Metformin for endometrial hyperplasia

Background Endometrial canceris one of the most common gynaecological cancers in the world. Rates of endometrial cancerare rising, in part because of rising obesity rates. Endometrial hyperplasiais a precancerous conditionin women that can lead to endometrial cancerif left untreated. Endometrial hyperplasiaoccurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasiaare associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device(Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleedingin 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasiais 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 hyperplasiaremain uncertain. Objectives To determine the effectiveness and safety of metformin in treating women with endometri al hyperplasia. Search methods We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar,OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproductionand Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine(ASRM) 2015. Selection criteria We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometri al hyperplasia of any type. Data collection and analysis Two review authors independently assessed studies for eligibility, extracted data from included studies, and assessed the risk of bias of included studies. We resolved disagreements by discussion or by deferment to a third review author. When study details were missing, review authors contacted study authors. The primary outcome of this review was regression of endometri al hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometri al hyperplasia, progression of endometri al hyperplasia to endometrial cancer, hysterectomy rate, abnormal uterine bleeding, health-related quality of life, and adverse effects during treatment. Main results We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision. We performed a meta-analysis of two trials with 59 participants. When metformin was compared with megestrol acetatein women with endometri al hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometri al hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low-quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low-quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low quality evidence). We found no data for recurrence of endometri al hyperplasia or health-related quality of life. Both studies (n = 59)provided data on progression of endometri al hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others. Another trial including 16 participants compared metformin plus megestrol acetateversus megestrol acetatealone in women with endometri al hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometri al hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low-quality evidence), recurrence of endometri al hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometri al hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low-quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37,one RCT, n = 16, very low-quality evidence). Investigators provided no data on abnormal uterine bleeding or health-related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetatestudy arm reported nausea. Authors’ conclusions At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy - specifically, megestrol acetate- versus megestrol acetatealone, for treatment of endometri al hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question.