Metformin for endometrial hyperplasia.

BACKGROUND: 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. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: 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. 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, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM. METHODS: A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve. RESULTS: Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (P<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (ß-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P=0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P<0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P<0.005). CONCLUSIONS: Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.

Multimodality Imaging for Cardiotoxicity: State of the Art and Future Perspectives.

ABSTRACT: Modern cancer therapies have significantly improved survival leading to a growing population of cancer survivors. Similarly, both conventional and newer treatments are associated with a spectrum of cardiovascular disorders with potential long-term sequelae. Prompt detection and treatment of these complications is, therefore, pivotal to enable healthy survivorship and reduce cardiovascular morbidity. Advanced multimodality imaging is a valuable tool for stratifying patient risk, identifying cardiovascular toxicity during and after therapy, and predicting recovery. This review summarizes the potential cardiotoxic complications of anticancer therapies and the multimodality approaches available in each case with special focus on newer techniques and the added value of biomarkers ultimately leading to earlier diagnosis and better prognostication.

Quantitative Myocardial Perfusion Predicts Outcomes in Patients With Prior Surgical Revascularization.

BACKGROUND: Patients with previous coronary artery bypass graft (CABG) surgery typically have complex coronary disease and remain at high risk of adverse events. Quantitative myocardial perfusion indices predict outcomes in native vessel disease, but their prognostic performance in patients with prior CABG is unknown. OBJECTIVES: In this study, we sought to evaluate whether global stress myocardial blood flow (MBF) and perfusion reserve (MPR) derived from perfusion mapping cardiac magnetic resonance (CMR) independently predict adverse outcomes in patients with prior CABG. METHODS: This was a retrospective analysis of consecutive patients with prior CABG referred for adenosine stress perfusion CMR. Perfusion mapping was performed in-line with automated quantification of MBF. The primary outcome was a composite of all-cause mortality and major adverse cardiovascular events defined as nonfatal myocardial infarction and unplanned revascularization. Associations were evaluated with the use of Cox proportional hazards models after adjusting for comorbidities and CMR parameters. RESULTS: A total of 341 patients (median age 67 years, 86% male) were included. Over a median follow-up of 638 days (IQR: 367-976 days), 81 patients (24%) reached the primary outcome. Both stress MBF and MPR independently predicted outcomes after adjusting for known prognostic factors (regional ischemia, infarction). The adjusted hazard ratio (HR) for 1 mL/g/min of decrease in stress MBF was 2.56 (95% CI: 1.45-4.35) and for 1 unit of decrease in MPR was 1.61 (95% CI: 1.08-2.38). CONCLUSIONS: Global stress MBF and MPR derived from perfusion CMR independently predict adverse outcomes in patients with previous CABG. This effect is independent from the presence of regional ischemia on visual assessment and the extent of previous infarction.

Metformin for endometrial hyperplasia.

BACKGROUND: 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 currently used to treat women with endometrial hyperplasia are 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 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. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial 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 Reproduction and 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 endometrial 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 endometrial hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometrial hyperplasia, progression of endometrial 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 acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial 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 endometrial hyperplasia or health-related quality of life. Both studies (n = 59) provided data on progression of endometrial 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 acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial 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 endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometrial 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 acetate study 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 acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question.

Metformin for endometrial hyperplasia: a Cochrane protocol.

INTRODUCTION: Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. METHODS AND ANALYSIS: We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. ETHICS AND DISSEMINATION: Dissemination of the completed review will be through the Cochrane Library as well as through presenting the results at appropriate conferences.