Levonorgestrel-releasing intrauterine system for endometrial hyperplasia.

In the absence of treatment, endometrial hyperplasia (EH) can progress to endometrial cancer, particularly in the presence of histologic nuclear atypia. The development of EH results from exposure of the endometrium to oestrogen unopposed by progesterone. Oral progestogens have been used as treatment for EH without atypia, and in some cases of EH with atypia in women who wish to preserve fertility or who cannot tolerate surgery. EH without atypia is associated with a low risk of progression to atypia and cancer; EH with atypia is where the cells are structurally abnormal, and has a higher risk of developing cancer. Oral progestogen is not always effective at reversing the hyperplasia, can be associated with side effects, and depends on patient adherence. The levonorgestrel-intrauterine system (LNG-IUS) is an alternative method of administration of progestogen and may have some advantages over non-intrauterine progestogens. To evaluate the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in women with endometrial hyperplasia (EH) with or without atypia compared to medical treatment with non-intrauterine progestogens, placebo, surgery or no treatment. We searched the following databases: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO, and conference proceedings of 10 relevant organisations. We handsearched references in relevant published studies. We also searched ongoing trials in ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, and other trial registries. We performed the final search in May 2020. Randomised controlled trials (RCTs) and cross-over trials of women with a histological diagnosis of endometrial hyperplasia with or without atypia comparing LNG-IUS with non-intrauterine progestogens, placebo, surgery or no treatment. Two review authors independently performed study selection, risk of bias assessment and data extraction. Our primary outcome measures were regression of EH and adverse effects associated with the LNG-IUS device (such as pelvic inflammatory disease, device expulsion, uterine perforation) when compared to treatment with non-intrauterine progestogens, placebo, surgery or no treatment. Secondary outcomes included hysterectomy, hormone-related adverse effects (such as bleeding/spotting, pelvic pain, breast tenderness, ovarian cysts, weight gain, acne), withdrawal from treatment due to adverse effects, satisfaction with treatment, and cost or resource use. We rated the overall quality of evidence using GRADE methods. Thirteen RCTs (1657 women aged 22 to 75 years) met the inclusion criteria. Two studies had insufficient data for meta-analysis, thus the quantitative analysis included 11 RCTs. All trials evaluated treatment duration of six months or less. The evidence ranged from very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding and poor reporting of study methods), inconsistency and imprecision. LNG-IUS versus non-intrauterine progestogens Primary outcomes Regression of endometrial hyperplasia The LNG-IUS probably improves regression of EH compared with non-intrauterine progestogens at short-term follow-up (up to six months) (OR 2.94, 95% CI 2.10 to 4.13; I² = 0%; 10 RCTs, 1108 participants; moderate-quality evidence). This suggests that if regression of EH following treatment with a non-intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG-IUS would be between 85% and 92%. Regression of EH may be improved by LNG-IUS compared with non-intrauterine progestogens at long-term follow-up (12 months) (OR 3.80, 95% CI 1.75 to 8.23; 1 RCT, 138 participants; low-quality evidence), Adverse effects associated with LNG-IUS There was insufficient evidence to determine device-related adverse effects; only one study reported on expulsion with insufficient data for analysis. Secondary outcomes The LNG-IUS may be associated with fewer hysterectomies (OR 0.26, 95% CI 0.15 to 0.46; I² = 19%; 4 RCTs, 452 participants; low-quality evidence), fewer withdrawals from treatment due to hormone-related adverse effects (OR 0.41, 95% CI 0.12 to 1.35; I² = 0%; 4 RCTs, 360 participants; low-quality evidence) and improved patient satisfaction with treatment (OR 5.28, 95% CI 2.51 to 11.10; I² = 0%; 2 RCTs, 202 participants; very low-quality evidence) compared to non-intrauterine progestogens. The LNG-IUS may be associated with more bleeding/spotting (OR 2.13, 95% CI 1.33 to 3.43; I² = 78%; 3 RCTs, 428 participants) and less nausea (OR 0.52, 95% CI 0.28 to 0.95; I² = 0%; 3 RCTs, 428 participants) compared to non-intrauterine progestogens. Data from single trials for mood swings and fatigue had a similar direction of effect as for bleeding/spotting, nausea and weight gain. There was insufficient evidence to determine cost or resource use. LNG-IUS versus no treatment Regression of endometrial hyperplasia One study demonstrated that the LNG-IUS is associated with regression of EH without atypia (OR 78.41, 95% CI 22.86 to 268.97; I² = 0%; 1 RCT, 190 participants; moderate-quality evidence) compared with no treatment. This study did not report on any other review outcome. There is moderate-quality evidence that treatment with LNG-IUS used for three to six months is probably more effective than non-intrauterine progestogens at reversing EH in the short term (up to six months) and long term (up to two years). Adverse effects (device-related and hormone-related) were poorly and incompletely reported across studies. Very low quality to low-quality evidence suggests the LNG-IUS may reduce the risk of hysterectomy, and may be associated with more bleeding/spotting, less nausea, less withdrawal from treatment due to adverse effects, and increased satisfaction with treatment, compared to non-intrauterine progestogens. There was insufficient evidence to reach conclusions regarding device-related adverse effects, or cost or resource use.

Mittermeier T ，Farrant C ，Wise MR 《Cochrane Database of Systematic Reviews》

Metformin for endometrial hyperplasia.

Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017. To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials. We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life. Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.

Shiwani H ，Clement NS ，Daniels JP ，Atiomo W ... -  《Cochrane Database of Systematic Reviews》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Antioxidants for female subfertility.

M.G. Showell, R. Mackenzie‐Proctor, V. Jordan, and R.J. Hart, “Antioxidants for Female Subfertility,” Cochrane Database of Systematic Reviews, no. 8 (2020): CD007807, https://doi.org/10.1002/14651858.CD007807.pub4 This Editorial Note is for the above article, published online on August 27, 2020, in Cochrane Library (cochranelibrary.com), and has been issued by the Publisher, John Wiley & Sons Ltd, in agreement with Cochrane. The Editorial note has been agreed due to concerns discovered by the Cochrane managing editor regarding the retraction of six studies in the Review (Badawy et al. 2006, 10.1016/j.fertnstert.2006.02.097; El Refaeey et al. 2014, 10.1016/j.rbmo.2014.03.011; El Sharkwy & Abd El Aziz 2019a, https://doi.org/10.1002/ijgo.12902; Gerli et al. 2007, https://doi.org/10.26355/eurrev_202309_33752, full text: https://europepmc.org/article/MED/18074942; Ismail et al. 2014, http://dx.doi.org/10.1016/j.ejogrb.2014.06.008; Hashemi et al. 2017, https://doi.org/10.1080/14767058.2017.1372413). In addition, expressions of concern have been published for two studies (Jamilian et al. 2018, https://doi.org/10.1007/s12011-017-1236-3; Zadeh Modarres 2018, https://doi.org/10.1007/s12011-017-1148-2). The retracted studies will be moved to the Excluded Studies table, and their impact on the review findings will be investigated and acted on accordingly in a future update. Initial checks indicate that removal of the six retracted studies did not make an appreciable difference to the results. Likewise, the studies for which Expressions of Concern were issued will be moved to the Awaiting classification table; they did not report any review outcomes, so removal will have no impact on the review findings. A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility. To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers. We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility. We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I2 = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I2 = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I2 = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I2 = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I2 = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I2 = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Showell MG ，Mackenzie-Proctor R ，Jordan V ，Hart RJ ... -  《Cochrane Database of Systematic Reviews》

Progestogens for prevention of luteinising hormone (LH) surge in women undergoing controlled ovarian hyperstimulation as part of an assisted reproductive technology (ART) cycle.

Currently, gonadotrophin releasing hormone (GnRH) analogues are used to prevent premature ovulation in ART cycles. However, their costs remain high, the route of administration is invasive and has some adverse effects. Oral progestogens could be cheaper and effective to prevent a premature LH surge. To evaluate the effectiveness and safety of using progestogens to avoid spontaneous ovulation in women undergoing controlled ovarian hyperstimulation (COH). We searched the Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase and PsycINFO in Dec 2021. We contacted study authors and experts to identify additional studies. We included randomised controlled trials (RCTs) that included progestogens for ovulation inhibition in women undergoing controlled ovarian hyperstimulation (COH). We used standard methodological procedures recommended by Cochrane, including the risk of bias (RoB) assessment. The primary review outcomes were live birth rate (LBR) and oocyte pick-up cancellation rate (OPCR). Secondary outcomes were clinical pregnancy rate (CPR), cumulative pregnancy, miscarriage rate (MR), multiple pregnancies, LH surge, total and MII oocytes, days of stimulation, dose of gonadotropins, and moderate/severe ovarian hyperstimulation syndrome (OHSS) rate. The primary analyses were restricted to studies at overall low and some concerns RoB, and sensitivity analysis included all studies. We used the GRADE approach to assess the certainty of evidence. We included 14 RCTs (2643 subfertile women undergoing ART, 47 women used oocyte freezing for fertility preservation and 534 oocyte donors). Progestogens versus GnRH antagonists We are very uncertain of the effect of medroxyprogesterone acetate (MPA) 10 mg compared with cetrorelix on the LBR in poor responders (odds ratio (OR) 1.25, 95% confidence interval (CI) 0.73 to 2.13, one RCT, N = 340, very-low-certainty evidence), suggesting that if the chance of live birth following GnRH antagonists is assumed to be 18%, the chance following MPA would be 14% to 32%. There may be little or no difference in OPCR between progestogens and GnRH antagonists, but due to wide Cs (CIs), we are uncertain (OR 0.92, 95%CI 0.42 to 2.01, 3 RCTs, N = 648, I² = 0%, low-certainty evidence), changing the chance of OPCR from 4% with progestogens to 2% to 8%. Given the imprecision found, no conclusions can be retrieved on CPR and MR. Low-quality evidence suggested that using micronised progesterone in normo-responders may increase by 2 to 6 the MII oocytes in comparison to GnRH antagonists. There may be little or no differences in gonadotropin doses. Progestogens versus GnRH agonists Results were uncertain for all outcomes comparing progestogens with GnRH agonists. One progestogen versus another progestogen The analyses comparing one progestogen versus another progestogen for LBR did not meet our criteria for primary analyses. The OPCR was probably lower in the MPA 10 mg in comparison to MPA 4 mg (OR 2.27, 95%CI 0.90 to 5.74, one RCT, N = 300, moderate-certainty evidence), and MPA 4 mg may be lower than micronised progesterone 100 mg, but due to wide CI, we are uncertain of the effect (OR 0.81, 95%CI 0.43 to 1.53, one RCT, N = 300, low-certainty evidence), changing the chance of OPCR from 5% with MPA 4 mg to 5% to22%, and from 17% with micronised progesterone 100 mg to 8% to 24%. When comparing dydrogesterone 20 mg to MPA, the OPCR is probably lower in the dydrogesterone group in comparison to MPA 10 mg (OR 1.49, 95%CI 0.80 to 2.80, one RCT, N = 520, moderate-certainty evidence), and it may be lower in dydrogesterone group in comparison to MPA 4 mg but due to wide confidence interval, we are uncertain of the effect (OR 1.19, 95%CI 0.61 to 2.34, one RCT, N = 300, low-certainty evidence), changing the chance of OPCR from 7% with dydrogesterone 20 to 6-17%, and in MPA 4 mg from 12% to 8% to 24%. When comparing dydrogesterone 20 mg to micronised progesterone 100 mg, the OPCR is probably lower in the dydrogesterone group (OR 1.54, 95%CI 0.94 to 2.52, two RCTs, N=550, I² = 0%, moderate-certainty evidence), changing OPCR from 11% with dydrogesterone to 10% to 24%. We are very uncertain of the effect in normo-responders of micronised progesterone 100 mg compared with micronised progesterone 200 mg on the OPCR (OR 0.35, 95%CI 0.09 to 1.37, one RCT, N = 150, very-low-certainty evidence). There is probably little or no difference in CPR and MR between MPA 10 mg and dydrogesterone 20 mg. There may be little or no differences in MII oocytes and gonadotropins doses. No cases of moderate/severe OHSS were reported in most of the groups in any of the comparisons. Little or no differences in LBR may exist when comparing MPA 4 mg with GnRH agonists in normo-responders. OPCR may be slightly increased in the MPA 4 mg group, but MPA 4 mg reduces the doses of gonadotropins in comparison to GnRH agonists. Little or no differences in OPCR may exist between progestogens and GnRH antagonists in normo-responders and donors. However, micronised progesterone could improve by 2 to 6 MII oocytes. When comparing one progestogen to another, dydrogesterone suggested slightly lower OPCR than MPA and micronised progesterone, and MPA suggested slightly lower OPCR than the micronised progesterone 100 mg. Finally, MPA 10 mg suggests a lower OPCR than MPA 4 mg. There is uncertainty regarding the rest of the outcomes due to imprecision and no solid conclusions can be drawn.

Glujovsky D ，Pesce R ，Miguens M ，Sueldo C ，Ciapponi A ... -  《Cochrane Database of Systematic Reviews》