Tolerability of endometriosis medical treatment: a comparison between combined hormonal contraceptives and progestins

Endometriosis is a chronic inflammatory disease that occurs in women of reproductive age. Much of the treatment involves hormone therapy that suppresses the proliferation of endometriosis lesions.

To compare discontinuation rates of pharmacological treatment with estrogen-progestins and pro- gestins medications. The secondary objective is to evaluate the main side effects of these drugs in patients with endometriosis.

This retrospective study analyzed data from 330 patients who attended the Hospital of the State Public Servant of São Paulo from August 1999 to September 2020 and received pharmacological treatment for endometrio- sis. The data were obtained by review of the files of medical appointments with specialized staff.

The median treatment time was 18 months, ranging from 1 to 168 months, and 177 patients interrupted the proposed treatment. The combined contraceptives with estrogens and progestins were significantly linked to treatment interruption, with a relative risk of 1,99 (p = 0,005). The most important side effects that resulted in treat- ment interruption were pain persistence (p = 0,043), weight gain (p = 0,017) and spotting (p < 0,001).

Endometriosis, Pharmacological treatment, Side effects, Tolerability

Endometriosis is a chronic inflammatory estrogen- dependent gynecological disease characterized by the development and growth of functional endometrium-like tissue outside the uterine cavity [1, 2]. It predominantly affects the ovaries but can also affect other organs such as the fallopian tubes, pelvic ligaments, appendix, bladder, and intestines [3–5]. The most common symptoms are dysmenorrhea, pelvic pain outside the menstrual period, dyspareunia, infertil - ity, urinary and evacuation symptoms. However, its clini - cal presentation can be non-specific and with symptoms disproportionate to the extent of the disease, making diagnosis difficult [6–10]. Endometriosis significantly impacts women’s quality of life, compromising their social and emotional relation - ships, work, and study performance. It is an important public health issue, affecting 6 to 10% of women of repro- ductive age, with a peak incidence between the ages of 25 and 35 years [4, 5]. *Correspondence: Denise Joffily Pereira da Costa Pinheiro [email protected] 1 Hospital Do Servidor Público Estadual - Francisco Morato de Oliveira (HSPE-FMO), Rua Pedro de Toledo 1800, São Paulo, SP 04029000, Brazil 2 CEDEP – Instituto de Assistência Médica ao Servidor Público Estadual (IAMSPE), São Paulo, Brazil Page 2 of 10da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 The treatment of endometriosis includes surgery, medi- cation therapy, and assisted reproductive techniques. As a chronic disease, patients should be monitored for many years and receive individualized treatment according to their clinical status and reproductive desire at each stage of life. The goal is to remove endometriotic foci surgically or suppress them with clinical treatment. However, the best approach has not been defined yet [11–14]. The medical treatment aims to induce a hypoestrogenic state of chronic anovulation, creating an inadequate envi- ronment for the growth and maintenance of endometrio- sis implants [7, 13, 15, 16]. The medical treatment is not curative, as it cannot eliminate the endometriotic foci, only making them temporarily inactive during medica - tion use [17]. Among the therapeutic options, we have combined hormonal contraceptives containing estrogens and pro - gestins (EP), isolated progestins (P), antiprogestins, GnRH agonists, GnRH antagonists, aromatase inhibitors, and medications that do not act as hormonal suppres - sants, such as analgesics and non-steroidal anti-inflam - matory drugs [9]. Considering the chronic use of these medications, it is important to evaluate not only their efficacy but also their tolerability, side effects, cost, and each patient’s preferences [7, 13, 17, 18]. The tolerability of treatment consists of the patient’s ability to tolerate the side effects and maintain the use of the medication. It can be evalu - ated through the rates of treatment interruption or fol - low-up losses in clinical studies [17]. It is recommended to start with low-cost drugs, such as combined oral contraceptives and some progestins, and then move on to high-cost drugs, such as GnRH agonists, in cases of low adherence, tolerability, or ineffectiveness [7 ]. Although widely prescribed, combined hormonal con - traceptives have no scientific basis to prove the supe - riority of this group of medications compared to other classes, and does not appear to be any advantage of any specific drug within this group [7]. Continuous admin - istration of combined contraceptives has been more favorable in controlling pain than cyclical administration. It is possible to perform a planned interruption only to control spotting, which is bleeding that occurs outside of the menstrual period [19]. Regarding ethinylestradiol dosage, low-dose options with 20 mcg are safer, with a lower risk of thromboembolic events [17]. According to some authors, progestins have fewer side effects than combined contraceptives and can be pre - scribed in various routes of administration, oral, inject - able, implants, and intrauterine devices [9 , 20– 25]. Desogestrel and dienogest are 19-nortestosterone- derived progestins widely studied for the treatment of endometriosis and have been shown effective in control - ling symptoms [20, 22]. Symptoms can be controlled by various drugs, many of them with great pain control results, the limiting factors are the side effects and tolerability related to these medi - cations. Adequate monitoring and control of unwanted effects are essential for achieving therapeutic success. Thus, studies that compare drug options, considering not only the efficacy but also the quality of life of patients, are necessary to guide conduct.

This study aims to compare the discontinuation rates of medical treatments for endometriosis with com - bined hormonal contraceptives and isolated proges - tins. The secondary objective is to evaluate the main adverse effects related to the discontinuation of these medications.

A retrospective study that evaluated the rate of medica - tion interruption by patients attended in the endome - triosis sector of the State Public Servant Hospital in São Paulo. The data was collected through forms filed in the spe - cialized outpatient clinic. Patients attended from August 1999 to September 2020 were evaluated. To be included in the study, a histological confirmation of endometriosis and a medical treatment prescription was necessary. Thus, it is important to highlight that all patients included in the study underwent surgical treat - ment prior to clinical intervention. Patients with incom - plete data for the study, those who were already in clinical or surgical postmenopause at the first consultation, hys - terectomized patients and finally, those patients who did not have a minimum follow-up time of 6 months in the presence of medical treatment were excluded. Epidemiological data were collected to trace the profile of attended patients. The time between the onset of symptoms and the sur - gery date was evaluated. The symptoms questioned were dysmenorrhea, dyspareunia, cyclic pain, pain while evac - uating, pericicatrical pain, infertility, urinary and intesti - nal symptoms. The surgical findings were raised, researching where endometriotic lesions were found. The surgical proce - dures performed and the staging of endometriosis were also researched. The classification of endometriosis from the American Society for Reproductive Medicine (ASRM) was used as a reference [8]. The prescribed medications for clinical treatment were chosen based on reliable guidelines such as ESHRE’s, on the opinion of the attending physician and Page 3 of 10 da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 on the patient’s preferences [6 ]. These treatments were verified for the type of hormone and dose. During the entire follow-up, patients were questioned about the symptoms and side effects presented during treatment. The use time of each medication was recorded, and once the patient opted for discontinuation, the reason for discontinuation was also recorded. A new medica - tion could be prescribed, containing the same hormone with a different dosage or a medication from a different class. An informed consent form was applied before data collection. This study was approved by Research Eth - ics Committee of State Public Servant Hospital and is registered in Plataforma Brasil under CAAE number 36271213.8.0000.5463. Statistical analyzes were performed for two distinct groups, isolated progestins (P) and combined contracep - tives (EP). Frequencies were calculated using the infor - mation available for each data point. The data obtained were grouped in an Excel spread - sheet for Windows ® and were analyzed using the statis - tical programs Epi Info7 ® an Open-Epi, online version [26]. Continuous variables were tested for their distribu - tion and are presented in means and standard deviation or medians and quartiles, depending on the normality of this distribution. Categorical variables are presented in percentages, according to the data available for analysis. The variables relating to adverse events and complaints reported during clinical treatment were correlated with the outcome of treatment interruption, and multiple analysis of logistic regression was conducted using the STATA 12.0® program, grouping the adverse events that presented potential statistical significance in the univari - ate analysis (value of p < 0.25 was used to select variables for multiple final analysis), except those that did not have enough outcome events to be included in the adjusted modeling. A p-value < 0,05 was considered statistically significant.

As reported in Fig.  1, we enrolled 392 patients in the study, and after applying exclusion criteria, 330 patients remained for analysis. The average age of patients at the time of the first consultation was 37.57  years (± 6.27), ranging from 17 to 53  years. The average age of symptom onset was 31.07 years (± 8.4), ranging from 8 to 51 years. The average age of menarche was 12.46 years (± 1.73), ranging from 8 to 17 years. Out of the total, 138 patients (42.72%) had no children at the time of the first consul - tation and 40 patients (12.39%) had had one or more abortions. Hormonal contraceptive methods were used by 145 patients (46.17%), 36 (11.46%) used permanent Fig. 1 Flowchart of patients attended by the Endometriosis sector of the State Public Servant Hospital in São Paulo Page 4 of 10da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 methods, and 96 (30.57%) used only condoms or no method. Three patients were using GnRH analogs at the time of the first consultation. Table  1 describes the most common conditions; arterial hypertension was the most frequent. Of the total, 18 patients (5.45%) were asymptomatic at the time of the first consultation and 3 (0.91%) received the diagnosis in surgeries indicated by other hypotheses, making endometriosis a surgical find - ing. Twenty-five patients (7.57%) did not have data for calculating the time of symptoms. Thus, 284 patients remained, with whom it was possible to calculate the time between the onset of symptoms and the diagnosis. The median time between symptoms and surgical diag - nosis of endometriosis was 31.1 (14.13—63.53) months, ranging from 1.03 to 426.13 months, data illustrated in Fig. 2. Table  2 illustrates the symptoms reported by the patients before starting prescribed treatment. In Table 3, it is possible to evaluate the main sites of endo - metriotic lesions described in surgical reports. According to the available surgical descrip - tions, 74 (48.05%) capsule resections, 40 (25.81%) oophorectomies, 37 (23.87%) cyst drains, and 13 (8.44%) cauterizations were performed. We obtained the description of the pelvic endometrio - sis stage according to the American Society for Repro - ductive Medicine (ASRM) classification for 248 patients, distributed as follows: 21 (8.47%) cases of minimal endo - metriosis, 26 (10.48%) cases of mild endometriosis, 90 (36.29%) cases of moderate endometriosis, 103 (41.53%) cases of severe endometriosis, and 8 patients with a diag - nosis of abdominal wall endometriosis (3.23%). Thus, 77.82% of the cases were in stages III or IV and 18.95% of the cases were in stages I or II. All patients included received drug treatment accord - ing to Table  4 below. These methods were studied according to composition, isolated progestins (P) or com- binations of estrogens and progestins (EP) to facilitate data interpretation. Therefore, 4 patients (1.21%) received GnRH analogs as the first option of medical treatment, 142 patients (43.03%) received combined methods prescriptions, and Table 1 Personal medical history reported by patients at the first visit Comorbidities Frequency Percentage Cancer 7 2.12% Cardiopathies 10 3.03% Diabetes Mellitus 16 4.85% Arterial Hypertension 43 13.03% Thyroidopathies 17 5.15% Gynecological Diseases 20 6.06% Psychiatric Diseases 0 0% Fig. 2 Time elapsed between onset of symptoms and surgical diagnosis Table 2 Symptoms reported by patients at the first appointment Percentages are calculated based on available data Symptoms Frequency Total Available Percentage Dysmenorrhea 266 329 80.85% Dyspareunia 144 327 44.04% Acyclic Pain 144 329 43.77% Painful Defecation 13 329 3.95% Pericicatricial Pain 14 329 4.26% Infertility 61 326 18.71% Hematuria/Urinary Symptoms 8 328 2.44% Constipation 102 320 31.88% Intestinal Bleeding 2 328 0.61% Tenesmus 5 329 1.52% Page 5 of 10 da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 184 patients (55.76%) received a prescription for iso - lated progestins. The preferred prescription form was continuous. Among the combined contraceptives, the most fre - quently prescribed dose was 30  µg of ethinylestradiol, prescribed for 95 patients (28.78%). Among the iso - lated progestins, the most frequent was desogestrel, prescribed for 87 (26.36%) patients. As shown in Fig.  3, the median treatment time was 18  months, rang - ing from 1 to 168  months. Of the total, 177 patients (53.63%) discontinued the proposed treatment. During de follow-up after starting treatment, the patients reported several complaints, as shown in Table 5. Figure 4 illustrates the evolution of the patients mon - itored during the study. Out of the total, 153 patients continued with the ini - tially prescribed medication, while 177 discontinued treatment. Among those who discontinued, 11 did so for reasons unrelated to treatment dissatisfaction, 3 chose not to receive medical treatment, and 19 were lost to follow-up after the initial 6 months, which were used as inclusion criteria for the study. The remaining 144 patients were prescribed a new medication. Considering the patients who maintained the medi - cation and those who required a treatment change, we obtained a discontinuation rate of 55.4% among EP users and 41.8% among P users. Analyzing only the patients who discontinued the use of medication, based on the reported side effects, we obtained headache in six patients (9.84%), breakthrough bleeding in 47 (77.08%), weight gain in eight (13.12%), persistence of pain in 23 (37.72%), nausea in six (9.84%), mastalgia in two (3.28%) and acne in one patient (1.64%). Given the complaints reported and the interruption of treatments, medication changes were proposed. Of these, 67 changes (46.52%) were made to medications in the same category and 77 changes (53.47%) to medi - cations in a different category, as shown in Table 6 . Six medication changes involved GnRH agonists. Of the four patients who started the follow-up with GnRH agonists, three switched to combined hormonal contra - ceptives and one to progestins. Two patients changed to GnRH agonists, one used EP and the other P , previously. Table 3 Location of endometriotic lesions Percentages are calculated based on available data Location Frequency Total Available Percentage Ovaries 214 326 65.64% Rectovaginal Septum 9 326 2.76% Rectum and Sigmoid Colon 19 326 5.83% Bladder 9 326 2.76% Appendix 4 57 7.02% Abdominal Wall 22 57 38.60% Fallopian Tube 22 57 38.60% Retrocervical Region and Uterosacral Ligament 22 228 9.63% Table 4 Medications prescribed at the start of the follow-up EP combined hormonal contraceptives, P progestins Medication Frequency Percentage Transdermal EP 1 0.30% Oral EP 137 41.52% Vaginal EP 4 1.21% GnRH Analogs 4 1.21% IUD P 15 4.55% Injectable P 73 22.12% Subcutaneous P 1 0.30% Oral P 95 28.79% Total 330 100% Fig. 3 Time of use of the medication proposed as the initial treatment Page 6 of 10da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 Of the 153 patients who did not interrupt the ini - tial proposed treatment, 96 received P and 57 received EP . The average follow-up time for these patients was 38.91 months. Among the users of EP , the events that showed an association with the interruption of treatment were per - sistence of pain, with a relative risk of 1.65 (p = 0.031) and breakthrough bleeding, with a relative risk of 2.76 (p < 0.001). All of this group who reported weight gain interrupted the treatment, but there was no statistical significance due to the low frequency of this complaint (p = 0.1345). It was observed that the highest risk of inter- ruption of EP occurs up to 9 months of treatment, with a relative risk of interruption of 2.32 (p = 0.026). Treatment time above 10 months did not correlate with the risk of interruption. Among the users of P , the events that had a greater impact on the risk of interrupting treatment were break - through bleeding and heavy bleeding, with a relative risk of 1.35 (p = 0.032). The time required for adaptation to treatment, and consequently not showing a correlation with medication interruption, was longer for P users. Up to 84 months of treatment, we have a relative risk of interruption of 1.74 (p = 0.04), becoming non-significant thereafter. When the two groups were compared, the patients who received P as the initial treatment had a significantly higher age range (p < 0.001) and had some reported per - sonal medical history (p < 0.001) compared to those who received EP . The multiple logistic regression analysis that corre - lated adverse events, type of medication, and treatment interruption showed that the complaint of breakthrough bleeding, weight gain, persistence of pelvic pain, and Table 5 Symptoms reported in follow-up consultations after starting the first proposed treatment Symptoms Frequency Percentage Headache 11 3.33% Persistence of Pain 110 33.33% Spotting 164 47.9% Intense Bleeding 14 4.24% Breast Pain 3 0.91% Nausea 7 2.12% Weight Gain 24 7.27% Fig. 4 Flowchart of medication treatment and evolution. EP Estrogen-progestins, P progestins, A GnRH analogs Page 7 of 10 da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 treatment with EP had a direct, significant, and inde - pendent association with clinical treatment interrup - tion, adjusted for the complaint of headache, as shown in Table 7. Considering only the patients who received EP , the multiple analysis showed that the adverse events of spot - ting and persistence of pain and the staging of mini - mal/mild endometriosis had a significant, direct and independent correlation with the interruption of treat - ment with EP . Infertility had an inverse correlation with the interruption of treatment. These data are shown in Table 8. The variables were adjusted for a treatment dura- tion of fewer than 9  months, education level, and com - plaint of headache. As shown in Table  9, the adverse event that had a sig - nificant and independent correlation with treatment interruption with P was the presence of spotting. There was also a direct correlation with duration of treatment less than 9  months and intraoperative endometriosis staged as minimal or mild. Considering that the systemic exposure to levonorg - estrel among LNG-IUS users is minimal, a multivariate analysis of the P group was conducted, excluding those patients who were prescribed LNG-IUS as the initial treatment. This analysis did not find significant differ - ences compared to the results presented in Table 9.

The medication therapy for endometriosis consists of long-term treatment, like therapies for other chronic diseases such as diabetes mellitus and systemic arterial hypertension. The pain symptoms related to endometrio- sis cause a huge impact on quality of life and can be con - trolled with the use of these medications [4, 5, 12]. It is natural for patients with endometriosis and pel - vic pain to receive medication therapy until there is a Table 6 Medication swaps after the first proposed treatment Source: the author (2022) EP combined hormonal contraceptives, P progestins, A GnRH analog Medication Changes Frequency Percentage From EP to EP 26 18.06% From EP to A 1 0.69% From EP to P 44 30.57% From A to EP 3 2.08% From A to P 1 0.69% From P to EP 27 18.75% From P to A 1 0.69% From P to P 41 28.47% Total 144 100% Table 7 Multiple analysis of side effects, type of medication used, and treatment interruption OR Odds Ratio, CI confidence interval, EP combined contraceptives containing estrogens and progestins Treatment Type and Side Effect "p" Value of Univariate Analysis Univariate Analysis OR (CI) "p" Value of Adjusted Analysis Adjusted Analysis OR (CI) Spotting < 0.001 2.267 (1.457–3.528) < 0.001 2.672 (1.672–4.269) EP 0.016 1.725 (1.106–2.692) 0.005 1.995 (1.237–3.219) Persistence of Pain 0.043 1.619 (1.015–2.582) 0.043 1.670 (1.017–2.743) Weight Gain 0.066 2.330 (0.946–5.740) 0.017 3.227 (1.237–8.418) Headache 0.080 3.994 (0.849–18.778) 0.076 4.440 (0.855–23.060) Table 8 Multivariate analysis of the correlation between side effects, education, staging, and follow-up time with the risk of interrupting EP treatment EP combined contraceptives containing estrogens and progestins, OR Odds Ratio, CI confidence interval Side Effect "p" Value of Univariate Analysis Univariate Analysis OR (CI) "p" Value of Adjusted Analysis Adjusted Analysis OR (CI) Spotting < 0.001 4.267 (2.028–8.978) < 0.001 8.432 (2.632–27.014) Persistence of Pain 0.117 1.769 (0.898–3.610) 0.006 6.388 (1.721–23.714) Infertility 0.136 0.533 (0.234–1.218) 0.010 0.153 (0.037–0.632) Duration of Treatment Less than 9 Months 0.041 3.291 (1.048–10.335) 0.067 4.550 (0.8990–23.009) Staging Minimal/Mild 0.155 2.106 (0.755–5.874) 0.026 5.578 (1.233–25.233) University Degree 0.236 0.636 (0.331–1.344) 0.429 0.619 (0.188–2.032) Headache 0.299 2.348 (0.469–11.742) 0.435 2.741 (0.217–34.491) Page 8 of 10da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 desire for reproduction or menopause [4 ]. Thus, stud - ies like this one, which seek to evaluate the efficacy and tolerability of the medications, are of extreme value. In the most recent recommendations for endome - triosis management, we find a trend towards patient- focused treatment, their desires and symptoms, rather than endometriotic lesions, so medication therapy can be implemented without delay, even in the absence of histological confirmation of the disease [4 ]. Despite this approach gaining strength, all the patients in the pre - sent study obtained a diagnostic confirmation through surgery and a large part of them only started to be fol - lowed by the specialized sector after the procedure. Given the wide range of clinical manifestations and differential diagnoses, the time between the onset of symptoms and the definitive diagnosis with special - ized endometriosis group monitoring is usually long [27– 29]. This study found an average of 4.8  years between these two events, with a non-parametric dis - tribution, so the median of 2.5 years should be consid - ered. In some scientific articles, the interval described is 6 to 8  years [9 , 10, 27]. The two most frequent symptoms were dysmenorrhea and dyspareunia, as reported by other studies [5 , 30]. The ovaries are the most affected areas by endome - triosis, as shown in this study, which demonstrated ovarian endometriotic foci in 65.64% of the proce - dures. Definitive surgical treatments, such as hyster - ectomy and bilateral salpingo-oophorectomy, were exclusion criteria. Among the conservative approaches performed, the resection of endometrioma capsules (48.05%) and unilateral oophorectomies (25.81%) were the most frequent. The two most prescribed drug classes were combined contraceptives and isolated progestins, in their various doses and administration routes. There is no evidence that demonstrates superiority in pain control by a spe - cific administration route. Considering the prolonged use of these medications, the administration route should facilitate treatment adherence and be in accord - ance with each patient’s preferences [9 , 17]. Continuous administration was preferred over cyclic administration for better control of dysmenorrhea. Peri - odic pauses were indicated only to control irregular bleeding and spotting. Combined contraceptives and progestins seem to have similar effectiveness in controlling pain symptoms, achieving this result in two-thirds of patients [5, 17, 21]. According to Vercellini et  al., combined contracep - tives containing the lowest possible dose of ethinylestra - diol and second-generation progestin can be considered first-line therapy in peritoneal lesions and endometrio - mas. Isolated progestins can be prescribed as an alter - native to combined contraceptives when there are side effects, deep endometriosis, and in case of a contrain - dication to estrogen use, such as a high risk of throm - boembolism [7 , 17, 31]. In fact, the group that received isolated progestins as a first-line therapeutic option was associated with a more advanced age and personal his - tory of chronic diseases. The most frequent adverse event among patients who discontinued the proposed treatment were breakthrough bleedings, present in 77.08% of cases. Breakthrough bleedings were found in both groups and with a direct and independent association with medication interrup - tion. This finding suggests that proper management of breakthrough bleedings may impact adherence and, con - sequently, therapeutic success. Pain persistence is expected in some patients using first-line therapies such as combined contraceptives and progestins. Some authors report a lack of response to these medications in up to 30% of patients, a therapeutic failure attributed to the progesterone resistance present in the disease’s pathophysiology [17, 32]. In this study, pain persistence was significantly correlated with treat - ment interruption only in patients using EP . EP treatments were significantly correlated with dis - continuation, and this risk was higher in the first nine Table 9 Multivariate analysis of the correlation between side effects, stage, and parity with the risk of treatment interruption with P P progestins, OR Odds Ratio, IC confidence interval Side Effect "p" Value of Univariate Analysis Univariate Analysis OR (CI) "p" Value of Adjusted Analysis Adjusted Analysis OR (CI) Duration of Treatment Less than 9 Months < 0.001 5.625 (2.410–13.130) < 0.001 9.398 (3.006–29.378) Spotting 0.057 1.775 (0.984–3.203) 0.024 2.638 (1.134–6.136) Weight Gain 0.073 2.405 (0.923–6.271) 0.211 2.110 (0.655–6.796) Intense Bleeding 0.086 4.062 (0.821–20.104) 0.308 3.443 (0.319–37.174) Staging Minimal/Mild 0.005 5.206 (1.654–16.382) 0.001 8.078 (2.291–28.482) Nulliparity 0.171 1.538 (0.830–2.852) 0.239 1.667 (0.711–3.907) Page 9 of 10 da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 months of treatment. They are widely used to control symptoms of endometriosis, but various authors ques - tion their benefits. Some, for example, cite the lack of response in pain outside the menstrual period and dys - pareunia, as well as the suspicion that EPs may induce the progression of endometriotic lesions [32–34]. The decrease in the rate of EP interruption over the months may represent patients’ adaptation to the side effects of these drugs, so if there is resilience and good guidance on side effects at the beginning of treatment, the chances of good tolerability are higher. It is necessary to highlight that all patients underwent some surgical treatment, which allowed the histologi - cal diagnosis to be used as an inclusion criterion for the study. Thus, the benefits acquired by surgery should be considered. The choice of medical therapy for endometriosis is not simple. Several factors must be evaluated, such as main symptoms, reproductive desire, types of lesions found, side effects, comorbidities, and personal preferences of the patient. The importance of the patient’s reception by the medical team with proper management of complica - tions must also be emphasized.

The treatment with combined contraceptives has been associated with a higher risk of discontinuation than treatment with isolated progestins. This risk was signifi - cantly higher in the first 9 months of treatment. Among all the described complaints, breakthrough bleeding, weight gain, and persistence of pelvic pain had a direct, significant and independent association with medication discontinuation.

The authors would like to express their gratitude to all patients assisted by our group. Authors’ contributions Denise Joffily Pereira da Costa Pinheiro and Ana Maria Gomes Pereira elaborated the structure of the study. Denise Joffily Pereira da Costa Pinheiro wrote the main manuscript text and prepared the figures and tables. Ana Maria Gomes Pereira did the statistical analyzes. All authors reviewed the manuscript. Funding This study was funded by the authors. Availability of data and materials The authors confirm that the data supporting the findings of this study are available within the article. Raw data that support the findings of this study are available from the corresponding author, upon request. Declarations Ethics approval and consent to participate Informed consent was obtained from all the participants. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Received: 7 March 2023 Accepted: 10 September 2023

1. Febrasgo (BR). Manual de endometriose 2014/2015. 2015 Available from: http:// profe ssor. pucgo ias. edu. br/ SiteD ocente/ admin/ arqui vosUp load/ 13162/ ma terial/Manual%20Endometriose%202015.pdf. Cited 29 Jun 2022. 2. National Institute for Health and Care Excellence. Endometriosis: diag- nosis and management. 2017. Available from: https:// www. nice. org. uk/ guida nce/ ng73/ resou rces/ endom etrio sis- diagn osis- and-management- pdf-1837632548293. Cited 29 Jun 2022. 3. Ministério da Saúde (BR). Protocolos Clínicos e Diretrizes Terapêuticas. Volume I.. 2010. Available from: http:// bvsms. saude. gov. br/ bvs/ publi cacoes/ proto colos_ clini cos_ diret rizes_ tera peuticas_v1.pdf. Cited 29 Jun 2022. 4. Chapron C, Marcellin L, Borghese B, Santulli P . Rethinking mechanisms, diagnosis and management of endometriosis. Nat. 2019;15:666–82. 5. Vercellini P , Vigano P , Somigliana E, Fedele L. Endometriosis:pathogenesis and treatment. Nat Rev Endocrinol. 2014;10:261–75. 6. Becker CM, Bokor A, Heikinheimo O, Horne A, Janses F, Kiesel L, et al. ESHRE guideline: endometriosis Hum Reprod Open. 2022;2:1–26. 7. Vercellini P , Buggio L, Frattaruolo MP , Borghi A, Dridi D, Somigliana E. Medical treatment of endometriosis-related pain. Best Pract Res Clin Obstet Gynaecol. 2018;51:68–91. 8. American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–21. 9. Falcone T, Flyckt R. Clinical Management of Endometriosis. Obstet Gynecol. 2018;131(3):557–71. 10. McLeod BS, Retzloff MG. Epidemiology of endometriosis: an assessment of risk factors. Clin Obstet Gynecol. 2010;53(2):389–96. 11. Kondo W, Ribeiro R, Trippia C, Zomer MT. Endometriose profunda infiltra- tiva: distribuição anatômica e tratamento cirúrgico. Rev Bras Ginecol Obs. 2012;34(6):278–84. 12. Zondervan KT, Phil D, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382:1244–56. 13. Nácul AP; Spritzer PM. Current aspects on diagnosis and treatment of endometriosis. Rev Bras Ginecol Obstet. 2010;32(6). Available from: https:// doi. org/ 10. 1590/ s0100- 72032010000600008. Cited 15 Jul 2022 14. Working group of ESGE, ESHRE and WES, Keckstein J, Becker CM, Canis M, et al. Recommendations for the surgical treatment of endometriosis. Part 2: deep endometriosis. Hum Reprod Open. 2022;12(1):1–25. 15. MIinistério da Saúde (BR). Protocolos clínicos e diretrizes terapêuticas endometriose goserrelina, leuprorrelina, triptorrelina, danazol. 2006. Available from: http:// bvsms. saude. gov. br/ bvs/ saude legis/ sctie/ 2006/ prt00 69_ 01_ 11_ 2006_ co mp.html. Cited 29 Jun 2022. 16. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P , Milad M, Wei J. Endometriosis. Endocr Rev. 2019;40(4):1048–79. 17. Barbara G, Buggio L, Facchin F, Vercellini P . Medical Treatment for Endo- metriosis: Tolerability, Quality of Life and Adherence. Front Glob Womens Health. 2021;2:729601. 18. Kalaitzopoulos DR, Samartzis N, Kolovos GN, Mareti E, Samartzis P , Eber- hard M, et al. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC Women’s Health. 2021;21:397. 19. Zorbas KA, Economopoulos KP , Vlahos NF. Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review. Arch Gynecol Obstet. 2015;292(1):37–43. 20. Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175–84. 21. Buggio L, Somigliana E, Barbara G, Frattaruolo MP , Vercellini P . Oral and depot progestin therapy for endometriosis: towards a personalized Page 10 of 10da Costa Pinheiro et al. BMC Women’s Health (2023) 23:510 • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • At BMC, research is always in progress. Learn more biomedcentral.com/submissions Ready to submit y our researc hReady to submit y our researc h ? Choose BMC and benefit fr om: ? Choose BMC and benefit fr om: medicine. Expert Opin Pharmacother. 2017;18(15):1569–81. https:// doi. org/ 10. 1080/ 14656 566. 2017. 13810 86. PMID: 28914561. 22. Remorgida V, Abbamonte LH, Ragni N, Fulcheri E, Ferrero S. Letrozole and Desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust N Z J Obstet Gynaecol. 2007;47(3):222–5. https:// doi. org/ 10. 1111/j. 1479- 828X. 2007. 00722.x. PMID: 17550490. 23. Vercellini P , Aimi G, Panazza S, Giorgi OD, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril. 1999;72(3):505–8. 24. Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a lev- onorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril. 2001;75(3):485–8. 25. Petta CA, Ferriani RA, Abrao MS, Hassan D, Silva JCR, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005;20(7):1993–8. 26. OpenEpi online version. 2013. Cited 15 Jul 2022 Available from: http:// www. opene pi. com/ Diagn ostic Test/ Diagn ostic Test. htm 27. Santos TMV, Pereira AMG, Lopes RGC, Depes DB. Tempo transcorrido entre o início dos sintomas e o diagnóstico de endometriose. Einstein. 2012;10(1):39–43. 28. Arruda MS, Petta CA, Abrão MS, Benetti-Pinto CL. Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003;18(4):756–9. 29. Soliman AM, Fuldeore M, Snabes MC. Factors associated with time to endometriosis diagnosis in the United States. J Womens Health. 2017;26(7):788–97. 30. Vercellini P . Endometriosis: What a pain it is. Semin Reprod Endocrinol. 1997;15(3):251–61. 31. Vercellini P , Buggio L, Berlanda N, Barbara G, Somigliana E, Bosari S. Estrogen-progestins and progestins for the management of endometrio- sis. Fertil Steril. 2016;106(7):1552–71. 32. Donnez J, Dolmans MM. Endometriosis and medical therapy: from progestogens to progesterone resistance to GnRH antagonists: a review. J Clin Med. 2021;10(5):1085. 33. Casper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril. 2017;107(3):533–6. 34. Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P , Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contra- ceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26(8):2028–35. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations.