Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. A retrospective cohort study.

Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. 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A retrospective cohort study. Simona Del Forno, Benedetta Orsini, Ludovica Verrelli, Martina Caroli, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2671149/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Jul, 2023 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose to compare the effects of Dienogest 2 mg (D) alone or combined with estrogens (D + ethinylestradiol 0.03 mg, D + EE; D + estradiol valerate 1–3 mg, D + EV) in terms of symptoms and endometriotic lesions variations. Methods This retrospective study included symptomatic patients in reproductive age with ultrasound diagnosis of ovarian endometriomas. Medical therapy for at least 12 months with D, D + EE or D + EV was required. Women were evaluated at baseline visit (V1) and after 6 (V2) and 12 months (V3) of therapy. Results 297 patients were enrolled (156 in the D group, 58 in the D + EE group, 83 in the D + EV group). There were no differences between groups in terms of lesions mean diameter variation. No variations were detected in terms of lesions reduction when comparing the two estroprogestins, cyclic versus continuous estroprogestin regimens, D alone versus D + EE/D + EV administered continuously. When comparing D and D + EE/D + EV groups, a significant decrease of dysmenorrhea was detected in the D group than in D + EE/D + EV group. Conversely, the reduction of dysuria was more significative in the D + EE/D + EV groups rather than in the D group. Regarding tolerability, treatment associated side effects were reported by 16.2% patients. The most frequent one was uterine bleeding/spotting, significantly higher in the D + EV group. Conclusion Dienogest alone or associated with estrogens (EE/EV) seems to be equally effective in reducing endometriotic lesions mean diameter. The reduction of dysmenorrhea was more significative when D was administered alone, while dysuria seems to improve more when D is associated with estrogens. endometriosis medical therapy ultrasound pelvic pain Figures Figure 1 What Does This Study Add To The Clinical Work To the best of our knowledge this is the first study comparing the effects of the three commercially available dienogest-containing in terms of pain symptoms and size of ovarian endometriomas changes. The results of our study could help clinicians to choose the correct therapy for patients with endometriosis, in the perspective of a long-term treatment. Introduction Endometriosis is a benign, chronic and inflammatory disease characterized by the presence of endometrium-like tissue outside the uterine cavity and is associated with pain and infertility ( 1 ). The prevalence of the disease is estimated to be 5–10% of women of reproductive age ( 2 , 3 ), and it may be found in 90% of women with pelvic pain ( 4 ). Endometriosis-related pain symptoms have a negative impact on women’s quality of life and psychological wellbeing ( 1 , 5 , 6 ). Ovarian endometriosis and in particular endometriotic cysts, also called endometriomas, represent the most frequent endometriotic lesion ( 7 ). Since surgical treatment of endometriomas is burdened by a high recurrence rate and can cause reduction of ovarian reserve, medical therapy should be preferable ( 8 – 11 ). Medical treatment is the first line treatment for symptomatic ovarian endometriomas ( 1 ), which rely on progestin with or without estrogens. As a matter of fact, the hypoestrogenism induced by medical therapy together with the induction of amenorrhea - which prevents the reflux of endometrial cells through the salpinx to the ovary or peritoneum - may reduce pain symptoms ( 12 ). Dienogest (D) is a semisynthetic progestin derived from 19-nortestosterone which binds progesterone receptors, blocking gonadotropin secretion. It also has a local antiproliferative and anti-inflammatory effect on endometriosis lesions and is effective in the reduction of pain symptoms with a favorable tolerability profile ( 13 , 14 ). Dienogest can be administered alone or in association with estrogens in two therapeutic formulations: ethinylestradiol (0.03mg) and dienogest 2mg in biphasic formulation, or estradiol valerate and dienogest in quadriphasic formulation. The main differences between the two estroprogestin (EP) formulations are the different metabolic impact, the thromboembolic risk and side effects related to the estrogen’s component ( 15 – 17 ). Previous studies investigated the effect of these therapies in women with endometriosis ( 18 – 20 ). Nevertheless, the comparison between the tree formulations has never been reported in literature. The aim of our study is to compare the effects of the three commercially available dienogest-containing therapies (dienogest 2 mg alone, dienogest 2 mg combined with ethinylestradiol 0.03mg or combined with estradiol valerate 1-3mg) in terms of pain symptoms and size of ovarian endometriomas changes. Secondary outcomes are: comparison in terms of symptoms variations and endometriotic lesion reduction respectively between cyclic and continuous EP regimens and between D and continuous EP regimen. treatment tolerability comparison in terms of changes in size of endometriotic nodules. Materials And Methods This retrospective study included 297 patients in reproductive age who referred to our Center from January 2017 to June 2021. Inclusion criteria were: a) age between 18 and 50 years; b) ultrasound diagnosis of ovarian endometrioma (> 10 mm in mean diameter) with or without deep infiltrating endometriosis or adenomyosis ( 21 , 22 ); c) the presence of at least one of the following pain symptoms (Numeric Rating Scale > 0) ( 23 ): dysmenorrhea, chronic pelvic pain, dyspareunia; d) medical therapy for at least 12 months with dienogest 2mg (D), or ethinylestradiol 0.03mg /dienogest 2mg (D + EE) or estradiol valerate 1-3mg /dienogest 2mg (D + EV). Exclusion criteria were: postmenopausal status, ongoing pregnancy or actual pregnancy desire, medical therapy in the 3 months before enrollment. We retrospectively reviewed data from our clinical records. As in our daily practice, women were evaluated at baseline visit (V1), when therapy was prescribed, and after 6 and 12 months of therapy (follow-up visits V2 and V3, respectively). According to the therapy prescribed at V1, women were divided into three groups: 1) the first group received Dienogest 2 mg/day (D group); 2) the second group received ethinylestradiol 0.03mg and dienogest 2mg/day (D + EE group); 3) the third group received estradiol valerate 1-3mg and dienogest 2mg/ day (D + EV group). The type of administration (cyclic regimen or continuous regimen) for the D + EV and D + EE groups was recorded. Medical history, detailed gynecological examination, transvaginal and transabdominal ultrasound were recorded in all women at each visit. Ultrasound examination was performed by sonographers experienced in endometriosis, making a subjective evaluation of grayscale and Doppler ultrasound “pattern recognition”: a “typical” ovarian endometrioma was diagnosed when a unilocular cyst with ultrasound features of regular wall, ‘ground glass’ echogenicity of the cyst content and poor capsular vascularization at Power Doppler was observed ( 24 ). To assess the size of ovarian endometriomas, the three diameters (longitudinal, transverse, and antero-posterior) were measured and the mean diameter was then calculated (d1 + d2 + d3/3). Data on demographic and clinical characteristics of the participants were collected: age, body mass index, parity, mean diameter of the cyst, presence of adenomyosis, presence of posterior nodule, presence of anterior endometriosis. Anatomic locations of endometriotic lesions at ultrasound were described according to IDEA consensus ( 22 ). During visits, women were asked to rank endometriosis related symptoms (dysmenorrhea, chronic pelvic pain, dyspareunia) using a numerical Numerical Rating Scale (NRS) from 0 (absence of pain) to 10 (“the maximum pain you could imagine”) ( 23 ). At each follow-up visits (V2 and V3), women were also asked to report any side effects related to the treatment (e.g.: weight gain, mood disorders, loss of libido, headache, nausea, acne, hair loss, breast tenderness, vaginal dryness, uterine bleeding including spotting). Statistical analysis Numerical variables were summarized as mean ± standard deviation; categorical variables were summarized as frequencies and percentages. To investigate the presence of systematic differences in change scores and sizes after 12 months of follow-up between patients treated with dienogest alone and patients treated with dienogest in combination with ethinylestradiol (EE) or estradiol valerate (EV), we performed a linear regression analysis with heteroskedasticity-consistent standard errors, including treatment as a binary covariate in the models. To control for potential differences in baseline scores and sizes, baseline figures were also included in the models as continuous covariates. For illustrative purposes, a multilevel mixed-effects linear regression analysis was performed to investigate the course of symptoms and lesion sizes over the entire follow-up period (including the third and last visit), with random intercepts for each patient. Time was treated as a categorical covariate, which resulted in the inclusion of 2 dummy variables in the model, to assess the presence of nonlinear time trends. More specifically, we modelled each outcome as a function of time-by-therapy interactions in order to investigate the presence of divergent trajectories over time between the 2 study groups; predicted means with their 95% confidence intervals (CIs) resulting from multilevel modelling were then displayed using line charts. All analyses described above were replicated on the subsample of patients in treatment with D plus EE or EV. First, we compared EE and EV; second, we compared continuous and cyclic estrogen regimen. Lastly, the same analyses were performed to examine differences in symptoms according to presence or absence of adenomyosis. All analyses were carried out using Stata software, version 15 (StataCorp, 2017, Stata Statistical Software: Release 15, College Station, Texas, USA: Stata Corp LP). The significance level was set at 5%, and all tests were 2-sided. Results We eventually included un our study 297 patients: 156 patients in the D group, 58 patients in the D + EE group and 83 patients in the D + EV group. The demographic and clinical characteristics are reported in Table 1 . Table 1 Baseline characteristics of the study sample, overall and by treatment. All ( n = 297) Treatment Variable Dienogest Alone Dienogest + EE Dienogest + EV P value ( n = 156) ( n = 58) ( n = 83) Age, y 33.6 ± 7.9 35.5 ± 7.6 28.9 ± 6.6 33.5 ± 8.2 < 0.001 *** Body mass index, kg/m² 22.7 ± 4.3 23.4 ± 5.0 22.0 ± 3.8 22.0 ± 2.8 0.061 Endometrial cyst, mm 23.5 ± 15.1 26.3 ± 14.8 22.7 ± 13.8 18.7 ± 15.3 < 0.001 Adenomyosis 158 (53.2%) 84 (53.9%) 35 (60.3%) 39 (47.0%) 0.286 Posterior nodule 118 (39.7%) 72 (46.2%) 22 (37.9%) 24 (28.9%) 0.033 * Anterior endometriosis 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) · *** P value ≤ 0.001; ** P value ≤ 0.01; * P value ≤ 0.05. Notes: Values are mean ± standard deviation or n (%). P values were obtained with the chi-squared test, Kruskal–Wallis test or analysis of variance, where appropriate. Mean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of >1 lesion, the largest one was analyzed. Abbreviations: EE, ethinylestradiol; EV, estradiol valerate. Effects on symptoms Regarding symptoms, when comparing women treated with D and women treated with D combined with estrogens, a significant decrease in terms of dysuria was detected in the EP groups (-0.30 in D + EE/EV groups) rather than the D group (0.08 in D group) between baseline and second follow-up evaluation V3 (Table 2 ). In contrast, the reduction of the dysmenorrhea was more significative in D group (-2.63 vs -2.04 in D + EE/EV groups). The statistically significant reduction in the dysmenorrhea in D group is also confirmed when comparing D group with continuous administration in the D + EE/EV groups (-1.73 in D + EE/EV groups VS -2.63 in D group, adjusted Δ for baseline NRS scores 0.96, P ≤ 0.05), as well as the significant reduction of dysuria in the EP groups (-0.45 in D + EE/EV groups vs 0.08 in D group, adjusted Δ for baseline NRS scores − 0.30, P ≤ 0.05). Furthermore, no significant difference regarding symptoms was found when comparing group D alone with group D + EE/EV in continuous regimen (Supplementary Material 1, S1). Table 2 Treatment-related changes in symptoms and in lesion mean diameter between the baseline (V1) and 2nd follow-up evaluation (V3, 12 months apart), and differences in changes between treatments (D + EE/EV vs D), both crude (Δ) and adjusted for baseline NRS scores and sizes (adj. Δ). Dienogest + EE/EV Dienogest Alone Variable ( n = 141) ( n = 156) Δ Adj. Δ Mean (95% CI) Mean (95% CI) Dyspareunia, NRS –0.79 *** –0.69 ** –0.10 –0.02 (–1.27, − 0.32) (–1.15, − 0.24) Chronic pelvic pain, NRS –0.46 –0.72 ** 0.26 0.01 (–0.94, 0.02) (–1.25, − 0.18) Dysmenorrhea –2.04 *** –2.63 *** 0.59 0.77 ** (–2.71, − 1.38) (–3.29, − 1.96) Dysuria w/ menses, NRS –0.86 *** 0.00 –0.86 *** –0.23 * (–1.25, − 0.47) (–0.16, 0.16) Dysuria, NRS –0.30 ** 0.08 –0.38 ** –0.23 * (–0.53, − 0.07) (–0.05, 0.21) Dyschezia w/ menses, NRS –0.38 * –0.44 * 0.05 –0.09 (–0.69, − 0.08) (–0.85, − 0.02) Dyschezia, NRS 0.06 –0.08 0.14 –0.12 (–0.22, 0.34) (–0.45, 0.28) Endometrial cyst, mm –5.16 *** –6.11 *** 0.95 –1.13 (–7.02, − 3.30) (–7.75, − 4.47) Posterior nodule, mm 0.17 –0.35 0.53 –0.03 (–0.83, 1.18) (–1.51, 0.80) *** P value ≤ 0.001; ** P value ≤ 0.01; * P value ≤ 0.05. Notes: Mean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of >1 lesion, the largest one was analyzed. Abbreviations: EE, ethinylestradiol; EV, estradiol valerate; CI, confidence interval; NRS, Numeric Rating Scale. When comparing cyclic and continuous administration of the EP groups (D + EE and D + EV), there were no statistically significant differences in terms of symptoms changes (Table 3 ). Table 3 Treatment-related changes in symptoms and in lesion mean diameter between the baseline (V1) and 2nd follow-up evaluation (V3, 12 months apart), and differences in changes between EP treatments (D + EV vs D + EE), both crude (Δ) and adjusted for baseline NRS scores and sizes (adj. Δ). Dienogest + EV Dienogest + EE Variable ( n = 83) ( n = 58) Δ Adj. Δ Mean (95% CI) Mean (95% CI) Dyspareunia, NRS –1.14 *** –0.29 –0.85 –0.68 (–1.67, − 0.62) (–1.15, 0.57) Chronic pelvic pain, NRS 0.24 –1.47 *** 1.71 *** 0.69 (–0.30, 0.78) (–2.28, − 0.65) Dysmenorrhea –1.75 *** –2.47 *** 0.72 0.37 (–2.65, − 0.84) (–3.43, − 1.50) Dysuria w/ menses, NRS –1.39 *** –0.10 –1.29 *** 0.00 (–2.03, − 0.75) (–0.25, 0.04) Dysuria, NRS –0.51 ** 0.00 –0.51 ** 0.00 (–0.89, − 0.12) (0.00, 0.00) Dyschezia w/ menses, NRS –0.34 –0.45 0.11 0.19 (–0.75, 0.08) (–0.90, 0.01) Dyschezia, NRS 0.10 0.00 0.10 0.27 (–0.31, 0.50) (–0.37, 0.37) Endometrial cyst, mm –4.52 *** –6.08 *** 1.56 0.04 (–7.07, − 1.96) (–8.78, − 3.38) Posterior nodule, mm 0.34 –0.07 0.41 0.05 (–0.47, 1.16) (–2.27, 2.12) *** P value ≤ 0.001; ** P value ≤ 0.01; * P value ≤ 0.05. Notes: Mean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of >1 lesion, the largest one was analyzed. Abbreviations: EV, estradiol valerate; EE, ethinylestradiol; CI, confidence interval; NRS, Numeric Rating Scale. Effects on lesions The differences in lesion mean diameter between baseline and second follow-up examination (V3) in women treated with D alone or D combined with estrogens (D + EE/EV) are shown in Table 2 . There were no statistically significant differences between the D group and the EP groups in lesion mean diameter variations (both endometriomas and endometriotic nodules). Regarding EPs, no differences in lesion mean diameter were found either with regard to the type of estrogen administered (D + EE vs D + EV) (Table 3 ) or the administration regimen (continuous vs cyclic) (Table 4 ) (ovarian endometriomas − 5.64 vs -6.11, Adjusted Δ for baseline sizes − 2.01; endometrial nodules 0.006 vs -0.35, Adjusted Δ for baseline sizes − 0.19). Moreover, when comparing D alone with continuous administration of EPs (D + EE/EV), no differences in lesion mean diameter were reported (Supplemental Material S1). Table 4 Treatment-related changes in symptoms and in lesion mean diameter between the baseline (V1) and 2nd follow-up evaluation (V3, 12 months apart), and differences in changes between cyclic and continuous EP treatments, both crude (Δ) and adjusted for baseline NRS scores and sizes (adj. Δ). Dienogest + cyclic Dienogest + contin. Variable EE/EV ( n = 86) EE/EV ( n = 55) Δ Adj. Δ Mean (95% CI) Mean (95% CI) Dyspareunia, NRS –0.73 ** –0.89 * 0.16 0.12 (–1.29, − 0.18) (–1.75, − 0.04) Chronic pelvic pain, NRS –0.62 –0.22 –0.40 –0.32 (–1.27, 0.04) (–0.90, 0.46) Dysmenorrhea –2.24 *** –1.73 *** –0.52 –0.31 (–3.00, − 1.49) (–2.97, − 0.49) Dysuria w/ menses, NRS –0.92 *** –0.76 –0.15 0.00 (–1.40, − 0.43) (–1.43, − 0.10) Dysuria, NRS –0.20 –0.45 0.26 0.00 (–0.43, 0.04) (–0.91, 0.00) Dyschezia w/ menses, NRS –0.52 * –0.16 –0.36 0.01 (–0.98, − 0.06) (–0.48, 0.16) Dyschezia, NRS 0.03 0.09 –0.06 0.08 (–0.36, 0.43) (–0.27, 0.45) Endometrial cyst, mm –4.85 *** –5.64 ** 0.79 1.04 (–6.97, − 2.73) (–9.11, − 2.17) Posterior nodule, mm 0.25 0.06 0.19 0.30 (–0.81, 1.30) (–1.96, 2.08) *** P value ≤ 0.001; ** P value ≤ 0.01; * P value ≤ 0.05. Notes: Mean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of >1 lesion, the largest one was analyzed. Abbreviations: EE, ethinylestradiol; EV, estradiol valerate; CI, confidence interval; NRS, Numeric Rating Scale. Tolerability Regarding tolerability, treatment associated side effects were reported by 16.2% of women, of which 7.1% treated with D, 6.7% treated with D + EV and 2.4% treated with D + EE. Side effects during treatment are reported in Table 5 . The most frequent side effect was uterine bleeding/spotting. Spotting was significantly more frequent in group D + EV than in the other two groups (P = 0.04) and was reported in particular by women who assumed treatment in continuous administration (4 of 28 patients who assumed D + EV continuously, 14.3%). No significant differences were found in other side effects between the three groups. Table 5 Distribution of side effects, overall and by treatment. Values are counts (percentages). Side effect All ( n = 297) Treatment Exact P value Dienogest Alone Dienogest + EV Dienogest + EE ( n = 156) ( n = 83) ( n = 58) Any 48 (16.2) 21 (13.5) 20 (24.1) 7 (12.1) 0.07 Spotting 14 (4.7) 5 (3.2) 8 (9.6) 1 (1.7) 0.04 * Headache 12 (4.0) 7 (4.5) 3 (3.6) 2 (3.4) 0.92 Mood swing 10 (3.4) 7 (4.5) 2 (2.4) 1 (1.7) 0.52 Weight gain 9 (3.0) 3 (1.9) 5 (6.0) 1 (1.7) 0.17 Bloating 8 (2.7) 2 (1.3) 4 (4.8) 2 (3.4) 0.25 Loss of libido 5 (1.7) 3 (1.9) 2 (2.4) 0 (0.0) 0.52 Vaginal dryness 3 (1.0) 3 (1.9) 0 (0.0) 0 (0.0) 0.25 Hair loss 1 (0.3) 1 (0.6) 0 (0.0) 0 (0.0) 0.64 Tachycardia 1 (0.3) 0 (0.0) 1 (1.2) 0 (0.0) 0.27 Double vision 1 (0.3) 0 (0.0) 1 (1.2) 0 (0.0) 0.27 *** P value ≤ 0.001; ** P value ≤ 0.01; * P value ≤ 0.05. Abbreviations: EE, ethinylestradiol; EV, estradiol valerate. Discussion In this retrospective study we analyzed the impact in terms of symptoms and endometriotic lesion mean diameter variations in patients treated with dienogest alone or dienogest combined with estrogens (D + EE and D + EV). Effects on lesions and symptoms Regarding symptoms, as previously demonstrated in literature ( 13 ), a statistically significant reduction in the severity of dysmenorrhea associated with D-only therapy was found in comparison with dienogest combined with estrogens (both EE and EV ) after 12 months of therapy ( 25 , 26 ). The greater reduction in dysmenorrhea may likely be related to the induction of amenorrhea together with the antiproliferative and anti-inflammatory effect of D. This result is in line with the prospective study by Caruso et al.: in their cohort of 44 patients, they reported amenorrhea in 88.3 % of patents after 24 months of D-only therapy, with a significant decrease of dysmenorrhea and pelvic pain ( 20 ). Moreover, in our study population the improvement of dysuria was greater in EP groups rather than the D group. This finding may be due to the trophic action of estrogens on the urethral mucosa ( 27 ) and to lower estrogen levels induced by dienogest ( 28 ). Our data showed that there are no differences between oral administration of D and D + EE or D + EV in terms of endometriotic lesion mean diameter changes. The effect of dienogest on the size of ovarian endometriomas has already been studied in Literature showing that the hypoestrogenic state induced by the therapy reduces inflammation and proliferation of ectopic endometrium-like tissue, leading to a possible decrease in lesion size ( 26 , 29 ). Different results regarding lesions variations are reported by other studies with smaller samples comparing D alone or associated with EE in women with endometriosis. In a retrospective observational study conducted on women with ovarian endometriomas ( 18 ), Xholli and colleagues reported a reduction in the size of endometriomas in patients treated with D alone (n = 34) and with D + EE (n = 36) after 12 months, but the reduction was greater in patients treated with D alone. On the other hand, a prospective study conducted on 81 women treated with D or D + EE detected a significant decrease in endometrioma’s volume only in the group treated with D after 3 and 6 months of follow up ( 19 ). Tolerability Regarding drug tolerability, uterine bleeding/spotting was reported more frequently in the D + EV group, especially when administered in a continuous regimen. Our data suggest that when D + EV is chosen, a cyclic administration may be preferable than continuous. Considering that endometriosis is a chronic disease, in the perspective of a long-term treatment, tolerability and consequent compliance to treatment are fundamental aspects of medical management of women with endometriosis. Strengths and limitations The main limitations of our study are its retrospective nature and the absence of a control group. Although the lack of histological confirmation, ultrasound has shown a high diagnostic accuracy for endometriosis in particular if performed by expert sonographers as in our study ( 22 ). Regarding patients’ characteristics, we found a statistically significant difference regarding the age of patients: women treated with D + EE therapy were younger than the rest of the study population. This may be due to the fact that EPs are usually prescribed to adolescents and younger patients rather than progestogen alone. The effect of dienogest on bone mineral density (BMD) is still controversial in the Literature and, according to some studies, it may reduce BMD ( 30 ), therefore especially in adolescent patients the choice of combining dienogest with an estrogen seems reasonable. In addition, we found a significant difference in the size of ovarian endometriomas at baseline visit; nevertheless, our primary outcome was the cysts size changes over time, therefore this finding was not a limitation for the analysis. This study has also some strengths: to the best of our knowledge, we reported the largest cohort of patients with ovarian endometriomas assuming dienogest-based hormonal therapies and investigate for the first-time differences among these three therapeutic options. Another strength is represented by the long-term follow-up. Conclusions In conclusion, the comparison of Dienogest alone or associated with estrogens (EE or EV) showed no difference in terms of lesion size variation and pain symptoms in women with ovarian endometriomas, except for dysmenorrhea, which seems to benefit more from progestin-only therapy, and dysuria, which improves more with EP treatment. In the light of our results, we believe that clinicians should consider efficacy of the different therapies on symptoms relief, together with tolerability, metabolic impact and thromboembolic risk of each hormonal treatment, as well as women’s age, comorbidities and preference. Balancing all these aspects will let clinicians choose the right treatment for each woman, in the perspective of a long-term treatment, improving adherence to treatment and consequently reducing the risk of disease progression over time. Declarations Conflict of Interest : The authors declare that they have no conflict of interest. Funding : The authors declare that no funds, grants, or other support were received during the preparation of this manuscript Competing interests : The authors have no relevant financial or non-financial interests to disclose. Author’s contribution: All authors contributed to the study conception and design . S. Del Forno: project development, manuscript writing; B. Orsini: manuscript writing; L. Verrelli: data collection; M. Caroli: data collection, data analysis; AC Aru: manuscript editing; J Lenzi: data analysis; D. Raimondo: manuscript editing; A. Arena: manuscript editing; G. Borghese: data collection; R. Paradisi: project development; MC Meriggiola: manuscript editing; R. Seracchioli: review of the manuscript; P. Casadio: review of the manuscript. Ethics approval: The study received approval by the Institutional review Board of the University of Bologna (149/2014/O/Oss). The study protocol conforms to the ethical guidelines of the “World Medical Association (WMA) Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects” adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 59th WMA General Assembly, Seoul, South Korea, October 2008. Consent to participate : Informed consent was obtained from all individual participants included in the study. Acknowledgments: none. References Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L et al (2022)ESHRE PAGES The members of the Endometriosis Guideline Core Group,. ;1–26 Parasar P, Ozcan P, Terry KL, Endometriosis (2017 Mar) Epidemiology, Diagnosis and Clinical Management. Curr Obstet Gynecol Rep 6(1):34–41 Eisenberg VH, Weil C, Chodick G, Shalev V (2018 Jan) Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members. 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Hum Reprod Update 15(4):441–461 Del Forno S, Mabrouk M, Arena A, Mattioli G, Giaquinto I, Paradisi R et al (2019 Jul) Dienogest or Norethindrone acetate for the treatment of ovarian endometriomas: Can we avoid surgery? Eur J Obstet Gynecol Reprod Biol 238:120–124 Schindler AE (2011) Dienogest in long-term treatment of endometriosis. Int J Womens Health 3:175–184 McCormack PL Dienogest: a review of its use in the treatment of endometriosis.Drugs. 2010 Nov; 70(16):2073–88 Strowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C (2015) Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 7:393–401 Grandi G, Piacenti I, Volpe A, Cagnacci A (2014 Sep) Modification of body composition and metabolism during oral contraceptives containing non-androgenic progestins in association with estradiol or ethinyl estradiol. Gynecol Endocrinol 30(9):676–680 Plu-Bureau G, Maitrot-Mantelet L, Hugon-Rodin J, Gompel A (2016 Jan) [Contraception and risk of venous thromboembolism]. Rev Prat 66(1):e7–8 Xholli A, Filip G, Previtera F, Cagnacci A (2020 Jun) Modification of endometrioma size during hormone therapy containing dienogest. Gynecol Endocrinol 36(2):545–549 Angioni S, Pontis A, Malune ME, Cela V, Luisi S, Litta P et al (2020 Jan) Is dienogest the best medical treatment for ovarian endometriomas? Results of a multicentric case control study. Gynecol Endocrinol 36(2):84–86 Caruso S, Iraci M, Cianci S, Vitale SG, Fava V, Cianci A (2019) Effects of long-term treatment with dienogest on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain. J Pain Res 12:2371–2378 Bosch TVANDEN, Dueholm M, Leone FPG, Valentin L, Rasmussen CK, Musa T et al (2015) Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses : a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. ;(January):284–98 Guerriero S, Condous G, van den Bosch T, Valentin L, Leone FPG, Van Schoubroeck D et al (2016) Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol 48(3):318–332 Bourdel N, Chauvet P, Billone V, Douridas G, Fauconnier A, Gerbaud L et al (2019) Systematic review of quality of life measures in patients with endometriosis. PLoS ONE 14:1–32 Van Holsbeke C, Van Calster B, Guerriero S, Savelli L, Paladini D, Lissoni AA et al (2010 Jun) Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol 35(6):730–740 Vercellini P, Buggio L, Frattaruolo MP, Borghi A, Dridi D, Somigliana E (2018 Aug) Medical treatment of endometriosis-related pain. Best Pract Res Clin Obstet Gynaecol 51:68–91 Mabrouk M, Paradisi R, Arena A, del Forno S, Matteucci C, Zannoni L et al (2018 May) Short-term histopathological effects of dienogest therapy on ovarian endometriomas: in vivo, nonrandomized, controlled trial. Gynecol Endocrinol 34(4):399–403 Hextall A (2000 Aug) Oestrogens and lower urinary tract function. Maturitas 36(2):83–92 Laganà AS, Vitale SG, Granese R, Palmara V, Ban Frangež H, Vrtačnik-Bokal E et al (2017) Clinical dynamics of Dienogest for the treatment of endometriosis: from bench to bedside. Expert Opinion on Drug Metabolism and Toxicology, vol 13. Taylor and Francis Ltd, pp 593–596 Uludag SZ, Demirtas E, Sahin Y, Aygen EM (2021) Dienogest reduces endometrioma volume and endometriosis-related pain symptoms. J Obstet Gynaecol (Lahore) 41(8):1246–1251 Ebert AD, Dong L, Merz M, Kirsch B, Francuski M, Böttcher B et al (2017 Oct) Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents. J Pediatr Adolesc Gynecol 30(5):560–567 Supplementary Files SUPPLEMENTARYMATERIAL.docx Cite Share Download PDF Status: Published Journal Publication published 11 Jul, 2023 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted Reviewers agreed at journal 08 May, 2023 Reviewers invited by journal 07 Apr, 2023 Editor invited by journal 14 Mar, 2023 Editor assigned by journal 09 Mar, 2023 First submitted to journal 08 Mar, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2671149","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":189912927,"identity":"8033bbcc-cb61-4c38-a51f-bb1c8714106a","order_by":0,"name":"Simona Del Forno","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"Del","lastName":"Forno","suffix":""},{"id":189912928,"identity":"42437919-601b-49a1-907d-a73e0d0a125f","order_by":1,"name":"Benedetta Orsini","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-4703-3665","institution":"IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico S Orsola-Malpighi","correspondingAuthor":true,"prefix":"","firstName":"Benedetta","middleName":"","lastName":"Orsini","suffix":""},{"id":189912929,"identity":"8886947e-d441-42ba-ae16-e9127581919c","order_by":2,"name":"Ludovica 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Seracchioli","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Renato","middleName":"","lastName":"Seracchioli","suffix":""},{"id":189912939,"identity":"bcff449b-251f-4b25-b5b4-be11ee5f4087","order_by":12,"name":"Paolo Casadio","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Casadio","suffix":""}],"badges":[],"createdAt":"2023-03-08 21:16:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2671149/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2671149/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00404-023-07125-2","type":"published","date":"2023-07-12T01:07:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":35546648,"identity":"a6dc05e2-b52a-4ebb-b21d-c818840a7f9c","added_by":"auto","created_at":"2023-04-10 18:04:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85725,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2671149/v1/fa17e2b59aa415b2ba8cbf3f.png"},{"id":41737057,"identity":"7d319cab-792e-4cbe-aa88-0213763d7aaf","added_by":"auto","created_at":"2023-08-18 04:14:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":549212,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2671149/v1/ab98796b-0776-4cbd-b69e-d48a7af3dac2.pdf"},{"id":35545734,"identity":"4f589c96-ec76-4163-85e1-145209051025","added_by":"auto","created_at":"2023-04-10 17:56:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29744,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYMATERIAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-2671149/v1/3c46afa990ea1c928d8d188f.docx"}],"financialInterests":"","formattedTitle":"Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. A retrospective cohort study.","fulltext":[{"header":"What Does This Study Add To The Clinical Work","content":"\u003cp\u003eTo the best of our knowledge this is the first study comparing the effects of the three commercially available dienogest-containing in terms of pain symptoms and size of ovarian endometriomas changes. The results of our study could help clinicians to choose the correct therapy for patients with endometriosis, in the perspective of a long-term treatment.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a benign, chronic and inflammatory disease characterized by the presence of endometrium-like tissue outside the uterine cavity and is associated with pain and infertility (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The prevalence of the disease is estimated to be 5\u0026ndash;10% of women of reproductive age (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), and it may be found in 90% of women with pelvic pain (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Endometriosis-related pain symptoms have a negative impact on women\u0026rsquo;s quality of life and psychological wellbeing (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Ovarian endometriosis and in particular endometriotic cysts, also called endometriomas, represent the most frequent endometriotic lesion (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSince surgical treatment of endometriomas is burdened by a high recurrence rate and can cause reduction of ovarian reserve, medical therapy should be preferable (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Medical treatment is the first line treatment for symptomatic ovarian endometriomas (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), which rely on progestin with or without estrogens. As a matter of fact, the hypoestrogenism induced by medical therapy together with the induction of amenorrhea - which prevents the reflux of endometrial cells through the salpinx to the ovary or peritoneum - may reduce pain symptoms (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDienogest (D) is a semisynthetic progestin derived from 19-nortestosterone which binds progesterone receptors, blocking gonadotropin secretion. It also has a local antiproliferative and anti-inflammatory effect on endometriosis lesions and is effective in the reduction of pain symptoms with a favorable tolerability profile (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Dienogest can be administered alone or in association with estrogens in two therapeutic formulations: ethinylestradiol (0.03mg) and dienogest 2mg in biphasic formulation, or estradiol valerate and dienogest in quadriphasic formulation. The main differences between the two estroprogestin (EP) formulations are the different metabolic impact, the thromboembolic risk and side effects related to the estrogen\u0026rsquo;s component (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious studies investigated the effect of these therapies in women with endometriosis (\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Nevertheless, the comparison between the tree formulations has never been reported in literature.\u003c/p\u003e \u003cp\u003eThe aim of our study is to compare the effects of the three commercially available dienogest-containing therapies (dienogest 2 mg alone, dienogest 2 mg combined with ethinylestradiol 0.03mg or combined with estradiol valerate 1-3mg) in terms of pain symptoms and size of ovarian endometriomas changes.\u003c/p\u003e \u003cp\u003eSecondary outcomes are:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ecomparison in terms of symptoms variations and endometriotic lesion reduction respectively between cyclic and continuous EP regimens and between D and continuous EP regimen.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003etreatment tolerability\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ecomparison in terms of changes in size of endometriotic nodules.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThis retrospective study included 297 patients in reproductive age who referred to our Center from January 2017 to June 2021. Inclusion criteria were: a) age between 18 and 50 years; b) ultrasound diagnosis of ovarian endometrioma (\u0026gt;\u0026thinsp;10 mm in mean diameter) with or without deep infiltrating endometriosis or adenomyosis (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e); c) the presence of at least one of the following pain symptoms (Numeric Rating Scale\u0026thinsp;\u0026gt;\u0026thinsp;0) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e): dysmenorrhea, chronic pelvic pain, dyspareunia; d) medical therapy for at least 12 months with dienogest 2mg (D), or ethinylestradiol 0.03mg /dienogest 2mg (D\u0026thinsp;+\u0026thinsp;EE) or estradiol valerate 1-3mg /dienogest 2mg (D\u0026thinsp;+\u0026thinsp;EV). Exclusion criteria were: postmenopausal status, ongoing pregnancy or actual pregnancy desire, medical therapy in the 3 months before enrollment.\u003c/p\u003e \u003cp\u003e We retrospectively reviewed data from our clinical records. As in our daily practice, women were evaluated at baseline visit (V1), when therapy was prescribed, and after 6 and 12 months of therapy (follow-up visits V2 and V3, respectively). According to the therapy prescribed at V1, women were divided into three groups: 1) the first group received Dienogest 2 mg/day (D group); 2) the second group received ethinylestradiol 0.03mg and dienogest 2mg/day (D\u0026thinsp;+\u0026thinsp;EE group); 3) the third group received estradiol valerate 1-3mg and dienogest 2mg/ day (D\u0026thinsp;+\u0026thinsp;EV group). The type of administration (cyclic regimen or continuous regimen) for the D\u0026thinsp;+\u0026thinsp;EV and D\u0026thinsp;+\u0026thinsp;EE groups was recorded.\u003c/p\u003e \u003cp\u003eMedical history, detailed gynecological examination, transvaginal and transabdominal ultrasound were recorded in all women at each visit. Ultrasound examination was performed by sonographers experienced in endometriosis, making a subjective evaluation of grayscale and Doppler ultrasound \u0026ldquo;pattern recognition\u0026rdquo;: a \u0026ldquo;typical\u0026rdquo; ovarian endometrioma was diagnosed when a unilocular cyst with ultrasound features of regular wall, \u0026lsquo;ground glass\u0026rsquo; echogenicity of the cyst content and poor capsular vascularization at Power Doppler was observed (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). To assess the size of ovarian endometriomas, the three diameters (longitudinal, transverse, and antero-posterior) were measured and the mean diameter was then calculated (d1\u0026thinsp;+\u0026thinsp;d2\u0026thinsp;+\u0026thinsp;d3/3).\u003c/p\u003e \u003cp\u003eData on demographic and clinical characteristics of the participants were collected: age, body mass index, parity, mean diameter of the cyst, presence of adenomyosis, presence of posterior nodule, presence of anterior endometriosis. Anatomic locations of endometriotic lesions at ultrasound were described according to IDEA consensus (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). During visits, women were asked to rank endometriosis related symptoms (dysmenorrhea, chronic pelvic pain, dyspareunia) using a numerical Numerical Rating Scale (NRS) from 0 (absence of pain) to 10 (\u0026ldquo;the maximum pain you could imagine\u0026rdquo;) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). At each follow-up visits (V2 and V3), women were also asked to report any side effects related to the treatment (e.g.: weight gain, mood disorders, loss of libido, headache, nausea, acne, hair loss, breast tenderness, vaginal dryness, uterine bleeding including spotting).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eNumerical variables were summarized as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation; categorical variables were summarized as frequencies and percentages. To investigate the presence of systematic differences in change scores and sizes after 12 months of follow-up between patients treated with dienogest alone and patients treated with dienogest in combination with ethinylestradiol (EE) or estradiol valerate (EV), we performed a linear regression analysis with heteroskedasticity-consistent standard errors, including treatment as a binary covariate in the models. To control for potential differences in baseline scores and sizes, baseline figures were also included in the models as continuous covariates. For illustrative purposes, a multilevel mixed-effects linear regression analysis was performed to investigate the course of symptoms and lesion sizes over the entire follow-up period (including the third and last visit), with random intercepts for each patient. Time was treated as a categorical covariate, which resulted in the inclusion of 2 dummy variables in the model, to assess the presence of nonlinear time trends. More specifically, we modelled each outcome as a function of time-by-therapy interactions in order to investigate the presence of divergent trajectories over time between the 2 study groups; predicted means with their 95% confidence intervals (CIs) resulting from multilevel modelling were then displayed using line charts. All analyses described above were replicated on the subsample of patients in treatment with D plus EE or EV. First, we compared EE and EV; second, we compared continuous and cyclic estrogen regimen. Lastly, the same analyses were performed to examine differences in symptoms according to presence or absence of adenomyosis. All analyses were carried out using Stata software, version 15 (StataCorp, 2017, Stata Statistical Software: Release 15, College Station, Texas, USA: Stata Corp LP). The significance level was set at 5%, and all tests were 2-sided.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe eventually included un our study 297 patients: 156 patients in the D group, 58 patients in the D\u0026thinsp;+\u0026thinsp;EE group and 83 patients in the D\u0026thinsp;+\u0026thinsp;EV group. The demographic and clinical characteristics are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study sample, overall and by treatment.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;297)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDienogest Alone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c7\" namest=\"c6\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;156)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index, kg/m\u0026sup2;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial cyst, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.7\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenomyosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158 (53.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (53.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (60.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 (47.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.286\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosterior nodule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118 (39.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (37.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (28.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.033\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnterior endometriosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u0026middot;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.001; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.01; \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003cem\u003eNotes:\u0026nbsp;\u003c/em\u003eValues are mean \u0026plusmn; standard deviation or \u003cem\u003en\u003c/em\u003e (%). \u003cem\u003eP\u003c/em\u003e values were obtained with the chi-squared test, Kruskal\u0026ndash;Wallis test or analysis of variance, where appropriate. Mean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of \u0026gt;1 lesion, the largest one was analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u0026nbsp;\u003c/em\u003eEE, ethinylestradiol; EV, estradiol valerate.\u003c/p\u003e\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEffects on symptoms\u003c/h2\u003e \u003cp\u003eRegarding symptoms, when comparing women treated with D and women treated with D combined with estrogens, a significant decrease in terms of dysuria was detected in the EP groups (-0.30 in D\u0026thinsp;+\u0026thinsp;EE/EV groups) rather than the D group (0.08 in D group) between baseline and second follow-up evaluation V3 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In contrast, the reduction of the dysmenorrhea was more significative in D group (-2.63 vs -2.04 in D\u0026thinsp;+\u0026thinsp;EE/EV groups). The statistically significant reduction in the dysmenorrhea in D group is also confirmed when comparing D group with continuous administration in the D\u0026thinsp;+\u0026thinsp;EE/EV groups (-1.73 in D\u0026thinsp;+\u0026thinsp;EE/EV groups VS -2.63 in D group, adjusted Δ for baseline NRS scores 0.96, P\u0026thinsp;\u0026le;\u0026thinsp;0.05), as well as the significant reduction of dysuria in the EP groups (-0.45 in D\u0026thinsp;+\u0026thinsp;EE/EV groups vs 0.08 in D group, adjusted Δ for baseline NRS scores \u0026minus;\u0026thinsp;0.30, P\u0026thinsp;\u0026le;\u0026thinsp;0.05). Furthermore, no significant difference regarding symptoms was found when comparing group D alone with group D\u0026thinsp;+\u0026thinsp;EE/EV in continuous regimen \u003cb\u003e(Supplementary Material 1, S1).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-related changes in symptoms and in lesion mean diameter between the baseline (V1) and 2nd follow-up evaluation (V3, 12 months apart), and differences in changes between treatments (D\u0026thinsp;+\u0026thinsp;EE/EV vs D), both crude (Δ) and adjusted for baseline NRS scores and sizes (adj. Δ).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EE/EV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDienogest Alone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;141)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;156)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eΔ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdj. Δ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspareunia, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.79\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.69\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;1.27, \u0026minus;\u0026thinsp;0.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.15, \u0026minus;\u0026thinsp;0.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pelvic pain, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.72\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.94, 0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.25, \u0026minus;\u0026thinsp;0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysmenorrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;2.04\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;2.63\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;2.71, \u0026minus;\u0026thinsp;1.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;3.29, \u0026minus;\u0026thinsp;1.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysuria w/ menses, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.86\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.86\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.23\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;1.25, \u0026minus;\u0026thinsp;0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.16, 0.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysuria, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.30\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.38\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.23\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.53, \u0026minus;\u0026thinsp;0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.05, 0.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyschezia w/ menses, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.38\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.44\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.69, \u0026minus;\u0026thinsp;0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.85, \u0026minus;\u0026thinsp;0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyschezia, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.22, 0.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.45, 0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial cyst, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;5.16\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;6.11\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;1.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;7.02, \u0026minus;\u0026thinsp;3.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;7.75, \u0026minus;\u0026thinsp;4.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosterior nodule, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.83, 1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.51, 0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.001; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.01; \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003cem\u003eNotes:\u0026nbsp;\u003c/em\u003eMean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of \u0026gt;1 lesion, the largest one was analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u0026nbsp;\u003c/em\u003eEE, ethinylestradiol; EV, estradiol valerate; CI, confidence interval; NRS, Numeric Rating Scale.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eWhen comparing cyclic and continuous administration of the EP groups (D\u0026thinsp;+\u0026thinsp;EE and D\u0026thinsp;+\u0026thinsp;EV), there were no statistically significant differences in terms of symptoms changes (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-related changes in symptoms and in lesion mean diameter between the baseline (V1) and 2nd follow-up evaluation (V3, 12 months apart), and differences in changes between EP treatments (D\u0026thinsp;+\u0026thinsp;EV vs D\u0026thinsp;+\u0026thinsp;EE), both crude (Δ) and adjusted for baseline NRS scores and sizes (adj. Δ).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eΔ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdj. Δ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspareunia, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;1.14\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;1.67, \u0026minus;\u0026thinsp;0.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.15, 0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pelvic pain, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;1.47\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.71\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.30, 0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;2.28, \u0026minus;\u0026thinsp;0.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysmenorrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;1.75\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;2.47\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;2.65, \u0026minus;\u0026thinsp;0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;3.43, \u0026minus;\u0026thinsp;1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysuria w/ menses, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;1.39\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;1.29\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;2.03, \u0026minus;\u0026thinsp;0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.25, 0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysuria, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.51\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.51\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.89, \u0026minus;\u0026thinsp;0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.00, 0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyschezia w/ menses, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.75, 0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.90, 0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyschezia, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.31, 0.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.37, 0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial cyst, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;4.52\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;6.08\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;7.07, \u0026minus;\u0026thinsp;1.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;8.78, \u0026minus;\u0026thinsp;3.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosterior nodule, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.47, 1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;2.27, 2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.001; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.01; \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003cem\u003eNotes:\u0026nbsp;\u003c/em\u003eMean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of \u0026gt;1 lesion, the largest one was analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u0026nbsp;\u003c/em\u003eEV, estradiol valerate; EE, ethinylestradiol; CI, confidence interval; NRS, Numeric Rating Scale.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEffects on lesions\u003c/h2\u003e \u003cp\u003eThe differences in lesion mean diameter between baseline and second follow-up examination (V3) in women treated with D alone or D combined with estrogens (D\u0026thinsp;+\u0026thinsp;EE/EV) are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. There were no statistically significant differences between the D group and the EP groups in lesion mean diameter variations (both endometriomas and endometriotic nodules).\u003c/p\u003e \u003cp\u003eRegarding EPs, no differences in lesion mean diameter were found either with regard to the type of estrogen administered (D\u0026thinsp;+\u0026thinsp;EE vs D\u0026thinsp;+\u0026thinsp;EV) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) or the administration regimen (continuous vs cyclic) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) (ovarian endometriomas \u0026minus;\u0026thinsp;5.64 vs -6.11, Adjusted Δ for baseline sizes \u0026minus;\u0026thinsp;2.01; endometrial nodules 0.006 vs -0.35, Adjusted Δ for baseline sizes \u0026minus;\u0026thinsp;0.19). Moreover, when comparing D alone with continuous administration of EPs (D\u0026thinsp;+\u0026thinsp;EE/EV), no differences in lesion mean diameter were reported (Supplemental Material S1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment-related changes in symptoms and in lesion mean diameter between the baseline (V1) and 2nd follow-up evaluation (V3, 12 months apart), and differences in changes between cyclic and continuous EP treatments, both crude (Δ) and adjusted for baseline NRS scores and sizes (adj. Δ).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;cyclic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;contin.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEE/EV (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEE/EV (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eΔ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdj. Δ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspareunia, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.73\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.89\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;1.29, \u0026minus;\u0026thinsp;0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.75, \u0026minus;\u0026thinsp;0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pelvic pain, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;1.27, 0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.90, 0.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysmenorrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;2.24\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;1.73\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;3.00, \u0026minus;\u0026thinsp;1.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;2.97, \u0026minus;\u0026thinsp;0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysuria w/ menses, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.92\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;1.40, \u0026minus;\u0026thinsp;0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.43, \u0026minus;\u0026thinsp;0.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysuria, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.43, 0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.91, 0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyschezia w/ menses, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;0.52\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.98, \u0026minus;\u0026thinsp;0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.48, 0.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyschezia, NRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.36, 0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;0.27, 0.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial cyst, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;4.85\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ndash;5.64\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;6.97, \u0026minus;\u0026thinsp;2.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;9.11, \u0026minus;\u0026thinsp;2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosterior nodule, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u0026ndash;0.81, 1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u0026ndash;1.96, 2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.001; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.01; \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003cem\u003eNotes:\u0026nbsp;\u003c/em\u003eMean diameter of cysts and nodules is the average of length (longitudinal diameter), width (transverse diameter) and antero-posterior diameter; in case of \u0026gt;1 lesion, the largest one was analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u0026nbsp;\u003c/em\u003eEE, ethinylestradiol; EV, estradiol valerate; CI, confidence interval; NRS, Numeric Rating Scale.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eTolerability\u003c/h2\u003e \u003cp\u003eRegarding tolerability, treatment associated side effects were reported by 16.2% of women, of which 7.1% treated with D, 6.7% treated with D\u0026thinsp;+\u0026thinsp;EV and 2.4% treated with D\u0026thinsp;+\u0026thinsp;EE. Side effects during treatment are reported in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The most frequent side effect was uterine bleeding/spotting. Spotting was significantly more frequent in group D\u0026thinsp;+\u0026thinsp;EV than in the other two groups (P\u0026thinsp;=\u0026thinsp;0.04) and was reported in particular by women who assumed treatment in continuous administration (4 of 28 patients who assumed D\u0026thinsp;+\u0026thinsp;EV continuously, 14.3%). No significant differences were found in other side effects between the three groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of side effects, overall and by treatment. Values are counts (percentages).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSide effect\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAll (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;297)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eExact \u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDienogest Alone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDienogest\u0026thinsp;+\u0026thinsp;EE\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;156)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpotting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.04\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMood swing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight gain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBloating\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLoss of libido\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaginal dryness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHair loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachycardia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDouble vision\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.001; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.01; \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003cp\u003e\u003cem\u003eAbbreviations:\u0026nbsp;\u003c/em\u003eEE, ethinylestradiol; EV, estradiol valerate.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective study we analyzed the impact in terms of symptoms and endometriotic lesion mean diameter variations in patients treated with dienogest alone or dienogest combined with estrogens (D\u0026thinsp;+\u0026thinsp;EE and D\u0026thinsp;+\u0026thinsp;EV).\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEffects on lesions and symptoms\u003c/h2\u003e \u003cp\u003eRegarding symptoms, as previously demonstrated in literature (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), a statistically significant reduction in the severity of dysmenorrhea associated with D-only therapy was found in comparison with dienogest combined with estrogens (both EE and EV\u003cem\u003e)\u003c/em\u003e after 12 months of therapy (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The greater reduction in dysmenorrhea may likely be related to the induction of amenorrhea together with the antiproliferative and anti-inflammatory effect of D. This result is in line with the prospective study by Caruso et al.: in their cohort of 44 patients, they reported amenorrhea in 88.3 % of patents after 24 months of D-only therapy, with a significant decrease of dysmenorrhea and pelvic pain (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMoreover, in our study population the improvement of dysuria was greater in EP groups rather than the D group. This finding may be due to the trophic action of estrogens on the urethral mucosa (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) and to lower estrogen levels induced by dienogest (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur data showed that there are no differences between oral administration of D and D\u0026thinsp;+\u0026thinsp;EE or D\u0026thinsp;+\u0026thinsp;EV in terms of endometriotic lesion mean diameter changes. The effect of dienogest on the size of ovarian endometriomas has already been studied in Literature showing that the hypoestrogenic state induced by the therapy reduces inflammation and proliferation of ectopic endometrium-like tissue, leading to a possible decrease in lesion size (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Different results regarding lesions variations are reported by other studies with smaller samples comparing D alone or associated with EE in women with endometriosis. In a retrospective observational study conducted on women with ovarian endometriomas (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), Xholli and colleagues reported a reduction in the size of endometriomas in patients treated with D alone (n\u0026thinsp;=\u0026thinsp;34) and with D\u0026thinsp;+\u0026thinsp;EE (n\u0026thinsp;=\u0026thinsp;36) after 12 months, but the reduction was greater in patients treated with D alone. On the other hand, a prospective study conducted on 81 women treated with D or D\u0026thinsp;+\u0026thinsp;EE detected a significant decrease in endometrioma\u0026rsquo;s volume only in the group treated with D after 3 and 6 months of follow up (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eTolerability\u003c/h2\u003e \u003cp\u003eRegarding drug tolerability, uterine bleeding/spotting was reported more frequently in the D\u0026thinsp;+\u0026thinsp;EV group, especially when administered in a continuous regimen. Our data suggest that when D\u0026thinsp;+\u0026thinsp;EV is chosen, a cyclic administration may be preferable than continuous. Considering that endometriosis is a chronic disease, in the perspective of a long-term treatment, tolerability and consequent compliance to treatment are fundamental aspects of medical management of women with endometriosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe main limitations of our study are its retrospective nature and the absence of a control group. Although the lack of histological confirmation, ultrasound has shown a high diagnostic accuracy for endometriosis in particular if performed by expert sonographers as in our study (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Regarding patients\u0026rsquo; characteristics, we found a statistically significant difference regarding the age of patients: women treated with D\u0026thinsp;+\u0026thinsp;EE therapy were younger than the rest of the study population. This may be due to the fact that EPs are usually prescribed to adolescents and younger patients rather than progestogen alone. The effect of dienogest on bone mineral density (BMD) is still controversial in the Literature and, according to some studies, it may reduce BMD (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), therefore especially in adolescent patients the choice of combining dienogest with an estrogen seems reasonable. In addition, we found a significant difference in the size of ovarian endometriomas at baseline visit; nevertheless, our primary outcome was the cysts size changes over time, therefore this finding was not a limitation for the analysis.\u003c/p\u003e \u003cp\u003eThis study has also some strengths: to the best of our knowledge, we reported the largest cohort of patients with ovarian endometriomas assuming dienogest-based hormonal therapies and investigate for the first-time differences among these three therapeutic options. Another strength is represented by the long-term follow-up.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, the comparison of Dienogest alone or associated with estrogens (EE or EV) showed no difference in terms of lesion size variation and pain symptoms in women with ovarian endometriomas, except for dysmenorrhea, which seems to benefit more from progestin-only therapy, and dysuria, which improves more with EP treatment. In the light of our results, we believe that clinicians should consider efficacy of the different therapies on symptoms relief, together with tolerability, metabolic impact and thromboembolic risk of each hormonal treatment, as well as women\u0026rsquo;s age, comorbidities and preference. Balancing all these aspects will let clinicians choose the right treatment for each woman, in the perspective of a long-term treatment, improving adherence to treatment and consequently reducing the risk of disease progression over time.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e: The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contribution:\u003c/strong\u003e All authors contributed to the study conception and design\u003cstrong\u003e\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eS. Del Forno: project development, manuscript writing; B. Orsini: manuscript writing; L. Verrelli: data collection; M. Caroli: data collection, data analysis; AC Aru: manuscript editing; J Lenzi: data analysis; D. Raimondo: manuscript editing; A. Arena: manuscript editing; G. Borghese: data collection; R. Paradisi: project development; MC Meriggiola: manuscript editing; R. Seracchioli: review of the manuscript; P. Casadio: review of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval: \u0026nbsp;\u003c/strong\u003eThe study received approval by the Institutional review Board of the University of Bologna (149/2014/O/Oss). The study protocol conforms to the ethical guidelines of the \u0026ldquo;World Medical Association (WMA) Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects\u0026rdquo; adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 59th WMA General Assembly, Seoul, South Korea, October 2008.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e: Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e none.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBecker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L et al (2022)ESHRE PAGES The members of the Endometriosis Guideline Core Group,. ;1\u0026ndash;26\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParasar P, Ozcan P, Terry KL, Endometriosis (2017 Mar) Epidemiology, Diagnosis and Clinical Management. Curr Obstet Gynecol Rep 6(1):34\u0026ndash;41\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEisenberg VH, Weil C, Chodick G, Shalev V (2018 Jan) Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members. BJOG 125(1):55\u0026ndash;62\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFauconnier A, Fritel X, Chapron C (2009) Relations entre endom\u0026eacute;triose et algie pelvienne chronique: quel est le niveau de preuve ? Gynecologie Obstetrique et Fertilite 37(1):57\u0026ndash;69\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoliman AM, Coyne KS, Zaiser E, Castelli-Haley J, Fuldeore MJ (2017 Dec) The burden of endometriosis symptoms on health-related quality of life in women in the United States: a cross-sectional study. 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Int J Gynecol Pathol 20(2):147\u0026ndash;154\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuzii L, Achilli C, Bergamini V, Candiani M, Garavaglia E, Lazzeri L et al (2016) Comparison between the stripping technique and the combined excisional / ablative technique for the treatment of bilateral ovarian endometriomas: a multicentre RCT. 31:339\u0026ndash;3442\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEndometriosis Treatment Italian Club (2014 Jul-Aug) Ovarian endometrioma: what the patient needs. J Minim Invasive Gynecol 21(4):505\u0026ndash;516. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jmig.2014.01.011\u003c/span\u003e\u003cspan address=\"10.1016/j.jmig.2014.01.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2014 Jan 24. 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Int J Womens Health 3:175\u0026ndash;184\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCormack PL Dienogest: a review of its use in the treatment of endometriosis.Drugs. 2010 Nov; 70(16):2073\u0026ndash;88\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C (2015) Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 7:393\u0026ndash;401\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrandi G, Piacenti I, Volpe A, Cagnacci A (2014 Sep) Modification of body composition and metabolism during oral contraceptives containing non-androgenic progestins in association with estradiol or ethinyl estradiol. Gynecol Endocrinol 30(9):676\u0026ndash;680\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlu-Bureau G, Maitrot-Mantelet L, Hugon-Rodin J, Gompel A (2016 Jan) [Contraception and risk of venous thromboembolism]. Rev Prat 66(1):e7\u0026ndash;8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXholli A, Filip G, Previtera F, Cagnacci A (2020 Jun) Modification of endometrioma size during hormone therapy containing dienogest. Gynecol Endocrinol 36(2):545\u0026ndash;549\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAngioni S, Pontis A, Malune ME, Cela V, Luisi S, Litta P et al (2020 Jan) Is dienogest the best medical treatment for ovarian endometriomas? Results of a multicentric case control study. Gynecol Endocrinol 36(2):84\u0026ndash;86\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaruso S, Iraci M, Cianci S, Vitale SG, Fava V, Cianci A (2019) Effects of long-term treatment with dienogest on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain. J Pain Res 12:2371\u0026ndash;2378\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBosch TVANDEN, Dueholm M, Leone FPG, Valentin L, Rasmussen CK, Musa T et al (2015) Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses : a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. ;(January):284\u0026ndash;98\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuerriero S, Condous G, van den Bosch T, Valentin L, Leone FPG, Van Schoubroeck D et al (2016) Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol 48(3):318\u0026ndash;332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourdel N, Chauvet P, Billone V, Douridas G, Fauconnier A, Gerbaud L et al (2019) Systematic review of quality of life measures in patients with endometriosis. PLoS ONE 14:1\u0026ndash;32\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Holsbeke C, Van Calster B, Guerriero S, Savelli L, Paladini D, Lissoni AA et al (2010 Jun) Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol 35(6):730\u0026ndash;740\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVercellini P, Buggio L, Frattaruolo MP, Borghi A, Dridi D, Somigliana E (2018 Aug) Medical treatment of endometriosis-related pain. Best Pract Res Clin Obstet Gynaecol 51:68\u0026ndash;91\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMabrouk M, Paradisi R, Arena A, del Forno S, Matteucci C, Zannoni L et al (2018 May) Short-term histopathological effects of dienogest therapy on ovarian endometriomas: in vivo, nonrandomized, controlled trial. Gynecol Endocrinol 34(4):399\u0026ndash;403\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHextall A (2000 Aug) Oestrogens and lower urinary tract function. Maturitas 36(2):83\u0026ndash;92\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLagan\u0026agrave; AS, Vitale SG, Granese R, Palmara V, Ban Frangež H, Vrtačnik-Bokal E et al (2017) Clinical dynamics of Dienogest for the treatment of endometriosis: from bench to bedside. Expert Opinion on Drug Metabolism and Toxicology, vol 13. Taylor and Francis Ltd, pp 593\u0026ndash;596\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUludag SZ, Demirtas E, Sahin Y, Aygen EM (2021) Dienogest reduces endometrioma volume and endometriosis-related pain symptoms. J Obstet Gynaecol (Lahore) 41(8):1246\u0026ndash;1251\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEbert AD, Dong L, Merz M, Kirsch B, Francuski M, B\u0026ouml;ttcher B et al (2017 Oct) Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents. J Pediatr Adolesc Gynecol 30(5):560\u0026ndash;567\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"endometriosis, medical therapy, ultrasound, pelvic pain","lastPublishedDoi":"10.21203/rs.3.rs-2671149/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2671149/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eto compare the effects of Dienogest 2 mg (D) alone or combined with estrogens (D\u0026thinsp;+\u0026thinsp;ethinylestradiol 0.03 mg, D\u0026thinsp;+\u0026thinsp;EE; D\u0026thinsp;+\u0026thinsp;estradiol valerate 1\u0026ndash;3 mg, D\u0026thinsp;+\u0026thinsp;EV) in terms of symptoms and endometriotic lesions variations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis retrospective study included symptomatic patients in reproductive age with ultrasound diagnosis of ovarian endometriomas. Medical therapy for at least 12 months with D, D\u0026thinsp;+\u0026thinsp;EE or D\u0026thinsp;+\u0026thinsp;EV was required. Women were evaluated at baseline visit (V1) and after 6 (V2) and 12 months (V3) of therapy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003e297 patients were enrolled (156 in the D group, 58 in the D\u0026thinsp;+\u0026thinsp;EE group, 83 in the D\u0026thinsp;+\u0026thinsp;EV group). There were no differences between groups in terms of lesions mean diameter variation. No variations were detected in terms of lesions reduction when comparing the two estroprogestins, cyclic versus continuous estroprogestin regimens, D alone versus D\u0026thinsp;+\u0026thinsp;EE/D\u0026thinsp;+\u0026thinsp;EV administered continuously. When comparing D and D\u0026thinsp;+\u0026thinsp;EE/D\u0026thinsp;+\u0026thinsp;EV groups, a significant decrease of dysmenorrhea was detected in the D group than in D\u0026thinsp;+\u0026thinsp;EE/D\u0026thinsp;+\u0026thinsp;EV group. Conversely, the reduction of dysuria was more significative in the D\u0026thinsp;+\u0026thinsp;EE/D\u0026thinsp;+\u0026thinsp;EV groups rather than in the D group. Regarding tolerability, treatment associated side effects were reported by 16.2% patients. The most frequent one was uterine bleeding/spotting, significantly higher in the D\u0026thinsp;+\u0026thinsp;EV group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDienogest alone or associated with estrogens (EE/EV) seems to be equally effective in reducing endometriotic lesions mean diameter. The reduction of dysmenorrhea was more significative when D was administered alone, while dysuria seems to improve more when D is associated with estrogens.\u003c/p\u003e","manuscriptTitle":"Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. 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