{"paper_id":"a7ac63d8-a9ab-4350-8e72-4d31cc4b29ca","body_text":"http://www.revistadechimie.ro REV .CHIM.(Bucharest)♦70♦ No. 4 ♦20191500\nThe Impact of Ulipristal Acetate (UPA) versus Dienogest on\nPain Related to Endometriomas Evaluated with Visual\nAnalogue Scale (VAS)\nROMINA MARINA SIMA 1 DRAGOS ALBU 2, ANTONIU CRINGU IONESCU 3, MIHAI DIMITRIU 3, MIHAI POPESCU 4,\nDANA-RODICA TOMESCU 4, RADU CHICEA 5, IULIANA CEAUSU 6, IOAN-IULIAN IORDACHE 7, MIRCEA-OCTAVIAN POENARU 1,\nALEXANDRA MATEI3, ALINA CALIN8*, LIANA PLES1\n1Carol Davila University of Medicine and Pharmacy, Department Obstetrics Gynecology, Bucur Maternity, St. John Hospital, 37\nDionisie Lupu Str., 020021, Bucharest, Romania\n2Carol Davila University of Medicine and Pharmacy, Maternal-Foetal and Reproductive Medicine Department, Medlife, 37\nDionisie Lupu Str., 020021, Bucharest, Romania\n3Carol Davila University of Medicine and Pharmacy, Department Obstetrics Gynecology, St Pantelimon Emergency Hospital, 37\nDionisie Lupu Str., 020021,Bucharest, Romania\n4Carol Davila, University of Medicine and Pharmacy, Department of Anesthesiology and Critical Care III, Fundeni Clinical\nInstitute, 37 Dionisie Lupu Str., 020021,Bucharest Romania.\n5University of Medicine and Pharmacy Lucian Blaga, Faculty of Medicine, 10Victoriei Blvd.,550024, Sibiu, Romania.\n6Carol Davila University of Medicine and Pharmacy, Department Obstetrics Gynecology, Dr. I. Cantacuzino Hospital, 37 Dionisie\nLupu Str., 020021, Bucharest, Romania\n7Department of Gynecology and Obstetrics, Saarland University Hospital, Kirrbergerstraße 100, 66421, Homburg, Germany\n8Dunarea de Jos University of Galati, 47 Domneasca Str, 800008, Galati, Romania\nVisual analogue scale (VAS) is a psychometric scale applied to measure subjective characteristics. The\npurpose of our study was to evaluate the efficiency of Ulipristal acetate (UPA) compared with Dienogest for\nendometriomas related pain using VAS. We performed a randomized study on women with symptomatic\nendometriomas. The study was realized between January 2016–December 2018. The patients were\nrandomized in two groups: Group A- that received UPA in doses of 5 mg daily for 12–13 weeks and Group B\nthat received 2 mg Dienogest for 12–13 weeks. Each group received de VAS (Visual Analogue Scale)\nquestionnaire before and after treatment.  70 women wereincluded in the study with 35 patients for each\ngroup. The age the mean age was 30.20 years.  For Numeric Rating Scale before treatment in the group with\nUPA the median value was 6 (CI= 5.26, 6.51) and for group B the median was 5 (CI= 5.13, 5.66). After\ntreatment for group A the median value was 4 (CI= 3.58, 4.29) and for group B the median value 4 (CI= 4.23,\n4.6).  For FRS before treatment in the group with UPA median value was 6 (CI= 5.87, 6.58) and for the group\nB median was 6 (CI= 6.16, 6.57). After treatment for group A the median value was 4 (CI= 4.12, 4.73) and\nfor group B the median value 5 (CI= 4.9, 5.06). The pain significantly improved for group A. (p< 0.05)\nVAS represent a good method to evaluate the quality of pain for patients with endometriomas. The UPA and\nDienogest treatment improve the VAS parameters with better results for UPA in the present study.\nKeywords: endometriosis, VAS, dienogest, ulipristal, pain\n*email:alina_calin@hotmail.com                                                                                             All authors contributed equally to the manuscript\nEndometriosis is represented by ectopic implants of\nendometrial cells that cause local inflammatory\nresponse[1]. The pathogenesis is controversial but it\nincludes altered immunity, aberrant endocrine signalling\nor genetic factors with six genomic regions affected[2].\nEndometriosis treatment is medical or surgical. The\nmedical classes used for endometriosis treatment are:\nnonsteroidal analgesics, gonadotropin-releasing hormone\n(GnRH), agonists hormonal contraceptives and aromatase\ninhibitors. There is a lack of data to prove that one treatment\nor combination is better than another. The treatment is\nguided by symptom severity, treatment efficacy,\nmedication side effects, contraceptive needs, costs, patient\npreferences and availability[3].\n It was observed that for women with pelvic pain\ncaused by endometriosis or for the ones who have\ncontraindications for combined estrogen-progestin\ncontraceptives, progestin-only represents a good treatment\noption. The most used progestins administered for the\ntreatment of endometriosis-related pain are medroxy-\nprogesteroneacetate norethindrone acetate and\nDienogest[4]. In recent systematic reviews about progestin\ntherapy for endometriosis Dienogest was superior to\nplacebo[5].\nProgesterone receptors antagonists were used in the\nearly 1990 by Philibert \net al as contraceptive drugs and\nnowadays there is produced a wide spectrum of similar\ndrugs with PR (progesterone receptor) agonist and\nantagonist effects[6]. Ulipristal acetate (UPA) is introduced\nand approved since 2009 for leiomyomas treatment and\ncontraceptive reasons by the EMA (European Medicines\nAgency) and in 2010 by FDA (U.S. Food and Drug\nAdministration). UPA is a dose dependent PR antagonist\nand agonist with impact on endometrium and\nmyometrium. It acts as PR antagonist with contraceptive\neffect, also inunique administration (emergency\ncontraception)[7]. Lately the therapeutic indication of UPA\nwereextended to endometriosis as well.\nThe therapeutic response for endometriosis use is\nrelated to symptoms reduction and quality of life\nimprovement. For quality of life and evaluation there are\nmany standard questionnaires. Among those visual\n\nREV .CHIM.(Bucharest)♦70♦No. 4 ♦2019 http://www.revistadechimie.ro 1501\nanalogue scales (VAS) are psychometric scales applied to\nmeasure subjective characteristics. At the beginning they\nwere used for different types of disorders, and for research\nand social investigationspurpose[8]. We performed a\nrandomized study about the efficiency of UPA compared\nwith dienogest for endometriomas related pain using VAS.\nExperimental part\nA randomized study was conducted on women with\nsymptomatic endometriomas. The study is multicentre\ncentre study, extended between January 2016–December\n2018. Ethical approval and patient’s informed consent for\ntreatment and study were obtained.\nThe study included women with symptomatic\nendometriomas that received conservative management.\nTransvaginal ultrasound was performed by two\nexperienced sonographists and the endometriomas were\nmeasured and mapped. It was considered only the largest\ndiameter of the endometrioma and in order to reduce\nbiasses the same doctor evaluated the same patient at\nthe beginning and at the end of the treatment.\nThe inclusion criteria were: women with symptomatic\nendometriomas, that involved one or both ovaries, the\nendometriomas dimension under 5 cm and patients that\nagreed with the study. Exclusion criteria were: patients\nwho didn‘t accept the study, other types of endometriosis\nsuch as deep infiltrative endometriosis, endometriomas\nwith diameters over 5 cm that had indication for surgical\napproach.\nA randomized controlled study was designed. The\npatients were randomized from the beginning in two\ngroups: Group A- that received UPA in doses of 5 mg daily\nstarting with the first or second menstrual day for 12-13\nweeks and Group B that received 2 mg Dienogest starting\nwith the first or second menstrual day for 12-13 weeks.\nEach group received de VAS (Visual Analogue Scale)\nquestionnaire before and after treatment.\nThe randomization was made according to seal\nenvelope method. The patient signed the inform and then\nthe patient selected a sealed envelope from a pile opened\nit in front of the person that was in charge for recruiting\npatients for the trial.  Then the patient was distributed in\none of the categories. The physicianshow performed  the\nultrasound scan were blinded. Patients were informed\nabout their treatment and signed the informed consent.\nThe statistician was informed that there were 2 groups: A\nand B. He did not have any information regarding the patient\ntreatment.  At the end of the treatment courses the patients\nwere examined by ultrasound and filled VAS questionnaire.\nStatistical analysis was carried out with Statistical\nPackage for Social Sciences (SPSS)Software 25.0. The\ndifferences between the treatment groups were evaluated\nby One W ay ANOVA and t-test. Data were expressed as\nmean ± standard deviation (std dev). Pearson’s correlation\nwas used as appropriate and two-sided \np-values of <0.05\nwere considered to indicate statistical significance.\nResults and discussions\nA group of 70 women was randomized in our study with\n35 patients for each group. The main group characteristics\nfor the entire study group are illustrated in Table 1. The age\nof the patients included in the study group varied between\n18 and 42 years, the mean age being 30.20 years.  Clincial\nsymptoms severity, timing and all other significant\ninformation related to endometriosis were obtained.\nHistory of each patient was obtained and it revealed that\n54.3% of the patients from the whole study group had\nprevious surgical interventions for endometriosis. The main\ncomplains were dyspareunia, dysmenorrhea as reported\nin Table 1. Overall the patients described an altered quality\nof life dueto endometriosis symptoms but it improved in\n74.3 % cases after treatment. For UPA group 80% patients\nadmitted that quality of life improved whereas 68.6%\npatients from Dienogest group described such association.\nAll the patients underwent ultrasound examination.\nRegarding endometriomas distribution it was observed\nthat 37.1 % involved the right ovary, 42.9 % affected the left\novary and 20% were bilateral. It was identified that before\ntreatment the mean endometrioma dimension was 3.63\ncm and decreased to the mean dimension of 3.49 cm (p<\n0.001) for the entire study groups. Endometriomas\ndimensions diminutionafter UPA and Dienogest treatment\n(p< 0.001) isdetailed in table 2.\nTable 1\nTHE STUDY GROUP CHARACTERISTICS\n\nhttp://www.revistadechimie.ro REV .CHIM.(Bucharest)♦70♦ No. 4 ♦20191502\nThe main purpose of the present study was to\ncharacterize the pain associated to endometriomas. To\nthe first point of the scale (Option 1) with 10 points for \nno\npaint and 0 points for worst pain ever it is observed from\nimages 1 (a and b) the characteristics of pain before and\nafter treatment. Before treatmentin the group with UPA\nthe median value was 4 (CI= 3.75, 4.64) and for the group\nB the median was 5 (CI= 4.22, 4.97). After treatment for\ngroup A the median value was 6 (CI= 5.33, 6.28) and for\ngroup B the median value 6 (CI= 5.38, 5.93). The pain\nsignificantly improved for group A(p< 0.001) (fig.  1 a,  b).\nfor \nno pain  it is observed from images 3 (a and b) the\ncharacteristics of pain before and after treatment. Before\ntreatment in the group with UPA the median value was 6\n(CI= 5.26, 6.51) and for group B the median was 5 (CI=\n5.13, 5.66). After treatment for group A the median value\nwas 4 (CI= 3.58, 4.29) and for group B the median value 4\n(CI= 4.23, 4.6). The pain significantly improved for group A\n(p< 0.001) (fig.  3 a,b).\nFor the fourth point of the scale (FRS-F ace Rating Scale)\nwith 10 points for \nhurts and 0 points for no hurt it is observed\nfrom images 4 (a and b) the characteristics of pain before\nand after treatment. Before treatment in the group with\nUPA median value was 6 (CI= 5.87, 6.58) and for the group\nB median was 6 (CI= 6.16, 6.57). After treatment forgroup\nA the median value was 4 (CI= 4.12, 4.73) and for group B\nthe median value 5 (CI= 4.9, 5.06). The pain significantly\nimproved for group A (p< 0.001)(fig. 4 a,b).\nFunctional Activity Score (FAS) was also evaluated\nbefore and after treatment. It can be observed from Table\n3 that there was significant improvement of activity\nbecause of endometriosis treatment. The group A had mild\nlimitation of activity in 88.6% cases and 11.4% cases before\nUPA administration. For group B the limitation of activity\nwas severe for 85.7% cases and mild for 14.3% cases and\nafter Dienogest administration the limitation was severe\nTable 2\n THE DIMENSION OF\nENDOMETRIOMAS BEFORE AND\nAFTER TREATMENT\nFig. 1 (a, b): Option 1 before and after treatment\nFor the second point of the scale (Option 2) with 10\npoints for worst pain ever  and 0 points for no paint it is\nobserved from images 2 (a and b) the characteristics of\npain before and after treatment. Before treatment in the\ngroup with UPA the median value was 6 (CI= 5.29, 6.18)\nand for group B the median was 6 (CI= 5.11, 5.85). After\ntreatment for group A the median value was 4 (CI= 3.6,\n4.39) and for group B the median value 5 (CI= 4.26, 4.93).\nThe pain significantly improved for group A (p< 0.001)(fig.\n2 a, b).\nFor the third point of the scale (NRS-Numeric Rating\nScale) with 10 points for \nworst possible pain and 0 points\nFig. 2 (a, b): Option 2 before and after treatment\n\nREV .CHIM.(Bucharest)♦70♦No. 4 ♦2019 http://www.revistadechimie.ro 1503\nfor 68.6% and remained severe for 31.4% cases. Overall\nthe treatment improved the activity  for patients with\nendometriosis but UPA was more efficient in this study\n(table 3).\nVAS was first introduced in 1921 and it was initiated as\na \ngraphic rating method  [9]. It is considered that the main\nadvantage of this method is that it offers the possibility to\nevaluate detailed subtypes of judgement of the patient. It\nalso requires the patient hand-eye coordination and visual\nability[10]. The most important disadvantage is that it can\nbe used in written (or digital) format and not for oral\ninterviews and considerable effort for data entry and\nstatistical analysis [11].This is the first study that compare\nthe therapeutic effect of UPA and Dienogest in\nendometriosis related symptoms evaluated using VAS. In\nthe present study we observed that overall both UPA and\nDienogest ameliorate the pain for patients with\nendometriomas. There are significant changes regarding\ndysmenorrhea (from 72.9 to 27.1%), dyspareunia (from\n71.4 to 28.6%) and quality of life improvement dyspareunia\n(from 74.3 to 25.7%). The parameters of VAS suffered\nsignificant changes after treatment. It was identified that\nUPA and Dienogest improved pain with impact on numeric\nFig. 3 (a, b): NRS before and after treatment\nFig. 4 (a, b): FRS before and after treatment\nTable 3\nFAS SCORE BEFORE AND AFTER\nTREATMENT\nrating scale and face rating scale, but UPA results were\nsuperior to Dienogest results. The pain significantly\nimproved for group A. (p< 0.05)\nThe purposes of endometriomas treatment are to\nremovethe symptoms as pain, to reduce the tumor\ndimensions, to improve subfertility or to avoid and prevent\ncomplications such as the cyst rupture or torsion. It was\nobserved that medical therapy did not resolve\nendometriomascompletely[12]. Symptomatic or rapidly\nincreasing endometriomas are treated laparoscopically. It\nwas proved that laparoscopy improves the quality  of life\nand sexual function after different procedures in pelvic area\nsuch myomectomy[13] and for all types of endometriosis\nwith laparoscopic approach [14,15]. The most important\ndisadvantage of endometriomas surgical removal is that\nthe ovarian reserve diminish with each procedure. For\novarian protection reserve, asymptomatic and small\novarian endometriomas (≤ 5 cm) can benefit from medical\napproach [16].\nEstrogen expresion suppression and progesterone\nreceptors activation represent the essential target for\ncurrent  drugs, and also for research and new drugs\ndevelopment. The most used and studied agents for\n\nhttp://www.revistadechimie.ro REV .CHIM.(Bucharest)♦70♦ No. 4 ♦20191504\nendometriosis treatment are oral GnRH antagonists,\naromatase inhibitors SERMs (Selective Estrogen Receptors\nModulators) and SPRMs [17-19]. UPA is generally prescribed\nfor conservative treatment of fibroids to preserve fertility.\nUPA was approved treatment for uterine fibroids since\n2012. The action on the myometrium are antiproliferative,\nantifibrotic and proapoptotic with reduction a fibroid\nvolume reduction to up 45%[20]. UPA effect is safe for\nendometrium[21].\n The clinical effects of Dienogest for endometriosis\ntreatment are reported in different studies and it was\nobserved that it reduces the size of endometriomas and\ndetermine symptome relief for women with\nrecurrent endometriosis [22]. Dienogest is efficient and\nsafe for management of endometriosis associated pelvic\npain[23] and avoidpain recurrence post surgery.\nDienogest is well tolerated and side effects can be\nclinically managed [24]. V aginal treatment with dienogest\nis innovative for symptomatic deeply infiltrating\nrectovaginal endometriosisand should receive further\ninvestigation in pharmacokinetic and clinical studies [25].\nOn the ovary, Duphaston and Dienogest are effective\nprogestins that can be used as oral contraceptivewith\ndifferent ovulation inhibitory effects [26,27]. The ovulation\ninhibitory effect induced by Dienogest could be reverse\nrapidly by stopping treatment [28,29]. Studies\ndemonstrated the beneficial effect on pain generated by\ncyst endometrioma[30] . Side effects of progestin are\nrepresented by irregular uterine amenorrhea (dienogest),\nmood changes (depression) weight gain, and bone\nloss[31].\nUPA and Dienogest are proved to be effective as anti-\nendometriosis drugs inducing apoptosis and reducing\nproliferation and adhesions.  UPA and Dienogest are very\nwell tolerable by the patient. For Dienogest use endometrial\nglandular hyperplasia was described and, follicle\naccumulation for UPA[32]. Ulipristal acetate can control\nirregular bleeding by inducing amenorrhea while Dienogest\nmay cause irregular uterine bleeding[33,34].\nThis study is a pilot research that compares the effects\nof UPA versus Dienogest insymptomatic patients with\nendometriomas evaluated by VAS. The strength of our study\nis represented by the accuracy of the protocol with good\napplicability before and after treatment. The limitation of\nthe study is the reduced number of patients.\nConclusions\nVAS represent a good method to evaluate the quality of\npain for patients with endometriomas. The UPA and\nDienogest treatment improve the VAS parameters with\nbetter results for UPA in the present study. Further research\nis needed aiming also other administration ways (vaginal)\nand on larger patients cohorts to asses the benefits and\nthe safety of UPA in endometriosis.\nAcknowledgement:This work was supported by University of\nMedicine and Pharmacy Carol Davila a project number 5781/08.03.2018\nReferences\n1.GIUDICE LC. Clinical practice. Endometriosis. N Engl J Med 2010;\n362:2389.\n2.RAHMIOGLU N, NYHOLT DR, MORRIS AP , ET AL. Genetic variants\nunderlying risk of endometriosis: insights from meta-analysis of\neight genome-wide association and replication datasets. Hum\nReprod Update 2014; 20:702.\n3.DUNSELMAN GA, VERMEULEN N, BECKER C, et al. ESHRE\nguideline: management of women with endometriosis. 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