Review question
Is metformin an effective and safe treatment for women 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 (thickening of the lining of the womb) 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 a levonorgestrel-releasing intrauterine system (LNG-IUS) into the womb, advising women with extra weight to lose weight, or performing a hysterectomy for women who do not want a 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 LNG-IUS is associated with irregular vaginal bleeding in up to 82% of women. Many women find it painful to use, or find it otherwise unacceptable. Therefore, an alternative treatment for endometrial hyperplasia is required.
Metformin, an oral tablet that is usually used to treat diabetes, has been shown to cure endometrial hyperplasia in some human studies. Although women 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, women would be more willing to complete treatment, and the cure rate would 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 seven randomised controlled trials in which a total of 387 women took part. Five studies compared metformin to megestrol (a form of progesterone), and one study compared metformin plus megestrol to megestrol alone. Women in all studies received treatment for three to six months. The evidence is current to 5 September 2022.
Key results
Studies on metformin alone versus megestrol alone provided insufficient evidence to show differences in effectiveness for curing endometrial hyperplasia.
Studies on metformin plus megestrol versus megestrol alone found that metformin may improve the thickened walls of the womb, but the evidence is uncertain about other outcomes.
One small study provided insufficient evidence to support or refute the use of metformin plus the LNG-IUS or the LNG-IUS alone.
Certainty of the evidence
We rated the certainty of the evidence as low to very-low for all outcomes, because of limitations in the way the studies were designed, and small sample sizes.
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.
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.