Rise and Rise of Endometriosis—An Enigma

Endometriosis is considered ‘silent disease’ but is debilitating that impacts quality of life. It is chronic, benign condition which is oestrogen dependent and has chronic inflammatory component. Endometriosis is associated with menstruation with increased sensitivity to oestrogen receptors and with low progesterone levels. Locally produced prostaglandins from endometriotic lesions leads to pain. There is delay in diagnosis by several years, as symptoms are not specific. This can lead to decline in fertility and quality of life. Imaging techniques and bio markers are not very specific but definitive diagnosis can be with Laparoscopy and histopathology. The first line of therapy will be medical, for relief of pain and fertility. Surgery is advised after failure of medical therapy, for severe degree of disease and deep infiltrating endometriosis (DIE). Assisted reproductive technology (ART) therapy is proposed for improved fertility outcome after surgery. Recurrence is known to occur after therapy.

Endometriosis · Oestrogen · DIE–deep infiltrating endometriosis · Laparoscopy

‘Endometriosis’ word is derived from Greek word endon, meaning ‘within’, metra means ‘uterus’ and osis means ‘abnormal or diseased condition’. Endometriosis (En’do- me-tri-o’sis) is ‘ectopic occurrence of endometrial tissue, frequently forming cysts containing blood’. It is complex gynaecological disease where functional endometrial glands/ stroma which are part of innermost lining of uterine cav - ity (endometrium) are present outside the uterine cavity. The locations being ovaries, fallopian tubes, outer surface of uterus, uterosacral ligaments, pelvic peritoneum, cervix, vagina, GI tract, bladder, ureter, urethra, rectovaginal sep- tum, abdominal wall and rarely pericardium/pleura/central nervous system [1]. It is highly prevalent in women of reproductive age group [2]. It is more common in Caucasians as compared to African/Asian and was more reported in developed countries [3]. It is oestrogen dependent and has chronic inflamma- tory component. Endometriosis is complex disease due to symptoms; fertility related issues hence negatively impact the quality of life. Incidence It affects 6–10% of women of reproductive age group. The American Society of Reproductive Medicine (ASRM) states that 24–50% of women with fertility issues and 20% with chronic pelvic pain has endometriosis [4]. It is estimated that 247 million women of reproductive age globally, of which 42 million in India are affected by Endometriosis [5 ]. This means 10% of women of reproductive age group are affected with endometriosis, which is 1/6 th of Global burden [5 , 6] (2024). Clinical Phenotypes of Endometriosis in India Endometriosis is heterogeneous condition with distinct lesion phenotypes. They are superficial peritoneal endome- triosis (SUP), cystic ovarian endometriosis or endometrioma Sujata Dalvi, Editor in Chief, MD, DGO, FCPS, FICOG, Hon. Clinical Associate, Nowrosjee Wadia Hospital, Consultant, Glen Eagles, Saifee, Bhatia, St. Elizabeth Hospitals, Ex-Associate Professor, Unit Head, KEM Hospital and Seth GS Medical College. Mumbai. * Sujata Dalvi [email protected] 1 Nowrosjee Wadia Maternity Hospital, Mumbai, India 186 S. Dalvi (OMA) and deep infiltrating endometriosis (DIE) lesions > 5 mm beneath peritoneum. Single lesion is found in 46%, two lesions in 38% and three in 18% of women [5 ]. Ovar- ian endometrioma is present in 17–44% with bilateral in 50%. These cysts are well defined, with chocolate coloured fluid due to degenerated blood products. Superficial lesions are accidental findings and are seen in obese women. DIE involves rectovaginal septum, bladder, ureter and bowel and are seen in underweight women [3]. With rising incidence and awareness, endometriosis has become one of the major benign gynaecological disorders leading to infertility and chronic pelvic pain. Predisposing/Risk Factors Early menarche, short menstrual cycle ( 7 days or 80 ml), nulliparity, low birth weight, obesity are related to high risk of endometriosis. Most factors are associated with elevated oestrogens or pro- longed menstruation, strengthening oestrogen dependency and association with menstruation [7 ]. Prostaglandins are locally produced leading to pain. It increases uterine contractility with vasoconstrictive effect leading to dysmenorrhoea. Exposure to environmental agents like dioxins, polyhalo- genated aromatic hydrocarbons, organochloride pesticides, phthalates, bisphenols causing growth factor activation, gene regulation, immune suppression and altered oestrogen sup- pression pathways causes endometriosis. Endometrial cells get implanted in pelvis through retro- grade menstruation, leading to inflammatory reaction. This increases the blood flow, initiates defence mechanism, caus- ing swelling, redness and release of cytokines from injured cells. This is followed by angiogenesis, adhesions, neuronal infiltration and oxidative stress. Genetic predisposition with strong link with heredity like monozygotic twins, first-Possibility of functional obstruction degree relatives are seen. Epigenetic changes occur due to genetic/environmental factors causing proliferation of endo- metriotic tissue and decreased apoptosis. Protecting Factors Parity, breast feeding, oral pills, tubal ligation and smoking leads to decrease in incidence. Tubal ligation hampers men- strual flow reflux whereas anovulation decreases irritation and inflammatory process. Smoking otherwise is risk factor for many health issues but not in endometriosis [3]. Theories on Endometriosis Sampson’s Theory: Retrograde menstruation, viable cells, implantation of viable cells that continue to grow and form lesions. Coelomic Metaplasia Theory: Ovaries and Muller - ian ducts are derived from coelomic epithelium, which undergoes metaplastic transformation to form tissue like endometrium. Embryonic Rest Theory: Cells of Mullerian origin in peritoneal cavity can be induced to form endometrial tissue with appropriate stimulation. Lymphatic and Vascular metastasis: Explains why endo- metriosis occurs in ovary and extra peritoneal sites. TIAR (Tissue Injury and Repair) Theory: Chronic peri- stalsis or hyper peristalsis causes micro-traumatization leading to injury/repair increasing production of local oestrogens. Quinn’s ‘Denervation—Reinnervation’ Theory: Injuries caused due to straining during defecation/vaginal delivery causes denervation. Ectopic endometrial cells from retro- grade menstruation adhere to this injured tissue, (peritoneal cavity/USL) followed by re innervation causing pelvic pain. Stem Cell Theory: Overt vaginal bleeding occurs in 5% of neonates, due to endometrium of foetus transforming into decidualized layer that sheds after birth. There is a possibil- ity of functional obstruction of endo cervical canal, leading to regurgitation of endometrial cells into peritoneal cavity. These cells later implant/survive long-term causing adoles- cent endometriosis [8]. Other Causative Factors Oxidative stress: Plays role locally and systematically. Anti- oxidants play major role in preventing damage and improv- ing rates of pregnancy in endometriotic patients. Iron in pathogenesis of Endometriosis: Increased iron lev- els have been found in endometrial lesions/peritoneal fluid/ peritoneal macrophages leading to growth of lesions. Iron chelator treatment could be beneficial to prevent iron load in peritoneal cavity and decrease in cellular proliferation [9 ]. Endometriosis and Ovarian cancer (EAOC): Endome- triosis associated ovarian carcinoma includes clear cell car- cinoma, serous–mucinous, endometroid carcinoma and is oestrogen dependent. Combined screening with CA 125, HE 4 and USG is recommended, as possible non-invasive test for specific diagnosis [10]. 187 Rise and Rise of Endometriosis—An Enigma Signs/Symptoms Symptoms vary widely and include pelvic pain (40–50%), dysmenorrhoea (58–80%), dyspareunia (40–50%), dysu - ria (1–2%), dyschezia (1–2%), GI discomfort (1–2%) and decreased libido [2 , 11]. The pain is chronic, cyclical and progressive. In addition, cyclical leg pain may be present [12]. Patients with DIE have allodynia, condition where with non-application of painful stimulus, there is intolerable pain- ful reaction. This is because of neuronal damage, release of mediators like serotonin, prostaglandins, nerve growth fac- tors and increase in local vascular permeability. The degree of clinical manifestation is not directly proportional to the extent of disease or size of endometrial lesion. Infertility, which is common finding, [13] may be due to inflammatory response impacting various aspect of concep- tion in early stage and later due to adhesions formation and distorted anatomy [14]. The symptoms associated with endometriosis are also present in other gynaecological disorders, leaving it mis- diagnosed or overlooked [15]. This contributes an average delay of 7–8 years from onset of symptoms to confirmation of diagnosis [7]. Endometriosis negatively impacts social, sexual and pro- fessional quality of life and is associated with depression, anxiety and stress. D/D needs to be kept in mind like adenomyosis, myoma, cervical stenosis, pelvic congestion—pain, pelvic inflamma- tory disease, irritable bowel syndrome (IBS) and interstitial cystitis. Neurologic and psychosomatic disorder should be ruled out in case of persistent pelvic pain. Diagnosis Diagnosis of endometriosis gets delayed being a chronic pathology with not very specific symptoms. It can take sev- eral years for the diagnosis, as pelvic pain is natural biologi- cal side effect related to menstrual cycles and non-availabil- ity of pathognomonic/bio marker test to detect the disease. Non‑invasive Tests USG—transvaginal ultrasound (TVS) is used for making diagnosis, as it can map the disease significantly and allows dynamic assessment. Implants outside peritoneum, adhe- sions, infiltrations are difficult to be diagnosed. ESHRE (European Society of Human Reproduction & Embryology) provided consensus protocol on International deep endometriosis analysis (IDEA). It requires evaluation of: Uterus, Ovaries and Adnexa (Component 1), DIE Deep infiltrating endometriosis (Component 2), Sliding sign (Component 3), presence of USG soft markers (Component 4) (Table  1). Transrectal sonography (TRUS) is recommended by ESHRE to diagnose endometriomas in unmarried and rec - tal endometriosis. It has good sensitivity and specificity but requires training. Doppler blood flow is limited in ovarian endometrioma. Those with dense vascularity do not prove to be Endome- trioma [16]. Magnetic Resonance Imaging (MRI): has limited role but offers larger field of view with effect of adhesions on sur - rounding structures. It is recommended to diagnose DIE, but small superficial implants < 5 mm cannot be picked up. MRI is advised when malignancy is suspected, doubtful diagnosis or when TVS not possible (Table 2). Biomarkers: CA 125 is elevated in ovarian endometrioma but is also increased in other ovarian pathology. Extra cellu- lar matrix (ECM) protein levels in peritoneal fluid, menstrual blood, eutopic endometrium related to endometriosis are under study [18]. MicroRNA may have potential in diagnostic/thera- peutic decisions [14]. Fertility: Tests for evaluation for ovarian reserve—FSH (early follicular phase), AMH (Anti Mullerian Hormone), AFC (Antral Follicle Count) and Ovarian volume should be done. Laparoscopy and histology give definite diagnosis; it is no longer Gold Standard [19]. Laparoscopy being an invasive procedure, current guidelines recommend laparoscopy, only if imaging results are negative or empirical treatment has not been successful/inappropriate. The lesions appear red, white, clear vesicular—peritoneal defects, black powder burnt—gun shot appearance. Direct visualization with histological biopsy is considered. If lesions are not visible—biopsy can be taken from suspicious area for HP diagnosis. ASRM—The American Society of Reproductive Medicine (1996) has classified endometriosis from stage I to IV with scoring system. It is done by surgical observation like appear- ance, location, type and depth of lesion [14], where symptoms of patient are not considered. Stage I (minimal)—superficial lesions—flimsy adhesions/ Stage II (mild)—additional deep lesions in cul de sac/Stage III (moderate)—additional presence of endometriomas/adhe- sions Stage IV (severe)—additional large lesions, extensive adhesions, implants beyond uterus. On histology for diagnosis, at least 2 of the 3 criteria should be present—presence of endometrial stroma, epithelium with glands, chronic haemorrhage with haemosiderin deposits. Endometriosis Fertility Index (EFI): Scoring system was developed in 2010 [20]. Age, duration of infertility, previ- ous fertility, severity of endometriosis, least function score (impact on adnexal structures), American Fertility Society 188 S. Dalvi (AFS) Endometriosis—total score. High score indicates bet- ter chance of conception. EFI does not consider age, male factor, lifestyle factors like smoking, alcohol, BMI and emo- tional impact. Rise of Endometriosis?? Prevalence of diagnosis of Endometriosis seems to be increasing. Incidence being variable, does not necessar - ily mean that endometriosis is increasing. Endometrio - sis is being diagnosed more frequently in different stages because of increased awareness, more women seeking medical help for pelvic pain and heavy menstrual bleed- ing (HMB), infertility, access to better diagnostic tools and changes in reporting system. [ 21] The age-adjusted preva - lence rate of endometriosis has increased from 2.12 per 1,000 in 2002 to 3.56 per 1,000 in 2013. This is because of genetic link (mother, sister, daughter) and early age of menarche (10—11 years). The prevalence of endome- triosis temporarily decreased in 2007, but it continued to increase over the next 5 years. This could be because of changes in lifestyle and environmental factors [22]. Table 1 TVS: ESHRE (European Society of Human Reproduction & Embryology) provided consensus protocol on International Deep Endome- triosis Analysis (IDEA) Compartment 1 Uterus—Adenomyosis Ovaries—Ovarian endometriomas—diagnosed as complex cyst with homogeneous low levels ground glass echoes, unilocular but can be multilocular. Bilateral cysts may be present Sensitivity of 80–90% and specificity of 60–98% Fertility patient, AFC—antral follicle count/ovarian margins should be assessed. Superficial endometriosis/adhesions may cause blurring of margins ASRM, ESHRE suggests surgery, if size > 4 cm Adnexa—Exclusion of hydrosalpinx, hematosalpinx and peritoneal inclusion cyst Compartment 2 DIE—Deep Infiltrating Endometriosis: Mapping of Disease: Divide pelvis into anterior/posterior by plane passing through endometrium and vagina Anterior pelvic area includes bladder, ureter, anterior serosa covering uterus—vagina done by placing probe in anterior vaginal fornix. Bladder is scanned in the end or in beginning. Moderately distended bladder gives accurate diagnosis of bladder dome. Ureteric involvement can be missed hence proper vigilance Posterior component is scanned by placing probe in posterior fornix. Structures that are seen are utero sacral space, USL, bowel (Recto- sigmoid), posterior serosa covering uterus, cervix and vaginal wall. USL ligaments change from hyperechoic to hypoechoic, with nodularity and thickening DIE nodule appears hypoechoic, linear—round, smooth—irregular border with minimal/nil vascularity. Nodule measured in three dimensions Compartment 3 Sliding sign: Assesses POD obliteration due to adhesions, fixity of rectum or recto-sigmoid with cervix with or without USL fusion. Done in sagittal plane pressing cervix and assessing movement of anterior rectum with cervix and by pressing abdominal wall against fundus, movement of bowel against posterior uterine fundus is assessed Positive—preservation of relative movement Negative—adhesions and obliterated spaces Compartment 4 Site Specific Tenderness: Soft markers Seeing specific probe tenderness and decreased ovarian—uterine mobility suggests presence of superficial endometriosis/adhe- sions. With severe adhesions, ovaries become fixed to each other in cul de sac ‘kissing ovaries’ sign. Usually associated with bowel and fallopian tube endometriosis Table 2 MRI Accuracy [17] Lesions Sensitivity (%) Speci- ficity (%) Endometrioma 95 91 USL 85 80 Bowel 83 88 POD Obliteration 89 94 189 Rise and Rise of Endometriosis—An Enigma Management Medical management includes hormonal therapy that can halt the progress of the disease and non-hormonal therapy to alleviate symptoms and increase fertility. An empirical medical therapy can be given even without confirmation, provided symptoms are like that of endometriosis. Therapy is to alleviate symptoms and not for cure, as endometriosis is a chronic disease. Relief of symptoms does not prove disease to be an endometriosis, and it may not improve fertility rate (Table  3). Dietary inclusion of anti-inflammatory, high fibre, anti - oxidants along with medical therapy helps in improvement of patients’ symptoms. Yoga/meditation/regular exercise is beneficial in improving stress/anxiety. Surgical Therapy Surgery is considered in cases of no response or contra indications to medical therapy. Aim of surgical therapy is fertility enhancing and pain relief. Recommenda- tion during surgery is to excise all endometriotic lesions (implants—lesions—nodules) and adhesions causing decrease in inflammatory environment. Management of ovarian endometrioma is challenging as removal of the capsule of the cyst can decrease ovarian reserve and follicular loss. Drainage or ablation can lead to recurrence and not much of pain relief. Final decision can be taken after proper counselling and weighing benefits. In DIE, after thorough counselling/informed choice, multidisciplinary surgical approach should be followed to avoid injury to affected organs. Innovative surgical devices like advanced bipolar, laser technology, robotic assisted surgery have been used to increase precision and effectiveness. Recurrence rate after surgery is 6–67% [3 ]. Fertility treatment: Surgery to remove deceased tissue with care to be taken to preserve ovarian function without much damage. Post surgery, hormonal suppression therapy (downregulation) helps in reducing recurrence and achieving pregnancy. ART therapy after surgical treatment is effective in improving fertility outcome. TVS guided endometrioma aspiration performed prior to ICSI/IVF cycle, preserves fol- licles by leaving behind pseudo capsule. The procedure is less invasive, but recurrence rate is high [24]. Hysterectomy was thought to be cure for those, who had finished with childbearing but not in current scenario. Dur - ing hysterectomy, endometriosis should be excised/removed. Complications Chronic pelvic pain, infertility and sub fertility are conse- quences. It leads to decrease in quality of life and affects social—emotional—sexual wellbeing. High degree of stress level, improper sleep and digestive dysfunction like con- stipation are seen. Though it is chronic benign condition, higher incidence of ovarian cancer has been noted [3 ]. In surgical therapy, there is risk of postoperative adhe - sions, that can lead to fertility issues and difficult repeat surgery. Removal of only cyst from ovary is safe option in ovarian endometriomas. In DIE, increased incidence of intra operative injury to affected organ (ureter, bowel, bladder) is Table 3 Medical management NSAIDs First line therapy (Pain Relief) COCs Cyclical/continuous—causes anovulation pelvic pain returns after stopping therapy Progesterone Only (Oral—LNG IUD—Implants) causes anovulation and hypoestrogenic milieu. Weight and acne are potential side effects Danazol Locally via vaginal (rings)/IU route (IUS)—effective in relieving pain/menorrhagia, avoiding systemic side effects (use restricted till strong evidence) [23] Dienogest (2 mg) Inhibits gonadotropin secretion/exerts anti proliferative and anti-inflammatory action on endometrial lesions. Can be given up to 5 years with good safety—tolerability Progesterone receptor modulators like Mifepristone Have potential to manage pain caused by endometriosis GnRh agonists Causes anovulation, hypoestrogenism and endometrial atrophy. Side effects are bone loss, hot flashes, vaginal atrophy, headache GnRh antagonists: Oral preparation—Elagolix 200 mg twice daily (6 months)/150 mg once a day (2 years) depending upon severity of symptoms. It is effective in improving dysmenorrhoea and non-menstrual pelvic pain. Side effects like hot flashes, nausea, night sweats and insomnia may be seen Aromatase Inhibitors Blocks formation of oestrogens Immunomodulators/ anti-angiogenic agents Under study—being chronic inflammatory condition 190 S. Dalvi seen. Proper precaution with intraoperative multidisciplinary surgical approach should be adopted. Proposed Newer Therapy Being chronic long-term disease, repeated therapy is needed to treat symptoms and prevent recurrence. Non hormonal, anti-inflammatory agents like TNF alpha inhibitors, apop- totic agents like metformin, anti-angiogenic agents like dopamine agonists, antioxidants are under study [25]. Focus on Adolescent Endometriosis Adolescent age group endometriosis is difficult to deter - mine due to invasive method of definitive diagnosis. About 60% of adult women with endometriosis experience symp- toms before age of 20 years. It takes more than 12 years to make diagnosis from onset of disease in adolescents [2 ]. The most common cause of secondary dysmenorrhoea in adolescence is endometriosis and is more likely to have non-cyclical pain. Risk factors are genetic, obstructed mullerian anomalies, early menarche and low body mass index. High degree of suspicion in adolescents with severe dys- menorrhoea interfering with daily activities, chronic pelvic pain not responding to therapy, GI symptoms and dyspareu- nia in sexually active should be kept. Clinical examination may be difficult. Rectal examination may reveal tenderness over USL and rectovaginal nodularity. TVS may not be feasible, transabdominal (TAS) or tran- srectal (TRS) scans or MRI may be considered to confirm diagnosis in advanced lesions. Early lesions may be difficult to be picked up. Laparoscopy can be considered only in those adolescents with suspected endometriosis where imaging is negative and medical therapy has not been successful. Atypical lesions like clear, white or red are more common. During laparos- copy it is recommended to take biopsy to confirm diagnosis on histology, but negative histology cannot rule out disease. Staging of endometriosis by Revised American Soci- ety for Reproductive Medicine (rASRM) has been devised where scoring system has been added—Stage 1 (score 1–5), stage 2 (score 6–15), stage 3 (score 15–40), stage 4 (score > 40). Management: NSAIDs for pain relief, COCs for anovula- tion with safety profile/effectiveness, progestins (Dienogest) are used. GnRh agonists can be used, if COCs or Progestins therapy has failed, with add back therapy only after counsel- ling patient and the relatives. Surgical therapy if considered, fertility preservation should be kept in mind.

Endometriosis is complex debilitating disease, in women of reproductive age groups. The risk factors are well estab- lished being hyper oestrogenic with chronic inflammatory pathology. Symptoms being non-specific, it takes several years to reach diagnosis. Non-invasive method of diagnosis has its own limitations and bio markers are inconclusive. Laparoscopy and histopathology are for definitive diagnosis. Endometriosis has been recognized, treated for many years, but no treatment has been able to cure the disease. The aeti- ology of disease being unclear, focus is mainly on relieving pain and improving fertility. Medical and surgical therapy has been effective; however, recurrence rate is high. WHO aims to have effective policy for Endometriosis globally, in low—middle income countries [26]. Specialized clinics for endometriosis have been set up. Declarations Conflict of interests The authors declare no competing interests.

1. Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39(4):535–49. 2. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99. 3. Eleni ST, Heba M National Institute of Health. 2023; https:// www. ncbi. nlm. nih. gov/ books/ NBK56 7777 4. Garcia- Velasco JA, Somigliana E. Management of Endome- trioma in women requiring IVF. To touch or not to touch. Hum Reprod (Oxford England). 2009;24(3):496–501. 5. Gajbhiye RK. Endometriosis and immune responses Indian experience. Am J Immunol. 2023;89(2):e13590. 6. Munshi H, Martlock S, Khan T: Endometriosis in India: Analy - sis from ECGRI study. 2024: https:// papers. ssm. com/so13/ 7. Falcone T, Lebovic DI. Clinical management of endometriosis. Obstet Gynaecol. 2011;118(3):691–705. 8. Gargett CE, Schwab KE, et al. Potential role of endometrial stem/progenitor cells in the pathogenesis of early onset endo- metriosis. Mol Hum Reprod. 2014;20(7):591–8. 9. Kobayashi H, Yamada Y, et al. Role of iron in pathogenesis of endometriosis. Gynecol Endocrinol. 2009;25(1):39–52. 10. Huhtinen K, Suvitie P, et al. Serum HE4 concentration differ - entiate malignant ovarian tumors from ovarian endometriotic cysts. Br J Cancer. 2009;100(8):1315–9. 11. Bulun SE. Endometriosis. New Engl J Med. 2009;360(3):268–79. 12. Walch K, Kernstock T, et al. Prevalence and severity of cyclic leg pain in women with endometriosis – effect of laparoscopic surgery. Eur J Obstet Gynaecol Reprod Biol. 2014;179:51–7. 13. Akande VA, Hunt LP, et al. Differences in time to natural conception between women with unexplained infertility and treatment of endometriosis. Hum Rep (Oxford, England). 2004;19(1):96–103. 191 Rise and Rise of Endometriosis—An Enigma 14. Wikipedia: Endometriosis: https:// en. wikip edia. org/ wiki/ Endom etrio sis 15. Kennedy S, Bergqvist A, et al. ESHRE guidelines for diagnosis and treatment of endometriosis. Hum Rep (Oxford England). 2005;20(10):2698–704. 16. Aleem F, Pennisi J, et al. The role of color Doppler in diagnosis of Endometriosis. USG Obstet Gynaecol. 1995;5(1):51–4. 17. Bazot M, Bharwani N, et al. European society of urogenital radi- ology (ESUR) guidelines: MR imaging of pelvic endometriosis. Eur Radiol. 2017;27(7):2765–75. 18. Harrington DJ, Lessey BA, et al. Tenascin is differentially expressed in endometrium and endometriosis. J Pathol. 1999;187(2):242–8. 19. Practice Bulletin no 114. Management of Endometriosis. Obstetrics & Gynaecology. 2010: 116 (1) 223 -236 20. Adamson GD, Pasta DJ. Endometriosis fertility index, the new validated endometriotic staging system. Fertil Steril. 2010;94(5):1609–15. 21. Ghiasi M, Kulkarni M, et al. Is Endometriosis more common and more severe than it was 30 years ago? J Minim Invasive Gynecol. 2020;27(2):452–61. 22. Yale Medicine – https://www. yalem edici ne. org/ condi tions. endom etrio sis 23. Godin R, Marcoux V. J Obstet Gynaecol Canada. 2015;37(12):1098–103. 24. Aflatoonian A, Rahmani E, et al. Assessing efficacy of aspiration and ethanol injection in recurrent endometriosis in IVF cycle: randomised clinical trial. Iran J Rep Med. 2013;11(3):179–84. 25. Laschke MW, Schwender C, et al. Epigallocatechin 3 gallate inhibits estrogen induced activation of endometrial cells in vitro and causes regression of endometriotic lesion in vivo. Hum Reprod (Oxford England). 2008;23(10):2308–18. 26. World Health Organization (WHO) – Endometriosis: https:// www. who. int/ news- room/ Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.