a primary diagnostic tool for endometriosis | | Laparoscopy with histology (gold standard) | Definitive diagnosis; allows simultaneous treatment and lesion mapping | Invasive; surgical risk; diagnostic accuracy varies with surgeon experience and lesion heterogeneity | High (visual 90–94%; definitive with histology) | High (definitive with histology) | Decision based on symptoms, exam, and imaging; histology confirms | | Biomarkers (blood/saliva/menstrual) | Potential non-invasive triage tools; objective measures | No validated single marker; variability with cycle and lab methods; limited phenotype discrimination | Varies by marker/panel | Varies by marker/panel | Promising panels (e.g., miRNAs) under investigation; not yet for routine diagnosis | 12.1 Delay in endometriosis diagnosis Diagnostic delays of 4–12 years are well-documented [41–43], exacerbated in resource-limited settings [43, 44]. This delay has significant clinical and socioeconomic consequences, including substantial productivity losses and healthcare costs [42]. Laparoscopy with histology remains the gold standard, although it is costly and invasive [45]. While potential biomarkers exist, none have been validated for routine clinical use, particularly in African populations [46]. 12.2 Clinical examination Routine clinical vaginal examination alone is insufficient for definitive diagnosis, though it may assist in localizing lesions and determining disease severity [40]. Symptoms are non-specific and vary with lesion location; common features include chronic pelvic pain, severe dysmenorrhea, dyspareunia, cyclical GI/urinary symptoms, dyschezia, and infertility in 30–50% of cases, with ~ 20–25% asymptomatic [47, 48]. 13. Biomarkers for endometriosis Promising but not yet clinically validated biomarkers include circulating microRNAs (miRNAs), CA-125, CA19-9, MIF, and inflammatory cytokines; performance is inconsistent across studies [49–60]. The inflammatory nature of endometriosis, with elevated peritoneal cytokines, guides biomarker research [61]. Accurate, non-invasive biomarkers could reduce delays and burden [46, 62]. Table 2 depicts the summaries of the studies conducted to investigate an overview of endometriosis biomarkers and their limitations[46, 51, 53, 55]. | Biomarker type | Biomarker(s) | Sample/fluid | Key findings | Limitations | |---|---|---|---|---| | Glycoprotein | CA‑125, CA19‑9 | Serum | Elevated particularly in moderate–severe disease; widely studied legacy markers | Non-specific; elevated in many gynecologic/inflammatory conditions | | Immune/inflammatory | CA‑125 + neutrophil‑to‑lymphocyte ratio (NLR) | Serum | Combination improved diagnostic value vs. CA‑125 alone | Needs reproducibility; thresholds vary across studies | | Multi‑marker panels | CA‑125 + MIF ± MCP‑1 + leptin | Serum | Panels can improve accuracy in subsets of patients | Small cohorts; require external validation | | Transcriptomics/proteomics | Gene/protein panels | Endometrium | Altered expression profiles distinguish cases from controls | Primarily research setting; standardization lacking | | miRNAs | Multiple circulating miRNAs | Serum/plasma | Consistent dysregulation patterns; potential for non‑invasive testing | Heterogeneity among panels; no clinical validation yet | | Menstrual effluent | Transcriptomic markers | Menstrual blood | Promising, patient‑friendly source for molecular testing | Experimental; protocols not standardised | 13.1 MicroRNAs (miRNA) miRNAs regulate gene expression and may serve as diagnostic indicators [63]. Dysregulated miRNAs (e.g., miR-200b family, let-7b, miR-135a, miR-125b-5p) have been linked to endometriosis pathogenesis and show diagnostic potential in serum/plasma profiling [49–52, 64–67]. Figure 5 depicts microRNA biogenesis and the mechanism of action [65]. Summaries of reported sensitivity/specificity appear in Tables 3 and 4 [66]. | Source (year) | Dysregulated miRNA(s) | Sensitivity (%) | Specificity (%) | Notes | |---|---|---|---|---| | Maria et al. (2010) | miR‑200a, miR‑200b, miR‑141 | 84.4 | 66.7 | | | Maria et al. (2010) | miR‑22 | 90.0 | 90.0 | | | Jia et al. [50] | miR‑17‑5p | 60.0 | 80.0 | Downregulated | | Jia et al. [50] | miR‑20a | 60.0 | 90.0 | Downregulated | | Jia et al. [50] | miR‑145 | 70.0 | 96.0 | | | Wang et al. (2013) | miR‑122 | 80.0 | 76.0 | | | Wang et al. (2013) | miR‑199a | 78.3 | 76.0 | | | Wang et al. (2013) | miR‑141‑5p | 71.7 | 96.0 | | | Suryawanshi et al. (2013) | miR‑195, miR‑16 | 88.0 | 60.0 | | | Suryawanshi et al. (2013) | miR‑191, miR‑200a‑3p | 71.9 | 70.8 | | | Rekker et al. (2015) | miR‑200b‑3p | 70.8 | 90.6 | | | Rekker et al. (2015) | miR‑141‑3p | 71.9 | 70.8 | | | Cosar et al. [52] | miR‑125b | 100.0 | 96.0 | Array‑based analysis | | Index test | No. of studies | Sample size | Sensitivity (95% CI) | Specificity (95% CI) | PLR (95% CI) | NLR (95% CI) | DOR (95% CI) | |---|---|---|---|---|---|---|---| | Aromatase | 13 | 858 | 0.79 (0.71–0.86) | 0.89 (0.82–0.94) | 7.22 (4.26–12.24) | 0.23 (0.16–0.33) | 31.27 (15.70–62.29) | | HCG/LH receptor | 1 | 45 | 0.30 (0.18–0.46) | 0.80 (0.65–0.90) | 1.49 (0.64–3.47) | 0.82 (0.33–2.09) | 1.56 (0.24–10.19) | | ER‑α | 1 | 90 | 0.75 (0.66–0.83) | 0.47 (0.34–0.60) | 1.41 (1.09–1.82) | 0.54 (0.36–0.81) | 2.62 (1.42–4.84) | | ER‑β | 1 | 90 | 0.65 (0.56–0.74) | 0.68 (0.55–0.80) | 2.05 (1.39–3.04) | 0.51 (0.38–0.69) | 4.03 (2.14–7.58) | | Serum prolactin | 2 | 187 | 0.45 (0.38–0.52) | 0.92 (0.85–0.97) | 4.86 (2.40–9.82) | 0.59 (0.39–0.91) | 10.22 (4.35–24.05) | | EST | 1 | 68 | 0.69 (0.51–0.83) | 0.30 (0.16–0.49) | 0.98 (0.72–1.35) | 1.04 (0.51–2.11) | 0.95 (0.34–2.66) | | 17β‑HSD2 | 1 | 53 | 0.73 (0.60–0.84) | 0.48 (0.33–0.63) | 2.38 (0.04–138.12) | 0.53 (0.36–0.79) | 3.22 (0.18–56.39) | 13.2 Hormonal markers Hormone-related markers (estradiol, progesterone, leptin, LH, activin) have shown variable results; none are consistent for diagnosis [61, 66, 68]. Aromatase expression has been proposed but remains debated [69–71]. Prolactin may be elevated in endometriosis-related infertility [72, 73]. Meta-analysis suggests aromatase shows pooled sensitivity of 79% and specificity of 89%, but it requires further validation [74]. Additional mechanistic background on aromatase and estrogen synthesis is provided elsewhere [75–78]. The combined diagnostic precision [74] of the studies investigating hormonal use as biomarkers for the non-invasive diagnosis of endometriosis is summarised in Table 4. However, more studies are needed to validate aromatase as a biomarker for endometriosis. 14. Conclusion Women with endometriosis should be screened for metabolic syndrome and its components to prevent long-term health complications. Women with endometriosis are at a higher risk of developing metabolic syndrome, characterised by high triglycerides, hypertension, and insulin resistance. Lifestyle interventions, such as diet and exercise, may help reduce the risk of metabolic syndrome in women with endometriosis. By addressing both endometriosis and metabolic syndrome, healthcare providers can improve fertility outcomes and overall health for infertile women with these conditions.

- 1. .Grundy SM Metabolic syndrome update . .2016 ;26 (4 ):364 –373 - 2. . ,Zondervan KT ,Becker CM Missmer SA Endometriosis . .2020 ;395 (10227 ):730 –743 - 3. , ,Hu Z ,Li S ,Liu L ,Xu X ,Song Y Wei Y et al. Endometriosis and risk of metabolic syndrome: Cross-sectional and Mendelian randomization study .2020 ;35 :2105 –2111 - 4. World Health Organization . .2021 . [Accessed: 2025-September-02] - 5. , ,Alberti KGMM ,Eckel RH ,Grundy SM ,Zimmet PZ ,Cleeman JI Donato KA et al. Harmonizing the metabolic syndrome: A joint interim statement .2009 ;120 :1640 –1645 - 6. . ,Esser N ,Legrand-Poels S Piette J Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes . .2014 ;105 (2 ):141 –150 - 7. .Bulun SE Endometriosis . .2019 ;380 (13 ):1244 –1256 - 8. . ,Guo SW Wang Y Sources of heterogeneities in estimating the prevalence of endometriosis in infertile and previously fertile women . .2006 ;86 (6 ):1584 –1595 - 9. . ,Rahmioglu N ,Nyholt DR ,Morris AP ,Missmer SA ,Montgomery GW Zondervan KT Genetic variants underlying risk of endometriosis . .2019 ;25 (2 ):228 –248 - 10. . ,Vercellini P ,Vigano P ,Somigliana E Fedele L Endometriosis: Pathogenesis and treatment . .2014 ;10 (5 ):261 –275 - 11. , ,Kvaskoff M ,Mu F ,Terry KL ,Harris HR ,Poole EM Farland LV et al. Endometriosis: A high-risk population for major chronic diseases? 2021 ;27 :821 –845 - 12. . ,de Ziegler D ,Borghese B Chapron C Endometriosis and infertility: Pathophysiology and management . .2010 ;376 (9742 ):730 –738 - 13. . ,Palomba S ,Santagni S ,Falbo A La Sala GB Complications and challenges associated with PCOS: Current perspectives . .2015 ;7 :745 –763 - 14. , ,Zullo F ,Spagnolo E ,Saccone G ,Acunzo M ,Xodo S Ceccaroni M et al. Endometriosis and obstetric complications .2017 ;108 :667 –672 - 15. . ,Liu L ,Zhang W ,Liu Y ,Huang Q Liang Y Endometriosis and adverse pregnancy outcomes: A systematic review and meta-analysis . .2018 ;16 (1 ):82 - 16. , ,Facchin F ,Barbara G ,Dridi D ,Alberico D ,Buggio L Somigliana E et al. Mental health in women with endometriosis .2015 ;30 :1119 –1125 - 17. . ,Farland LV ,Prescott J ,Sasamoto N ,Tobias DK ,Gaskins AJ ,Stuart JJ ,Carusi DA ,Chavarro JE ,Horne AW ,Rich-Edwards JW Missmer SA Endometriosis and risk of adverse pregnancy outcomes . .2019 ;134 (3 ):527 –536 - 18. ESHRE Guideline Group on Endometriosis .ESHRE guideline: Endometriosis . .2022 ;2022 (2 ):hoac009 - 19. . ,Cheng J ,Li C ,Ying Y ,Lv J ,Qu X ,McGowan E ,Lin Y Zhu X Metformin alleviates endometriosis and potentiates endometrial receptivity via decreasing VEGF and MMP9 and increasing leukemia inhibitor factor and HOXA10 . .2022 ;13 :750208 - 20. . ,Zhao Y ,Sun H ,Feng M ,Zhao J ,Zhao X ,Wan Q Cai D Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling . .2018 ;34 (5 ):428 –432 - 21. . ,Li Y ,Zeng X ,Lu D ,Yin M ,Shan M Gao Y Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis . .2021 ;36 (4 ):951 –964 - 22. . ,Taylor HS ,Giudice LC ,Lessey BA ,Abrao MS ,Kotarski J ,Archer DF ,Diamond MP ,Surrey E ,Johnson NP ,Watts NB Gallagher JC Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist . .2017 ;377 (1 ):28 –40 - 23. . ,Donnez J ,Taylor HS ,Taylor RN ,Akin MD ,Tatarchuk TF ,Wilk K ,Gotteland JP ,Lecomte V Bestel E Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone–antagonist: A randomized clinical trial . .2020 ;114 (1 ):44 –55 - 24. . ,Maruyama T Yoshimura Y Stem cell theory for the pathogenesis of endometriosis . .2012 ;4 :2754 –2763 - 25. . ,Yao Y ,Chen R ,Wang G ,Zhang Y Liu F Exosomes derived from mesenchymal stem cells reverse EMT via TGF-β1/Smad pathway and promote repair of damaged endometrium . .2019 ;10 (1 ):225 - 26. . ,Ata B ,Yildiz S ,Turkgeldi E ,Brocal VP ,Dinleyici EC Moya A The Endobiota Study . .2019 ;9 :2204 - 27. Practice Committee of the American Society for Reproductive Medicine .Endometriosis and infertility: A committee opinion . .2012 ;98 (3 ):591 –598 - 28. . ,Adamson GD Pasta DJ Endometriosis fertility index . .2010 ;94 (5 ):1609 –1615 - 29. . ,Legro RS ,Dodson WC ,Kunselman AR ,Stetter CM ,Kris-Etherton PM Williams NI Delayed fertility therapy after preconception weight loss in obese women with PCOS . .2015 ;100 (4 ):1619 –1628 - 30. . ,Barnhart K ,Dunsmoor-Su R Coutifaris C Effect of endometriosis on IVF . .2002 ;77 (6 ):1148 –1155 - 31. . ,Bellver J ,Pellicer A García-Velasco JA Obesity and ART outcomes . .2010 ;21 (4 ):433 –446 - 32. , ,Culley L ,Law C ,Hudson N ,Denny E ,Mitchell H Baumgarten M et al. The social and psychological impact of endometriosis .2013 ;19 :625 –639 - 33. . ,Nnoaham KE ,Hummelshoj L ,Webster P ,d’Hooghe T ,de Cicco Nardone F ,de Cicco Nardone C ,Jenkinson C ,Kennedy SH ,Zondervan KT Study WERFG Impact of endometriosis on quality of life and work productivity: A multicenter study across ten countries . .2011 ;96 (2 ):366 –373 - 34. . ,Moradi M ,Parker M ,Sneddon A ,Lopez V Ellwood D Impact of endometriosis on women’s lives: A qualitative study . .2014 ;14 (1 ):1 –12 - 35. . ,Stefanaki C ,Bacopoulou F ,Livadas S ,Kandaraki A ,Karachalios A ,Chrousos GP Diamanti-Kandarakis E Impact of a mindfulness stress management program on stress, anxiety, depression and quality of life in women with polycystic ovary syndrome: A randomized controlled trial . .2015 ;18 (1 ):57 –66 - 36. . ,Johnson NP Hummelshoj L World Endometriosis Society Montpellier Consortium. Consensus on current management . .2022 ;37 (3 ):400 –410 - 37. . ,Raffi F ,Metwally M Amer S The impact of excision of ovarian endometrioma on ovarian reserve: A systematic review and meta-analysis . .2012 ;97 (9 ):3146 –3154 - 38. , ,Pascoal E ,Wessels JM ,Aas‐Eng MK ,Abrao MS ,Condous G Jurkovic D et al. Strengths and limitations of diagnostic tools for endometriosis .2022 ;60 :309 –327 - 39. . ,Woodward PJ ,Sohaey R Mezzetti Jr TP Endometriosis: Radiologic-pathologic correlation . .2001 ;21 (1 ):193 –216 - 40. , ,Hudelist G ,Fritzer N ,Staettner S ,Tammaa A ,Tinelli A Sparic R et al. TVUS vs clinical exam in deep endometriosis .2011 ;37 :480 –487 - 41. . ,Ballard K ,Lowton K Wright J What’s the delay? .2006 ;86 (5 ):1296 –1301 - 42. .Schenken RS Delayed diagnosis of endometriosis . .2006 ;86 (5 ):1305 –1306 - 43. , ,Hudelist G ,Fritzer N ,Thomas A ,Niehues C ,Oppelt P Haas D et al. Diagnostic delay in Austria and Germany .2012 ;27 :3412 –3416 - 44. . ,Ghai V ,Jan H ,Shakir F ,Haines P Kent A Diagnostic delay in the United Kingdom . .2020 ;40 (1 ):83 –89 - 45. . ,Vercellini P ,Vigano P ,Somigliana E Fedele L Endometriosis: Pathogenesis and treatment . .dup. of ref 10; cited once .2014 ;10 (5 ):261 –275 . - 46. .Baloyi S Non-invasive diagnosis of endometriosis: The quest for a diagnostic biomarker . .2020 ;30 (1 ):1 –2 - 47. . ,Ballard KD ,Seaman HE ,de Vries CS Wright JT Symptomatology and diagnosis . .2008 ;115 (11 ):1382 –1391 - 48. . ,Bulletti C ,Coccia ME ,Battistoni S Borini A Endometriosis and infertility . .2010 ;27 (8 ):441 –447 - 49. . ,Naqvi H ,Mamillapalli R ,Krikun G Taylor HS Endometriosis located proximal to or remote from the uterus differentially affects uterine gene expression . .2016 ;23 (2 ):186 –191 - 50. . ,Jia SZ ,Yang Y ,Lang J ,Sun P Leng J Plasma miR-17-5p, miR-20a and miR-22 in endometriosis . .2013 ;28 (2 ):322 –330 - 51. . ,Cho S ,Mutlu L ,Grechukhina O Taylor HS Circulating microRNAs as potential biomarkers for endometriosis . .2015 ;103 (5 ):1252 –1260 - 52. . ,Cosar E ,Mamillapalli R ,Ersoy GS ,Cho S ,Seifer B Taylor HS Serum microRNAs as diagnostic markers . .2016 ;106 (2 ):402 –409 - 53. . ,Xavier P ,Beires J Belo L CA-125 and CA19-9 cut-offs . .2005 ;123 (2 ):254 –255 - 54. . ,Cho S ,Cho H ,Nam A ,Kim HY ,Choi YS ,Park KH ,Cho DJ Lee BS Neutrophil-to-lymphocyte ratio as an adjunct to CA-125 for the diagnosis of endometriosis . .2008 ;90 (6 ):2073 –2079 - 55. . ,Seeber B ,Sammel MD Fan X Marker panel to predict endometriosis .2008 ;89 (5 ),1073 –1080 - 56. , ,Fassbender A ,Vodolazkaia A ,Saunders P ,Lebovic D ,Waelkens E De MB et al. Combined mRNA microarray and proteomics .2012 ;27 :2020 –2029 - 57. . ,Wang L ,Huang W ,Ren C ,Zhao M ,Jiang X Fang X Serum microRNA profile in endometriosis . .2016 ;23 (10 ):1359 –1370 - 58. , ,LA W ,Shih A ,SM R ,Seckin T ,Blau B Simons SS et al. Menstrual effluent analysis . .2018 ;24 :1 - 59. , ,Vanhie A ,O D ,Peterse D ,Kyama C ,Fassbender A Meuleman C et al. Plasma miRNAs as biomarkers . .2019 ;34 :1650 –1660 - 60. ,Nisenblat V et al. .2016 . [details needed: full citation] - 61. . ,Giudice LC Kao LC Endometriosis . .2004 ;364 (9447 ):1789 –1799 - 62. . ,Agrawal S ,Tapmeier TT ,Rahmioglu N ,Kirtley S ,Zondervan KT Becker CM The miRNA Mirage . .2018 ;19 (2 ):599 - 63. . ,Santamaria X Taylor H MicroRNA and gynecological reproductive diseases . .2014 ;101 (6 ):1545 –1551 - 64. , ,Eggers JC ,Martino V ,Reinbold R ,Sd S ,Kiesel L Schüring AN et al. miR-200b and endometriotic cells .2016 ;32 :434 –445 - 65. . ,Ryan B ,Joilin G Williams JM Plasticity-related microRNA . .2015 ;8 :4 - 66. , ,Anastasiu CV ,Moga MA ,Neculau AE ,Bălan A ,Scârneciu I Dragomir RM et al. Biomarkers for non-invasive diagnosis .2020 ;21 :1750 - 67. , ,Condrat CE ,Thompson DC ,Barbu MG ,Bugnar OL ,Boboc A Cretoiu D et al. miRNAs as Biomarkers in Disease . .2020 ;9 :276 - 68. . ,Liu Y ,Shi X ,Xu B ,Wang Z ,Chen Y Deng M Differential expression of plasma derived exosomal miRNAs in polycystic ovary syndrome as a circulating biomarker . .2023 ;19 (6 ):92 - 69. . ,Kitawaki J ,Noguchi T ,Amatsu T ,Yamamoto T ,Okada H Honjo H Aromatase P-450 in endometrial biopsy . .1999 ;72 (6 ):1100 –1106 - 70. . ,Dheenadayalu K ,Mak I ,Gordts S Campo R Aromatase mRNA in eutopic endometrium not specific . .2002 ;78 (4 ):825 –829 - 71. , ,Kitawaki J ,Noguchi T ,Amatsu T ,Maeda K ,Tsukamoto K Yamamoto T et al. Aromatase in endometriotic/adenomyotic tissues .1997 ;57 :514 –519 - 72. . ,Cunha-Filho JSLD ,Gross JL ,Lemos NA ,Brandelli A ,Castillos M Passos EP Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis . .2001 ;33 (04 ):216 –220 - 73. . ,Lima AP ,Moura MD Rosa E Silva AAM Prolactin and cortisol in endometriosis . .2006 ;39 (8 ):1121 –1127 - 74. . ,Gao Y ,Liu X ,Gu Y ,Song D ,Ding M ,Liao L ,Wang J ,Ni J He G The effect of bisphosphonates on fracture healing time and changes in bone mass density: A meta-analysis . .2021 ;12 :688269 - 75. . ,Simpson ER ,Mahendroo MS ,Means GD ,Kilgore MW ,Hinshelwood MM ,Graham-Lorence S ,Amarneh B ,Ito Y ,Fisher CR ,Michael MD Mendelson CR Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis . .1994 ;15 (3 ):342 –355 - 76. . ,Coumailleau P Kah O Cyp19a1 expression in Xenopus brain . .2014 ;26 (4 ):226 –236 - 77. , ,Bouchoucha N ,Samara-Boustani D ,Pandey AV ,Bony-Trifunovic H ,Hofer G Aigrain Y et al. Novel CYP19A1 (aromatase) R192H mutation . .2014 ;390 :8 –17 - 78. .Simpson ER Aromatase: Biologic relevance of tissue-specific expression . In: .22 .New York, NY, USA :Seventh Avenue ;2004 . p.11 –23