{"paper_id":"6cf8c96f-ea09-41f1-8bee-c2a1fa8e429d","body_text":"Endometriosis, a chronic disease, is defined as the presence of functional endometrial mucosa outside the uterine\ncavity, often in the pelvis, but also more rarely in locations\nsuch as the pericardium, pleura cavity and even in the\nbrain tissue. It is one of the most common benign gynecological diseases in pre-menopausal women. Symptoms\nof endometriosis re included pelvic pain, dysmenorrhea,\nperiovulatory pain, dyspareunia, dyschezia, dysuria and\ninfertility. Endometriosis affects approximately 5-10% of\nreproductive age woman, which equates to around 190\nmillion women worldwide, with prevalence peaking between 25 and 35 years of age ( 1 - 3 ).\nDespite of benign proliferative nature, endometriosis\nshares certain characteristics with neoplastic processes,\nincluding inflammatory state, invasion of adjacent tissues, induction of angiogenesis, and resistance to apoptosis ( 4 ).\nFurther research, new therapeutic options have come\nto the market. Subsequent of this improved knowledge,\nawareness of endometriosis has increased in the medical\ncommunities and the general population. Although therapeutic options have improved, one of the main problems\nhas been remained : correct diagnosis. According to the\nEuropean Society of Human Reproduction and Embryology (ESHRE) guidelines (2014), the gold standard endometriosis diagnosis is a combination of laparoscopy\nvisualization and histological confirmation subsequent:\nendometrial glands and/or stroma existence ( 5 ).\nThe laparoscopic surgery is defined as a gold standard\nfor diagnosis, while it is invasive and costly, and endometriosis remains undiagnosed ( 6 ).\nDespite of various therapeutic options for this condition, medical therapy is placed in the secondary stage\nafter surgical treatment , a gold standard ( 7 - 9 ).\nSeveral medical therapies aim to create a hypoestrogenic state in the endometriosis affected women Examples of\nthese treatments include gonadotropin-releasing hormone\nagonist (GnRHa), GnRH antagonist (GnRH-ant) and synthetic androgens ( 10 ).\nSince laparoscopy is often perceived as excessively invasive by patients, especially young women, it seems impractical as a first-line diagnostic tool. As a result, investigators have sought to identify non-invasive tools such\nas biomarkers for early diagnosis that might prevent or\ndelay the progression of endometriosis ( 7 ). However, a\nstudy in 2016 that tested various biomarkers for clinical\nreliability showed that none of the tested biomarkers had\na clinical reliability that was comparable to the current\ngold standard ( 8 ).\nOverall, the therapeutic approach for endometriosis\nmust be adapted individually for each patient, as age, fertility, desire to have children, family planning measures,\ndegree of pain and personal impairment and the mode of\naction and side effects of the medications vary from patient to patient. Above all, it is essential to weigh up the\nside effects of the preparations.\nThe aim of this study is to investigate whether the prevalence and the therapy patterns of endometriosis was different in 2010 and 2019.\n\nThis retrospective cross-sectional study was based on\ndata from the Disease Analyzer database (IQVIA), which\nincludes diagnoses, drug prescriptions, and basic demographic data obtained directly and in anonymous format\nfrom computer systems used in the practices of general\npractitioners and specialists. The database covers approximately 3% of all outpatient practices in Germany. Diagnoses, prescriptions, and the quality of reported data are\nmonitored by IQVIA on an ongoing basis. IQVIA uses\nsummary statistics from all doctors in Germany published\nyearly by the German Medical Association to determine\nthe panel design according to specialist group, German\nfederal state, community size category, and physician age.\nThis sampling method is appropriate for obtaining a representative database of general and specialized practices ( 11 ).\nThis study included girls and women (14 years\nor older) with at least one visit to one of the 136\nprivate gynecologist practices in Germany in 2010\nor 2019. The selection of the study samples from\nthe database is shown in the Figure 1. The first outcome of the study was the change in the prevalence\nof endometriosis diagnosis (ICD 10: N80) in the\nyear 2019 compared to 2010. The prevalence was\ndefined as the number of women diagnosed with endometriosis in the selected year divided by the total\nnumber of women with at least one visit in the same\nyear. The second outcome was the change in the\nendometriosis therapy prevalence as estimated for\nthree treatments: Dienogest (ATC: G03DB08), other Progestins than Dienogest (ATC: G03DA04), and Gonadotropin-releasing hormones (ATC: L02AE).\nThe therapy prevalence was defined as the number\nof women with at least one prescription of a defined\ndrug in the selected year divided by the total number of women with diagnosed with endometriosis in\nthe same year. Both prevalence analyses were also\ncalculated by age group (age 14-20 years, age 21-\n30 years, age 31-40 years, age 41-50 years, age >50\nyears).\nTotally, all data were analyzed using chi-squared\ntests for categorical variables and t tests for continuous variables. Chi-squared tests were used to compare endometriosis prevalence and the prevalence of\ndefined treatments. Analyses were carried out using\nSAS version 9.4 (SAS Institute, Cary, USA).\nSelection of study sample.\nGerman law allows the use of anonymous electronic\nmedical records for research purposes under certain conditions. According to this legislation, it is not necessary to\nobtain informed consent from patients or approval from a\nmedical Ethics Committee for this type of observational\nstudy that contains no directly identifiable data. Because\npatients were only queried as aggregates and no protected\nhealth information was available for queries, no institutional review board approval was required for the use of\nthis database or the completion of this study.\n\nThe present study included 346,249 girls and women\ndocumented in 2010 and 343,486 women documented in\n2019 who visited one of 136 gynecologist practices. In\ntotal, 1,830 women had a documented diagnosis of endometriosis in 2010 and 2,272 in 2019, resulting in a prevalence of 0.53% in 2010 versus 0.66% in 2019 (P<0.001).\nThe prevalence significantly increased from 2010 to 2019\nin all age groups investigated with the exception of the\ngroup aged 14-20 years ( Fig .2 ).\nPrevalence of endometriosis diagnosis in the gynecological practices in the Germany in 2010 and 2019.\nThe basic characteristics of our patients are displayed in\nthe Table 1. There were no significant differences between\n2010 and 2019 in terms of mean age (37.6 years vs. 37.1\nyears), history of hysterectomy (6.8 vs. 7.8%) and history of\nother surgical treatment for endometriosis (21.0 vs. 21.3%),\nrespectively. The most common endometriosis diagnosis was unspecified endometriosis (ICD-10: N80.9) with 59.5\nin 2010 vs. 61.3% in 2019, followed by endometriosis of\nthe uterus (ICD-10: N80.0), which occurred slightly less frequently in 2019 (13.3%) than in 2010 (16.9%).\nTable 2 shows the results of the treatment prevalence\nanalysis. The proportion of women with other Progestins\nthan Dienogest prescription has not changed significantly\nbetween 2010 and 2019 (8.4 vs. 8.3%, P=0.912). The proportion of endometriosis patients treated with Dienogest\nincreased significantly between 2010 and 2019 (18.1 vs.\n35.0%, P<0.001). Although this increase was observed in\nall age groups, the proportion of patients treated with Dienogest was highest in the youngest age group (60.4%)\nand lowest in women >50 years (15.6%). Gonadotropin-releasing hormones were prescribed rarely in both 2010\nand 2019, with a significant decrease in prescriptions by\n2019 (3.7 vs. 2.0%, P<0.001).\nBaseline characteristics of our patients\nData are presented as mean (SD) or n (%).\nMedication treatment of women diagnosed with endometriosis diagnosis in gynecological practices in the Germany in 2010 and 2019\nData are presented as n (%).\n\nThis retrospective study shows that the prevalence of\nendometriosis increased significantly between 2010 and\n2019. Furthermore, the proportion of endometriosis patients treated with Dienogest increased substantially between 2010 and 2019, while the proportion of women\nprescribed other Progestins than Dienogest and Gonadotropin-releasing hormones has not changed significantly.\nThe prevalence of women with endometriosis and those\nreceiving endometriosis therapy found in this study is\nlower than other studies, 0.53% and 0.66% vs. up to 10%,\nrespectively ( 12 ,  13 ). This significant difference in the\nprevalence is most likely due to the different layout of\nthese studies. Some studies include the general population, whereas others focus on women in a high-risk population, for example infertile women ( 13 ,  14 ). The prevalence given in the ESHRE guideline falls within the range\nof 2 to 10% ( 5 ), whereas the guideline of the Association\nof the Scientific Medical Societies in German ( 15 ) shows\na prevalence of 0.8% to 2%. Although prevalence differs\namong studies, most studies have two findings in common\n( 5 ,  15 ). First, there are a large number of patients with undetected endometriosis, which may result from misdiagnosis, non-diagnosis or incorrect coding of endometriosis.\nSecond, there is a general trend indicating that the overall\nprevalence of the disease is increasing over the years. This\ntrend may be influenced by new diagnosis standards and\nguidelines for the ICD-10 classification of endometriosis\nor the increased relevance and awareness of endometriosis over the last decade. The growing prevalence of endometriosis is a positive trend. Period pain is not seen solely\nas an incidental secondary symptom of menstruation, but\nmay be increasingly understood as a part of the pathology\nof endometriosis and used for diagnosis. In the majority\nof patients, the suspected diagnosis is made on the basis\nof a thorough history supported by clinical examination,\nincluding vaginal ultrasound and, less frequently, accompanied by MRI or laparoscopy ( 16 ).\nDrug therapy is not claimed to cure the condition, although is rather considered as a symptomatic and suppressive approach. The therapy need to be tailored individually to each patient in terms of its duration and side\neffects. In addition, a rapid recurrence of symptoms and\ndisease is observed when therapy is discontinued ( 9 ).\nThe essential principle of hormonal therapy for endometriosis is the induction of therapeutic amenorrhea ( 15 ). As\nseen in the study, Dienogest seem to be the treatment of\nchoice for most patients ( 17 ). A narrative literature review\nand expert commentary by Murji et al. ( 17 ) stated that Dienogest in a 2 mg doses presents an effective and tolerable\nalternative to surgical intervention for the long-term management of endometriosis, offering several important advantages over combined oral contraceptive pills. Studies\nhave provided evidence of the effectiveness of Dienogest\nin several respects. These effects showed that a 2 mg/day\ndose of Dienogest inhibits ovulation and downregulates\nproinflammatory cytokines, including IL-6 and IL-8, and monocyte chemoattractant protein-1 ( 17 ,  18 ). Another\nstudy showed that Dienogest has a direct inhibitory effect on aromatase expression in endometrial cells ( 19 ),\nwhile a further paper found that Dienogest may have the\nability to overcome Progestins resistance by directly increasing the Progestin receptor-B ( 20 ). The guideline for\nthe treatment of endometriosis by the AWMF states that\nDienogest reduces the pain associated with endometriosis\nby inducing decidualization and atrophy of endometriosis\nlesions, suppressing growth mediated by matrix metalloproteinases and inhibiting angiogenesis. To date, only\nDienogest and Gonadotropin-releasing hormones have\nbeen approved for hormonal therapy, in German-speaking countries (DGGG, OEGGG, SGGG) ( 14 ). The consensus-based recommendations for the treatment of endometriosis by the AWMF suggest Dienogest as a first-line\nsubstance only. Treatment with GnRH or other Progestins\nthan Dienogest is only suggested as a second-line therapy,\nwhich could explain the following: Comparing guidelines\nfrom 2010 and 2019, the recommendation for GnRH has\nchanged so that other substances such as Dienogest are\npreferred. This shift is due to the negative side effects of\nGnRH, which include hot flashes or metabolic abnormalities ( 15 ,  21 ). This study shows that the total number of\npatients treated with GnRH in 2010 and in 2019 was far\nbelow the number treated with Dienogest or other Progestins, at 3.7 and 2%, respectively, compared to 8.4 and\n8.3% respectively for other Progestins and 18.1 and 35%\nrespectively for Dienogest. GnRH caused a 4-6% decrease in the bone mineral density (BMD) after 24 weeks\nof treatment in comparison with a decrease of just 0.5-\n2.7% in the BMD in the women who were treated with\nDienogest without add-back therapy. While both drugs\ninduce a hypoestrogenic state that falls outside the recommended therapeutic window of 20-60 pg/mg this state is\nmore moderate level with Dienogest than with GnRH or\neven other Progestins ( 22 ).\nThis study has several limitations. Since endometriosis\ndiagnosis was based on the ICD codes and not on the biological data, the prevalence of endometriosis might have\nbeen underestimated. Furthermore, no information was\navailable on how endometriosis diagnoses were made, the\nsymptoms exhibited by patients, and how treatment responses were evaluated by gynecologists. Moreover, even\nif women included in this study were also treated in hospitals, we did not have access to the related data. The next\nlimitation is a lack of several variables which were not\ndocumented in the database used, which include smoking\nbehavior, alcohol use, family status, family history of endometriosis and other risk factors. Finally, we were able\nto analyze prescriptions for different drugs, but not laparoscopy, which as already mentioned is the gold standard\nin the treatment of endometriosis. The main strength of\nthis work was the number of patients and gynecologists\nincluded.\n\nThere were significant changes in the prevalence and medical therapeutic patterns of endometriosis between\n2010 and 2019, reflecting changes in therapy guidelines\nand possibly in diagnostic methods.","source_license":"CC0","license_restricted":false}