BACKGROUND: Endometriosis is a condition characterised by the presence of ectopic deposits of endometrial-like tissue outside the uterus, usually in the pelvis. The impact of laparoscopic treatment on overall pain is uncertain and a significant proportion of women will require further surgery. Therefore, adjuvant medical therapies following surgery, such as the levonorgestrel-releasing intrauterine device (LNG-IUD), have been considered to reduce recurrence of symptoms. OBJECTIVES: To determine the effectiveness and safety of post-operative LNG-IUD in women with symptomatic endometriosis.
SEARCH METHODS: We searched the following databases from inception to January 2021: The Specialised Register of the Cochrane Gynaecology and Fertility Group, CENTRAL (which now includes records from two trial registries), MEDLINE, Embase, PsycINFO, LILACS and Epistemonikos. We handsearched citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies. We contacted experts in the field for information about any additional studies.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing women undergoing surgical treatment of endometriosis with uterine preservation who were assigned to LNG-IUD insertion, versus control conditions including expectant management, post-operative insertion of placebo (inert intrauterine device), or other medical treatment such as gonadotrophin-releasing hormone agonist (GnRH-a) drugs.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, and extracted data to allow for an intention-to-treat analysis. For dichotomous data, we calculated the risk ratio (RR) and 95% confidence interval (CI) using the Mantel-Haenszel fixed-effect method. For continuous data, we calculated the mean difference (MD) and 95% CI using the inverse variance fixed-effect method.
MAIN RESULTS: Four RCTs were included, with a total of 157 women. Two studies are ongoing. The GRADE certainty of evidence was very low to low. The certainty of evidence was graded down primarily for serious risk of bias and imprecision. LNG-IUD versus expectant management Overall pain: No studies reported on the primary outcome of overall pain. Dysmenorrhoea: We are uncertain whether LNG-IUD improves dysmenorrhoea at 12 months. Data on this outcome were reported on by two RCTs; meta-analysis was not possible (RCT 1: delta of median visual analogue scale (VAS) 81 versus 50, P = 0.006, n = 55; RCT 2: fall in VAS by 50 (35 to 65) versus 30 (25 to 40), P = 0.021, n = 40; low-certainty evidence). Quality of life: We are uncertain whether LNG-IUD improves quality of life at 12 months. One trial demonstrated a change in total quality of life score with postoperative LNG-IUD from baseline (mean 61.2 (standard deviation (SD) 14.8) to 12 months (mean 70.3 (SD 16.2) compared to expectant management (baseline 55.1 (SD 17.0) to 57.0 (SD 33.2) at 12 months) (n = 55, P = 0.014, very low-certainty evidence). Patient satisfaction: Two studies found higher rates of satisfaction with LNG-IUD compared to expectant management; however, combining the studies in meta-analysis was not possible (n = 95, very low-certainty evidence). One study found 75% (15/20) of those given post-operative LNG-IUD were "satisfied" or "very satisfied", compared to 50% (10/20) of those in the expectant management group (RR 1.5, 95% CI 0.90-2.49, 1 RCT, n=40, very low-certainty evidence). The second study found that fewer were "very satisfied" in the expectant management group when compared to LNG, but there were no data to include in a meta-analysis. Adverse events: One study found a significantly higher proportion of women reporting melasma (n = 55, P = 0.015, very low-certainty evidence) and bloating (n = 55, P = 0.021, very low-certainty evidence) following post-operative LNG-IUD. There were no differences in other reported adverse events, such as weight gain, acne, and headaches. LNG-IUD versus GnRH-a Overall pain: No studies reported on the primary outcome of overall pain. Chronic pelvic pain: We are uncertain whether LNG-IUD improves chronic pelvic pain at 12 months when compared to GnRH-a (VAS pain scale) (MD -2.0, 95% CI -20.2 to 16.2, 1 RCT, n = 40, very low-certainty evidence). Dysmenorrhoea: We are uncertain whether LNG-IUD improves dysmenorrhoea at six months when compared to GnRH-a (measured as a reduction in VAS pain score) (MD 1.70, 95%.CI -0.14 to 3.54, 1 RCT, n = 18, very low-certainty evidence). Adverse events: One study suggested that vasomotor symptoms were the most common adverse events reported with patients receiving GnRH-a, and irregular bleeding in those receiving LNG-IUD (n = 40, very low-certainty evidence) AUTHORS' CONCLUSIONS: Post-operative LNG-IUD is widely used to reduce endometriosis-related pain and to improve operative outcomes. This review demonstrates that there is no high-quality evidence to support this practice. This review highlights the need for further studies with large sample sizes to assess the effectiveness of post-operative adjuvant hormonal IUD on the core endometriosis outcomes (overall pain, most troublesome symptom, and quality of life).
BACKGROUND: Endometriosis is a chronic inflammatory condition that occurs during the reproductive years. It is characterised by endometrium-like tissue developing outside the uterine cavity. This endometriotic tissue development is dependent on oestrogen produced primarily by the ovaries and partially by the endometriotic tissue itself, therefore traditional management has focused on ovarian suppression. In this review we considered the role of modulation of the immune system as an alternative approach. This is an update of a Cochrane Review previously published in 2012.
OBJECTIVES: To determine the effectiveness and safety of pentoxifylline in the management of endometriosis. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED on 16 December 2020, together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing pentoxifylline with placebo or no treatment, other medical treatment, or surgery in women with endometriosis. The primary outcomes were live birth rate and overall pain (as measured by a visual analogue scale (VAS) of pain, other validated scales, or dichotomous outcomes) per woman randomised. Secondary outcomes included clinical pregnancy rate, miscarriage rate, rate of recurrence, and adverse events resulting from the pentoxifylline intervention.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies against the inclusion criteria, extracted data, and assessed risk of bias, consulting a third review author where required. We contacted study authors as needed. We analysed dichotomous outcomes using Mantel-Haenszel risk ratios (RRs), 95% confidence intervals (CIs), and a fixed-effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups presented with 95% CIs. We used the I2 statistic to evaluate heterogeneity amongst studies. We employed the GRADE approach to assess the quality of the evidence.
MAIN RESULTS: We included five parallel-design RCTs involving a total of 415 women. We included one additional RCT in this update. Three studies did not specify details relating to allocation concealment, and two studies were not blinded. There were also considerable loss to follow-up, with four studies not conducting intention-to-treat analysis. We judged the quality of the evidence as very low. Pentoxifylline versus placebo No trials reported on our primary outcomes of live birth rate and overall pain. We are uncertain as to whether pentoxifylline treatment affects clinical pregnancy rate when compared to placebo (RR 1.38, 95% CI 0.91 to 2.10; 3 RCTs, n = 285; I2 = 0%; very low-quality evidence). The evidence suggests that if the clinical pregnancy rate with placebo is estimated to be 20%, then the rate with pentoxifylline is estimated as between 18% and 43%. We are also uncertain as to whether pentoxifylline affects the recurrence rate of endometriosis (RR 0.84, 95% CI 0.30 to 2.36; 1 RCT, n = 121; very low-quality evidence) or miscarriage rate (Peto OR 1.99, 95% CI 0.20 to 19.37; 2 RCTs, n = 164; I2 = 0%; very low-quality evidence). No trials reported on the effect of pentoxifylline on improvement of endometriosis-related symptoms other than pain or adverse events. Pentoxifylline versus no treatment No trials reported on live birth rate. We are uncertain as to whether pentoxifylline treatment affects overall pain when compared to no treatment at one month (MD -0.36, 95% CI -2.12 to 1.40; 1 RCT, n = 34; very low-quality evidence), two months (MD -1.25, 95% CI -2.67 to 0.17; 1 RCT, n = 34; very low-quality evidence), or three months (MD -1.60, 95% CI -3.32 to 0.12; 1 RCT, n = 34; very low-quality evidence). No trials reported on adverse events caused by pentoxifylline or any of our other secondary outcomes. Pentoxifylline versus other medical therapies One study (n = 83) compared pentoxifylline to the combined oral contraceptive pill after laparoscopic surgery to treat endometriosis, but could not be included in the meta-analysis as it was unclear if the data were presented as +/- standard deviation and what the duration of treatment was. No trials reported on adverse events caused by pentoxifylline or any of our other secondary outcomes. Pentoxifylline versus conservative surgical treatment No study reported on this comparison.
AUTHORS' CONCLUSIONS: No studies reported on our primary outcome of live birth rate. Due to the very limited evidence, we are uncertain of the effects of pentoxifylline on clinical pregnancy rate, miscarriage rate, or overall pain. There is currently insufficient evidence to support the use of pentoxifylline in the management of women with endometriosis with respect to subfertility and pain relief outcomes.
BACKGROUND: Endometriosis is a common gynaecological condition affecting 10% to 15% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is combining surgery and medical therapy to reduce the recurrence of endometriosis. Though the combination of surgery and medical therapy appears to be beneficial, there is a lack of clarity about the appropriate timing of when medical therapy should be used in relation with surgery, that is, before, after, or both before and after surgery, to maximize treatment response.
OBJECTIVES: To determine the effectiveness of medical therapies for hormonal suppression before, after, or both before and after surgery for endometriosis for improving painful symptoms, reducing disease recurrence, and increasing pregnancy rates.
SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in November 2019 together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) which compared medical therapies for hormonal suppression before, after, or before and after, therapeutic surgery for endometriosis.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Where possible, we combined data using risk ratio (RR), standardized mean difference or mean difference (MD) and 95% confidence intervals (CI). Primary outcomes were: painful symptoms of endometriosis as measured by a visual analogue scale (VAS) of pain, other validated scales or dichotomous outcomes; and recurrence of disease as evidenced by EEC (Endoscopic Endometriosis Classification), rAFS (revised American Fertility Society), or rASRM (revised American Society for Reproductive Medicine) scores at second-look laparoscopy.
MAIN RESULTS: We included 26 trials with 3457 women with endometriosis. We used the term "surgery alone" to refer to placebo or no medical therapy. Presurgical medical therapy compared with placebo or no medical therapy Compared to surgery alone, we are uncertain if presurgical medical hormonal suppression reduces pain recurrence at 12 months or less (dichotomous) (RR 1.10, 95% CI 0.72 to 1.66; 1 RCT, n = 262; very low-quality evidence) or whether it reduces disease recurrence at 12 months - total (AFS score) (MD -9.6, 95% CI -11.42 to -7.78; 1 RCT, n = 80; very low-quality evidence). We are uncertain if presurgical medical hormonal suppression decreases disease recurrence at 12 months or less (EEC stage) compared to surgery alone (RR 0.88, 95% CI 0.78 to 1.00; 1 RCT, n = 262; very low-quality evidence). We are uncertain if presurgical medical hormonal suppression improves pregnancy rates compared to surgery alone (RR 1.16, 95% CI 0.99 to 1.36; 1 RCT, n = 262; very low-quality evidence). No trials reported pelvic pain at 12 months or less (continuous) or disease recurrence at 12 months or less. Postsurgical medical therapy compared with placebo or no medical therapy We are uncertain about the improvement observed in pelvic pain at 12 months or less (continuous) between postsurgical medical hormonal suppression and surgery alone (MD -0.48, 95% CI -0.64 to -0.31; 4 RCTs, n = 419; I2 = 94%; very low-quality evidence). We are uncertain if there is a difference in pain recurrence at 12 months or less (dichotomous) between postsurgical medical hormonal suppression and surgery alone (RR 0.85, 95% CI 0.65 to 1.12; 5 RCTs, n = 634; I2 = 20%; low-quality evidence). We are uncertain if postsurgical medical hormonal suppression improves disease recurrence at 12 months - total (AFS score) compared to surgery alone (MD -2.29, 95% CI -4.01 to -0.57; 1 RCT, n = 51; very low-quality evidence). Disease recurrence at 12 months or less may be reduced with postsurgical medical hormonal suppression compared to surgery alone (RR 0.30, 95% CI 0.17 to 0.54; 4 RCTs, n = 433; I2 = 58%; low-quality evidence). We are uncertain about the reduction observed in disease recurrence at 12 months or less (EEC stage) between postsurgical medical hormonal suppression and surgery alone (RR 0.80, 95% CI 0.70 to 0.91; 1 RCT, n = 285; very low-quality evidence). Pregnancy rate is probably increased with postsurgical medical hormonal suppression compared to surgery alone (RR 1.22, 95% CI 1.06 to 1.39; 11 RCTs, n = 932; I2 = 24%; moderate-quality evidence). Pre- and postsurgical medical therapy compared with surgery alone or surgery and placebo There were no trials identified in the search for this comparison. Presurgical medical therapy compared with postsurgical medical therapy We are uncertain about the difference in pain recurrence at 12 months or less (dichotomous) between postsurgical and presurgical medical hormonal suppression therapy (RR 1.40, 95% CI 0.95 to 2.07; 2 RCTs, n = 326; I2 = 2%; low-quality evidence). We are uncertain about the difference in disease recurrence at 12 months or less (EEC stage) between postsurgical and presurgical medical hormonal suppression therapy (RR 1.10, 95% CI 0.95 to 1.28; 1 RCT, n = 273; very low-quality evidence). We are uncertain about the difference in pregnancy rate between postsurgical and presurgical medical hormonal suppression therapy (RR 1.05, 95% CI 0.91 to 1.21; 1 RCT, n = 273; very low-quality evidence). No trials reported pelvic pain at 12 months or less (continuous), disease recurrence at 12 months - total (AFS score) or disease recurrence at 12 months or less (dichotomous). Postsurgical medical therapy compared with pre- and postsurgical medical therapy There were no trials identified in the search for this comparison. Serious adverse effects for medical therapies reviewed There was insufficient evidence to reach a conclusion regarding serious adverse effects, as no studies reported data suitable for analysis.
AUTHORS' CONCLUSIONS: Our results indicate that the data about the efficacy of medical therapy for endometriosis are inconclusive, related to the timing of hormonal suppression therapy relative to surgery for endometriosis. In our various comparisons of the timing of hormonal suppression therapy, women who receive postsurgical medical therapy compared with no medical therapy or placebo may experience benefit in terms of disease recurrence and pregnancy. There is insufficient evidence regarding hormonal suppression therapy at other time points in relation to surgery for women with endometriosis.
BACKGROUND: Endometriosis is associated with pain and infertility. Surgical interventions aim to remove visible areas of endometriosis and restore the anatomy.
OBJECTIVES: To assess the effectiveness and safety of laparoscopic surgery in the treatment of pain and infertility associated with endometriosis.
SEARCH METHODS: This review has drawn on the search strategy developed by the Cochrane Gynaecology and Fertility Group including searching the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, reference lists for relevant trials, and trial registries from inception to April 2020.
SELECTION CRITERIA: We selected randomised controlled trials (RCTs) that compared the effectiveness and safety of laparoscopic surgery with any other laparoscopic or robotic intervention, holistic or medical treatment, or diagnostic laparoscopy only.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed selection of studies, assessment of trial quality and extraction of relevant data with disagreements resolved by a third review author. We collected data for the core outcome set for endometriosis. Primary outcomes included overall pain and live birth. We evaluated the quality of evidence using GRADE methods.
MAIN RESULTS: We included 14 RCTs. The studies randomised 1563 women with endometriosis. Four RCTs compared laparoscopic ablation or excision with diagnostic laparoscopy only. Two RCTs compared laparoscopic excision with diagnostic laparoscopy only. One RCT compared laparoscopic ablation or excision with laparoscopic ablation or excision and uterine suspension. Two RCTs compared laparoscopic ablation and uterine nerve transection with diagnostic laparoscopy only. One RCT compared laparoscopic ablation with diagnostic laparoscopy and gonadotropin-releasing hormone (GnRH) analogues. Two RCTs compared laparoscopic ablation with laparoscopic excision. One RCT compared laparoscopic ablation or excision with helium thermal coagulator with laparoscopic ablation or excision with electrodiathermy. One RCT compared conservative laparoscopic surgery with laparoscopic colorectal resection of deep endometriosis infiltrating the rectum. Common limitations in the primary studies included lack of clearly described blinding, failure to fully describe methods of randomisation and allocation concealment, and poor reporting of outcome data. Laparoscopic treatment versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic treatment on overall pain scores compared to diagnostic laparoscopy only at six months (mean difference (MD) 0.90, 95% confidence interval (CI) 0.31 to 1.49; 1 RCT, 16 participants; very low quality evidence) and at 12 months (MD 1.65, 95% CI 1.11 to 2.19; 1 RCT, 16 participants; very low quality evidence), where a positive value means pain relief (the higher the score, the more pain relief) and a negative value reflects pain increase (the lower the score, the worse the increase in pain). No studies looked at live birth. We are uncertain of the effect of laparoscopic treatment on quality of life compared to diagnostic laparoscopy only: EuroQol-5D index summary at six months (MD 0.03, 95% CI -0.12 to 0.18; 1 RCT, 39 participants; low quality evidence), 12-item Short Form (SF-12) mental health component (MD 2.30, 95% CI -4.50 to 9.10; 1 RCT, 39 participants; low quality evidence) and SF-12 physical health component (MD 2.70, 95% CI -2.90 to 8.30; 1 RCT, 39 participants; low quality evidence). Laparoscopic treatment probably improves viable intrauterine pregnancy rate compared to diagnostic laparoscopy only (odds ratio (OR) 1.89, 95% CI 1.25 to 2.86; 3 RCTs, 528 participants; I2 = 0%; moderate quality evidence). We are uncertain of the effect of laparoscopic treatment compared to diagnostic laparoscopy only on ectopic pregnancy (MD 1.18, 95% CI 0.10 to 13.48; 1 RCT, 100 participants; low quality evidence) and miscarriage (MD 0.94, 95% CI 0.35 to 2.54; 2 RCTs, 112 participants; low quality evidence). There was limited reporting of adverse events. No conversions to laparotomy were reported in both groups (1 RCT, 341 participants). Laparoscopic ablation and uterine nerve transection versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic ablation and uterine nerve transection on adverse events (more specifically vascular injury) compared to diagnostic laparoscopy only (OR 0.33, 95% CI 0.01 to 8.32; 1 RCT, 141 participants; low quality evidence). No studies looked at overall pain scores (at six and 12 months), live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. Laparoscopic ablation versus laparoscopic excision There was insufficient evidence to determine whether there was a difference in overall pain, measured at 12 months, for laparoscopic ablation compared with laparoscopic excision (MD 0.00, 95% CI -1.22 to 1.22; 1 RCT, 103 participants; very low quality evidence). No studies looked at overall pain scores at six months, live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy, miscarriage and adverse events. Helium thermal coagulator versus electrodiathermy We are uncertain whether helium thermal coagulator compared to electrodiathermy improves quality of life using the 30-item Endometriosis Health Profile (EHP-30) at nine months, when considering the components: pain (MD 6.68, 95% CI -3.07 to 16.43; 1 RCT, 119 participants; very low quality evidence), control and powerlessness (MD 4.79, 95% CI -6.92 to 16.50; 1 RCT, 119 participants; very low quality evidence), emotional well-being (MD 6.17, 95% CI -3.95 to 16.29; 1 RCT, 119 participants; very low quality evidence) and social support (MD 5.62, 95% CI -6.21 to 17.45; 1 RCT, 119 participants; very low quality evidence). Adverse events were not estimable. No studies looked at overall pain scores (at six and 12 months), live birth, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage.
AUTHORS' CONCLUSIONS: Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. No data were reported on live birth. There is moderate quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only. No studies were found that looked at live birth for any of the comparisons. Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.
BACKGROUND: Endometriosis is a common gynaecological condition which affects many women of reproductive age worldwide and is a major cause of pain and infertility. The combined oral contraceptive pill (COCP) is widely used to treat pain occurring as a result of endometriosis, although the evidence for its efficacy is limited.
OBJECTIVES: To determine the effectiveness, safety and cost-effectiveness of oral contraceptive preparations in the treatment of painful symptoms ascribed to the diagnosis of laparoscopically proven endometriosis.
SEARCH METHODS: We searched the following from inception to 19 October 2017: the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane CENTRAL Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the trial registers ClinicalTrials.gov and the World Health Organization Clinical Trials Registry Platform (WHO ICTRP). We also handsearched reference lists of relevant trials and systematic reviews retrieved by the search.
SELECTION CRITERIA: We included randomised controlled trials (RCT) of the use of COCPs in the treatment of women of reproductive age with symptoms ascribed to the diagnosis of endometriosis that had been made visually at a surgical procedure.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality and extracted data. One review author was an expert in the content matter. We contacted study authors for additional information. The primary outcome was self-reported pain (dysmenorrhoea) at the end of treatment.
MAIN RESULTS: Five trials (612 women) met the inclusion criteria. Only three trials (404 women) provided data that were suitable for analysis.Combined oral contraceptive pill versus placeboTwo trials compared COCP with a placebo. These studies were at high risk of bias. For GRADE outcomes (self-reported pain (dysmenorrhoea) at the end of treatment), the quality of the evidence very low. Evidence was downgraded for imprecision as it was based on a single, small trial and for the visual analogue scale data there were wide confidence intervals (CIs). There appeared to have been substantial involvement of the pharmaceutical company funding the trials.Treatment with the COCP was associated with an improvement in self-reported pain at the end of treatment as evidenced by a lower score on the Dysmenorrhoea verbal rating scale (scale 0 to 3) compared with placebo (mean difference (MD) -1.30 points, 95% CI -1.84 to -0.76; 1 RCT, 96 women; very low quality evidence), a lower score on the Dysmenorrhoea visual analogue scale (no details of scale) compared with placebo (MD -23.68 points, 95% CI -28.75 to -18.62, 2 RCTs, 327 women; very low quality evidence) and a reduction in menstrual pain from baseline to the end of treatment (MD 2.10 points, 95% CI 1.38 to 2.82; 1 RCT, 169 women; very low quality evidence).Combined oral contraceptive pill versus medical therapiesOne underpowered trial compared the COCP with another medical treatment (goserelin). The study was at high risk of bias; the trial was unblinded and there was insufficient detail to judge allocation concealment and randomisation. For GRADE outcomes (self-reported pain (dysmenorrhoea) at the end of treatment), the quality of the evidence ranged from low to very low.At the end of treatment, the women in the goserelin group were amenorrhoeic and therefore no comparisons could be made between the groups for the primary outcome. At six months' follow-up, there was no clear evidence of a difference between women treated with the COCP and women treated with goserelin for measures of dysmenorrhoea on a visual analogue scale (scale 1 to 10) (MD -0.10, 95% CI -1.28 to 1.08; 1 RCT, 50 women; very low quality evidence) or a verbal rating scale (scale 0 to 3) (MD -0.10, 95% CI -0.99 to 0.79; 1 RCT, 50 women; very low quality evidence). At six months' follow-up, there was no clear evidence of a difference between the COCP and goserelin groups for reporting complete absence of pain as measured by the visual analogue scale (risk ratio (RR) 0.36, 95% CI 0.02 to 8.43; 1 RCT, 50 women; very low quality evidence) or the verbal rating scale (RR 1.00, 95% CI 0.93 to 1.08; 1 RCT, 49 women; low quality evidence).
AUTHORS' CONCLUSIONS: Based on the limited evidence from two trials at high risk of bias and limited data for the prespecified outcomes for this review, there is insufficient evidence to make a judgement on the effectiveness of the COCP compared with placebo and the findings cannot be generalised.Based on the limited evidence from one small trial that was at high risk of bias, there is insufficient evidence to make a judgement on the effectiveness of the COCP compared with other medical treatments. Only one comparison was possible, with the medical intervention being goserelin, and the findings cannot be generalised.Further research is needed to fully evaluate the role of COCPs in managing pain-related symptoms associated with endometriosis. There are other formulations of the combined hormonal contraception such as the transdermal patch, vaginal ring or combined injectable contraceptives which this review did not cover but should be considered in future updates.
CONTEXTO: A endometriose é uma condição ginecológica comum que afeta mulheres e pode levar a sintomas dolorosos e infertilidade. Isso afeta muito a qualidade de vida das mulheres, afetando suas carreiras, atividades cotidianas, relações sexuais e não-sexuais e fertilidade. Os fármacos anti-inflamatórios não esteróides (AINEs) são mais comumente usados como tratamento de primeira linha para mulheres com dor associada à endometriose. OBJETIVOS: Avaliar os efeitos dos AINE utilizados para o tratamento da dor em mulheres com endometriose em comparação com placebo, outros AINEs, outros medicamentos para tratamento da dor ou nenhum tratamento. MÉTODOS DE PESQUISA: Buscamos o Registro Especializado de Ensaios Controlados do Cochrane Gynecology and Fertility Group (outubro de 2016), publicado no Cochrane Central Register of Controlled Trials (CENTRAL) na Cochrane Library, bem como MEDLINE (janeiro de 2008 a outubro de 2016), Embase (data limitada de 1 de janeiro de 2016 a 19 de outubro de 2016, pois todas as referências anteriores estão incluídas no resultado CENTRAL como resultado do projeto Embase), registros de ensaios em andamento e as listas de referência de publicações relevantes. Não identificamos novos ensaios clínicos randomizados. A menos que identifiquemos novas evidências no futuro, não vamos atualizar esta revisão. CRITÉRIOS DE SELECÇÃO: Incluímos todos os ensaios clínicos randomizados (ECA) que descrevem o uso de AINEs para o tratamento da dor associada à endometriose em mulheres de todas as idades. COLETA E ANÁLISE DE DADOS: Na atualização de 2009 desta revisão, dois autores da revisão (CA e SH) leram e extraíram os dados de cada um dos estudos incluídos. Analisamos ensaios cruzados usando o método de variância inversa do RevMan para calcular odds ratios para resultados binários. PRINCIPAIS RESULTADOS: Não identificamos novos ensaios para a atualização de 2016. Esta revisão inclui dois ensaios, mas incluímos apenas um teste, com 24 mulheres, na análise. O risco geral de viés não era claro devido à falta de detalhes metodológicos. Usando o método GRADE, consideramos que a qualidade da evidência é muito baixa. Providenciamos evidências de risco de parcialidade e de imprecisão (amplos intervalos de confiança e provas baseadas em um único teste pequeno). A comparação de AINEs (naproxeno) versus placebo não revelou evidência de um efeito positivo no alívio da dor (odds ratio (OR) 3.27, Intervalo de confiança de 95% (IC) 0,61 a 17,69, um ensaio, 24 mulheres, evidência de muito baixa qualidade) em mulheres com endometriose. Evidências que indicam se as mulheres que tomaram AINEs (naproxeno) foram menos propensas a requerer analgesia adicional (OR 0,12, IC 95% 0,01 a 1,29, um teste, 24 mulheres, evidência de muito baixa qualidade) ou a sofrerem efeitos colaterais (OR 0,46, 95% CI 0,09 a 2,47, um teste, 24 mulheres, evidência de muito baixa qualidade) quando comparado com o placebo não foi conclusivo. Estudos não forneceram dados sobre qualidade de vida, efeitos nas atividades diárias, ausência do trabalho ou escola, necessidade de tratamento mais invasivo ou Satisfação dos participantes com o tratamento. CONCLUSÕES DOS AUTORES: devido à falta de evidências de alta qualidade e à falta de notificação de resultados de interesse para esta revisão, não podemos julgar se os AINEs (naproxeno) são efetivos no manejo da dor causada pela endometriose. Nenhuma evidência mostra se qualquer AINE individual é mais eficaz do que outro. Conforme mostrado em outras revisões Cochrane, as mulheres que tomam AINEs devem estar conscientes de que essas drogas podem causar efeitos não intencionais.
JUSTIFICATIVA: A endometriose é uma doença crônica, recorrente, que pode desenvolver-se durante os anos reprodutivos. É caracterizado por o desenvolvimento do tecido endometrial fora da cavidade uterina. É a causa mais comum de dor pélvica em mulheres. Este desenvolvimento do tecido endometrial é dependente de estrógeno produzido principalmente pelos ovários e, por isso, a gestão tradicional centrou-se na supressão da função ovariana. Montagem mostra evidências de que a função imune alterada desempenha um papel crucial na gênese e desenvolvimento da endometriose. Nesta revisão, considerado modulação da inflamação como uma abordagem alternativa.
OBJETIVOS: Determinar a eficácia e segurança do fator de necrose α tratamento anti-tumoral (anti-TNF-α) na gestão de endometriose em mulheres na pré-menopausa.
Métodos de pesquisa: Para a primeira publicação desta revisão, buscamos os ensaios nas seguintes bases de dados (a partir de sua criação até agosto de 2009): Distúrbios menstruais Cochrane e Subfertility Grupo Especializado Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library ), MEDLINE, EMBASE, CINAHL e PsycINFO. Além disso, buscamos todas as listas de referências dos estudos incluídos e contatou especialistas na área na tentativa de localizar os ensaios. Nós reran esta pesquisa a 3 de Setembro de 2012, para esta atualização.
Critério de seleção: Ensaios clínicos randomizados (ECR) comparando as drogas anti-TNF-α com o placebo, nenhum tratamento, tratamento médico, ou cirurgia para a dor pélvica associada à endometriose foram incluídos.
COLETA DE DADOS E ANÁLISE: Dois autores da revisão estudos selecionados de forma independente para a inclusão, a qualidade dos ensaios avaliados, e os dados extraídos através de formulários de extração de dados. Os domínios avaliados para o risco de viés foram geração de seqüência, ocultação de alocação, mascaramento de dados de resultados incompletos e relatórios de resultado seletivo. Usamos razões de risco (RR) para relatar dados dicotômicos com intervalos de confiança de 95% (CI), enquanto que expressa dados contínuos como as diferenças médias (MD). Foram avaliadas heterogeneidade estatística usando a estatística I2.
PRINCIPAIS RESULTADOS: Apenas um estudo envolvendo 21 participantes foi incluído. Os resultados não mostraram nenhuma evidência de um efeito de infliximab, um dos conhecidos medicamentos anti-TNF-α, na redução da dor pélvica usando o Biberoglu-Behrman (BB) pontuação (0-3 escala) para os participantes (MD -0,14, 95% CI -0,43 a 0,15), a pontuação BB para os médicos (MD -0,14, IC -0,39 a 0,11 95%), ou um escore de dor visual analógica (EVA, escala de 100 mm) (MD -5,60, IC 95 para -16,10% 4,90), ou a utilização de analgésicos (ibuprofeno, g / dia) (MD -0,10 -0,30 IC para 95% 0,10). Não houve evidência de um aumento nos eventos adversos no grupo infliximabe, quando comparada com o placebo (RR 3,73, IC 0,22-63,66 95%). Nós não encontramos nenhuma evidência de benefícios clínicos do infliximabe para lesões de endometriose, dismenorreia, dispareunia ou sensibilidade pélvica. Até o momento, não há nenhuma prova que relatou uma análise de custo-eficácia dos medicamentos anti-TNF-α, ou as chances de recorrência.
Conclusão dos autores: Esta revisão foi atualizado em 2012. Os resultados da revisão original publicado em 2010 permanecem inalteradas. Ainda não existe evidência suficiente para suportar a utilização de fármacos anti-TNF-α no tratamento de mulheres com endometriose, para o alívio da dor pélvica.
ANTECEDENTES: A endometriose é um estado inflamatório crónico definida pela presença de glândulas e estroma fora da cavidade uterina. Ela ocorre em 7% a 10% de todas as mulheres em idade reprodutiva e podem apresentar-se como a dor ou a infertilidade. A dor pélvica pode estar na forma de dismenorreia, dispareunia ou dor pélvica. Inicialmente uma combinação de estrogénios e progestagénios foi usado para criar uma pseudogravidez e aliviar os sintomas associados com a endometriose. Progestagénios sozinho ou anti-progestagénios têm sido considerados como alternativas porque são baratos e podem ter um melhor perfil de efeitos colaterais do que outras escolhas.
OBJECTIVOS: Para determinar a eficácia de ambos os progestagénios e anti-progestagénios no tratamento de sintomas dolorosos atribuídos para o diagnóstico da endometriose.
Métodos de pesquisa: Usamos a estratégia de busca dos distúrbios menstruais e Grupo Subfertility para identificar todas as publicações que descrevem ou ter descrito ensaios clínicos randomizados (ECR) de qualquer progestagénio ou qualquer anti-progesterona no tratamento da endometriose sintomática. Nós atualizamos a revisão em 2011.
Critério de seleção: Foram considerados apenas ECRs que compararam o uso de progestágenos e anti-progestágenos com outras intervenções, placebo ou nenhum tratamento para o alívio sintomático da endometriose.
COLETA DE DADOS E ANÁLISE: Nós adicionamos seis novos estudos, elevando o total de estudos incluídos a 13 na atualização desta revisão. Os seis estudos recém-incluídos avaliados progestágenos (comparações com placebo, danazol contraceptivo, oral ou subcutânea, pílula anticoncepcional oral e, danazol hormona de libertação da gonadotrofina (GnRH) drogas analógicas e outros). Os demais estudos compararam a gestrinone anti-progestagénio com danazol, análogos de GnRH ou de si mesmo.
PRINCIPAIS RESULTADOS: O progestágeno acetato de medroxiprogesterona (100 mg por dia) parece ser mais eficaz em reduzir todos os sintomas até 12 meses de follow-up (MD -0,70, IC 95% -8,61 a -5,39, P <0,00001) em comparação com placebo. Houve evidência de casos significativamente mais do acne (seis contra um) e edema (11 contra um) no grupo de acetato de medroxiprogesterona em comparação com o placebo. Não houve evidência de uma diferença de eficácia objectiva entre didrogesterona e placebo.
Não houve evidência de um benefício com a administração de depósito de progestagénios, versus outros tratamentos (dose baixa contraceptivo oral ou acetato de leuprolide) para os sintomas reduzidos. O depósito de progestagénio grupo apresentaram efeitos significativamente mais adversos.
Não houve evidência geral de um benefício de progestágenos orais sobre outros tratamentos médicos, seis meses de follow-up para o auto-relato eficácia. Amenorréia e sangramento foram mais freqüentemente relatados no grupo progestagénio comparação com outros grupos de tratamento.
Não houve evidência de um benefício de anti-progestágenos (gestrinone) em comparação com danazol. GnRH análogo (leuprorrelina) foi encontrado para melhorar significativamente a dismenorréia em comparação com gestrinone (MD 0,82, IC 95% 0,15-1,49, P = 0,02) embora tenha sido também associado ao aumento de fogachos (OR 0,20, IC 95% 0,06 a -0,63; P = 0,006).
Conclusão dos autores: Há apenas evidência limitada para apoiar o uso de progestágenos e anti-progestágenos para a dor associada à endometriose.
ANTECEDENTES: A endometriose é caracterizada pela presença de tecido que é morfologicamente e biologicamente semelhante ao endométrio normal em locais fora do útero. O tratamento cirúrgico e hormonal da endometriose ter efeitos colaterais desagradáveis e altas taxas de recaída. Na China, o tratamento da endometriose usando fitoterapia chinesa (CHM) é de rotina e pesquisa considerável para o papel de CHM para aliviar a dor, promovendo a fertilidade e prevenir a recidiva ocorreu.
Esta revisão é uma atualização de uma revisão anterior, publicado na Cochrane Database of Systematic Reviews 2009, Edição N. º 3.
OBJETIVOS: Para avaliar a eficácia e segurança do CHM em aliviar a dor relacionada com endometriose e infertilidade.
Métodos de pesquisa: Foram pesquisados os distúrbios menstruais e Subfertility Grupo Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library) e as seguintes bases de dados eletrônicos da língua inglesa (a partir de sua criação até 31/10/2011): MEDLINE, EMBASE , AMED, CINAHL, e NLH.
Nós também procurou bancos de dados de língua chinesa: Banco de dados eletrônicos Literatura Chinesa Biomédicas (CBM), China Infra-estrutura Nacional de Conhecimento (CNKI), chinês Ciência & Revistas Tech (VIP), Análise de Literatura da Medicina Tradicional Chinesa e sistema de recuperação (TCMLARS) e chinês médica atual Conteúdo (CMCC).
Critério de seleção: Ensaios clínicos randomizados (ECR), envolvendo CHM versus placebo, o tratamento biomédico, outra intervenção CHM, CHM ou mais tratamento biomédico versus tratamento biomédico foram selecionados. Ensaios apenas com procedimentos de randomização confirmados e diagnóstico laparoscópico de endometriose foram incluídos.
COLETA DE DADOS E ANÁLISE: Risco de avaliação viés, e extração de dados e análises foram realizadas independentemente por três autores da revisão. Os dados foram combinados para meta-análise com risco relativo (RR) para dados dicotômicos. Um modelo de efeito fixo estatística foi utilizado, quando necessário. Os dados não adequados para meta-análise foram apresentados como dados descritivos.
PRINCIPAIS RESULTADOS: Dois ECRs chineses envolvendo 158 mulheres foram incluídos nesta revisão. Ambos estes ensaios descritos metodologia adequada. Nem estudo comparou CHM com o tratamento placebo.
Não houve evidência de uma diferença significativa nas taxas de alívio sintomático entre CHM e gestrinone administrado após a cirurgia laparoscópica (95,65% versus 93,87%; relação de risco (RR) 1,02, intervalo de confiança de 95% (CI) 0,93-1,12, um RCT) . A intenção de tratar análise também mostrou não haver diferença significativa entre os grupos (RR 1,04, IC 95% 0,91-1,18). Não houve diferença significativa entre o MHC e grupos Gestrinone no que respeita à taxa total de gravidez (69,6% versus 59,1%; RR 1,18, 95% CI 0,87-1,59, um RCT).
CHM administrado por via oral e, em seguida, em conjunto com um enema de ervas resultou em uma maior proporção de mulheres que obtêm o alívio sintomático do que com o danazol (RR 5,06, 95% CI 1,28-20,05; RR 5,63, 95% CI 1,47-21,54, respectivamente). No geral, 100% das mulheres em todos os grupos apresentaram melhora em seus sintomas.
Oral além de administração de enema CHM mostrou uma redução maior nos escores médios de dor dismenorreia do que danazol (média das diferenças (MD) -2,90, IC 95% -4,55 a -1,25, P <0,01). Combinado a administração oral e enema de CHM também mostrou uma melhora maior medida como o desaparecimento ou encolhimento de massas anexiais que com danazol (RR 1,70, IC 95% 1,04-2,78). Para dor na região lombossacral, desconforto retal, ou ternura nódulos vaginal, não houve diferença significativa entre CHM e danazol.
Conclusão dos autores: Pós-cirúrgico administração de CHM pode ter benefícios comparáveis aos gestrinone mas com menos efeitos colaterais. Oral CHM pode ter um efeito de tratamento total melhor do que o danazol, que pode ser mais eficaz no alívio de dismenorreia e encolhendo massas anexiais quando usado em conjunto com um enema CHM. No entanto, mais rigorosa investigação é necessária para avaliar com precisão o papel potencial do CHM no tratamento da endometriose.
INTRODUÇÃO: A endometriose é uma condição ginecológica muito frequente que afeta significativamente a vida das mulheres. As manifestações clínicas podem variar desde ausência de sintomas até queixas de dor pélvica crônica, especialmente dismenorréia. O controle da dor da endometriose ainda é inadequado. A acupuntura tem sido estudada para algumas doenças ginecológicas, mas sua efetividade no controle da dor da endometriose ainda é incerta.
OBJETIVOS: Avaliar a efetividade e segurança da acupuntura no controle da dor da endometriose.
MÉTODOS DE BUSCA: Nós procuramos nas seguintes bases de dados eletrônicas: Cochrane Menstrual Disorders and Subfertility Group (MSDG) Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL, AMED, PsycINFO, CNKI and TCMDS (desde o começo até 2010) e também nas listas de referência dos artigos incluídos.
CRITÉRIO DE SELEÇÃO: Ensaios clínicos controlados uni- ou duplo-cegos envolvendo mulheres em idade reprodutiva com diagnóstico de endometriose confirmado por laparoscopia que compararam acupuntura (corporal, nocouro cabeludo ou auricular) com placebo ou acupuntura fictícia (sham), nenhum tratamento, terapias convencionais ou medicina chinesa com ervas.
COLETA DOS DADOS E ANÁLISES: Três autores independentes avaliaram o risco de viés e extraíram os dados dos estudos; os autores dos estudos foram contatados para se obter informações adicionais. Não foi possível fazer meta-análises já que encontramos apenas um estudo. O desfecho primário foi diminuição da dor decorrente da endometriose. Os desfechos secundários foram modificações na qualidade de vida avaliada através de escalas, taxa de gravidez, efeitos colaterais e taxa de recorrência da endometriose.
PRINCIPAIS RESULTADOS: Foram encontrados 24 estudos que analisaram a acupuntura para o tratamento da dor na endometriose. Porém, apenas um ensaio clínico, com 67 participantes preencheu todos os critérios de inclusão. Este único estudo usou o Guideline for Clinical Research on New Chinese Medicine para avaliar a dor e a taxa de cura. A pontuação na escala de dismenorréia foi menor no grupo que recebeu acupuntura (diferença média -4.81 pontos, intervalo de confiança de 95% -6.25 a -3.37, P < 0,00001) na escala de 15 pontos Pelvic Endometriosis scale recomendada pelo Guideline. A taxa total de efetividade (‘curado’, ‘significativamente efetivo’ ou ‘efetivo’) da acupuntura auricular foi de 91,9% e de 60% para a medicina chinesa (risco relativo 3,04, IC 95% 1,65 a 5,62, P = 0,0004). A taxa de melhora não foi significativamente diferente entre o grupo de acupuntura auricular e de medicina chinesa com ervas para as participantes com dismenorréia leve a moderada. Por outro lado, a acupuntura auricular reduziu significativamente a dor em casos de dismenorréia grave. Não encontramos dados sobre os desfechos secundários.
CONCLUSÃO DOS AUTORES: As evidências para apoiar a efetividade da acupuntura para o tratamento da dor na endometriose são limitadas, sendo provenientes de apenas um único estudo. Esta revisão aponta para a necessidade da condução de novos ensaios clínicos de boa qualidade, duplo-cegos, comparando diversos tipos de acupuntura com técnicas convencionais de tratamento para dor em pacientes com endometriose.
Endometriosis is a condition characterised by the presence of ectopic deposits of endometrial-like tissue outside the uterus, usually in the pelvis. The impact of laparoscopic treatment on overall pain is uncertain and a significant proportion of women will require further surgery. Therefore, adjuvant medical therapies following surgery, such as the levonorgestrel-releasing intrauterine device (LNG-IUD), have been considered to reduce recurrence of symptoms.
OBJECTIVES:
To determine the effectiveness and safety of post-operative LNG-IUD in women with symptomatic endometriosis.
SEARCH METHODS:
We searched the following databases from inception to January 2021: The Specialised Register of the Cochrane Gynaecology and Fertility Group, CENTRAL (which now includes records from two trial registries), MEDLINE, Embase, PsycINFO, LILACS and Epistemonikos. We handsearched citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies. We contacted experts in the field for information about any additional studies.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) comparing women undergoing surgical treatment of endometriosis with uterine preservation who were assigned to LNG-IUD insertion, versus control conditions including expectant management, post-operative insertion of placebo (inert intrauterine device), or other medical treatment such as gonadotrophin-releasing hormone agonist (GnRH-a) drugs.
DATA COLLECTION AND ANALYSIS:
Two review authors independently selected studies for inclusion, and extracted data to allow for an intention-to-treat analysis. For dichotomous data, we calculated the risk ratio (RR) and 95% confidence interval (CI) using the Mantel-Haenszel fixed-effect method. For continuous data, we calculated the mean difference (MD) and 95% CI using the inverse variance fixed-effect method.
MAIN RESULTS:
Four RCTs were included, with a total of 157 women. Two studies are ongoing. The GRADE certainty of evidence was very low to low. The certainty of evidence was graded down primarily for serious risk of bias and imprecision. LNG-IUD versus expectant management Overall pain: No studies reported on the primary outcome of overall pain. Dysmenorrhoea: We are uncertain whether LNG-IUD improves dysmenorrhoea at 12 months. Data on this outcome were reported on by two RCTs; meta-analysis was not possible (RCT 1: delta of median visual analogue scale (VAS) 81 versus 50, P = 0.006, n = 55; RCT 2: fall in VAS by 50 (35 to 65) versus 30 (25 to 40), P = 0.021, n = 40; low-certainty evidence). Quality of life: We are uncertain whether LNG-IUD improves quality of life at 12 months. One trial demonstrated a change in total quality of life score with postoperative LNG-IUD from baseline (mean 61.2 (standard deviation (SD) 14.8) to 12 months (mean 70.3 (SD 16.2) compared to expectant management (baseline 55.1 (SD 17.0) to 57.0 (SD 33.2) at 12 months) (n = 55, P = 0.014, very low-certainty evidence). Patient satisfaction: Two studies found higher rates of satisfaction with LNG-IUD compared to expectant management; however, combining the studies in meta-analysis was not possible (n = 95, very low-certainty evidence). One study found 75% (15/20) of those given post-operative LNG-IUD were "satisfied" or "very satisfied", compared to 50% (10/20) of those in the expectant management group (RR 1.5, 95% CI 0.90-2.49, 1 RCT, n=40, very low-certainty evidence). The second study found that fewer were "very satisfied" in the expectant management group when compared to LNG, but there were no data to include in a meta-analysis. Adverse events: One study found a significantly higher proportion of women reporting melasma (n = 55, P = 0.015, very low-certainty evidence) and bloating (n = 55, P = 0.021, very low-certainty evidence) following post-operative LNG-IUD. There were no differences in other reported adverse events, such as weight gain, acne, and headaches. LNG-IUD versus GnRH-a Overall pain: No studies reported on the primary outcome of overall pain. Chronic pelvic pain: We are uncertain whether LNG-IUD improves chronic pelvic pain at 12 months when compared to GnRH-a (VAS pain scale) (MD -2.0, 95% CI -20.2 to 16.2, 1 RCT, n = 40, very low-certainty evidence). Dysmenorrhoea: We are uncertain whether LNG-IUD improves dysmenorrhoea at six months when compared to GnRH-a (measured as a reduction in VAS pain score) (MD 1.70, 95%.CI -0.14 to 3.54, 1 RCT, n = 18, very low-certainty evidence). Adverse events: One study suggested that vasomotor symptoms were the most common adverse events reported with patients receiving GnRH-a, and irregular bleeding in those receiving LNG-IUD (n = 40, very low-certainty evidence)
AUTHORS' CONCLUSIONS:
Post-operative LNG-IUD is widely used to reduce endometriosis-related pain and to improve operative outcomes. This review demonstrates that there is no high-quality evidence to support this practice. This review highlights the need for further studies with large sample sizes to assess the effectiveness of post-operative adjuvant hormonal IUD on the core endometriosis outcomes (overall pain, most troublesome symptom, and quality of life).
