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 consultation 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 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 finding. 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 diagnosis 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 endometriotic lesions described in surgical reports.
According to the available surgical descriptions, 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 endometriosis stage according to the American Society for Reproductive Medicine (ASRM) classification for 248 patients, distributed as follows: 21 (8.47%) cases of minimal endometriosis, 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 diagnosis 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 according to Table 4 below. These methods were studied according to composition, isolated progestins (P) or combinations 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 184 patients (55.76%) received a prescription for isolated progestins. The preferred prescription form was continuous.
Among the combined contraceptives, the most frequently prescribed dose was 30 µg of ethinylestradiol, prescribed for 95 patients (28.78%). Among the isolated progestins, the most frequent was desogestrel, prescribed for 87 (26.36%) patients. As shown in Fig. 3, the median treatment time was 18 months, ranging 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 monitored during the study.
Out of the total, 153 patients continued with the initially 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 medication 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 medications 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 contraceptives and one to progestins. Two patients changed to GnRH agonists, one used EP and the other P, previously.
Of the 153 patients who did not interrupt the initial 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 persistence 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 interruption 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 breakthrough 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 personal medical history (p < 0.001) compared to those who received EP.
The multiple logistic regression analysis that correlated adverse events, type of medication, and treatment interruption showed that the complaint of breakthrough bleeding, weight gain, persistence of pelvic pain, and treatment with EP had a direct, significant, and independent association with clinical treatment interruption, 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 spotting and persistence of pain and the staging of minimal/mild endometriosis had a significant, direct and independent correlation with the interruption of treatment 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 duration of fewer than 9 months, education level, and complaint of headache.
As shown in Table 9, the adverse event that had a significant 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 levonorgestrel 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 differences compared to the results presented in Table 9.