{"paper_id":"6cabb004-c4aa-4ec6-84a3-59e9982e3dac","body_text":"Gynecological Endocrinology\nISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: www.tandfonline.com/journals/igye20\nLong-term treatment for endometriosis with\ndienogest: efficacy, side effects and tolerability\nFrancesco La Torre, Silvia Vannuccini, Federico Toscano, Ernesto Gallucci,\nGretha Orlandi, Virginia Manzi & Felice Petraglia\nTo cite this article: Francesco La Torre, Silvia Vannuccini, Federico Toscano, Ernesto Gallucci,\nGretha Orlandi, Virginia Manzi & Felice Petraglia (2024) Long-term treatment for endometriosis\nwith dienogest: efficacy, side effects and tolerability, Gynecological Endocrinology, 40:1,\n2336121, DOI: 10.1080/09513590.2024.2336121\nTo link to this article:  https://doi.org/10.1080/09513590.2024.2336121\n© 2024 The Author(s). Published by Informa\nUK Limited, trading as Taylor & Francis\nGroup\nPublished online: 05 Apr 2024.\nSubmit your article to this journal \nArticle views: 15466\nView related articles \nView Crossmark data\nCiting articles: 26 View citing articles \nFull Terms & Conditions of access and use can be found at\nhttps://www.tandfonline.com/action/journalInformation?journalCode=igye20\n\nReseaR ch aR ticle\nGynecoloGical endocrinoloGy\n2024, Vol. 40, no . 1, 2336121\nLong-term treatment for endometriosis with dienogest: efficacy, side effects \nand tolerability\nFrancesco la t orre*, silvia Vannuccini *, Federico toscano, ernesto Gallucci, Gretha Orlandi, Virginia Manzi \nand Felice Petraglia\ndivision of obstetrics and Gynecology, d epartment of experimental and clinical Biomedical Sciences “Mario Serio” , University of Florence, aoU \nc areggi, Florence, i taly\nABSTRACT\nBackground: Dienogest (DNG) improves endometriosis-associated pain (eaP) and patients’ quality of life; \nhowever, the modern cornerstone of the management of endometriosis is the long-term adherence of the \npatient to medical treatment.\nObjective: to evaluate DNG as a long-term treatment of endometriosis, focusing on patients’ compliance \nand side effects, also correlating with different phenotypes of endometriosis.\nMethods: t his was a cohort study on a group of patients with endometriosis ( n = 114) undergoing \nlong-term treatment with DNG. During the follow up visits (12, 24, and 36 months) patients were interviewed: \nan assessment of eaP was performed by using a visual analogue scale (V as) and side effects were evaluated \nby using a specific questionnaire of 15 items.\nResults:  a t 12 months, 81% were continuing the DNG treatment, with a significant reduction of \ndysmenorrhea, dyspareunia, dyschezia, dysuria and chronic pelvic pain. Of the 19% that discontinued the \ntreatment: 62% was due to spotting, reduced sexual drive, vaginal dryness, and mood disorders. t he \nimprovement of eaP was significant for all endometriosis phenotypes, especially in patients with the deep \ninfiltrating type. a t 36 months, 73% of patients were continuing the treatment, showing a significant \nreduction of eaP through the follow up, along with an increase of amenorrhea (from 77% at 12 months to \n93% at 36 months). i n a subgroup of 18 patients with gastrointestinal disorders, DNG was administered \nvaginally at the same dosage, showing similar results in terms of efficacy and tolerability.\nConclusions: DNG was an effective long-term treatment for all endometriosis phenotypes, with few side \neffects that caused the discontinuation of the treatment mainly during the first year. t hus, the course of \n1-year treatment is a predictive indicator for long-term treatment adherence.\nIntroduction\nEndometriosis is a benign chronic inflammatory disease of \nreproductive age women [ 1]. In the last decade, its prevalence \nhas increased and currently it remains a complex condition, \naffecting deeply female quality of life (QoL) [ 2]. Treatment needs \nto be tailored to each patient, according to their age, pregnancy \ndesire, symptoms and endometriosis phenotypes [ 3,4].\nMedical treatment with hormonal drugs is the first line thera -\npeutical option [ 5,6]. They block the menstrual cycle and reduce \nendometriosis related symptoms by inducing a pseudo-pregnancy \nstate and/or reducing estrogen ovarian secretion by blocking the \nhypothalamic-pituitary-ovary axis. The first-choice treatment are \nprogestins, due to their efficacy and good tolerability despite their \nlow costs: dienogest (DNG), norethisterone acetate and medroxy -\nprogesterone acetate are the compounds approved by different \ngovernment agencies. By binding to progesterone receptors, pro -\ngestins act through different mechanisms: they reduce the secre -\ntion of follicle stimulating hormone (FSH) and luteinizing hormone \n(LH), inducing anovulation and endometrial pseudo-decidualization, \nin addition to inhibiting angiogenesis, decreasing oxidative stress \nand increasing apoptosis of endometrial cells [ 7–9].\nDNG is a 19-nortestosterone derivative labeled for endometri -\nosis [ 10–12]. It improves endometriosis related symptoms and \npatients’ QoL, reducing the size of endometriomas and prevent -\ning recurrences after surgery [ 13–20]. The most frequent reported \nside effects are abnormal uterine bleeding (AUB) and headache.\nThe primary aim of the present study was to evaluate DNG as \na long-term treatment for endometriosis, from 12 months of follow \nup to 36 months, focusing on compliance of the patient and \nreported side effects. A secondary objective was to correlate differ -\nent phenotypes of endometriosis with the efficacy of the treatment.\nMethods\nThis was a cohort study of prospectively collected data from fer -\ntile aged patients who came to our Endometriosis Center \n© 2024 The a uthor(s). Published by i nforma UK limited, trading as Taylor & Francis Group\nCONTACT Felice Petraglia  felice.petraglia@unifi.it   d epartment of experimental, clinical and Biomedical Sciences, d ivision of obstetrics and Gynecology, \nUniversity of Florence, largo Brambilla 3, Florence 50134, i taly\n*Francesco la Torre and Silvia Vannuccini are joint first authors.\nhttps://doi.org/10.1080/09513590.2024.2336121\nThis is an o pen a ccess article distributed under the terms of the c reative c ommons a ttribution license ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri -\nbution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the a ccepted Manuscript in \na repository by the author(s) or with their consent.\nARTICLE HISTORY\nr eceived 1 February 2024\nr evised 20 March 2024\na ccepted 22 March 2024\nPublished online 6 a pril \n2024\nKEYWORDS\nendometriosis; dienogest; \nlong-term treatment; \nchronic pelvic pain; \ntolerability\n\n2 F. la t ORRe et al.\n(between July 2019 and August 2021) with the diagnosis of \nendometriosis and undergoing treatment with DNG (2 mg). Our \ninclusion criteria were reproductive age, presence of endometrio -\nsis related symptoms, whereas those with contraindications for \nhormonal treatment, the desire of pregnancy or seeking hor -\nmonal contraception were excluded. A group of 114 patients \nwere included in the study. During the first visit, we collected all \nthe clinical data (age, family history of gynecological disorders, \nparity, age at menarche, characteristics of the cycle in \nadolescence, previous hormonal treatment, gastrointestinal or \nurinary symptoms, past medical history (including questions \nabout headache, autoimmune disorders, psychological disorders), \nprevious surgery, endometriosis related symptoms ( Table 1).\nThe phenotypes of endometriosis were as follows: ovarian \nendometrioma (OMA, n = 23), deep infiltrating endometriosis \n(DIE, n = 38) and mixed phenotype with both OMA and DIE \n(n = 53). According to the patient’s clinical history, symptoms and \nimaging (transvaginal ultrasound or MRI), we planned the first \nfollow up visit to our clinic after 6 months and then every \n12 months. During the follow up visits (12, 24, and 36 months) \npatients were interviewed.\nA visual analog scale (V AS) of 10 points (measured in cm) \nwas used to assess EAP: dysmenorrhea, dyspareunia, chronic pel -\nvic pain (CPP), dysuria, dyschezia. Baseline values were com -\npared to values obtained at each follow up.\nSide effects were evaluated by using a specific questionnaire \nof 15 items, regarding weight gain or hydric retention, moods \ndisorders, libido, gastrointestinal symptoms, headache, dermato -\nlogical symptoms, hot flushes, breast tenderness, and break -\nthrough bleeding. Each item can be rated from 0 (absence of \nsymptoms), 1 (few/mild), 2 (often/moderate), 3 (daily/severe, \ninterfering with QoL). Then if the symptom was already present \nat the beginning of the treatment, at follow-up, if this got worst \n(four), unchanged (five) or improved (six). The questionnaire \nwas always filled out by the patients with the help of a health -\ncare professional of the clinic. After the DNG prescription, \nTable 1. Baseline characteristics of the study population.\nn = 114\na ge (years) 34 ± 6.9\na ge at menarche 12.4 ± 1.7\nd ysmenorrhea since adolescence 94 (82.5%)\nParous 20 (17.5%)\nPrevious hormonal treatment 93 (81.6%)\nSurgery for endometriosis 24 (21.1%)\nendometriosis Phenotype\n OMA 23 (20.2%)\n DIE 38 (33.3%)\n Mixed phenotypes 53 (46.5%)\nMean months of treatment [range] 20.0 ± 12.7 [2 − 72]\neaP\n Dysmenorrhea 109 (95.6%)\n  VAS 8.1 ± 2.4\n  Severe (VAS > 7) 95 (87.2%)\n Dyspareunia 92 (80.7%)\n  VAS 7.2 ± 3.2\n  Severe (VAS > 7) 65 (70.7%)\n Dyschezia 21 (18.4%)\n  VAS 6.2 ± 2.7\n  Severe (VAS > 7) 10 (47.6%)\n Dysuria 38 (33.3%)\n  VAS 6.1 ± 3.1\n  Severe (VAS > 7) 15 (39.5%)\n Chronic pelvic pain 79 (69.3%)\n  VAS 6.3 ± 3.5\n  Severe (VAS > 7) 40 (50.6%)\neaP: endometriosis-associated pain; oM a: ovarian endometrioma; die: deep infil -\ntrating endometriosis.\nTable 2.  d elta change of V aS for endometriosis-associated pain (eaP) in study \npopulation and according to endometriosis phenotypes (mean ± standard devia -\ntion). cPP , chronic pelvic pain.\na ll cases o Ma die Mixed p value\nDysmenorrhea −7.2 (±3.1) −5.8 (±3.2) −8.2 (±1.7) −7.3 (±3.6) .014*\nCPP −2.8 (±4.5) −2.7 (±4.4) −2.9 (±4.4) −2.8 (±4.7) .997\nDyspareunia −2.9 (±4.2) −0.4 (±3.5) −3.9 (±3.8) −3.2 (±4.6) .025#\nDyschezia −0.2 (±3.5) 0.5 (±2.5) −0.4 (±3.4) −0.5 (±4.0) .693\nDysuria −1.9 (±3.2) −0.3 (±3.3) −2.0 (±3.6) −2.6 (±3.3) .035§\n*die and Mixed vs oM a; #die and Mixed vs oM a; §die and Mixed vs oM a.\nFigure 1.  VaS change of eaP from baseline to 12-months follow up. data represent in box and whiskers plot.\n\nGyNec Ol OGical eNDOcRiNOl OGy 3\npatients were requested to report side effects by mail or by \nphone calls; if this was judged as clinically relevant, the consul -\ntant could anticipate the follow up visit.\nThe comparison between EAP and side effects was conducted \nby evaluating data from the same cohort of patients during sub -\nsequent follow-up visits. Specifically, all data collected pertained \nto patients who remained under DNG treatment at each time \npoint (12, 24, 36 months), adhering to a per-protocol analysis \napproach.\nEthical approval\nThe study protocol was approved by the local Ethics Committee \n(n.14558_oss approved on 28 May 2019). Prior to initiation of \ntreatment, patients were informed that DNG does not offer a \ndefinitive cure for the disease, but rather constitutes a long-term \nmedical regimen aimed at improving their QoL. It was empha -\nsized that the treatment may lead to the reduction of symptoms, \ndespite it can be associated with some side effects. Before being \nenrolled in the study, patients provided informed written consent \nfor their clinical data to be used for scientific research purposes.\nStatistical analysis\nCollected data were entered in an electronic database and ana -\nlyzed with SPSS software (Statistical Package for Social Science; \nIBM SPSS Statistics 23, IBM Corporation). Continuous data were \nchecked for normality by using normal probability plots. A \ndescriptive analysis was conducted with the evaluation of posi -\ntion measures (mean, median) and dispersion indices (standard \ndeviation, range) for the quantitative variables. Binomial variables \nare described as frequencies n (%). According to normality dis -\ntribution of data, the Mann Whitney U test or independent-sample \nT test was used to compare continuous variables. One-way \nANOV A was used to compare pain scores according to endome -\ntriosis phenotypes. A p value < .05 was considered as statistically \nsignificant.\nResults\nAfter 12 months of DNG treatment, a statistically significant \nreduction of dysmenorrhea ( p < .05), dyspareunia ( p < .05), \ndyschezia ( p < .05), dysuria ( p < .05) and CPP ( p < .05) was \nachieved ( Figure 1 ). Comparing changes of endometriosis \nTable 3. Side effects at 12 months follow up. data are presented as frequencies n (%).\nnew symptom preexisting symptom\nSide e ffects no Few/mild o ften/moderate daily/severe worsening unchanged improvement\nhydric retention 65 (70.7) 13 (14.1) 10 (10.9) 4 (4.3) / / /\naUB 71 (77.2) 11 (12) 8 (8.7) 2 (2.2) / / /\nreduced sexual drive 70 (76.1) 9 (9.8) 4 (4.3) 1 (1.1) 6 (6.5) 2 (2.1) /\nbreast tenderness 71 (77.1) 10 (10.9) 7 (7.6) 2 (2.2) / 2 (2.1) /\nheadache 58 (63) 5 (5.4) 9 (9.8) 1 (1.1) 3 (3.2) 9 (9.7) 7 (7.6)\nabdominal bloating 61 (66.3) 3 (3.3) 11 (12) 3 (3.3) 1 (1.1) 9 (9.7) 4 (4.3)\nmood disorders 74 (80.4) 3 (3.3) 9 (9.8) 4 (4.3) / 2 (2.1) /\nvaginal dryness 77 (83.7) 3 (3.3) 7 (7.6) 4 (4.3) / 1 (1.1) /\nhot flushes 80 (87) 5 (5.4) 2 (2.2) 3 (3.3) 2 (2.1) / /\nacne 79 (85.9) 5 (5.4) 5 (5.4) / / / 3 (3.2)\nhair loss 81 (88) 4 (4.3) 3 (3.3) 2 (2.2) / 2 (2.1) /\ninsomnia 84 (91.3) 8 (8.7) / / / / /\nseborrhea 85 (92.4) 1 (1.1) 2 (2.2) 3 (3.3) / 1 (1.1) /\nhirsutism 86 (93.5) 3 (3.3) 2 (2.2) 1 (1.1) / / /\nFigure 2.  Flow chart diagram of study population follow up.\n\n4 F. la t ORRe et al.\nassociated pain (EAP) according to endometriosis phenotypes, \nthe reduction of dysmenorrhea ( p = .014), dyspareunia ( p = .025) \nand dysuria ( p = .035) were significantly better in the DIE and \nmixed phenotypes ( Table 2).\nAt 12 months, amenorrhea was reached by 77%; meanwhile, \n23% reported breakthrough bleeding, of whom 52% was spotting, \n38% was mild bleeding and 10% was moderate bleeding. At \n12 months follow up, ninety-two patients (81%) were continuing \nthe therapy, whereas twenty-two patients (19%) suspended it. \nThe reported causes of discontinuation were: side effects (36%), \ninefficacy (27%), both inefficacy and side effects (23%), desire of \npregnancy (9%), and one seeking contraception (5%). Among the \nside effects reported for discontinuing DNG treatment, the most \nfrequent were AUB, reduced sexual drive, vaginal dryness, and \nmood disorders. The average time for discontinuation was \n7.2 months. The overall reported side effects were hydric reten -\ntion (29.3%), weight gain (26% with a mean value of 2.0 kg), \nAUB (22.9%), breast tenderness (20.7%), abdominal bloating \n(18.7%), mood disorders (17.4%), headache (16.3%), reduced \nsexual drive (15.2%), vaginal dryness (15.2%), hot flushes \n(10.9%), acne (10.8%), hair loss (9.8%), insomnia (8.7%), sebor -\nrhea (6.6%) and hirsutism (6.6%) ( Table 3). In a subgroup of 18 \npatients with persistent irregular bleeding and other side effects, \nalong with the presence of preexisting gastrointestinal symptoms \npotentially impairing the oral adsorption of the drug, DNG was \nsuccessfully administered vaginally with similar efficacy on EAP .\nAt 24 months, 76% were continuing the treatment. Three \npatients suspended DNG due to a desire of pregnancy, one was \nlost to follow up, and one reported inefficacy and side effects \n(AUB, headache, alopecia, and hot flushes). At 36 months, 73% \nwere continuing the treatment ( Figure 2 ). Two patients sus -\npended it to undergo surgery, one due to pregnancy desire and \none due to side effects. This last patient interrupted DNG at \n34 months despite her great improvement regarding EAP (V AS \nscore 0 for all evaluated aspects) due to an important reduction \nof sexual drive with consecutive abstention of sexual intercourse, \nweight gain (+8 kg), headache, and hair loss.\nDuring the follow up, we reported a higher frequency of \nreduced sexual drive (23/87, 26% at 24 months; 25/83, 30% at \n36 months), vaginal dryness (17/87, 20% at 24 months; 18/83, \n22% at 36 months), hot flushes (15/87, 17% at 24 months; 17/83, \n20% at 36 months). On the other hand, there was a progressive \ndecrease of AUB (11/87 [13%] referred spotting at 24 months; \n6/83 [7%] at 36 months) and mood disorders (13/87 [15%] at \n24 months; 10/83 [12%] at 36 months) ( Figure 3 ).\nDiscussion\nThe present study shows that DNG is a suitable option for a \nlong-term treatment of endometriosis, with good efficacy in \ndecreasing EAP , independently of endometriosis phenotype. \nMoreover, the highest reduction of pain scores was observed \nwhen DIE lesions were present. Nevertheless, it has already been \nreported the non-inferiority of DNG compared to GnRH ago -\nnists as a post-operative treatment of DIE, with better tolerability \nindeed [ 14]. In our study, a significant reduction of dysmenor -\nrhea, dyspareunia, dyschezia, dysuria and CPP was achieved and \nmaintained over the follow up, supporting the increased QoL in \npatients undergoing DNG treatment [ 12,21].\nThe patients’ adherence to the treatment regimen remained \nhigh throughout the follow up, with 81% of individuals continu -\ning DNG at 12 months, followed by 76% at 24 months, and 73% \nat the 36-month visit, confirming recent studies of long-term \nFigure 3.  Side effects occurrence as frequency (%) at 12, 24 and 36 months follow up.\n\nGyNec Ol OGical eNDOcRiNOl OGy 5\nobservation of DNG treatment [ 11,17]. Furthermore, the course \nof the first 6 months of treatment resulted crucial, both in terms \nof response and tolerance, since the average time for treatment \ndiscontinuation was 7 months. The rate of amenorrhea increased \nup 93% at 36 months, showing a progressive reduction in bleed -\ning across time, supporting the importance of counseling patients \nregarding bleeding irregularities especially during the first months \nof treatment, to increase the compliance [ 22].\nThe primary reason for discontinuation of treatment was due \nto side effects (including those patients that interrupted the \ntreatment for both side effects and inefficacy of the drug) and \noverall, nearly 90% of them discontinued the treatment during \nthe first year. Given that the initial year signifies the period with \nthe highest observed prevalence of therapy withdrawal, it could \nbe used as a predictive indicator for long-term treatment toler -\nance, potentially enabling the assessment of a patient’s likelihood \nto tolerate the drug over an extended duration [ 13].\nThe withdrawal from treatment was notably influenced by \nspecific side effects, including reduced sexual drive, AUB, vaginal \ndryness, and mood disorders. Throughout the follow-up, these \nside effects underwent changes in frequency, along with the \nonset of hot flushes, despite an overall low rate observed in our \nstudy as in others [ 11,23]. Particularly, reduced sexual drive, vag -\ninal dryness, and hot flushes demonstrated an increase during \nthe 36-month follow-up, whereas AUB and mood disorders sig -\nnificantly decreased. Common side effects such as weight gain, \nhydric retention, headache, breast tenderness remained unchanged \nin frequency over the study period. In case of symptoms already \npresent before DNG treatment, for instance a preexisting head -\nache, this was improved after initiating DNG therapy. In addi -\ntion, the observation that the vaginal administration of DNG pill \nmay overcome some of these side effects is of interest for some \nendometriosis patients who require a long-term treatment. The \nvagina has previously shown to be a good route of administra -\ntion for hormones [ 24], and notably for progestins labeled for \nthe treatment of endometriosis, such as danazol, resulted efficient \nalso by vaginal administration with less systemic side effects [ 25].\nIn our cohort, despite the presence of side effects, patients con -\ntinued DNG treatment due to the significant reduction of EAP in \nall evaluated aspects, hence, significantly improving their QoL. \nBesides, all the side effects were from mild to moderate in inten -\nsity. Furthermore, the use of a specific questionnaire with 15-items \nallowed a detailed collection of side effects, representing a strength \nof the study. Nevertheless, the influence of comorbidities should \nbe considered when evaluating symptoms such as abdominal \nbloating, headache and mood disorders, as confounding factors for \nside effects profile. Despite the limited sample size, the long follow \nup of patients is a strength of the study and provides a reliable \noverview of real-life experience of DNG treatment.\nIn conclusion, DNG is an effective long-term treatment for all \nphenotypes of endometriosis, with few side effects, causing the \ndiscontinuation of the treatment mainly during the first year. \nThus, the course of 1-year treatment is a predictive indicator for \nlong-term treatment adherence.\nAuthors contributors\nF . La Torre, S. Vannuccini and F . Petraglia were involved in the \nstudy conception and design. F . Toscano, E. Gallucci, G. Orlandi \nand V . Manzi carried out the surveys and collected the data.  \nF . La Torre and S. Vannuccini performed the statistical analysis. \nF . La Torre and S. Vannuccini performed the drafting of the \nmanuscript. All authors were involved in critically revising the \nmanuscript for its intellectual content, and the final approval of \nthe manuscript was performed by all authors.\nDisclosure statement\nNo potential competing interest was reported by the authors related to the \npresent study.\nFunding\nThe author(s) reported there is no funding associated with the work featured \nin this article.\nData availability statement\nThe data that support the findings of this study are available from the corre -\nsponding author (F .P) upon reasonable request.\nReferences\n [ 1] Bulun SE, Yilmaz BD, Sison C, et  al. Endometriosis. Endocr Rev. \n2019;40(4):1–7. doi: 10.1210/er.2018-00242.\n [ 2] Vannuccini S, Reis FM, Coutinho LM, et  al. Surgical treatment of endo -\nmetriosis: prognostic factors for better quality of life. Gynecol Endocrinol. \n2019;35(11):1010–1014. doi: 10.1080/09513590.2019.1616688.\n [ 3] Saunders PTK, Horne AW . Endometriosis: etiology, pathobiology, and \ntherapeutic prospects. 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