{"paper_id":"fbab4102-1483-44e0-92fd-f5813d1ebd18","body_text":"Manuscript accepted for publication\n1 \nProvisionally accepted for publication \nPOSITION STATEMENT \nA new approach in the Italian landscape of chronic pelvic pain and endometriosis \nNew medical approach for treatment of endometriosis \nMa\nssimo Candiani 1, Lucia Lazzeri 2, Antonio Maiorana 3, Ludovico Muzii 4,*, Michele Vignali 5, \nEnrico Vizza 6, Errico Zupi 2 \n1 Gynaecology and Obstetrics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.\n2 Gynaecology and Obstetrics Clinic, Department of Molecular and Developmental Medicine,\nUniversity of Siena, Siena, Italy.\n3 Gynaecologic and Obstetric Unit, ARNAS Civico Di Cristina Fatebenefratelli, Palermo, Italy.\n4Department of Mother, Child and Urological Sciences, “Sapienza” University of Rome, Rome,\nItaly.\n5 D epartment of Biomedical Sciences for Health, University of Milan, Macedonio Melloni Hospital, \nMilan, Italy.\n6Gynecologic Oncology Unit, Department of Experimental Clinical Oncology, IRCCS Regina Elena \nNational Cancer Institute, Rome, Italy.\nThe authors contributed equally to this work. The order of author names was alphabetically\ndetermined.\n*C\norresponding author: Ludovico Muzii, Department of Mother, Child and Urological Sciences,\n“Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome –Italy. \nE-mail: ludovico.muzii@uniroma1.it.\nORCID: 0000-0001-7195-9583.\nD\nOI: 10.36129/jog.2026.258 \nABS\nTRACT \nEndometriosis entails a huge burden: it  is estimated that affects 10% of women in their \nreproductive age. Symptoms  may be severe (chronic pelvic pain, dysmenorrhea, dyspareunia, \ndysuria, dyschezia and fatigue) affecting women’s quality of life from a personal, familiar, social  \nand professional point of view . Endometriosis may also affect fertility . T he economic burden of \n\nManuscript accepted for publication\n \n 2 \nendometriosis is relevant. Despite the recent improvements patients ‘journey before diagnosis is \nstill long and difficult. \nDifferent options for the treatment have been proposed: hormonal therapies that suppress \novulation and menstruation, surgical treatment or a combination of both. \nThe most recent tools for the medical management of endometriosis are the oral GnRH \nantagonists with add-back therapy (ABT). Relugolix Combination Therapy (CT) (40mg Relugolix + \n1mgoestradiol as  hemihydrate + 0.5mg norethisterone acetate), one tablet daily, is licensed in \nadult women of reproductive age for symptomatic  treatment of endometriosis in women with a \nhistory of previous medical or  surgical treatment for their endometriosis  as well as for treatment of \nmoderate to severe symptoms of uterine fibroids . The triple combination has the aim of combining \nthe activity on endometriosis’s symptoms with the maintenance of oestradiol and progesterone \nlevels in an optimal therapeutic range, in order to minimize the adverse effects. \nNowadays oral relugolix CT may help to solve an unmet need for a condition with such a severe \nimpact on all aspects of women’s lives  with an effective, well -tolerated, and convenient medical \ntreatment for endometriosis, maintaining a long -term care on women’s health, preserving their \nbone mass.  \nKey words \nEndometriosis; medical therapy; drug combination; GnRH antagonists; relugolix. \n \nIntroduction \nEndometriosis is a very treacherous  issue; even the history of the disease is matter of debate. \nOfficially the disease was identified by von Rokitansky [1]in 1860, but about two centuries before \nDaniel Shroen had described peritoneal ulcers that tended to form lesions and  were susceptible to \nhemorrhage in women in reproductive age [2]. In our opinion the most interesting description was \nprovided by a Scottish physician, Louis Brotherson, in 1776: he talked about the c hronic pelvic \npain experienced by women. He also added that “in its worst stages, this disease affects the well -\nbeing of the female patient totally and adversely, her whole spirit is broken, and yet she lives in \nfear of still more symptoms”[3].  \n\nManuscript accepted for publication\n \n 3 \nA cornerstone in endometriosis knowledge is that it is a polygenically inherited  disease with a \ncomplex, multifactorial  etiology[4]. Several theories have been suggested to explain the \ndevelopment of endometrial glands and stroma within the pelvic peritoneum and other \nextrauterinesites, but the most intriguing aspect of endometriosis  pathogenesis is that is a \nhormone-driven disease [5], dependent on estrogen[6], similar to that seen in eutopicendometrium, \nbut with a lack of consistent response to progesterone or synthetic progestins[7]. \nCurrent scenario – The burden of disease \nIt is estimated that endometriosis affects 10% of women in their reproductive age[8]. In Italy a \nrecent publication using national -level hospital data estimated endometriosis incidence in 0.839 \nper 1000 women (CI95% 0.834– 0.844), while the prevalence rate stood at 14.0 per 1000[9]. It has \nto be considered that this study only took into account cases intercepted by hospital admissions \nwith a diagnosis of endometriosis(ICD -9-CM, codes 617.x), supported by the presence of a \nprocedure code of laparoscopy or any other surgical  procedure allowing for direct visualisation of \nthe lesions; conversely according to other studies [10]it can be speculated that only one-third of \nwomen with endometriosis  reach a confirmed diagnosis . Therefore, in Italy, there would be more \nthan 500,000 women with endometriosis [9]affected by chronic pelvic pain, dysmenorrhea, \ndyspareunia, dysuria, dyschezia and fatigue. According to the Ministry of Health the number of \nwomen with endometriosis would be 3,000,000 [11]. Endometriosis may also affect fertility by \ntampering the peritoneal environment or by deforming the pelvic anatomy; about 30% of patients \nwith endometriosis have difficulty conceiving[12]. \nIn Italy around 300, 000 women with moderate or severe endometriosis (III or IV degree according \nto r -ASRM [13])have the right to benefit from certain healthcare services free of charge[14]. The \nexemption is granted during a gynecological examination at a public centre specialized in \nendometriosis and then submitted by the woman to the Local Health Unit[14]. \nEndometriosis is associated with a high burden of comorbidities [15], endometriosis -associated \npelvic pain is combined with reduced HRQoL, including impaired mental and sexual functioning, as \nwell as reduced work performance and productivity social relationships[16]. \n\nManuscript accepted for publication\n \n 4 \nThe economic burden of endometriosis should not be underestimated, both individually and for the \ncommunity, as this pathology leads to a loss of productivity at work and large utilization of \nhealthcare resources and personnel costs [15–17]. \nDespite the recent improvements, due to increased awareness of women and training involvement \nfor healthcare professionals, patients  ‘journey before diagnosis is long and difficult [15]. . It is \nestimated a delay up to 10-years before diagnosis after the onset of symptoms [15, 18]. \nMore and more scientific evidence is accumulating on the importance of an early  diagnosis of \nendometriosis to limit the psychophysical damage for women[18– 20]and the risk of chronic pain \ndevelopment [21]; it has been demonstrated that the efficacy of endometriosis therapeutical \napproaches due to lack of confidence in the medical profession and in treatment are inversely \nrelated to duration of untreated endometriosis [20]. \nCurrent scenario – Surgical and medical approaches \nDifferent options for the treatment of patients with symptomatic endometriosis have been \nproposed: hormonal therapies that suppress ovulation and menstruation, surgical treatment or a \ncombination of both. The management of the disease is driven by symptoms, individual risk factors \nand informed patient preferences. Nonsteroidal anti-inflammatory drugs may be a helpful first-line \ntreatment for symptoms of dysmenorrhea, but no evidence suggests that they improve non \nmenstrual symptoms[22]. \nPharmacologic management of endometriosis includes therapies to decrease endogenous \noestrogen, on the basis that oestradiol is a key driver of endometrial growth and local inflammation \nand pain [23, 24]. \nHormonal contraception and progestins are strongly recommended in women suffering from \nendometriosis-associated symptoms [25]but few drugs are approved specifically for management \nof pain associated with endometriosis[26]and reimbursed by Italian National Health Services [27]. \nOral contraceptives, either administered with a cycle or continuous schedule, or dienogest, a \nfourth-generation progestin, are generally considered as first-option medical treatment for \nendometriosis associated with pain symptoms or for preventing postoperative recurrences[25, 28, \n29]. \n\nManuscript accepted for publication\n \n 5 \nGonadotropin-releasing hormone (GnRH) agonist therapy  provides a profound oestradiol \nsuppression, but due to its hypoestrogenic side  effects, mainly the diminished bone density  ,the \nduration of use is limited  and should require additional concomitant hormonal administration[24, \n25, 30]. \nSurgical treatment is an option when drug therapies are contraindicated (such as for patients who \nare trying to conceive), are not tolerated or have failed to provide adequate relief or as for patient’s \nchoice. A minimally invasive approach with complete treatment of the disease is considered best \npractice by most international guidelines [25, 31, 32]. Surgical approach is mandatory when \nendometriosis has conducted to obstructions at ureteric or bowel  level. Systematic reviews have \nshown a persistence or recurrence rate of 22% at 2 years and of 40% –50% at 5 years after \nsurgery[24, 33]. \nNew pharmacological approaches \nThe most recent tools for the medical management of endometriosis  are the oral GnRH \nantagonists with add-back therapy (ABT) . The efficacy is based on the fast binding to the GnRH \nreceptor, blocking endogenous GnRH activity with suppression of LH and FSH \nproduction[34]avoiding the flare-up effects observed with GnRH agonists [35, 36].Considering the \nneed of a long-term use, theABT with oestrogen/progestin is an unmissable issue acting  as \nprevention of the side effects of hypoestrogenism (mainly bone loss). \nEven if estrogens are considered the primary driver of lesion development, with the loss of \nprogesterone signaling in these tissues [37], however, it is well known that there is a hierarchy of \norgan response to oestradiol [38]. The current medical position is to consider as not necessary to \nraze to the ground the oestrogenic concentrations to treat in the long-term women with \nendometriosis, in order not to expose them to all the dangerous consequences of a prolonged \noestrogen deficiency.  The goal is  to maintain the oestradiol  concentrations in the range of 30-\n45pg/ml, instead. This is the right threshold that does not stimulate endometriotic lesion to growth, \nand in the meantime, it can avoid the short and long-term consequences, mainly on osteocalcium \nmetabolism and bone structure, badly affected by a profound hypoestrogenism [39]. The bone \nhealth is a major health objective since 1998, when the European Commission report on \n\nManuscript accepted for publication\n \n 6 \nosteoporosis was published with the objective to reach a significant reduction in the incidence of \nosteoporosis and related fractures [40]. The burden of osteoporosis for  Italian women is huge, \nconsidering the epidemiological figures and the scarce awareness among patients (only one in two \nwomen knows she is affected) and healthcare professionals[41]. \nRelugolix Combination Therapy  (CT) (40mg Relugolix + 1mgo estradiol as  hemihydrate + 0.5mg \nnorethisterone acetate), one tablet daily, is licensed in adult women of reproductive age for \nsymptomatic treatment of endometriosis in women with a history of previous medical or  surgical \ntreatment for their endometriosis  as well as for treatment of moderate to severe symptoms of \nuterine fibroids [42]. \nThe pharmacodynamic properties of the combination are the following: \n1. Relugolixis a phenylurea derivative, with an affinity 52 times higher for GnRH receptor in \nthe anterior pituitary than endogenous GnRH; it has the aim of decreasing oestrogen and \nprogesterone production [43, 44]. \n2. oestradiol maintained at concentrations consistent to those detectable in the early \nfollicular phase of the menstrual cycle; it has the aim of preserv ing bone mineral density \nand significantly improving the patient's quality of life[45, 46]. In the phase 3 clinical \nstudies, in patients with endometriosis oestradiol concentrations were approximately 38 \npg/mL, corresponding to oestradiol  concentrations in the early follicular phase of the \nmenstrual cycle[42], thus completely within the oestrogen therapeutic window stated by \nthe oestrogen threshold hypothesis [39]. \n3. norethisterone acetate a synthetic progestin; it has the aim of reducing the risk of \noestrogen-induced endometrial hyperplasia[42]. Furthermore, the action this progestin on \nbone density is well documented [47–49]. \nIn the phase 3 double-blind trials ( SPIRIT 1 & SPIRIT 2), involving nearly 1.300 women with  \nconfirmed endometriosis, a higher proportion of the sample met the dysmenorrhea responder \ncriteria and the non-menstrual pelvic pain responder criteria in the Relugolix CTgroup compared to \nplacebo group(Figure 1)with a similar incidence of adverse events . The evaluation of time to \nresponse indicates benefit as early as 4 weeks after starting treatment with maximum effect at 8 \n\nManuscript accepted for publication\n \n 7 \nweeks for dysmenorrhoea and 12 weeks for non-menstrual pelvic  pain. The endometriosis Health \nProfile-30 pain domain, mirroring the effects of pain on daily function, improved significantly in the \nRelugolix CT group compared with placebo. Lastly, more women in the Relugolix CT group were \nopioid free at week 24 compared to the placebo group.  \nIn addition, RelugolixCT is able to provide inhibition of ovulation in women taking the \nrecommended dose and provides adequate contraception after at least one month of use, but the \nmedian time of menses return was 31 days(IQR 21– 36) after stopping treatment for  the \nRelugolixCT[50]. \nWithin a single cohort study , the return of ovulation after discontinuation of treatment occurred \nwithin 43 days (mean 23.5 d ays) in the whole sample of healthy premenopausal women \nparticipating in the study[42]. \nIn the SPIRIT open-label extension study the proportion of responders at Week 104/End of \ntreatment was 84.8% for dysmenorrhea and 75.8%  for non-menstrual pelvic pain; both decreases \nin dyspareunia and improvement in EHP-30 pain domain were also sustained for the whole period. \nEventually, at Week 104/End of treatment75% of patients were analgesic -free and 91% were \nopioid-free. After initial least squares mean BMD loss <1% at Week 24, at Week 36 a BMD plateau \nwas evident and was sustained up to 104 weeks of treatment[26](Figure2). \nConclusions \nEndometriosis is a widely diffused condition; in most cases patients’ journey to receive diagnosis \nand treatment is troublesome and exhausting. Endometriosis may cause considerable distress and \ncan heavily affect women’s lives, potentially leading to the development of chronic  pelvic pain, \ninfertility or end-organ damage. Therefore, early recognition and diagnosis are crucial to providing \ntimely treatment: all healthcare professionals  in contact with women should enhance their ability to \nmake a prompt clinical diagnosis of endometriosis and engage their patients in the correct disease’ \nmanagement.  \nNowadays oral relugolix CT may help to solve an unmet need for an effective, well -tolerated, and \nconvenient medical treatment for endometriosis , maintaining a long-term care on women’s health, \n\nManuscript accepted for publication\n \n 8 \npreserving their bone mass . Thereby new efforts from our community are required to identify and \ntackle a condition with such a severe impact on all aspects of women’s lives. \n \nCOMPLIANCE WITH ETHICAL STANDARDS \n \nAuthors’ contributions \nAll authors contributed to the conceptualization, methodology, writing of the original draft, writing, \nreview and editing, and have read and agreed to the published version of the manuscript. \nFunding \nNot applicable. \nStudy registration \nNot applicable. \nDisclosure of interests \nNone of the authors have any conflicts of interest for the present manuscript.  \nIn the past 36 months: \nMC, LL, AM, LM, EV, EZ declare no conflict of interest. AM and MV declare participation in \nAdvisory Boards and receipt of speakers honoraria by Gedeon Richter. \nEthical approval \nNot applicable. \nInformed consent \nNot applicable. \nData sharing \nNot applicable. \n \nReferences \n[1]  Benagiano G, Brosens I. The history of endometriosis: identifying the disease. 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Norethisterone acetate in combination with estrogen: \neffects on the skeleton and other organs. A review. Am J Obstet Gynecol. \n2002;187(4):1101-1116. doi:10.1067/mob.2002.126300.  \n[49]  Osmanağaoğlu MA, Osmanağaoğlu S, Osmanağaoğlu T, et al. Effect of different \npreparations of hormone therapy on lipid and glucose metabolism, coagulation \nfactors, and bone mineral density in overweight and obese postmenopausal women. \nFertil Steril. 2005;84(2):384-393. doi:10.1016/j.fertnstert.2005.02.028. \n[50] Giudice LC, As-Sanie S, Arjona Ferreira JC, Becker CM, Abrao MS, Lessey BA, et al. \nOnce daily oral relugolix combination therapy versus placebo in patients with \nendometriosis-associated pain: two replicate phase 3, randomised, double-blind, \nstudies (SPIRIT 1 and 2). Lancet. 2022 Jun 18;399(10343):2267-2279. doi: \n10.1016/S0140-6736(22)00622-5.   \nManuscript accepted for publication\n\n \n 12 \n \nFigure 1. \nClinical trials: reduction in pain symptoms \nResults of the registrative trials of Relugolix-CT Spirit 1 and Spirit 2.  \nProportion of patients who respondedto treatment (%) for dysmenorrhoea and non-menstrual \npelvic pain in Spirit 1 and Spirit 2 at week 24. The responder rates are both based on Numerical \nRating Scores NRS and analgesic use \n(Modified from Giudice, LC et al.“Once daily oral relugolix combination therapy versus placebo in \npatients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, \nstudies (SPIRIT 1 and 2).” Lancet (London, England) vol. 399,10343 (2022): 2267-2279. \ndoi:10.1016/S0140-6736(22)00622-5) \n \nFigure 2. \nClinical trials: impact on BMD \n \n \nPercentage change from baseline in bone mineral density over time for lumbar spine and total hip. \nDuring the first 24 weeks of treatment, \npatients receive one of three randomized treatments: relugolix CT (combination therapy), relugolix \nfor 12 weeks +relugolix CT for 12 weeks, or placebo. At Week 24, with the beginning of the SPIRT \nlong-term extension study, all patients received relugolix CT. \nManuscript accepted for publication\n\n \n 13 \n(A) Data for lumbar spine.(B) Data for hip. \nBecker, Christian M et al. “Two-year efficacy and safety of relugolix combination therapy in women \nwith endometriosis-associated pain: SPIRIT open-label extension study.” Human reproduction \n(Oxford, England) vol. 39,3 (2024): 526-537. doi:10.1093/humrep/dead263 \n \n \nManuscript accepted for publication","source_license":"CC0","license_restricted":false}