{"paper_id":"e262a721-0e19-4096-9d5e-eaaee9427ede","body_text":"da Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510  \nhttps://doi.org/10.1186/s12905-023-02647-y\nRESEARCH Open Access\n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom-\nmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBMC Women’s Health\nTolerability of endometriosis medical \ntreatment: a comparison between combined \nhormonal contraceptives and progestins\nDenise Joffily Pereira da Costa Pinheiro1,2*  , Ana Maria Gomes Pereira1  , Marcelo Antonini1  , \nIsabella Maria Albuquerque Salgado1  , Alexandre Torchio Dias2 and Reginaldo Guedes Coelho Lopes1,2   \nAbstract \nEndometriosis is a chronic inflammatory disease that occurs in women of reproductive age. Much of the treatment \ninvolves hormone therapy that suppresses the proliferation of endometriosis lesions.\nObjective To compare discontinuation rates of pharmacological treatment with estrogen-progestins and pro-\ngestins medications. The secondary objective is to evaluate the main side effects of these drugs in patients \nwith endometriosis.\nMethods This retrospective study analyzed data from 330 patients who attended the Hospital of the State Public \nServant of São Paulo from August 1999 to September 2020 and received pharmacological treatment for endometrio-\nsis. The data were obtained by review of the files of medical appointments with specialized staff.\nResults The median treatment time was 18 months, ranging from 1 to 168 months, and 177 patients interrupted \nthe proposed treatment. The combined contraceptives with estrogens and progestins were significantly linked \nto treatment interruption, with a relative risk of 1,99 (p = 0,005). The most important side effects that resulted in treat-\nment interruption were pain persistence (p = 0,043), weight gain (p = 0,017) and spotting (p < 0,001).\nKeywords Endometriosis, Pharmacological treatment, Side effects, Tolerability\nIntroduction\nEndometriosis is a chronic inflammatory estrogen-\ndependent gynecological disease characterized by the \ndevelopment and growth of functional endometrium-like \ntissue outside the uterine cavity [1, 2]. It predominantly \naffects the ovaries but can also affect other organs such as \nthe fallopian tubes, pelvic ligaments, appendix, bladder, \nand intestines [3–5].\nThe most common symptoms are dysmenorrhea, pelvic \npain outside the menstrual period, dyspareunia, infertil -\nity, urinary and evacuation symptoms. However, its clini -\ncal presentation can be non-specific and with symptoms \ndisproportionate to the extent of the disease, making \ndiagnosis difficult [6–10].\nEndometriosis significantly impacts women’s quality of \nlife, compromising their social and emotional relation -\nships, work, and study performance. It is an important \npublic health issue, affecting 6 to 10% of women of repro-\nductive age, with a peak incidence between the ages of 25 \nand 35 years [4, 5].\n*Correspondence:\nDenise Joffily Pereira da Costa Pinheiro\ndenisejoffily@gmail.com\n1 Hospital Do Servidor Público Estadual - Francisco Morato de Oliveira \n(HSPE-FMO), Rua Pedro de Toledo 1800, São Paulo, SP 04029000, Brazil\n2 CEDEP – Instituto de Assistência Médica ao Servidor Público Estadual \n(IAMSPE), São Paulo, Brazil\n\nPage 2 of 10da Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \nThe treatment of endometriosis includes surgery, medi-\ncation therapy, and assisted reproductive techniques. As \na chronic disease, patients should be monitored for many \nyears and receive individualized treatment according to \ntheir clinical status and reproductive desire at each stage \nof life. The goal is to remove endometriotic foci surgically \nor suppress them with clinical treatment. However, the \nbest approach has not been defined yet [11–14].\nThe medical treatment aims to induce a hypoestrogenic \nstate of chronic anovulation, creating an inadequate envi-\nronment for the growth and maintenance of endometrio-\nsis implants [7, 13, 15, 16]. The medical treatment is not \ncurative, as it cannot eliminate the endometriotic foci, \nonly making them temporarily inactive during medica -\ntion use [17].\nAmong the therapeutic options, we have combined \nhormonal contraceptives containing estrogens and pro -\ngestins (EP), isolated progestins (P), antiprogestins, \nGnRH agonists, GnRH antagonists, aromatase inhibitors, \nand medications that do not act as hormonal suppres -\nsants, such as analgesics and non-steroidal anti-inflam -\nmatory drugs [9].\nConsidering the chronic use of these medications, it \nis important to evaluate not only their efficacy but also \ntheir tolerability, side effects, cost, and each patient’s \npreferences [7, 13, 17, 18]. The tolerability of treatment \nconsists of the patient’s ability to tolerate the side effects \nand maintain the use of the medication. It can be evalu -\nated through the rates of treatment interruption or fol -\nlow-up losses in clinical studies [17].\nIt is recommended to start with low-cost drugs, such \nas combined oral contraceptives and some progestins, \nand then move on to high-cost drugs, such as GnRH \nagonists, in cases of low adherence, tolerability, or \nineffectiveness [7 ].\nAlthough widely prescribed, combined hormonal con -\ntraceptives have no scientific basis to prove the supe -\nriority of this group of medications compared to other \nclasses, and does not appear to be any advantage of any \nspecific drug within this group [7]. Continuous admin -\nistration of combined contraceptives has been more \nfavorable in controlling pain than cyclical administration. \nIt is possible to perform a planned interruption only to \ncontrol spotting, which is bleeding that occurs outside \nof the menstrual period [19]. Regarding ethinylestradiol \ndosage, low-dose options with 20 mcg are safer, with a \nlower risk of thromboembolic events [17].\nAccording to some authors, progestins have fewer side \neffects than combined contraceptives and can be pre -\nscribed in various routes of administration, oral, inject -\nable, implants, and intrauterine devices [9 , 20– 25]. \nDesogestrel and dienogest are 19-nortestosterone-\nderived progestins widely studied for the treatment of \nendometriosis and have been shown effective in control -\nling symptoms [20, 22].\nSymptoms can be controlled by various drugs, many of \nthem with great pain control results, the limiting factors \nare the side effects and tolerability related to these medi -\ncations. Adequate monitoring and control of unwanted \neffects are essential for achieving therapeutic success. \nThus, studies that compare drug options, considering not \nonly the efficacy but also the quality of life of patients, are \nnecessary to guide conduct.\nObjectives\nThis study aims to compare the discontinuation rates \nof medical treatments for endometriosis with com -\nbined hormonal contraceptives and isolated proges -\ntins. The secondary objective is to evaluate the main \nadverse effects related to the discontinuation of these \nmedications.\nMethods\nA retrospective study that evaluated the rate of medica -\ntion interruption by patients attended in the endome -\ntriosis sector of the State Public Servant Hospital in São \nPaulo.\nThe data was collected through forms filed in the spe -\ncialized outpatient clinic. Patients attended from August \n1999 to September 2020 were evaluated.\nTo be included in the study, a histological confirmation \nof endometriosis and a medical treatment prescription \nwas necessary. Thus, it is important to highlight that all \npatients included in the study underwent surgical treat -\nment prior to clinical intervention. Patients with incom -\nplete data for the study, those who were already in clinical \nor surgical postmenopause at the first consultation, hys -\nterectomized patients and finally, those patients who did \nnot have a minimum follow-up time of 6 months in the \npresence of medical treatment were excluded.\nEpidemiological data were collected to trace the profile \nof attended patients.\nThe time between the onset of symptoms and the sur -\ngery date was evaluated. The symptoms questioned were \ndysmenorrhea, dyspareunia, cyclic pain, pain while evac -\nuating, pericicatrical pain, infertility, urinary and intesti -\nnal symptoms.\nThe surgical findings were raised, researching where \nendometriotic lesions were found. The surgical proce -\ndures performed and the staging of endometriosis were \nalso researched. The classification of endometriosis \nfrom the American Society for Reproductive Medicine \n(ASRM) was used as a reference [8].\nThe prescribed medications for clinical treatment \nwere chosen based on reliable guidelines such as \nESHRE’s, on the opinion of the attending physician and \n\nPage 3 of 10\nda Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \n \non the patient’s preferences [6 ]. These treatments were \nverified for the type of hormone and dose. During the \nentire follow-up, patients were questioned about the \nsymptoms and side effects presented during treatment. \nThe use time of each medication was recorded, and \nonce the patient opted for discontinuation, the reason \nfor discontinuation was also recorded. A new medica -\ntion could be prescribed, containing the same hormone \nwith a different dosage or a medication from a different \nclass.\nAn informed consent form was applied before data \ncollection. This study was approved by Research Eth -\nics Committee of State Public Servant Hospital and is \nregistered in Plataforma Brasil under CAAE number \n36271213.8.0000.5463.\nStatistical analyzes were performed for two distinct \ngroups, isolated progestins (P) and combined contracep -\ntives (EP). Frequencies were calculated using the infor -\nmation available for each data point.\nThe data obtained were grouped in an Excel spread -\nsheet for Windows ® and were analyzed using the statis -\ntical programs Epi Info7 ® an Open-Epi, online version \n[26]. Continuous variables were tested for their distribu -\ntion and are presented in means and standard deviation \nor medians and quartiles, depending on the normality of \nthis distribution. Categorical variables are presented in \npercentages, according to the data available for analysis.\nThe variables relating to adverse events and complaints \nreported during clinical treatment were correlated with \nthe outcome of treatment interruption, and multiple \nanalysis of logistic regression was conducted using the \nSTATA 12.0® program, grouping the adverse events that \npresented potential statistical significance in the univari -\nate analysis (value of p < 0.25 was used to select variables \nfor multiple final analysis), except those that did not have \nenough outcome events to be included in the adjusted \nmodeling.\nA p-value < 0,05 was considered statistically significant.\nResults\nAs reported in Fig.  1, we enrolled 392 patients in the \nstudy, and after applying exclusion criteria, 330 patients \nremained for analysis.\nThe average age of patients at the time of the first \nconsultation was 37.57  years (± 6.27), ranging from \n17 to 53  years. The average age of symptom onset was \n31.07 years (± 8.4), ranging from 8 to 51 years.\nThe average age of menarche was 12.46 years (± 1.73), \nranging from 8 to 17 years. Out of the total, 138 patients \n(42.72%) had no children at the time of the first consul -\ntation and 40 patients (12.39%) had had one or more \nabortions.\nHormonal contraceptive methods were used by \n145 patients (46.17%), 36 (11.46%) used permanent \nFig. 1 Flowchart of patients attended by the Endometriosis sector of the State Public Servant Hospital in São Paulo\n\nPage 4 of 10da Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \nmethods, and 96 (30.57%) used only condoms or no \nmethod. Three patients were using GnRH analogs at \nthe time of the first consultation. Table  1 describes the \nmost common conditions; arterial hypertension was \nthe most frequent.\nOf the total, 18 patients (5.45%) were asymptomatic \nat the time of the first consultation and 3 (0.91%) \nreceived the diagnosis in surgeries indicated by other \nhypotheses, making endometriosis a surgical find -\ning. Twenty-five patients (7.57%) did not have data for \ncalculating the time of symptoms. Thus, 284 patients \nremained, with whom it was possible to calculate the \ntime between the onset of symptoms and the diagnosis. \nThe median time between symptoms and surgical diag -\nnosis of endometriosis was 31.1 (14.13—63.53) months, \nranging from 1.03 to 426.13 months, data illustrated in \nFig. 2.\nTable  2 illustrates the symptoms reported by the \npatients before starting prescribed treatment. In \nTable 3, it is possible to evaluate the main sites of endo -\nmetriotic lesions described in surgical reports.\nAccording to the available surgical descrip -\ntions, 74 (48.05%) capsule resections, 40 (25.81%) \noophorectomies, 37 (23.87%) cyst drains, and 13 \n(8.44%) cauterizations were performed.\nWe obtained the description of the pelvic endometrio -\nsis stage according to the American Society for Repro -\nductive Medicine (ASRM) classification for 248 patients, \ndistributed as follows: 21 (8.47%) cases of minimal endo -\nmetriosis, 26 (10.48%) cases of mild endometriosis, 90 \n(36.29%) cases of moderate endometriosis, 103 (41.53%) \ncases of severe endometriosis, and 8 patients with a diag -\nnosis of abdominal wall endometriosis (3.23%). Thus, \n77.82% of the cases were in stages III or IV and 18.95% of \nthe cases were in stages I or II.\nAll patients included received drug treatment accord -\ning to Table  4 below. These methods were studied \naccording to composition, isolated progestins (P) or com-\nbinations of estrogens and progestins (EP) to facilitate \ndata interpretation.\nTherefore, 4 patients (1.21%) received GnRH analogs \nas the first option of medical treatment, 142 patients \n(43.03%) received combined methods prescriptions, and \nTable 1 Personal medical history reported by patients at the first \nvisit\nComorbidities Frequency Percentage\nCancer 7 2.12%\nCardiopathies 10 3.03%\nDiabetes Mellitus 16 4.85%\nArterial Hypertension 43 13.03%\nThyroidopathies 17 5.15%\nGynecological Diseases 20 6.06%\nPsychiatric Diseases 0 0%\nFig. 2 Time elapsed between onset of symptoms and surgical diagnosis\nTable 2 Symptoms reported by patients at the first \nappointment\nPercentages are calculated based on available data\nSymptoms Frequency Total Available Percentage\nDysmenorrhea 266 329 80.85%\nDyspareunia 144 327 44.04%\nAcyclic Pain 144 329 43.77%\nPainful Defecation 13 329 3.95%\nPericicatricial Pain 14 329 4.26%\nInfertility 61 326 18.71%\nHematuria/Urinary \nSymptoms\n8 328 2.44%\nConstipation 102 320 31.88%\nIntestinal Bleeding 2 328 0.61%\nTenesmus 5 329 1.52%\n\nPage 5 of 10\nda Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \n \n184 patients (55.76%) received a prescription for iso -\nlated progestins. The preferred prescription form was \ncontinuous.\nAmong the combined contraceptives, the most fre -\nquently prescribed dose was 30  µg of ethinylestradiol, \nprescribed for 95 patients (28.78%). Among the iso -\nlated progestins, the most frequent was desogestrel, \nprescribed for 87 (26.36%) patients. As shown in Fig.  3, \nthe median treatment time was 18  months, rang -\ning from 1 to 168  months. Of the total, 177 patients \n(53.63%) discontinued the proposed treatment.\nDuring de follow-up after starting treatment, the \npatients reported several complaints, as shown in \nTable 5.\nFigure 4 illustrates the evolution of the patients mon -\nitored during the study.\nOut of the total, 153 patients continued with the ini -\ntially prescribed medication, while 177 discontinued \ntreatment. Among those who discontinued, 11 did so \nfor reasons unrelated to treatment dissatisfaction, 3 \nchose not to receive medical treatment, and 19 were \nlost to follow-up after the initial 6 months, which were \nused as inclusion criteria for the study. The remaining \n144 patients were prescribed a new medication.\nConsidering the patients who maintained the medi -\ncation and those who required a treatment change, we \nobtained a discontinuation rate of 55.4% among EP \nusers and 41.8% among P users.\nAnalyzing only the patients who discontinued the use \nof medication, based on the reported side effects, we \nobtained headache in six patients (9.84%), breakthrough \nbleeding in 47 (77.08%), weight gain in eight (13.12%), \npersistence of pain in 23 (37.72%), nausea in six (9.84%), \nmastalgia in two (3.28%) and acne in one patient (1.64%).\nGiven the complaints reported and the interruption \nof treatments, medication changes were proposed. Of \nthese, 67 changes (46.52%) were made to medications \nin the same category and 77 changes (53.47%) to medi -\ncations in a different category, as shown in Table 6 .\nSix medication changes involved GnRH agonists. Of \nthe four patients who started the follow-up with GnRH \nagonists, three switched to combined hormonal contra -\nceptives and one to progestins. Two patients changed to \nGnRH agonists, one used EP and the other P , previously.\nTable 3 Location of endometriotic lesions\nPercentages are calculated based on available data\nLocation Frequency Total Available Percentage\nOvaries 214 326 65.64%\nRectovaginal Septum 9 326 2.76%\nRectum and Sigmoid \nColon\n19 326 5.83%\nBladder 9 326 2.76%\nAppendix 4 57 7.02%\nAbdominal Wall 22 57 38.60%\nFallopian Tube 22 57 38.60%\nRetrocervical Region and \nUterosacral Ligament\n22 228 9.63%\nTable 4 Medications prescribed at the start of the follow-up\nEP combined hormonal contraceptives, P progestins\nMedication Frequency Percentage\nTransdermal EP 1 0.30%\nOral EP 137 41.52%\nVaginal EP 4 1.21%\nGnRH Analogs 4 1.21%\nIUD P 15 4.55%\nInjectable P 73 22.12%\nSubcutaneous P 1 0.30%\nOral P 95 28.79%\nTotal 330 100%\nFig. 3 Time of use of the medication proposed as the initial treatment\n\nPage 6 of 10da Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \nOf the 153 patients who did not interrupt the ini -\ntial proposed treatment, 96 received P and 57 received \nEP . The average follow-up time for these patients was \n38.91 months.\nAmong the users of EP , the events that showed an \nassociation with the interruption of treatment were per -\nsistence of pain, with a relative risk of 1.65 (p = 0.031) \nand breakthrough bleeding, with a relative risk of 2.76 \n(p < 0.001). All of this group who reported weight gain \ninterrupted the treatment, but there was no statistical \nsignificance due to the low frequency of this complaint \n(p = 0.1345). It was observed that the highest risk of inter-\nruption of EP occurs up to 9 months of treatment, with a \nrelative risk of interruption of 2.32 (p = 0.026). Treatment \ntime above 10 months did not correlate with the risk of \ninterruption.\nAmong the users of P , the events that had a greater \nimpact on the risk of interrupting treatment were break -\nthrough bleeding and heavy bleeding, with a relative risk \nof 1.35 (p = 0.032). The time required for adaptation to \ntreatment, and consequently not showing a correlation \nwith medication interruption, was longer for P users. \nUp to 84 months of treatment, we have a relative risk of \ninterruption of 1.74 (p = 0.04), becoming non-significant \nthereafter.\nWhen the two groups were compared, the patients \nwho received P as the initial treatment had a significantly \nhigher age range (p < 0.001) and had some reported per -\nsonal medical history (p < 0.001) compared to those who \nreceived EP .\nThe multiple logistic regression analysis that corre -\nlated adverse events, type of medication, and treatment \ninterruption showed that the complaint of breakthrough \nbleeding, weight gain, persistence of pelvic pain, and \nTable 5 Symptoms reported in follow-up consultations after \nstarting the first proposed treatment\nSymptoms Frequency Percentage\nHeadache 11 3.33%\nPersistence of Pain 110 33.33%\nSpotting 164 47.9%\nIntense Bleeding 14 4.24%\nBreast Pain 3 0.91%\nNausea 7 2.12%\nWeight Gain 24 7.27%\nFig. 4 Flowchart of medication treatment and evolution. EP Estrogen-progestins, P progestins, A GnRH analogs\n\nPage 7 of 10\nda Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \n \ntreatment with EP had a direct, significant, and inde -\npendent association with clinical treatment interrup -\ntion, adjusted for the complaint of headache, as shown in \nTable 7.\nConsidering only the patients who received EP , the \nmultiple analysis showed that the adverse events of spot -\nting and persistence of pain and the staging of mini -\nmal/mild endometriosis had a significant, direct and \nindependent correlation with the interruption of treat -\nment with EP . Infertility had an inverse correlation with \nthe interruption of treatment. These data are shown in \nTable 8. The variables were adjusted for a treatment dura-\ntion of fewer than 9  months, education level, and com -\nplaint of headache.\nAs shown in Table  9, the adverse event that had a sig -\nnificant and independent correlation with treatment \ninterruption with P was the presence of spotting. There \nwas also a direct correlation with duration of treatment \nless than 9  months and intraoperative endometriosis \nstaged as minimal or mild.\nConsidering that the systemic exposure to levonorg -\nestrel among LNG-IUS users is minimal, a multivariate \nanalysis of the P group was conducted, excluding those \npatients who were prescribed LNG-IUS as the initial \ntreatment. This analysis did not find significant differ -\nences compared to the results presented in Table 9.\nDiscussion\nThe medication therapy for endometriosis consists of \nlong-term treatment, like therapies for other chronic \ndiseases such as diabetes mellitus and systemic arterial \nhypertension. The pain symptoms related to endometrio-\nsis cause a huge impact on quality of life and can be con -\ntrolled with the use of these medications [4, 5, 12].\nIt is natural for patients with endometriosis and pel -\nvic pain to receive medication therapy until there is a \nTable 6 Medication swaps after the first proposed treatment\nSource: the author (2022)\nEP combined hormonal contraceptives, P progestins, A GnRH analog\nMedication Changes Frequency Percentage\nFrom EP to EP 26 18.06%\nFrom EP to A 1 0.69%\nFrom EP to P 44 30.57%\nFrom A to EP 3 2.08%\nFrom A to P 1 0.69%\nFrom P to EP 27 18.75%\nFrom P to A 1 0.69%\nFrom P to P 41 28.47%\nTotal 144 100%\nTable 7 Multiple analysis of side effects, type of medication used, and treatment interruption\nOR Odds Ratio, CI confidence interval, EP combined contraceptives containing estrogens and progestins\nTreatment Type and Side \nEffect\n\"p\" Value of Univariate \nAnalysis\nUnivariate Analysis OR (CI) \"p\" Value of Adjusted \nAnalysis\nAdjusted Analysis OR (CI)\nSpotting  < 0.001 2.267 (1.457–3.528)  < 0.001 2.672 (1.672–4.269)\nEP 0.016 1.725 (1.106–2.692) 0.005 1.995 (1.237–3.219)\nPersistence of Pain 0.043 1.619 (1.015–2.582) 0.043 1.670 (1.017–2.743)\nWeight Gain 0.066 2.330 (0.946–5.740) 0.017 3.227 (1.237–8.418)\nHeadache 0.080 3.994 (0.849–18.778) 0.076 4.440 (0.855–23.060)\nTable 8 Multivariate analysis of the correlation between side effects, education, staging, and follow-up time with the risk of \ninterrupting EP treatment\nEP combined contraceptives containing estrogens and progestins, OR Odds Ratio, CI confidence interval\nSide Effect \"p\" Value of Univariate \nAnalysis\nUnivariate Analysis OR (CI) \"p\" Value of Adjusted \nAnalysis\nAdjusted Analysis OR (CI)\nSpotting  < 0.001 4.267 (2.028–8.978)  < 0.001 8.432 (2.632–27.014)\nPersistence of Pain 0.117 1.769 (0.898–3.610) 0.006 6.388 (1.721–23.714)\nInfertility 0.136 0.533 (0.234–1.218) 0.010 0.153 (0.037–0.632)\nDuration of Treatment Less \nthan 9 Months\n0.041 3.291 (1.048–10.335) 0.067 4.550 (0.8990–23.009)\nStaging Minimal/Mild 0.155 2.106 (0.755–5.874) 0.026 5.578 (1.233–25.233)\nUniversity Degree 0.236 0.636 (0.331–1.344) 0.429 0.619 (0.188–2.032)\nHeadache 0.299 2.348 (0.469–11.742) 0.435 2.741 (0.217–34.491)\n\nPage 8 of 10da Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \ndesire for reproduction or menopause [4 ]. Thus, stud -\nies like this one, which seek to evaluate the efficacy and \ntolerability of the medications, are of extreme value.\nIn the most recent recommendations for endome -\ntriosis management, we find a trend towards patient-\nfocused treatment, their desires and symptoms, rather \nthan endometriotic lesions, so medication therapy can \nbe implemented without delay, even in the absence of \nhistological confirmation of the disease [4 ]. Despite this \napproach gaining strength, all the patients in the pre -\nsent study obtained a diagnostic confirmation through \nsurgery and a large part of them only started to be fol -\nlowed by the specialized sector after the procedure.\nGiven the wide range of clinical manifestations and \ndifferential diagnoses, the time between the onset of \nsymptoms and the definitive diagnosis with special -\nized endometriosis group monitoring is usually long \n[27– 29]. This study found an average of 4.8  years \nbetween these two events, with a non-parametric dis -\ntribution, so the median of 2.5 years should be consid -\nered. In some scientific articles, the interval described \nis 6 to 8  years [9 , 10, 27]. The two most frequent \nsymptoms were dysmenorrhea and dyspareunia, as \nreported by other studies [5 , 30].\nThe ovaries are the most affected areas by endome -\ntriosis, as shown in this study, which demonstrated \novarian endometriotic foci in 65.64% of the proce -\ndures. Definitive surgical treatments, such as hyster -\nectomy and bilateral salpingo-oophorectomy, were \nexclusion criteria. Among the conservative approaches \nperformed, the resection of endometrioma capsules \n(48.05%) and unilateral oophorectomies (25.81%) were \nthe most frequent.\nThe two most prescribed drug classes were combined \ncontraceptives and isolated progestins, in their various \ndoses and administration routes. There is no evidence \nthat demonstrates superiority in pain control by a spe -\ncific administration route. Considering the prolonged \nuse of these medications, the administration route \nshould facilitate treatment adherence and be in accord -\nance with each patient’s preferences [9 , 17].\nContinuous administration was preferred over cyclic \nadministration for better control of dysmenorrhea. Peri -\nodic pauses were indicated only to control irregular \nbleeding and spotting.\nCombined contraceptives and progestins seem to \nhave similar effectiveness in controlling pain symptoms, \nachieving this result in two-thirds of patients [5, 17, 21].\nAccording to Vercellini et  al., combined contracep -\ntives containing the lowest possible dose of ethinylestra -\ndiol and second-generation progestin can be considered \nfirst-line therapy in peritoneal lesions and endometrio -\nmas. Isolated progestins can be prescribed as an alter -\nnative to combined contraceptives when there are side \neffects, deep endometriosis, and in case of a contrain -\ndication to estrogen use, such as a high risk of throm -\nboembolism [7 , 17, 31]. In fact, the group that received \nisolated progestins as a first-line therapeutic option was \nassociated with a more advanced age and personal his -\ntory of chronic diseases.\nThe most frequent adverse event among patients who \ndiscontinued the proposed treatment were breakthrough \nbleedings, present in 77.08% of cases. Breakthrough \nbleedings were found in both groups and with a direct \nand independent association with medication interrup -\ntion. This finding suggests that proper management of \nbreakthrough bleedings may impact adherence and, con -\nsequently, therapeutic success.\nPain persistence is expected in some patients using \nfirst-line therapies such as combined contraceptives and \nprogestins. Some authors report a lack of response to \nthese medications in up to 30% of patients, a therapeutic \nfailure attributed to the progesterone resistance present \nin the disease’s pathophysiology [17, 32]. In this study, \npain persistence was significantly correlated with treat -\nment interruption only in patients using EP .\nEP treatments were significantly correlated with dis -\ncontinuation, and this risk was higher in the first nine \nTable 9 Multivariate analysis of the correlation between side effects, stage, and parity with the risk of treatment interruption with P\nP progestins, OR Odds Ratio, IC confidence interval\nSide Effect \"p\" Value of Univariate \nAnalysis\nUnivariate Analysis OR (CI) \"p\" Value of Adjusted \nAnalysis\nAdjusted Analysis OR (CI)\nDuration of Treatment Less \nthan 9 Months\n < 0.001 5.625 (2.410–13.130)  < 0.001 9.398 (3.006–29.378)\nSpotting 0.057 1.775 (0.984–3.203) 0.024 2.638 (1.134–6.136)\nWeight Gain 0.073 2.405 (0.923–6.271) 0.211 2.110 (0.655–6.796)\nIntense Bleeding 0.086 4.062 (0.821–20.104) 0.308 3.443 (0.319–37.174)\nStaging Minimal/Mild 0.005 5.206 (1.654–16.382) 0.001 8.078 (2.291–28.482)\nNulliparity 0.171 1.538 (0.830–2.852) 0.239 1.667 (0.711–3.907)\n\nPage 9 of 10\nda Costa Pinheiro et al. BMC Women’s Health          (2023) 23:510 \n \nmonths of treatment. They are widely used to control \nsymptoms of endometriosis, but various authors ques -\ntion their benefits. Some, for example, cite the lack of \nresponse in pain outside the menstrual period and dys -\npareunia, as well as the suspicion that EPs may induce the \nprogression of endometriotic lesions [32–34].\nThe decrease in the rate of EP interruption over the \nmonths may represent patients’ adaptation to the side \neffects of these drugs, so if there is resilience and good \nguidance on side effects at the beginning of treatment, \nthe chances of good tolerability are higher.\nIt is necessary to highlight that all patients underwent \nsome surgical treatment, which allowed the histologi -\ncal diagnosis to be used as an inclusion criterion for the \nstudy. Thus, the benefits acquired by surgery should be \nconsidered.\nThe choice of medical therapy for endometriosis is not \nsimple. Several factors must be evaluated, such as main \nsymptoms, reproductive desire, types of lesions found, \nside effects, comorbidities, and personal preferences of \nthe patient. The importance of the patient’s reception by \nthe medical team with proper management of complica -\ntions must also be emphasized.\nConclusion\nThe treatment with combined contraceptives has been \nassociated with a higher risk of discontinuation than \ntreatment with isolated progestins. This risk was signifi -\ncantly higher in the first 9 months of treatment. Among \nall the described complaints, breakthrough bleeding, \nweight gain, and persistence of pelvic pain had a direct, \nsignificant and independent association with medication \ndiscontinuation.\nAcknowledgements\nThe authors would like to express their gratitude to all patients assisted by our \ngroup.\nAuthors’ contributions\nDenise Joffily Pereira da Costa Pinheiro and Ana Maria Gomes Pereira \nelaborated the structure of the study. Denise Joffily Pereira da Costa Pinheiro \nwrote the main manuscript text and prepared the figures and tables. Ana \nMaria Gomes Pereira did the statistical analyzes. All authors reviewed the \nmanuscript.\nFunding\nThis study was funded by the authors.\nAvailability of data and materials\nThe authors confirm that the data supporting the findings of this study are \navailable within the article. Raw data that support the findings of this study \nare available from the corresponding author, upon request.\nDeclarations\nEthics approval and consent to participate\nInformed consent was obtained from all the participants.\nAll methods were carried out in accordance with relevant guidelines and \nregulations.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nReceived: 7 March 2023   Accepted: 10 September 2023\nReferences\n 1. Febrasgo (BR). 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Endometriosis and medical therapy: from \nprogestogens to progesterone resistance to GnRH antagonists: a review. \nJ Clin Med. 2021;10(5):1085.\n 33. Casper RF. Progestin-only pills may be a better first-line treatment for \nendometriosis than combined estrogen-progestin contraceptive pills. \nFertil Steril. 2017;107(3):533–6.\n 34. Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P , Bijaoui G, et al. \nOral contraceptives and endometriosis: the past use of oral contra-\nceptives for treating severe primary dysmenorrhea is associated with \nendometriosis, especially deep infiltrating endometriosis. Hum Reprod. \n2011;26(8):2028–35.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}