Review question
Is metformin an effective and safe treatment for people with endometrial hyperplasia?
Background
Endometrial cancer (cancer of the lining of the womb) is a common cancer that affects the reproductive organs in women worldwide. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer, if left untreated. Successful treatment of women with endometrial hyperplasia can prevent endometrial cancer. Endometrial hyperplasia is usually treated by providing progesterone hormone tablets, inserting the levonorgestrel intrauterine system (Mirena Coil) into the womb, advising overweight women to lose weight, or performing a hysterectomy for women who do not want any future pregnancy. However, progesterone tablets are associated with side effects in up to 84% of women, and this can prevent women from completing treatment. Also, progesterone tablets do not always work, and endometrial hyperplasia can return in up to 14% to 30% of women after treatment. The Mirena Coil is associated with irregular vaginal bleeding in up to 82% of women, and many women find it painful to use or otherwise unacceptable. Therefore, an alternative treatment for endometrial hyperplasia is required. Metformin, an oral tablet that usually is used to treat diabetes, has been shown to cure endometrial hyperplasia in some human studies. Although people taking metformin may experience side effects, treatment is usually well tolerated. If women experience fewer side effects when taking metformin rather than progesterone tablets, and if metformin effectively treats endometrial hyperplasia, then compliance will be better and the cure rate will improve. This could reduce the number of women who end up with endometrial cancer. However, the effectiveness and safety of metformin used to treat women with endometrial hyperplasia remain uncertain.
Study characteristics
We included three randomised controlled trials in which a total of 77 women took part. Two studies compared metformin versus megestrol acetate (a form of progesterone), and one study compared metformin plus megestrol acetate versus megestrol acetate alone. Women in all studies received treatment for approximately 12 weeks. The evidence is current to 10 January 2017.
Key results
Comparisons of metformin versus megestrol acetate have provided insufficient evidence to show differences in effectiveness for curing endometrial hyperplasia. It remains uncertain whether there is any difference between metformin and megestrol acetate in reducing hysterectomy rates or abnormal uterine bleeding in women with endometrial hyperplasia. Although both studies provided data on progression of endometrial hyperplasia to endometrial cancer, there were no events in either arm, and study authors reported no data on adverse effects.
When metformin plus megestrol acetate is compared with megestrol acetate, differences in effectiveness between groups treating endometrial hyperplasia remain unclear. Three of eight patients in the metformin plus megestrol acetate study arm reported nausea. Occurrence of other adverse events is unclear.
Quality of the evidence
We rated the quality of 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.
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.
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.
To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia.
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.
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.
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.
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.