{"paper_id":"3fd40daf-e2ea-4eb2-83f3-b1450249897a","body_text":"Mitchell et al. BMC Women’s Health  2023, 22(1):526 \nhttps://doi.org/10.1186/s12905-022-02122-0\nRESEARCH\n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nOpen Access\nBMC Women’s Health\nProgestins in the symptomatic management \nof endometriosis: a meta-analysis on their \neffectiveness and safety\nJon‑Benay Mitchell1, Sarentha Chetty1* and Fatima Kathrada2 \nAbstract \nBackground Endometriosis is a complex chronic disease that affects approximately 10% of women of reproductive \nage worldwide and commonly presents with pelvic pain and infertility.\nMethod & outcome measures A systematic review of the literature was carried out using the databases Pubmed, \nScopus, Cochrane and ClinicalTrials.gov in women with a confirmed laparoscopic diagnosis of endometriosis receiv‑\ning progestins to determine a reduction in pain symptoms and the occurrence of adverse effects.\nResults Eighteen studies were included in the meta‑analysis. Progestins improved painful symptoms compared to \nplacebo (SMD = −0.61, 95% CI (−0.77, −0.45), P < 0.00001) with no comparable differences between the type of \nprogestin. After median study durations of 6–12 months, the median discontinuation rate due to adverse effects was \n0.3% (range: 0 − 37.1%) with mild adverse effects reported.\nConclusion The meta‑analysis revealed that pain improvement significantly increased with the use of progestins \nwith low adverse effects.\nSystematic Review Registration PROSPERO CRD42021285026.\nKeywords Endometriosis, Progestins, Pain relief, Adverse effects\nBackground\nEndometriosis is a chronic condition defined by the pres-\nence of endometrial-like tissue outside the uterus in the \novaries, the rectovaginal septum, and the pelvic peri -\ntoneum [1]. The disease occurs globally and more com -\nmonly affects women of reproductive age, causing a \nsignificant impact on quality of life [2]. The presentation \nof endometriosis ranges from lesions within the pel -\nvic cavity to extra pelvic lesions. Endometriotic lesions \nwithin the pelvic cavity vary from superficial lesions to \ndeep endometrial lesions which may be accompanied \nby scarring and adhesions. Extra pelvic endometriotic \nlesions invade the respiratory tract including the nasal \nmucosa and lungs, the gastrointestinal tract and abdomi -\nnal wall, the urinary tract, as well as the diaphragm, \npleura, pericardium, inguinal canal, cervix, vagina, vulva, \nand central nervous system [3].\nThe pathogenicity of endometriosis includes trans -\nplantation of endometrial tissue through retrograde \nmenstruation, coelomic metaplasia of the peritoneal \nlining, and lymphatic and vascular metastasis particu -\nlarly in extra pelvic lesions, however, the most widely \naccepted theory is retrograde menstruation [4]. Steroid \n*Correspondence:\nSarentha Chetty\nSarentha.Chetty@wits.ac.za\n1 Division of Pharmacology, Department of Pharmacy and Pharmacology, \nFaculty of Health Sciences, University of the Witwatersrand, \nJohannesburg, South Africa\n2 Division of Clinical Pharmacy, Department of Pharmacy \nand Pharmacology, Faculty of Health Sciences, University \nof the Witwatersrand, Johannesburg, South Africa\n\nPage 2 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nhormone-sensitive endometrial cells and tissues are \ndeposited on the peritoneal surfaces, causing an inflam -\nmatory response. This reaction has been found to co-\noccur with adhesions, angiogenesis anatomical (tubal) \nalterations, fibrosis scarring, and neuronal infiltration, \nresulting in pain and infertility [1]. In an attempt to iden -\ntify new biomarkers in endometriosis, a recent study \nevaluating metabolomics highlighted new insights into \nthe pathophysiology of the disease highlighting changes \nin the metabolic profile of such patients with increases in \nβ-hydroxybutyric acid and glutamine metabolites and a \ndecrease in tryptophan as promising potential biomark -\ners [5]. Another study outlined new insights into the \npossible relationship between the host microbiome and \nendometriosis which could serve as possible targets for \npreventative and therapeutic therapy if a strong link is \nconfirmed [6].\nEndometriosis affects approximately 6–10% of women \nof reproductive age [7]. Ghiasi, Kulkarni, and Missmer \nin 2020 [8], conducted a review of the global prevalence \nof endometriosis between January 1989 and June 2019. \nAmongst the 28 research papers that reported preva -\nlence, 17 provided prevalence estimations in women with \ninfertility, showing a total prevalence of endometriosis \nof 27%. Likewise, 11 studies looked at the prevalence \nof endometriosis in females presenting with persistent \npelvic pain, showing a 29% overall prevalence of endo -\nmetriosis. Twelve studies looked at the prevalence of \nendometriosis in patients who have had a hysterectomy, \novarian cancer, and tubal sterilization and reported a \nprevalence of 16%, 10%, and 5% respectively. This study \nalso reported the range prevalence of endometriosis in \ndifferent geographical regions. In Africa, the prevalence \nranged from 0.2 to 48%, and in Australia, the range was \n3.4–3.7%. The prevalence estimation ranges were much \nlarger in America, Asia, and Europe, being 0.7–70%, \n1–72%, and 0.8–70% respectively. A large limitation of \nthis review is the complexity of endometriosis diagnosis, \ncreating challenges in defining a true population preva -\nlence [8].\nA variety of risk factors have been suggested but due \nto the limited knowledge of the initiation processes of \nendometriosis and the lack of early detection, a distinct \ndiscernment between causation and consequence cannot \nbe made. Women with a short menstrual cycle interval, \nlow body mass index, low parity, early age at menarche \nand family history of endometriosis have been reported \nto have an increased risk of developing endometriosis \n[9, 10]. More recent evidence from a systematic review \nby Shigesi et  al. in 2019 [11], suggests that there is an \nincreased risk of autoimmune diseases among women \nwith endometriosis. The study found that systemic lupus \nerythematous, Sjogren’s syndrome, autoimmune thyroid \ndisease, coeliac disease, rheumatoid arthritis, multi -\nple sclerosis, inflammatory bowel disease and Addison’s \ndisease increased the risk for developing endometriosis, \nhowever, the studies were of low quality [11]. The varying \nstudy populations and low diagnostic precision among \nthe various studies create a challenge in quantifying the \nrisk factors associated with endometriosis [9].\nThere are multiple classification systems of endo -\nmetriosis that were developed by several professional \norganisations, mainly based on lesion appearance, pel -\nvic adhesions, and anatomic location of the disease [12]. \nThe revised American Society for Reproductive Medi -\ncine (rASRM) classification system is the most widely \nused worldwide and is based on intraoperative findings. \nIt includes one to four stages to quantify the number of \nlesions and depth of infiltration (Table  1). The ENZIAN \nclassification system is used as a supplementary tool to \nthe rASRM to provide a morphological classification of \ndeep infiltrating endometriosis [13].\nThe gold standard for diagnosis in the past was lapa -\nroscopic identification with histological verification, \nhowever, transvaginal ultrasonography and magnetic \nresonance imaging are also currently accepted as the pri -\nmary diagnostic tools. These methods have the advantage \nof being less invasive. Other disadvantages associated \nwith laparoscopy are the increased risks and costs asso -\nciated with surgery and the limited number of skilled \nspecialists in endometriosis excision technique. Accord -\ning to a systematic review conducted in 2019, less inva -\nsive tests show promising diagnostic potential, however, \nfurther research is required before they can be used in \na clinical setting [14]. The average interval between the \nonset of pain and a definitive diagnosis is 10.4 years [1]. \nIn a study conducted by Bontempo and Mikesell in 2020 \n[15], it was found that 75.2% of patients reported being \nmisdiagnosed with another physical or mental health \nproblem. Endometriosis remains a serious disease that \npresents complex diagnostic challenges, including non-\nspecific symptoms, symptom normalisation, lack of \nTable 1 Classification of endometriosis into one of four stages \nbased on a scoring system [12]\nStages Score Characteristics of lesions\nI (Minimal) 1–5 Minimal with few superficial implants\nII (Mild) 6–15 Mild with deeper implants\nIII (Moderate) 16–40 Moderate with many deep implants\nSmall cysts on one or both ovaries\nFilmy adhesions present\nIV (Severe) > 40 Severe with many deep implants\nLarge cysts present on one or both ovaries\nDense adhesions present\n\nPage 3 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nawareness amongst the population, and stigma associ -\nated with the disease [10].\nPain is one of the most common symptoms of endo -\nmetriosis, however, this is not an indicator of the sever -\nity of the disease and there are a variety of symptoms \ndepending on the location of the endometriomas. Ade -\nquate knowledge regarding the signs and symptoms of \nendometriosis aids in the early detection and diagnosis \nof the disease [16]. In a qualitative, interview-based study \nconducted by Fauconnier et al. [16], five classifications of \nexcruciating symptoms due to endometriosis was iden -\ntified. These include “severe pelvic pain and dysmenor -\nrhoea, dyspareunia, gastrointestinal symptoms, bladder \nsymptoms, such as dysuria, and other symptoms, which \nincluded physical and psychological impairment of daily \nactivity, difficulties in daily life and work activities as well \nas impairment of the participant’s sexual life and their \nrelationship with their partner” (p2689) [16]. These cat -\negories consist of distinct symptoms comprising of pain -\nful menstruation, paralyzing pain that affects mobility, \nlower abdominal pain, sharp pain during intercourse, \npain on passing stool, bloating, nausea, vomiting, feeling \nthe need to urinate often, extreme exhaustion, dizziness, \nand fainting as well as pain radiating towards the patient’s \nbreasts or shoulders, amongst many others. The symp -\ntoms reported by the participants to be the most ‘severe’ , \n‘incapacitating’ , and ‘getting worse with time’ was pelvic \npain and dysmenorrhoea [16].\nManagement of endometriosis includes both phar -\nmacological therapy and/or surgical intervention aimed \nat symptomatic relief of pain, improving quality of life \n(QoL), delaying recurrence, and preserving fertility. The \nchoice of therapy depends on patient factors, cost, extent \nand location of disease, patient preferences, and previous \ntreatment. Medications indicated for the management \nof endometriosis include either hormonal therapy (com -\nbined oral contraceptives, GnRH agonists, aromatase \ninhibitors, and danazol) or pain therapy (NSAIDs) with \nhormonal therapy not indicated in women who wish \nto conceive [1]. Surgical excision of endometriomas \nimproves fertility however expert technique is required \nto reduce the risk of complications and morbidity associ -\nated with surgery, particularly in deep infiltrating endo -\nmetriosis [17]. Among the hormonal therapy indicated in \nthe treatment of endometriosis are progestins. Progester-\none is a steroid hormone predominantly produced in the \novaries, adrenal glands, and placenta. This hormone has \nan important role in inhibiting the proliferation of the \nendometrium and stimulating tissue remodelling until \ngestation or menstruation. Progestin is a synthetic form \nof progesterone designed to imitate its action. Progestins \nwere reported to have decreased or eradicated painful \nsymptoms in roughly 90% of patients with endometriosis \n[7]. Different forms of progestins are widely used in the \ntreatment of endometriosis and are available in differ -\nent dosages. They are available in the following dosage \nforms: oral, injectable, intrauterine devices, transdermal \npatches, vaginal rings as well as subcutaneous implants \n[18].\nThe fundamental mechanism by which endometrio -\nsis occurs is still unknown, therefore, the exact mecha -\nnism whereby progestins control pain is unknown. \nThere are, however, three main mechanisms proposed \nand these include: (1) the result of active haemorrhaging \nfrom endometriotic abrasions; (2) the overexpression of \ngrowth factors and pro-inflammatory cytokines, and (3) \nthe inflammation or direct attack of pelvic nerves. Pro -\ngestin has inhibitory effects on growth factors and angio -\ngenesis, anti-inflammatory actions as well as the ability \nto induce anovulation. Progestins inhibit gonadotropin-\nreleasing hormone, which in turn suppresses follicular-\nstimulating hormone and luteinizing hormone secretion \n[7]. As mentioned above, endometriosis occurs in the \npresence of oestrogen, however, when progestins are pre-\nsent, it prevents oestrogen-dependent proliferation of the \nendometrium [19].\nThe primary progestins used in the symptomatic treat -\nment of endometriosis include dienogest, medroxypro -\ngesterone acetate, norethisterone, and cyproterone which \nare oral forms of the drug that have been found to have \nan effective role in decreasing endometriosis-related \npelvic pain, controlling excessive uterine bleeding, and \nimproving patient quality of life. Depot medroxyproges -\nterone acetate and the levonorgestrel intrauterine system \nare effective in the suppression of endometriosis-related \nsymptoms [7]. A new approach to pain relief in endome -\ntriosis patients is the etonogestrel subdermal implant. \nThis drug is well-tolerated and safe to use [11]. Bloating, \nweight gain, hot flushes, acne, loss of libido and fatigue \nare commonly reported side effects of progestins with \nless common reports of mood swings and depression [7].\nEndometriosis is a chronic disease that is under-\nresearched, under-reported, and underdiagnosed [20]. \nA qualitative descriptive study that was conducted \nusing focus group discussions in Australia conducted \nby Moradi et  al. provides comprehensive experiences of \nwomen that are living with endometriosis [20]. All the \nwomen in this study suffered from severe and progres -\nsive pain both cyclical and non-cyclical and presented \nwith other non-specific symptoms such as exhaustion, \ndiarrhoea, and sleep disturbances. The study participants \nreported that the medical experts arbitrarily dismissed \ntheir symptoms as insignificant due to their non-specific \nnature and link to the menstrual cycle [20]. The debili -\ntating nature of the disease has a significant impact on \nthe psychological well-being of the patient, leading to \n\nPage 4 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nabsenteeism from school or work and overall poor QoL \n[20]. Even though endometriosis impacts patient QoL, \nrecent studies have found that hormonal treatment, espe-\ncially progestins compared to combined oral contracep -\ntives, significantly improved participants’ QoL and led \nto a greater reduction in endometriotic lesions and pain \nsymptoms [21]. However, recurrence of pain symptoms, \nregardless of the type of hormonal therapy, following \ncessation of therapy is common and chronic therapy is \nrequired [17].\nThe treatment of endometriosis-associated pain \nfocuses on systemic or local oestrogen suppression, inhi -\nbition of tissue proliferation and inflammation or both \n[22]. Due to the complexity of the disease, treatment \nneeds to be modified and personalised based on the dis -\nease severity, symptoms as well as fertility goals of each \npatient. Some goals of treatment include egg preserva -\ntion, hormonal suppression, decreased recurrence, limit -\ning the amount of deformation of anatomical structures \nwhen performing surgery, as well as psychotherapy [22]. \nEndometriosis therapy requires a multimodal approach \nfrom experienced experts including experts in other \norgan systems that may be affected [10].\nGiven the high burden, high prevalence, multi-faceted \nimpact and rapid progression of the disease, increased \nattempts at improved awareness and education regarding \nendometriosis require emphasis to ensure early detection \nand intervention. Furthermore, training medical profes -\nsionals in the individualised therapeutic approach of \nendometriosis taking all patient factors into account are \nimperative for positive outcomes [23].\nMethods\nLiterature search\nUsing the Preferred Reporting Items for Systematic \nReviews and Meta-Analyses (PRISMA) guidelines [24], a \nreview was conducted on the efficacy and safety of pro -\ngestins. Four databases, Pubmed, Scopus, Cochrane and \nClinicalTrials.gov were searched for the relevant pub -\nlished literature - on clinical trials and observational \nstudies published between 1 January 2011 and 1 Janu -\nary 2021 using the following MeSH terms: “endometrio -\nsis” , “progestins” , “pain relief” and “adverse effects. ” The \nresults were compiled into a Mendeley Reference Man -\nager v1.19.6 library [25].\nRelevant articles were identified using PICO (popula -\ntion, intervention, comparison, outcome) as a starting \npoint for inclusion criteria.\nP - Woman with a validated diagnosis of endometriosis.\nI - Progestins\nC- Placebo/No treatment\nO - Primary outcome measure was pain improvement/\nreduction in pain intensity.\nSecondary outcome measure was the occurrence of \nadverse effects.\nInclusion criteria: Studies with women with a validated \ndiagnosis of endometriosis, and treatment with proges -\ntins were included. Observational (cohort studies) and \nexperimental (randomised controlled and uncontrolled \ntrials) studies were included in the study. The search \nwas restricted to research articles originally written in \nEnglish.\nExclusion criteria: Non-human (animal & in-vitro) \nstudies, case series and case reports were excluded. \nStudies that did not measure pain improvement as an \noutcome measure, included patients with extra pelvic \nendometriosis, and studies with asymptomatic partici -\npants were excluded.\nScreening of articles retrieved was independently car -\nried out by two reviewers (JM and YP), following a two-\nstep process. The first step was the screening of the titles \nand abstracts, followed by full-text screening using the \nPICO statement and predefined inclusion and exclusion \ncriteria. Discrepancies were resolved by discussion or \nbringing in a third reviewer (SC or FK).\nQuality evaluation\nThe CASP (Critical Appraisal Skill Program), due to its \nsuitability and usability in cohort study types, was used \nto appraise the quality of the observational studies [27]. \nThis appraisal tool consisted of 12 questions that cov -\nered three main issues in an observational study: (1) Are \nthe results of the study valid?; (2) What are the results? \nand (3) Will the results help locally? Most questions \nrequired a ‘yes’ , ‘no’ or ‘can’t tell’ as an answer, while oth-\ners required more detailed explanations.\nThe RoB 2.0 Cochrane Risk of Bias Tool for Ran -\ndomised Trials was used to appraise randomised con -\ntrolled trials (RCTs) [28]. This assessment consisted of 5 \ndomains with 3–7 questions each requiring a ‘yes’ or ‘no’ \nanswer. At the end of each domain, the bias is rated using \njudgement (high, low, unclear) based on domains (selec -\ntion, performance, attrition, reporting and others). The \nresults are summarized graphically in Fig. 2 [28].\nThe final systemic review was subjected to the PRISMA \nChecklist Tool [24] to ensure inclusion of all components \nfor a systematic review (Additional file 1)..\nData extraction\nThe following information was extracted from the arti -\ncles included: authors, publication year, study design, \nnumber of participants, interventions, comparisons, and \nstudy outcomes (pain improvement and adverse effects).\n\nPage 5 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nStatistics\nDescriptive statistics were used to summarise study char-\nacteristics. Review Manager (RevMan) Version 5.4.1, [29] \nwas used to perform the meta-analysis of the two-arm \nstudies. For the single-arm studies, the meta-analysis was \ncarried out using Comprehensive Meta-Analysis (CMA) \nVersion 3.3.070 [30] and the forest plot was created using \nStata Statistical Software Release 17 [31]. All funnel plots \nwere created in RevMan.\nRelative risk was used as the summary statistic for \ndichotomous data and mean difference (MD), or stand -\nardised mean difference (SMD) was used for the continu-\nous data. Standardised mean difference, 95% confidence \nintervals (CI), MD, effect size and heterogeneity were cal-\nculated using both the RevMan and CMA software. The \nI² was used to determine heterogeneity. A fixed-effect \nmodel was used when it was hypothesized that the effect \nwould be similar in every study; otherwise, a random-\neffect model was used. The random-effect model was \nuseful when comparing many studies to estimate the dis -\ntribution of effects. The random-effect model was used \nfor the analysis of the single-arm studies and the studies \nreporting adverse effects, while a fixed-effect model was \nused when analysing the studies comparing progestins \nand placebos as well as studies in which an etonogestrel-\nreleasing implant is compared to a levonorgestrel-\nreleasing intrauterine system. Statistical significance was \nattributed to P-values less than 0.05.\nIn the study conducted by Margatho et al. [32] in 2020 \nthe results were presented as Mean ± SE and the follow -\ning formula, found in the Cochrane Handbook for Sys -\ntematic Reviews of Interventions, was used to calculate \nthe SD (Eq. 1).\nEquation  1: Calculation to determine the standard \ndeviation (SD) from reported standard error (SE) [33].\nResults\nArticle inclusion\nIn the initial search, 266 relevant articles were retrieved, \nwith 166 articles remaining following the removal of \nduplicates. After reviewing the titles and abstracts, \n138 articles were excluded. Of the 28 full-text articles \nreviewed, 14 were excluded. The most common reasons \nfor exclusion were that the studies were done post-oper -\natively (n = 4), they compared the efficacy and safety of \nprogestins to other endometriosis treatment options \nsuch as gonadotropin-releasing hormone agonists and \ncombined oral contraceptives (n = 3), and some of the \nstudies were reviews (n = 5). A manual search of the ref -\nerence lists of the full-text articles was conducted and 19 \narticles were further retrieved and reviewed. Of these, 4 \nSD = SE ×\n√\nN\nstudies met the inclusion criteria. This process resulted in \na total of 18 articles included for analysis (Fig. 1).\nTable  2 summarises the study designs, participants, \nprogestins used and study outcomes of the final 18 stud -\nies included in this systematic review. Four studies were \nRCTs and 14 were observational studies.\nPublication bias\nThe Cochrane Collaboration’s risk of bias tool [17] was \nused to conduct a quality assessment of the RCTs (n = 4) \nreviewed in this study. The risk of bias graph (Fig.  2) was \ncreated using RevMan.\nEffect of progestin on pain improvement\nIn 12 articles, the visual analogue scale (VAS) was used to \nevaluate chronic pelvic pain in women with endometrio -\nsis. These articles were separated into 2 groups, studies \nin which progestins were compared to a placebo (n = 3) \nor a different progestin (n = 2) (Fig. 3), and studies which \nincluded no comparator (n = 7) (Fig. 4). The results were \nanalysed to determine the efficacy of progestins in reduc-\ning pelvic pain.\nAs seen in Fig.  3, progestins showed a statistically sig -\nnificant effect in improving painful symptoms caused \nby endometriosis (SMD=−0.61, 95% CI (−0.77, −0.45), \nP < 0.00001). The I² value of 92% suggests very high \nheterogeneity.\nThe asymmetry of the funnel plot for studies which \nincluded a comparator (Fig.  4) is attributed to the high \nheterogeneity of the studies.\nFigure 5 shows that there was no significant difference \nbetween the etonogestrel-releasing implant and the lev -\nonorgestrel-releasing intrauterine system (SMD=−0.10, \n95% CI (−0.37, 0.18), P = 0.48) in providing pain relief.\nThe corresponding funnel plot (Fig.  6) is symmetrical \nshowing that there is little to no bias, good methodologi -\ncal quality and low heterogeneity.\nAs seen in Fig.  7, the total MD is −2.60 with a 95% CI \n(−3.58, −1.62), proving that progestins are effective in \nimproving chronic pelvic pain caused by endometriosis. \nThe I² value of 99.45% indicates very high heterogeneity \nand the P < 0.00001 suggests that the results are statisti -\ncally significant.\nThe asymmetry of the funnel plot in Fig.  8 indicates \nthat there may be some publication bias. The high het -\nerogeneity demonstrates the differences in the interven -\ntions and methods used in the various studies.\nThe studies by Vercellini et  al. in 2016 [36] and 2018 \n[40] measured non-menstrual pelvic pain improvement \nusing a numerical rating scale (NRS). In the 2016 study \n[36] the severity of pain symptoms caused by endo -\nmetriosis was assessed by a 0 to 10-point NRS at base -\nline and after 6 months of treatment in women with \n\nPage 6 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nendometriosis. In the norethindrone acetate (n = 31) \nand the dienogest (n = 29) groups, the median (inter -\nquartile range) baseline NRS was 7 (6–7) and decreased \nto 0 (0–2) after 6 months. The 2018 study [40] produced \nsimilar results, where the median (interquartile range) for \nthe baseline NRS was 5 (0–7) and decreased to 0 (0–2) \nafter 12 months in the 125 participants using norethister-\none acetate. This indicates that progestins are effective in \nimproving painful symptoms caused by endometriosis.\nAdverse effects caused by progestins\nFifteen of the studies reviewed reported adverse effects. \nVercellini et  al. 2016 [36] reported adverse effects as a \nmean and not a percentage and were therefore excluded \nfrom the graph.\nFigure  9 depicts 3 forest plots for the most common \nadverse effects that occurred across the remaining 14 \nstudies that reported on adverse effects. All three adverse \neffects presented considerable heterogeneity and were \nstatistically significant. The subtotal risk ratio (95% CI) \nfor breakthrough bleeding, headaches and weight gain \nwas 0.13 (0.06, 0.32), 0.07 (0.02, 0.22) and 0.13 (0.04, 0.42) \nrespectively, indicating that there is a low risk that pro -\ngestins will cause the occurrence of an adverse effect.\nThe complete list of adverse effects and their percent -\nage of occurrence across the 14 studies are presented in a \ntable (Table 3).\nThe funnel plot (Fig.  10) asymmetry is due to the high \nheterogeneity in each subgroup. Publication bias is an \nunlikely cause, however, selective outcome reporting and \nanalysis reporting may be a cause for the asymmetry, due \nto the subjective nature of the responses in each study. It \ncould also be attributed to the varying methods used in \neach study.\nFig. 1 The PRISMA flow diagram, outlining the organization of the selection process through the different steps of the systematic review [26]\n\nPage 7 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nTable 2 Characteristics of the studies on the use of progestins for the symptomatic relief of endometriosis pain\nSource Study design Year\nof enrolment\nDescription \nof main \nsymptoms\nNumber \nof patients \nenrolled\nStudy drug Comparator Number\nof patients \ntreated with \nthe study drug\nNumber\nof patients \ntreated with \ncomparator\nTreatment \nperiod\nStudy outcomes\nPetraglia et al. \n[34]\nRandomised \nopen‑label, \nplacebo‑con‑\ntrolled trial\n2004–2007 Pelvic Pain 168 Dienogest \n2 mg/d\nPlacebo 87 81 52 weeks Pain improve‑\nment (VAS)\nAdverse effects\nMorotti et al. \n[35]\nOpen‑label pro‑\nspective trial\n2014 Pelvic Pain 25 Norethister‑\none acetate \n2.5‑5 mg/d\nDienogest \n2 mg/d\n25 25 6 months Adverse effects\nVercellini et al. \n[36]\nRetrospective \nand prospective \nstudy\n2012–2014 Pelvic Pain 180 Norethisterone \nacetate 2.5\nDienogest \n2 mg/d\n90 90 6 months Pain improve‑\nment (NRS)\nMorotti et al. \n[37]\nRetrospective \nstudy\n2004–2016 Pelvic Pain 103 Norethister‑\none acetate \n2.5‑5 mg/d\nN/A 103 N/A 60 months Pain improve‑\nment (VAS)\nAdverse effects\nMaiorana et al. \n[38]\nObservational, \nsingle‑centre \ncohort study\n2013–2014 Pelvic Pain 132 Dienogest \n2 mg/d\nN/A 132 N/A 12 months Pain improve‑\nment (VAS)\nAdverse effects\nRömer [39] Retrospective \nstudy\n2016 Pelvic Pain 37 Dienogest \n2 mg/d\nN/A 37 N/A 60 months Adverse effects\nVercellini et al. \n[40]\nProspective \nstudy\n2014 Pelvic Pain 153 Norethisterone \n2.5 mg/d\nN/A 153 N/A 12 months Pain improve‑\nment (NRS)\nAdverse effects\nSansone et al. \n[41]\nMulticenter \nprospective \nobservational \nstudy\n2016 Pelvic Pain 25 Etonogestrel \nimplant\nN/A 25 N/A 12 months Pain improve‑\nment (VAS)\nAdverse effects\nLang et al. [42] Randomised \ndouble‑blind, \nplacebo‑con‑\ntrolled trial\n2013 Pelvic Pain 255 Dienogest \n2 mg/d\nPlacebo 126 129 24 weeks Pain improve‑\nment (VAS)\nAdverse effects.\nYu et al. [43] Open‑label \nextension study\n2018 Pelvic Pain 220 Dienogest \n2 mg/d\nPlacebo 111 109 28 weeks Pain improve‑\nment (VAS)\nAdverse effects\nCarvalho et al. \n[44]\nOpen‑label \nparallel‑group, \nnon‑inferiority, \nrandomised \nclinical trial\n2016 Pelvic Pain 103 Etonogestrel \nimplant\n52 mg \nLevonorgestrel‑\nreleasing intrau‑\nterine system\n52 51 6 months Pain improve‑\nment (VAS)\nDel Forno et al. \n[45]\nRetrospective \nstudy\n2015 Pelvic Pain 135 Dienogest \n2 mg/d\nNorethister‑\none acetate \n2.5 mg/d\n69 66 12 months Adverse effects\n\nPage 8 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nVAS Visual analogue scale, NRS Numerical rating scale\nTable 2 (continued)\nSource Study design Year\nof enrolment\nDescription \nof main \nsymptoms\nNumber \nof patients \nenrolled\nStudy drug Comparator Number\nof patients \ntreated with \nthe study drug\nNumber\nof patients \ntreated with \ncomparator\nTreatment \nperiod\nStudy outcomes\nFerrero et al. [46] Retrospective \nstudy\n2019 Pelvic Pain 44 Etonogestrel \nimplant\nN/A 44 N/A 24 months Pain improve‑\nment (VAS)\nAdverse effects\nCho et al. [47] Prospective \ncohort study\n2011–2017 Pelvic Pain 3356 Dienogest \n2 mg/d\nN/A 3356 N/A 12 months Pain improve‑\nment (VAS)\nAdverse effects\nBarra et al. [48] Retrospective \nstudy\n2019 Pelvic Pain 83 Dienogest \n2 mg/d\nN/A 83 N/A 36 months Pain improve‑\nment (VAS)\nAdverse effects\nMargatho et al. \n[32]\nRandomised \ncontrol trial\n2016–2019 Pelvic Pain and \ndysmenorrhoea\n103 Etonogestrel \nimplant\n52 mg \nLevonorgestrel‑\nreleasing intrau‑\nterine system\n52 51 24 months Pain improve‑\nment (VAS)\nNirgianakis et al. \n[49]\nRetrospective \ncohort study\n2017–2018 Pelvic Pain 130 Dienogest \n2 mg/d\nN/A 130 N/A 36 weeks Pain improve‑\nment (VAS)\nAdverse effects\nKitawaki et al. \n[50]\nPost‑marketing \nobservational \nstudy\n2016–2017 Pelvic Pain 59 Dydrogesterone \n10 mg twice \ndaily\nN/A 59 N/A six 21‑day \ncycles\nPain improve‑\nment (VAS)\nAdverse effects\n\nPage 9 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nFig. 2 Risk of bias graph: a review of authors’ judgements about each risk of bias item presented as percentages across all RCTs.\nFig. 3 Forest plot of studies in which dienogest (2 mg/d) is compared to a placebo using the VAS to evaluate chronic pelvic pain\nFig. 4 Funnel plot for a meta‑analysis of the studies in which dienogest is compared to a placebo\n\nPage 10 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nFig. 5 Studies in which an etonogestrel‑releasing implant is compared to a levonorgestrel‑releasing intrauterine system\nFig. 6 Funnel plot for meta‑analysis of studies in which an etonogestrel‑releasing implant is compared to a levonorgestrel‑releasing intrauterine \nsystem\nFig. 7 Forest plot for the single‑arm studies using VAS to evaluate chronic pelvic pain\n\nPage 11 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nDiscussion\nAmong the approximate 10% of women presenting with \nendometriosis globally, about 80% experience chronic \npelvic pain [51]. In a condition with no cure, improve -\nment of pain is essential in improving disease outcomes \nand quality of life. Therapies with progestins are a more \nreliable option compared to the usually sought after \nNSAIDs which do not alter the disease course and are \nnot ideal for long-term use due to the adverse gastro -\nintestinal effects. Progestins, on the other hand, display \noestrogen suppressive effects useful in decreasing the \ngrowth of endometrial tissue and possess anti-inflamma -\ntory, anti-proliferative and anti-angiogenic effects appli -\ncable in the mechanisms associated with the course of \ndisease in endometriosis. Based on the existing literature, \nthis study reveals that progestins are an effective sympto-\nmatic therapy in patients with endometriosis.\nIn the 3 studies comparing progestins to placebos, the \nuse of progestins was associated with a positive reduction \nin pelvic pain in women with endometriosis. All 3 stud -\nies had a similar design with the use of 2 mg/day of dien -\nogest reporting pain outcomes using the same VAS scale. \nAll 3 studies also reported a favourable safety and toler -\nability profile, and a low rate of treatment-related dis -\ncontinuations over periods of up to 52 weeks. Although \nthe dienogest displayed de-synchronous uterine bleed -\ning effects in the short-term, the frequency and intensity \nof menstrual bleeding were reduced with long-term use \n(24–52 weeks), however, bleeding frequency and inten -\nsity returned on discontinuation of the drug, indicat -\ning the need for long-term use for a sustained beneficial \neffect. The studies done by Lang et al. (2018) [42] and Yu \net al. (2019) [43] were conducted in a Chinese population, \nwhile the study done by Petraglia et  al. (2011) [34] was \ndone on women in Germany, Italy, and Ukraine, indicat -\ning that the effects apply to both Caucasian and Chinese \npopulations. This highlights the need for further similar \nstudies in other population groups to ascertain if these \npositive outcomes apply to all population groups.\nIn a comparison between non-oral progestins, there \nwas no significant difference between the pain-relieving \neffects of the etonorgestrel subdermal implant compared \nto the levonorgestrel intrauterine system (LNG-IUS), \nwith both producing similar pain-relieving effects [32, \n44]. The implant and the intrauterine device provide the \noption of convenience in removing the daily pill burden, \nhowever, as seen in both studies, there was a large dis -\ncontinuation rate, many of which were due to uterine \nbleeding irregularities which highlight the need for larger \nscale studies in the long-term acceptability of these alter -\nnatives to oral progestins.\nIn the study by Vercellini et  al. (2016), the non-men -\nstrual pelvic pain associated with endometriosis was \ndiminished in both the norethindrone acetate (pre-study) \nand the dienogest (post study) groups, however, there \nFig. 8 Funnel plot for meta‑analysis of the single‑arm studies using VAS to evaluate chronic pelvic pain\n\nPage 12 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nwas no significant ameliorations in pain relief following \nthe introduction of dienogest [36].\nThe findings among the single-arm studies were con -\nsistent in showing a beneficial effect of progestins in \nproviding pain relief in patients with endometriosis \n(P < 0.00001). Of the 7 studies included in this analysis, 4 \nused dienogest, 2 used norethindrone acetate, 2 used the \netonogestrel implant and 1 used dydrogesterone. All four \nof these progestins significantly reduced the severity of \nnon-menstrual pelvic pain experienced by women with \nendometriosis and the adverse effects related to these \ndrugs was minimal and mild in nature. It must be noted \nhowever that these studies lacked a placebo or compara -\ntor group.\nOne of the most common adverse effects that occurred \ndue to progestin use across the studies was weight gain, \nwith 2 studies on norethindrone acetate, Morotti et  al. \n(2017) [37] and Del Forno et al. (2019) [45], and 1 study \non dienogest by Barra et al. [48] reporting a 30% occur -\nrence. Breakthrough bleeding, another common adverse \neffect occurred in 13 out of the 14 studies reviewed on \nreported adverse effects.\nThe majority of the studies included reported on oral \nprogestins, particularly dienogest and/or norethisterone \nwith a limited number of studies reporting on subdermal \nFig. 9 Forest plot showing the adverse effects caused by progestins that occurred most frequently across 14 studies. ‘AE’ represents adverse events \nand ‘No AE’ represents no adverse events\n\nPage 13 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nTable 3 Percentage of adverse effects experienced by participants across the studies reviewed\nSource Year Number \nof patients \nenrolled\nBreast \ndiscomfort \n% (n)\nNausea % \n(n)\nIrritability \n% (n)\nHeadaches \n% (n)\nBreakthrough \nbleeding\n% (n)\nWeight gain\n% (n)\nDecreased \nLibido\n% (n)\nDepression \n% (n)\nVaginal \ndryness \n% (n)\nAcne\n% (n)\nHair Loss \n% (n)\nPetraglia \net al.\n2012 168 4.2 (7) 3 (5) 2.4 (4)\nMorotti et al. 2014 25 4 (1) 8 (2) 16 (4) 20 (5) 8 (2) 4 (1)\nMorotti et al. 2017 103 8.7 (9) 23.3 (24) 30.1 (31) 10.7 (11) 6.8 (7) 4.8 (5)\nMaiorana \net al.\n2017 132 8.1 (11) 3.6 (5) 42.3 (56) 17.1 (23) 8.1 (11) 16.2 (22) 3.6 (5)\nRömer 2018 37 10.8 (4) 18.9 (7) 10.8 (4)\nVercellini \net al.\n2018 153 0.65 (1) 0.65 (1) 4.5 (7) 3.9 (6) 2.6 (4) 0.65 (1) 0.65 (1) 1.3 (2)\nSansone \net al.\n2018 25 12.5 (3)\nLang et al. 2018 255 7.9 (20)\nYu et al. 2019 220 1.8 (4) 0 (0) 1.8 (4)\nDel Forno \net al.\n2019 69 1.4 (1) 0 (0) 1.4 (1) 2.9 (2) 8.7 (6) 14.5 (10) 7.2 (5) 7.2 (5) 1.4 (1) 2.9 (2)\n66 7.6 (5) 0 (0) 7.6 (5) 3 (2) 21.2 (14) 30.3 (20) 18.2 (12) 10.6 (7) 1.5 (1) 0\nFerrero et al. 2020 44 23.3 (10) 7 (3)\nCho et al. 2020 3356 1.25 (42) 0.64 (22) 1.32 (45) 4.18 (141) 2.6 (88) 0.77 (26) 0.77 (26) 0.32 (11)\nBarra et al. 2020 83 21.2 (18) 26.9 (23) 30.1 (25) 2.8 (3) 9.6 (8) 1.9 (2)\nMargatho \net al.\n2020 103\nNirgianakis \net al.\n2020 130 15 (20) 8 (11) 31 (40) 20 (26) 19 (25) 33 (43) 10 (13) 6 (8)\nKitawaki \net al.\n2021 59 5.1 (3)\n\nPage 14 of 16Mitchell et al. BMC Women’s Health  2023, 22(1):526\nimplants and/or the LNG-IUS. There was homogeneity \nin the VAS score pain management tool used across the \nmajority of the studies, however, the treatment periods \nand sample sizes varied from 24 weeks to 5 years and 25 \nto 3356 respectively.\nIn addition to pelvic pain relief, many of the studies \nprovided consistent reports on the effects of progestins in \nrelieving dyspareunia which ultimately plays a major role \nin the quality of life in patients with endometriosis. The \nstudies included patients with all stages of endometrio -\nsis with no specific correlations being made in progestin \nresponses between the mild stages (I, II) and advanced \nstages (III, IV) of endometriosis to identify phenotypes \nwith possible poor response to progestins. Further large \nstudies aimed specifically at the staging and response to \nprogestins would be beneficial. No clear distinguishable \ndifferences can be drawn from the current studies con -\ncerning the effects of the treatment with progestins alone \nin comparison to the use of progestins following surgery \nto inform clinical practice guidelines.\nThe high heterogeneity in this review can be attributed \nto the differences between the methods of the included \nstudies. This review included observational studies and \nrandomised controlled trials which additionally contrib -\nuted to the high percentage of heterogeneity. The var -\nied sample sizes and progestin formulations across the \nstudies contributed to the variability of the results with \nthe single-arm studies lacking a comparator and varying \nstudy designs as clear contributors to heterogeneity.\nLimitations\nThe main limitation of this systematic review is the small \nnumber of studies that met the strict inclusion criteria. \nAnother limitation is that a few studies were open-label \nrandomised control trials that did not use blinding and/\nor allocation concealment, which increases the risk of \npotential bias. The CASP tool used to appraise the quality \nof the observational studies revealed that there is poten -\ntial bias when measuring the outcomes in some studies \nbecause occasionally questionnaires were used, and this \nis not always an accurate measure of outcomes. In the \nprogestin vs. placebo studies, the decrease in pain for the \nprogestin arm was informative, however, the decrease \nin pain measurements from baseline in the placebo arm \ncan potentially be misleading due to the placebo effect. \nAnother limitation is selection bias, where study partici -\npants could potentially have less severe forms of endo -\nmetriosis, which would make the study less generalisable. \nThis study only evaluates the effect progestins have on \nchronic pain from the start of treatment until the end \nof treatment and does not take into consideration the \neffects of discontinuing treatment, and whether chronic \npain recurs once treatment has ceased. The results of this \nstudy should be considered with caution and expanded \non in future studies.\nFuture studies should consider the efficacy and \nsafety of the long-term use of progestins. Only 2 stud -\nies in this review had a duration of up to 5 years and \nendometriosis is a chronic disease that requires long-\nterm treatment. Five different types of progestins were \nreviewed in this study, and the effects of the individual \ntypes and dosages should be studied in the future.\nConclusion\nThere is no known cure for endometriosis [52], which has \npsychological, physical and social effects impacting social \nactivity engagement, fertility, productivity in the work -\nplace, sexual practices and mental health. A demand for \nmore research and awareness regarding treatment effec -\ntiveness worldwide is of growing importance to ensure \nearly diagnosis as well as effective and improved man -\nagement of the disease and its debilitating symptoms. In \na systematic review conducted by D’Alterio et al., it was \nfound that medical and surgical interventions for endo -\nmetriosis improved patients’ quality of life, however, \nrecurrence is frequent [23]. This study demonstrated that \nprogestins produced positive pain relief and improve -\nments in quality of life in patients with endometriosis. \nHowever, treatment needs to be personalised taking into \naccount the goals of the patient, surgical candidacy, fertil-\nity planning and patient preference [23].\nThis review of 18 studies concluded that progestins \nprove to be a safe and effective treatment for chronic \npelvic pain in women with endometriosis, with a good \ntolerability profile.\nFig. 10 Funnel plot for studies showing the common adverse effects \nreported by progestins\n\nPage 15 of 16\nMitchell et al. BMC Women’s Health  2023, 22(1):526\n \nAbbreviations\nBMI  Body mass index\nQoL  Quality of life\nNSAID  Non‑steroidal anti‑inflammatory drugs\nGnRH  Gonadotropin‑releasing hormone\nPRISMA  Preferred reporting items for systematic reviews and \nmeta‑analyses\nMeSH  Medical subject headings\nPICO  Patient/population, intervention, comparison, and outcomes\nRCT   Randomised control trials\nCASP  Critical appraisal skills programme\nRevMan  Review manager\nCMA  Comprehensive meta‑analysis\nMD  Mean difference\nSMD  Standardised mean difference\nCI  Confidence interval\nVAS  Visual analogue scale\nNRS  Numerical rating scale\nSupplementary Information\nThe online version contains supplementary material available at https:// doi. \norg/ 10. 1186/ s12905‑ 022‑ 02122‑0.\nAdditional file 1. PRISMA Checklist Tool.\nAcknowledgements\nThe authors would like to thank the University of the Witwatersrand for the \nprovision of facilities to enable the conduction of this systematic review, and \nYaseera Patel (YP) for reviewing relevant published literature required for \nthe completion of this systematic review. The authors would like to thank Dr \nInnocent Maposa (Division of Epidemiology and Biostatistics, University of \nWitwatersrand) for his advice on the generation and interpretation of the for‑\nest and funnel plots used in this study.\nAuthor contributions\nJM, SC and FK were involved in the conceptualization of the project. SC and \nFK were involved in the supervision of JM’s research. JM drafted the article. \nSC and FK were involved in the reviewing and editing of the manuscript. All \nauthors (JM, SC, and FK) have read and approved the final manuscript.\nFunding\nNo funding was obtained for this study.\nData availability\nThe datasets used and/or analysed during the current study is available from \nthe corresponding author on reasonable request.\nDeclarations\nEthics approval and consent to participate\nNo ethics approval is required for conducting a systematic review.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare that they have no competing interests.\nReceived: 1 June 2022   Accepted: 12 December 2022\nPublished: 17 December 2022\nReference list\n 1. Giudice LC, Kao LC. Endometriosis. The Lancet. 2004;364(9447):1789–99.\n 2. Pospisilova E, Kiss I, Souckova H, Tomes P , Spicka J, Matkowski R, et al. Cir‑\nculating endometrial cells: a new source of information on endometriosis \ndynamics. J Clinic Med. 2019;8(11):1938.\n 3. Machairiotis N, Stylianaki A, Dryllis G, Zarogoulidis P , Kouroutou P , Tsiamis \nN, et al. 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