Sistema intrauterino liberador de levonorgestrel para la hiperplasia endometrial
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en curso
Referencias adicionales
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Prospective randomised trial Single‐centre | |
| Participants | Country: Egypt Population: women with abnormal uterine bleeding attending the gynaecology outpatient clinic Mean age 41.7 years (33 to 51) N = 84 women (68 pre‐menopausal, 16 post‐menopausal) Inclusion criteria: simple endometrial hyperplasia without atypia (Kurman criteria) Exclusion criteria: patients with other pathology e.g. submucosal myomas or polyps, adnexal abnormality, genital infection, hormone therapy or any medication which might affect the menstrual blood loss within the previous 6 months e.g. steroid hormones or anticoagulants, previous endometrial ablation, diabetic and/or hypertensive patients Recruitment from June 2011 to April 2013 | |
| Interventions | 1. Levonorgestrel intrauterine system (n = 42) inserted 1 day after cessation of bleeding with transvaginal ultrasonography to confirm accurate position versus 2. Norethisterone acetate (n = 42) continuously 15 mg/day orally for 3 months, commenced between bleeding attacks Duration of treatment: 3 months (Phase I) | |
| Outcomes | 1. Regression of endometrial hyperplasia. This was defined by authors as the number of responders after 3 months of treatment measured by pipelle catheter biopsy (responders: resolution; non‐responders: persistence of simple endometrial hyperplasia, or progression to complex endometrial hyperplasia) 2. Adverse effects associated with hormones. The authors recorded the duration and severity of uterine bleeding (points‐based pictorial blood assessment chart) 3. Satisfaction with treatment (Likert‐type scale) | |
| Notes | Funding source not reported Ethical approval obtained Informed consent obtained No trial registration or study protocol found | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "Patients were randomly, using sealed envelopes, allocated into two groups." Process of random sequence generation not described. |
| Allocation concealment (selection bias) | Unclear risk | "Sealed envelopes" used for allocation. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects and satisfaction. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | The study does not provide information on those performing histological diagnosis or outcome assessors, and whether they were blinded to the treatment groups. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | No blinding of participants ‒ self‐report. |
| Incomplete outcome data (attrition bias) | Low risk | Data for all participants recorded. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | Baseline demographics similar, no obvious bias detected. |
| Study characteristics | ||
| Methods | Randomised controlled trial Single‐centre | |
| Participants | Country: Egypt Population: women complaining of abnormal uterine bleeding attending the gynaecology outpatient clinic in Mansoura University Hospitals, Egypt Age range 40 to 50 years N = 120 (pre‐menopausal) Inclusion criteria: those with histologically confirmed non‐atypical simple or complex endometrial hyperplasia, age between 40 and 50 years with an ongoing menstrual cycle for at least 6 months before the onset of AUB and no contraindication to either LNG‐IUS or NET e.g. current or a history of deep venous thrombosis, active thrombophlebitis, thromboembolic disorder, or cerebrovascular accident, myocardial infarction or ischaemic heart disease and liver disease Exclusion criteria: endometrial hyperplasia with atypia, age > 50 years, other pathology e.g. submucosal myomas or polyps, adnexal abnormality, genital infection, hormone therapy or any medication which might affect the menstrual blood loss within the previous 6 months e.g. steroid hormones or anticoagulants, previous endometrial ablation, diabetic and/or hypertensive patients and those unwilling for medical management Recruitment from May 2009 to November 2011 | |
| Interventions | 1. LNG‐IUS (Mirena, Bayer Schering Pharma Oy, Turku, Finland) (n = 59). Duration of treatment for 12 months. versus 2. Norethisterone acetate (Cidolut Nor, Chemical Industries Development, Cairo, Egypt) (n = 61). 5 mg tablet 3 times daily for 3 weeks over 3 months. Ongoing treatment depending on outcomes. | |
| Outcomes | 1. Regression of endometrial hyperplasia. This was measured by pipelle catheter biopsy and the authors also reported on the median time to regression during the 12 months' follow‐up period 2. Proportion of women undergoing hysterectomy 3. Adverse effects associated with hormones | |
| Notes | Funding source not reported Ethical approval obtained Informed consent obtained Study protocol was registered on ClinicalTrials.gov (Identifier: NCT01499602) Sample size power calculation performed | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Women were randomised according to a computer‐generated random numeric table." |
| Allocation concealment (selection bias) | Low risk | "...prepared by an independent statistician with concealment of treatment allocation by use of sealed opaque envelopes that were given to a third party (nurse) who assigned patients to study arms." |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. This was considered in the discussion “because of different nature of treatments.” |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." For hysterectomy rate, some hysterectomies done due to patient request/symptoms with potential bias. |
| Blinding of outcome assessment (detection bias): EH regression | Low risk | Outcome assessment i.e. those performing histological diagnosis (2 independent gynaecological pathologists) and statistical analysis were blinded to the treatment groups. |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Adverse effects were self‐reported/measured. Hysterectomy rate was influenced by patient preference. |
| Incomplete outcome data (attrition bias) | Low risk | After randomisation and allocation some participants were lost to follow‐up. 5% (3/59) attrition rate in LNG‐IUS group and 6.5% (4/61) attrition rate in NET group is similar. Both intention‐to‐treat and per protocol analysis done. |
| Selective reporting (reporting bias) | Low risk | Primary outcomes listed in the trial registry were reported in the results. |
| Other bias | Low risk | "No significant differences between both groups as regards baseline characteristics, clinical presentation and histological types of EH." |
| Study characteristics | ||
| Methods | Randomised, parallel‐group, double‐blind clinical trial Single‐centre | |
| Participants | Country: Iran Population: women with the initial histopathological diagnosis of endometrial hyperplasia who were referred to the hospital clinic Median age 38.4 ± 4.8 N = 60 Inclusion criteria: endometrial hyperplasia (simple or complex) who had no desire for pregnancy in the coming 3 years, and did not receive hormonal treatment prior to therapy for endometrial hyperplasia Exclusion criteria: sleeping disorders, breastfeeding, congenital uterine abnormality, history of vascular or coagulation disorders, concomitant use of medication or presence of an underlying disease/condition known to affect the metabolism or pharmacokinetics of the study medications, allergy to progestin and family history of breast cancer Recruitment from July to December 2016 | |
| Interventions | 1. LNG‐IUS (Bayer Schering Pharma, Berlin, Germany, with release rate of LNG 20 mcg/day) (n = 30). Duration of treatment 3 months versus 2. Medroxyprogesterone acetate (Aburaihan Pharmaceutical Company, Iran) (n = 30). 10 mg/day orally for 12 days/month for 3 months | |
| Outcomes | 1. Regression of endometrial hyperplasia. This was defined by the authors as response to treatment measured by pipelle endometrial biopsy (resolution, persistence progression) 2. Adverse effects associated with hormones 3. Withdrawal secondary to adverse effects | |
| Notes | Funding grant support from Isfahan University of Medical Sciences, Isfahan, Iran Ethics approval obtained Written informed consent obtained No trial registration or study protocol found; searches included the Iranian Registry of Clinical Trials | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random‐maker software. "Random Allocation." |
| Allocation concealment (selection bias) | Unclear risk | It is not described how participants were allocated after randomisation. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | Low risk | The gynaecologic pathologist was blinded to the modality of treatment. |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Adverse effects and satisfaction were self‐reported. |
| Incomplete outcome data (attrition bias) | High risk | After randomisation and allocation, women were excluded due to adverse effects. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | Baseline characteristics of patients reported and "no significant differences were noted between groups". |
| Study characteristics | ||
| Methods | Randomised controlled trial Single‐centre | |
| Participants | Country: China Population: consecutive women with PCOS defined according to the 2003 Rotterdam criteria, undergoing IVF embryo transfer Median age 32.36 years N = 190 Inclusion criteria: PCOS with simple endometrial hyperplasia were randomised. Those with PCOS without simple endometrial hyperplasia formed the control arm Exclusion criteria: complex hyperplasia Recruitment from August 2004 to March 2011 | |
| Interventions | 1. LNG‐IUS inserted 1 week after endometrial biopsy (n = 90). Duration of treatment 6 months versus 2. Non‐LNG‐IUS group (n = 100) | |
| Outcomes | 1. Regression of endometrial hyperplasia. Defined by the authors as response to treatment measured by pipelle endometrial biopsy (resolution, regression, persistence, progression) | |
| Notes | No financial support received Ethics approval obtained Written informed consent obtained No trial registration or study protocol found; searches included the Chinese Clinical Trial Registry | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Patients with PCOS and simple EH were "allocated randomly to 2 independent arms by centralised computer software." |
| Allocation concealment (selection bias) | Unclear risk | Not specified whether concealed. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | Whilst this RCT did not evaluate any subjective measures as outcomes, for consistency of comparing risk of bias between trials, if they had this would be rated high risk as blinding between LNG‐IUS and oral progesterone is not possible without placebo. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | Low risk | The gynaecologic pathologist was blinded to the modality of treatment. |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Whilst this RCT did not evaluate any subjective measures as outcomes, for consistency of comparing risk of bias between trials, if they had as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Incomplete outcome data (attrition bias) | Low risk | After randomisation, no missing data. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | "In general the groups did not differ". |
| Study characteristics | ||
| Methods | Open‐label, prospective randomised controlled trial Single‐centre | |
| Participants | Country: Turkey Population: patients who presented to the outpatient clinic with abnormal uterine bleeding and diagnosed with endometrial hyperplasia Age 30 to 50 years N = 104 Inclusion criteria: endometrial hyperplasia without atypia, below 50 years of age Exclusion criteria: patients aged above 50 years, atypia, submucous myoma, ovarian tumour, uterine myomatosis greater than 12 cm Recruitment from 2 January 2005 to 31 December 2009 | |
| Interventions | 1. LNG‐IUD (n = 52). 3‐month treatment subgroup (n = 26); 6‐month treatment subgroup (n = 26) versus 2. Medroxyprogesterone acetate (n = 52). 3‐month treatment subgroup (n = 26); 6‐month treatment subgroup (n = 26). 10 mg/d orally given 10 days per month | |
| Outcomes | 1. Regression of endometrial hyperplasia measured by endometrial biopsy with a suction catheter or curettage if insufficient (persistent, regression, reversion) 2. Proportion of women undergoing hysterectomy | |
| Notes | 2 patients did not complete 2‐year follow‐up and were excluded from the study Funding source not reported Ethics approval obtained Informed consent obtained No trial registration or study protocol found | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Randomisation was conducted by using a computer‐generated table of random numbers." |
| Allocation concealment (selection bias) | Unclear risk | "With allocation concealment." |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | Whilst this RCT did not evaluate any subjective measures as outcomes, for consistency of comparing risk of bias between trials, if they had this would be rated high risk as blinding between LNG‐IUS and oral progesterone is not possible without placebo. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | Open‐label trial design, blinding of outcome assessment not stated. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Whilst this RCT did not evaluate any subjective measures as outcomes, for consistency of comparing risk of bias between trials, if they had as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Incomplete outcome data (attrition bias) | Low risk | After randomisation and allocation, only 1 participant in LNG‐IUD group, and 1 in the progesterone group were lost to follow‐up. All outcome data recorded and explained. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | For baseline data "there was no difference between the groups." |
| Study characteristics | ||
| Methods | Randomised controlled trial Single‐centre | |
| Participants | Country: Egypt Population: women attending the outpatient clinic with abnormal uterine bleeding Age range 30 to 50 years N = 138 Inclusion criteria: age between 30 and 50 years old, those with histologically confirmed non‐atypical simple or complex endometrial hyperplasia, a desire to avoid hysterectomy, and no contraindications against progestin hormones Exclusion criteria: uterine anomaly, women with fibroids (more than 12 weeks' size or distorting the uterine cavity), malignancy, genital infection, liver disease or liver tumour (benign or malignant), thromboembolic disease, deep vein thrombosis, hypercoagulable state, a history of coronary artery disease, or myocardial infarction Recruitment from May 2011 to November 2012 | |
| Interventions | 1. LNG‐IUD (Mirena, Bayer Schering Oy, Turku, Finland) (n = 60). Inserted in the uterine cavity in the postmenstrual phase in the outpatient department and kept in situ for 6 months versus 2. Dydrogesterone (Duphaston, Solvay pharmaceuticals B V, the Netherlands) (n = 78). 10 mg, 2 tablets twice daily orally from fifth day of menstruation for 21 days for 6 months | |
| Outcomes | 1. Regression of endometrial hyperplasia. This was measured by dilation and curettage biopsy at 6 months. The authors reported on recurrence of endometrial hyperplasia during a 12 months' follow‐up period. 2. Proportion of women undergoing hysterectomy 3. Adverse effects associated with hormones | |
| Notes | After randomisation 18 women withdrew from the oral group before completion of the study because of non‐compliance to progesterone side effects, and another 2 women withdrew from the LNG‐IUD group because of noncompliance due to menstrual spotting. Therefore, the final studied group included 118 women – 18 women were lost to follow‐up and thus excluded, leaving a final 100 women completing the study (50 in each group) No financial support received Ethics approval obtained Informed consent obtained No trial registration or study protocol found | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomisation using computer‐generated random numbers. Randomisation uneven: "78 were assigned to receive oral progesterone and 60 were assigned to insert LNG‐IUD." |
| Allocation concealment (selection bias) | Unclear risk | Not stated. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects, as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | No blinding and the study does not provide information on those performing histological diagnosis or outcome assessment, and whether they were blinded to the treatment groups. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Adverse effects and satisfaction were self‐reported. Hysterectomy rate was influenced by patient preference. |
| Incomplete outcome data (attrition bias) | High risk | "After randomisation, 20 women withdrew (18 oral vs 2 IUS) and 18 were lost to follow‐up (10 oral vs. 8 IUS) which translates to 36% ([18+10]/78) attrition rate for the oral group and 17% 9[2+8]/60) attrition rate for the IUS group. Higher chance of patients continuing the LNG‐IUS treatment resulted in higher compliance and better efficacy in treating EH compared to oral progestogens". |
| Selective reporting (reporting bias) | Unclear risk | Side effects were asked but the time frame unclear. The reason for hysterectomy is unclear, whether hysterectomy rates linked to side effects. |
| Other bias | Low risk | Baseline characteristics reported and no obvious significant differences. |
| Study characteristics | ||
| Methods | Randomised comparative study Single‐centre | |
| Participants | Country: Kuwait Population: premenopausal women with histological diagnosis of simple endometrial hyperplasia without cytological atypia The initial histologic diagnosis was based on endometrial curettage specimens obtained by dilation and curettage performed under general anaesthesia and assessed by a gynaecologic pathologist using the 1994 WHO classification of EH Premenopausal status was defined by measuring serum FSH (<20 IU/L) and the ongoing menstrual cycle for at least 6 months before inclusion Age range 35 to 50 years N = 90 Inclusion criteria: age 35 to 50 years with abnormal uterine bleeding Exclusion criteria: hormonal treatment in the previous 6 months, associated pathologies of the endometrial cavity or adnexa, atypical EH or complex EH, hot flushes, sleeping disorders or changes in mood within the 3 months preceding the study, breastfeeding, congenital uterine abnormality, hypothyroidism, hypertension, history of vascular or coagulation disorders, concomitant use of medication or presence of an underlying disease/condition known to affect the metabolism or pharmacokinetics of the study medications, allergy to progestins, family history of breast cancer, and a BMI > 40 | |
| Interventions | 1. LNG‐IUS (Mirena, Schering, Germany) (n = 30). Duration of treatment 3 months versus 2. Medroxyprogesterone acetate (Provera, Pfizer, New York) (n = 30). 10 mg/day orally for 10 days a month (16th to 25th day of the menstrual cycle) for 3 months versus 3. Norethisterone (Primolut‐Nor, Schering, Germany) (n = 30). 15 mg/day orally for 10 days a month (16th to 25th day of the menstrual cycle) for 3 months | |
| Outcomes | 1. Regression of endometrial hyperplasia. The authors defined this as the proportion of patients requiring further treatment for another 3 months (follow‐up pipelle endometrial biopsy ‒ classified as resolution, regression or persistence) 2. Proportion of women undergoing hysterectomy 3. Adverse effects associated with hormones 4. Withdrawal secondary to adverse effects | |
| Notes | No financial support received 10 patients dropped out before randomisation (5 patients refused to undergo dilation and curettage and another 5 decided not to participate in the study) Ethics approval obtained Written informed consent obtained No trial registration or study protocol found | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Computer generated, random number list." |
| Allocation concealment (selection bias) | Low risk | "The group assignment numbers were sealed in an envelope and kept by the study supervisor. After written informed consent was signed, the opaque envelope was unsealed to determine which treatment modality would be performed." |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects, as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | Low risk | The gynaecologic pathologist was blinded to the modality of treatment. |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | No blinding of participants ‒ self‐report. |
| Incomplete outcome data (attrition bias) | Low risk | All those randomised were analysed. All outcome data stated for the primary outcome (low risk), however other outcomes not pre‐specified had patchy results e.g. adverse effects. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | "The three groups were similar." |
| Study characteristics | ||
| Methods | Prospective randomised controlled study Single‐centre | |
| Participants | Country: Iran Population: women with endometrial hyperplasia suffering from abnormal uterine bleeding who referred to Shahid Sadoughi Hospital for treatment Age range 22 to 47 years N = 40 Inclusion criteria: abnormal uterine bleeding due to endometrial hyperplasia confirmed by pathology, women of reproductive age group who intend to preserve their fertility Exclusion criteria: not specified | |
| Interventions | 1. LNG‐IUD which releases 20 mcg levonorgestrel per day (n = 20). Treatment duration for 3 months versus 2. Medroxyprogesterone acetate (n = 20). 20 mg daily for 10 days in each menstrual cycle, for 3 months | |
| Outcomes | 1. Regression of endometrial hyperplasia. The authors defined this as response to treatment 3 months following treatment (evaluated using vaginal ultrasound and reviewing of pathology reports) Pathological status after treatment (progestational effect, proliferative, atrophic, simple, atypia) Endometrial thickness compared Menstrual conditions of patients compared 2. Adverse effects associated with hormones 3. Satisfaction with treatment | |
| Notes | Recruitment period not specified Funding source not specified Ethics approval not specified No trial registration or study protocol found; searches included the Iranian Registry of Clinical Trials | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information: "...patients were randomly divided." |
| Allocation concealment (selection bias) | Unclear risk | Not specified. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects and satisfaction. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | Not stated. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | No blinding of participants ‒ self‐report. |
| Incomplete outcome data (attrition bias) | Low risk | After randomisation, no missing data. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Unclear risk | Baseline characteristics reported and no obvious significant differences. Discrepancy in table 2 and text on response to treatment data (different denominator). |
| Study characteristics | ||
| Methods | Randomised controlled trial Multicentre ‒ 17 gynaecological centres | |
| Participants | Country: Norway Population: women presenting with clinical symptoms and ultrasound related signs Age range 30 to 70 years N = 170 Inclusion criteria: women between 30 and 70 years of age, with histologically confirmed endometrial hyperplasia according to WHO94 classification and D‐score Exclusion criteria: hypersensitivity to progestin, active genital infection, a history of genital or mammary cancer, undiagnosed vaginal bleeding, liver disease, serious thrombophlebitis or pregnancy Recruitment from 1 January 2005 to November 2011; the 2016 study until 1 May 2014 | |
| Interventions | 1. LNG‐IUS (Mirena) 20 mcg levonorgestrel per 24 hours (n = 56). Treatment duration for 6 months versus 2. Medroxyprogesterone acetate (n = 57). 10 mg orally administered for 10 days per cycle for 6 months versus 3. Medroxyprogesterone acetate (n = 57). Continuous 10 mg orally daily for 6 months | |
| Outcomes | 1. Regression of endometrial hyperplasia, assessed by light microscopy. The 2016 study examined the relapse of endometrial hyperplasia (endometrial biopsy and light microscopy) at 24 months 2. Adverse effects associated with hormones 3. Withdrawal secondary to adverse effects | |
| Notes | 278 women were eligible for randomisation. 108 unwilling to participate/criteria not fulfilled. Withdrawals – 5 from progestin cycle, 9 from continuous progestin, 3 from LNG‐IUS. Funders: research grants by the Norwegian Cancer Association, the Regional Research Board of Northern Norway (Helse Nord), and the Bank of North Norway. Annual funding granted from the University of Tromsø. Progestogen tablets and LNG‐IUS funded by the coordinator of the study and were given free to the women for the entire treatment period. The coordinator has received fees from Bayer for invited lectures. Ethics approval obtained Written informed consent obtained Study protocol registered at ClinicalTrials.gov (Identifier: NCT01074892) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Randomisation unit at the Clinical Research Centre, University Hospital of North Norway – computer random number generator with two strata and fixed block size." |
| Allocation concealment (selection bias) | Low risk | "For allocation a computer‐generated list of random numbers was used. The people involved in the randomisation procedure were unaware of the block size used. To secure concealed allocation, central telephone randomisation at the Clinical Research Centre was used." |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. “Participating gynaecologists as well as women in all three therapy groups might have been biased as blinding of the therapy was not performed. Although the possibility was evaluated before study start, it was concluded that the intrauterine and oral therapy were so principally different that placebo medication would have been difficult to implement. Construction of an intrauterine placebo device was considered a possible alternative; however, this was not within reach from an economical view. Of great importance is the fact that when dealing with premalignant diseases, treatment with placebo might be considered unethical.” |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects, as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | Low risk | "On investigation of endometrial biopsies the pathologists and engineers were always blinded to which treatment group the woman belonged. Treatment effect was obtained after consensus between two different pathologists." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | No blinding of participants ‒ adverse effects self‐reported. |
| Incomplete outcome data (attrition bias) | Low risk | No interim analyses were performed during the inclusion period to avoid bias, as the first included women had completed treatment before the last were included. “A simple sensitivity analysis was performed to ensure that withdrawals from the study were not influencing the main conclusions of the study.” |
| Selective reporting (reporting bias) | Low risk | Primary outcomes listed in the trial registry were reported in the results. |
| Other bias | Low risk | For demographic data there was "no difference between treatment groups." |
| Study characteristics | ||
| Methods | Randomised parallel group study Single‐centre | |
| Participants | Country: Egypt Population: menstruating perimenopausal women presenting with abnormal uterine bleeding Age range: Group 1 (MPA) 44.56 ± 0.7 years Group 2(NETA) 45.53 ± 3.89 years Group 3 (LNG‐IUS) 44.63 ± 4.19 years N = 162 Inclusion criteria: above the age of 40 years presenting with AUB with histologically confirmed endometrial hyperplasia without atypia, following clinical examination, transvaginal sonography and endometrial sampling by pipelle Exclusion criteria: women with associated lesions as uterine fibroid, cervical or vaginal pathology, bleeding tendency, hormonal contraception in the past 3 months, chronic medical diseases such as diabetes mellitus, hypertension, chronic liver disease, any contraindication to progestin therapy and postmenopausal women Study period from June 2012 to June 2016 | |
| Interventions | 1. Group 3: LNG‐IUS (Mirena, Bayer HealthCare, Berlin, Germany) (n = 50). Treatment duration for 6 months versus 2. Group 1: Medroxyprogesterone acetate Provera 5 mg tablets, Pfizer, USA (n = 50). 5 mg tablet 3 times per day orally for 14 days per month for 6 months versus 3. Group 2: Norethisterone acetate (Cidolut nor 5 mg tablets, CID pharmaceuticals, Cairo, Egypt) (n = 50). 5 mg tablet 3 times per day orally for 14 days per month for 6 months | |
| Outcomes | 1. Regression of endometrial hyperplasia on subsequent biopsy 2. Adverse effects associated with hormones 3. Withdrawal secondary to adverse effects 4. Satisfaction. The authors defined this as patient acceptability (compliance, satisfaction, recommendability of the method) 5. Cost of treatment | |
| Notes | 12 patients dropped out (stopped treatment and lost to follow‐up) Funding source not specified Ethics approval obtained Written informed consent obtained No trial registration or study protocol found. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Computer generated simple random tables according to the ratio 1:1:1." |
| Allocation concealment (selection bias) | Unclear risk | It is not described how participants were allocated after randomisation. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects and satisfaction. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." For cost of treatment it is not clear if participants or personnel knew the costs. |
| Blinding of outcome assessment (detection bias): EH regression | High risk | The study did not address this. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Adverse effects and satisfaction with treatment self‐reported, participants/assessors not blind. |
| Incomplete outcome data (attrition bias) | High risk | After randomisation and allocation, there were participants per group who were lost to follow‐up or discontinued drug. Discrepancy in Figure 1 of the paper regarding how many lost to follow‐up/discontinued after allocation and the number analysed. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | In baseline characteristics there was "no significant difference between the three groups." |
| Study characteristics | ||
| Methods | Randomised controlled trial Single centre | |
| Participants | Country: Pakistan Population: women with endometrial thickness > 7 mm on transvaginal ultrasound Age range: 37 to 75 years N = 140 Inclusion criteria: above the age of 35 years, diagnosed with endometrial hyperplasia, confirmed on histopathology of endometrial specimen obtained by dilation and curettage Exclusion criteria: women taking progesterone by any other route, hypertension, diabetes, endometrial carcinoma or other intrauterine pathologies, allergy to progesterone agents Study period from August 2016 to February 2017 | |
| Interventions | Group 1: LNG‐IUS 14 mcg/day (n = 70). Treatment duration 3 months versus Group 2: injectable (intramuscular) Medroxyprogesterone 150 mg/mL (n = 70). Treatment duration 3 months | |
| Outcomes | 1. Regression of endometrial hyperplasia defined as thickness of the endometrium measured by transvaginal ultrasonography < 5 mm and secretory, proliferative, inactive or atrophic | |
| Notes | Funding source not specified Ethics approval not documented Informed consent obtained No trial registration or study protocol found | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Lottery method." |
| Allocation concealment (selection bias) | Unclear risk | Method of concealment is not described. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | Whilst this RCT did not evaluate any subjective measures as outcomes, for consistency of comparing risk of bias between trials, if they had this would be rated high risk as blinding between LNG‐IUS and oral progesterone is not possible without placebo. As per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | The study did not address this. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Whilst this RCT did not evaluate any subjective measures as outcomes, for consistency of comparing risk of bias between trials, if they had as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Incomplete outcome data (attrition bias) | Low risk | After randomisation, no missing data. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes listed in the paper's methods were reported in the results. No trial registration or study protocol identified. |
| Other bias | Low risk | Baseline demographics reported in text similar between groups. |
| Study characteristics | ||
| Methods | Randomised trial Single‐centre | |
| Participants | Country: China Population: women younger than 50 years old, diagnosed with simple hyperplasia by pathologic results Age < 50 years old N = 243 Study period from August 2010 to June 2013 | |
| Interventions | 1. LNG‐IUS versus 2. Progestins, not further specified versus 3. COCs, not further specified Duration 6 months | |
| Outcomes | 1. Regression of EH, assessed by endometrial curettage for pathologic examination 2. Adverse effects associated with hormones | |
| Notes | Abstract only Funding source not specified Ethics approval not specified | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Methodology not described in abstract therefore unable to assess risk of bias. |
| Allocation concealment (selection bias) | Unclear risk | Not described. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects, as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | Not described. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Self‐reported. |
| Incomplete outcome data (attrition bias) | Unclear risk | Not described. |
| Selective reporting (reporting bias) | Unclear risk | Not described. |
| Other bias | Unclear risk | Not described. |
| Study characteristics | ||
| Methods | Randomised trial Single‐centre | |
| Participants | Country: China Population: women younger than 50 years old, diagnosed with complex hyperplasia Age < 50 years old N = 116 Study period from January 2009 to December 2012 | |
| Interventions | 1. LNG‐IUS versus 2. Non‐intrauterine progestogens, not further specified versus 3. COCs, not further specified Duration 6 months | |
| Outcomes | 1. Regression of EH, assessed by endometrial curettage for pathologic examination 2. Adverse effects associated with hormones | |
| Notes | Abstract only Funding source not specified Ethics approval not specified | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described. |
| Allocation concealment (selection bias) | Unclear risk | Not described. |
| Blinding of participants and personnel (performance bias): EH regression | Low risk | No blinding/not possible; the review authors judge that the outcome (regression of endometrial hyperplasia) was not likely to be influenced by lack of blinding. |
| Blinding of participants and personnel (performance bias): Other outcomes | High risk | For adverse effects, as per review protocol: "for subjective measures, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): EH regression | High risk | Not described. As per review protocol: "if the pathologists reading the slides are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias." |
| Blinding of outcome assessment (detection bias): Other outcomes | High risk | Self‐reported. |
| Incomplete outcome data (attrition bias) | Unclear risk | Not described. |
| Selective reporting (reporting bias) | Unclear risk | Not described. |
| Other bias | Unclear risk | Not described. |
cm: centimetre
mg: milligram
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| Not RCT | |
| Not RCT | |
| Participants were taking tamoxifen therapy | |
| Intervention not LNG‐IUS. Compares oral progestins versus surgical treatment | |
| Not RCT | |
| Not RCT | |
| Comparator unclear. The Mirena was administered with the addition or transition to combined therapy with Klimonorm or Livial (hormone replacement therapy) | |
| Not RCT | |
| Intervention not LNG‐IUS | |
| Not RCT, intervention not LNG‐IUS | |
| Not RCT, no comparator | |
| Not RCT | |
| Not RCT | |
| Not RCT | |
| Article in Chinese. Translator used ‒ not RCT. |
Characteristics of ongoing studies [ordered by study ID]
| Study name | Megestrol acetate plus LNG‐IUS to megestrol acetate or LNG‐IUS in young women with endometrial atypical hyperplasia |
| Methods | Randomised, parallel assignment |
| Participants | 120 women with endometrial atypical hyperplasia |
| Interventions | Arm I: patients will receive MA (megestrol acetate) 160 mg by mouth daily for at least 3 months Arm II: patients will receive LNG‐IUS insertion Arm III: MA 160 mg plus LNG‐IUS insertion |
| Outcomes | Primary outcome: pathological response rate (regression) and time Secondary outcomes: adverse effects, relapse, pregnancy rate, compliance |
| Starting date | 4 July 2017 |
| Contact information | Xiaojun Chen, PhD; [email protected] |
| Notes | Clinicaltrials.gov NCT03241888 |
| Study name | Value of levonorgestrel‐releasing intrauterine system (LNG‐IUS) in the fertility‐preserving treatment of atypical endometrial hyperplasia and early endometrial carcinoma |
| Methods | Randomised, parallel assignment |
| Participants | 224 women with atypical endometrial hyperplasia or early endometrial carcinoma, fertility sparing treatment |
| Interventions | 1. MPA 2. MPA + LNG‐IUS 3. LNG‐IUS |
| Outcomes | Primary: pathological response rate (regression), pregnancy rate, live birth rate Secondary: side effects rate |
| Starting date | 1 April 2018 |
| Contact information | Professor Ying Zheng; [email protected] |
| Notes | Clinicaltrials.gov NCT03463252 |
| Study name | Vaginal micronized progesterone versus levonorgestrel for treatment of non‐atypical endometrial hyperplasia |
| Methods | Randomised, parallel assignment |
| Participants | Women age 18 to 55 years with histologically confirmed endometrial hyperplasia without atypia |
| Interventions | 1. Vaginal micronized progesterone 2. LNG‐IUS |
| Outcomes | Primary: regression and remission rate of endometrial hyperplasia Secondary: mean reduction from baseline in menstrual blood loss, number of participants with adverse events associated with medication and device |
| Starting date | 20 June 2019 |
| Contact information | Şener Gezer; [email protected] |
| Notes | ClinicalTrials.gov NCT03992937 |
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Regression of EH; by length of follow‐up Show forest plot | 10 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.1  Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 1: Regression of EH; by length of follow‐up | ||||
| 1.1.1 Short follow‐up ≤ 6 months | 10 | 1108 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.94 [2.10, 4.13] |
| 1.1.2 Long follow‐up ≥ 1 year | 1 | 138 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.80 [1.75, 8.23] |
| 1.2 Hysterectomy; histologically and non‐histologically indicated Show forest plot | 4 | 452 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.15, 0.46] |
| Analysis 1.2  Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 2: Hysterectomy; histologically and non‐histologically indicated | ||||
| 1.3 Adverse effects associated with hormones Show forest plot | 4 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.3  Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 3: Adverse effects associated with hormones | ||||
| 1.3.1 Bleeding/spotting | 3 | 428 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.13 [1.33, 3.43] |
| 1.3.2 Nausea | 3 | 428 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.28, 0.95] |
| 1.3.3 Weight gain | 3 | 318 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.56, 2.96] |
| 1.4 Withdrawal secondary to adverse effects Show forest plot | 4 | 360 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.12, 1.35] |
| Analysis 1.4  Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 4: Withdrawal secondary to adverse effects | ||||
| 1.5 Satisfaction with treatment Show forest plot | 2 | 202 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.28 [2.51, 11.10] |
| Analysis 1.5  Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 5: Satisfaction with treatment | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Regression of EH Show forest plot | 1 | 190 | Odds Ratio (M‐H, Fixed, 95% CI) | 78.41 [22.86, 268.97] |
| Analysis 2.1  Comparison 2: LNG‐IUS versus no treatment, Outcome 1: Regression of EH | ||||
PRISMA flow diagram of the systematic literature search
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 LNG‐IUS versus non‐intrauterine progestogen, outcome: 1.1 Regression of EH; by length of follow‐up.
Funnel plot of comparison: 1 LNG‐IUS versus non‐intrauterine progestogen, outcome: 1.1 Regression of EH; by length of follow‐up.
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 1: Regression of EH; by length of follow‐up
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 2: Hysterectomy; histologically and non‐histologically indicated
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 3: Adverse effects associated with hormones
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 4: Withdrawal secondary to adverse effects
Comparison 1: LNG‐IUS versus non‐intrauterine progestogen, Outcome 5: Satisfaction with treatment
Comparison 2: LNG‐IUS versus no treatment, Outcome 1: Regression of EH
| LNG‐IUS compared to non‐intrauterine progestogen for endometrial hyperplasia | ||||||
| Patient or population: endometrial hyperplasia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with non‐intrauterine progestogen | Risk with LNG‐IUS | |||||
| Regression of EH; by length of follow‐up ‒ Short follow‐up ≤ 6 months | 723 per 1000 | 885 per 1000 | OR 2.94 | 1108 | ⊕⊕⊕⊝ | |
| Regression of EH; by length of follow‐up ‒ Long follow‐up ≥ 1 year | 513 per 1000 | 800 per 1000 | OR 3.80 | 138 | ⊕⊕⊝⊝ | |
| Hysterectomy; histologically and non‐histologically indicated | 263 per 1000 | 85 per 1000 | OR 0.26 | 452 | ⊕⊕⊝⊝ | |
| Adverse effects associated with hormones: Nausea Weight gain | 383 per 1000 | 570 per 1000 | OR 2.13 | 428 | ⊕⊝⊝⊝ | |
| 213 per 1000 | 124 per 1000 | OR 0.52 | 428 | ⊕⊕⊝⊝ | ||
| 65 per 1000 | 82 per 1000 | OR 1.28 | 318 | ⊕⊝⊝⊝ | ||
| Withdrawal secondary to adverse effects | 54 per 1000 | 23 per 1000 | OR 0.41 | 360 | ⊕⊕⊝⊝ | |
| Satisfaction with treatment | 531 per 1000 | 857 per 1000 | OR 5.28 | 202 | ⊕⊝⊝⊝ | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 1 level for serious risk of bias: 6 in 10 studies high risk for detection bias as outcome assessors were not blinded, various studies with unclear selection bias and selection bias 2 Downgraded 1 level for serious risk of bias: high risk as not stated if pathologists measuring EH regression were blinded, and unclear allocation concealment and reporting bias. 3 Substantial heterogeneity for this comparison (I² = 66%), but the quality of the evidence was not downgraded for inconsistency, as the direction of effect was consistent. 4 Downgraded 1 level for serious imprecision with few events and wide confidence intervals. 5 Downgraded 1 level for serious risk of bias: all 4 studies high risk as participants/assessors were not blinded for outcome assessment of subjective measures and in 2 studies blinding of the pathologist was not mentioned. Selective reporting assessed as unclear in 3 of studies. 6 Downgraded 1 level for serious risk of bias: all studies with high risk of performance and detection bias (no blinding of participants to LNG‐IUS and self‐evaluation of adverse effects); other studies with high risk of attrition bias, and unclear allocation concealment and selective reporting. 7 Downgraded 1 level for serious inconsistency; unexplained inconsistency, with point estimates widely different in studies and confidence intervals not overlapping. 8 Downgraded 1 level for serious risk of bias: all 4 studies with high risk of performance and detection bias, 1 study with high risk of attrition bias, 2 studies with unclear allocation concealment and 3 with unclear selective reporting, 1 study with unclear selection bias. 9 Downgraded 2 levels for very serious risk of bias: both studies with high risk of performance and detection bias, 1 in 2 studies with high risk of attrition bias, both studies with unclear allocation concealment and selective reporting, 1 study with unclear selection bias. 10 Downgraded 1 level for serious imprecision: small sample size. | ||||||
| LNG compared to no treatment for endometrial hyperplasia | ||||||
| Patient or population: women with endometrial hyperplasia | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with no treatment | Risk with LNG‐IUS | |||||
| Regression of EH ‐ Short | 270 per 1000 | 967 per 1000 | OR 78.41 | 190 | ⊕⊕⊝⊝ | |
| Adverse effects associated with LNG‐IUS | No study reported on this outcome in this comparison | |||||
| Hysterectomy | No study reported on this outcome in this comparison | |||||
| Adverse effects associated with hormones | No study reported on this outcome in this comparison | |||||
| Withdrawal secondary to adverse effects | No study reported on this outcome in this comparison | |||||
| Satisfaction | No study reported on this outcome in this comparison | |||||
| Cost of treatment | No study reported on this outcome in this comparison | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded 1 level for serious risk of bias: unclear allocation concealment and selective reporting. 2 Downgraded 1 level for serious imprecision: small sample size and wide confidence interval. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Regression of EH; by length of follow‐up Show forest plot | 10 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Short follow‐up ≤ 6 months | 10 | 1108 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.94 [2.10, 4.13] |
| 1.1.2 Long follow‐up ≥ 1 year | 1 | 138 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.80 [1.75, 8.23] |
| 1.2 Hysterectomy; histologically and non‐histologically indicated Show forest plot | 4 | 452 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.15, 0.46] |
| 1.3 Adverse effects associated with hormones Show forest plot | 4 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Bleeding/spotting | 3 | 428 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.13 [1.33, 3.43] |
| 1.3.2 Nausea | 3 | 428 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.28, 0.95] |
| 1.3.3 Weight gain | 3 | 318 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.56, 2.96] |
| 1.4 Withdrawal secondary to adverse effects Show forest plot | 4 | 360 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.12, 1.35] |
| 1.5 Satisfaction with treatment Show forest plot | 2 | 202 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.28 [2.51, 11.10] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Regression of EH Show forest plot | 1 | 190 | Odds Ratio (M‐H, Fixed, 95% CI) | 78.41 [22.86, 268.97] |
