Abstract
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.
Keywords: Female, Humans, Endometrial Hyperplasia, Endometrial Hyperplasia/drug therapy, Hypoglycemic Agents, Hypoglycemic Agents/therapeutic use, Metformin, Metformin/therapeutic use, Randomized Controlled Trials as Topic
Plain language summary
Metformin for endometrial hyperplasia
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.
Summary of findings
Summary of findings 1. Summary of findings table ‐ Metformin compared to megestrol for endometrial hyperplasia.
| Metformin compared to megestrol for endometrial hyperplasia | ||||||
| Patient or population: endometrial hyperplasia Setting: hospital outpatient clinic Intervention: metformin Comparison: megestrol | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with megestrol | Risk with metformin | |||||
| Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium follow‐up: 3 months | 610 per 1000 | 884 per 1000 (709 to 960) | OR 4.89 (1.56 to 15.32) | 83 (2 RCTs) | ⊕⊝⊝⊝ Very lowa,b | It is uncertain whether metformin increases regression of endometrial hyperplasia (with or without atypia) towards normal histology over megestrol. |
| Recurrence of endometrial hyperplasia ‐ not reported | (0 studies) | ‐ | No study reported this outcome | |||
| Progression of endometrial hyperplasia to endometrial cancer follow‐up: 3 months | Not pooled | Not pooled | Not pooled | (2 RCTs) | ⊕⊝⊝⊝ Very lowa,c | No progression reported in either arm of the included studies. |
| Hysterectomy rate follow‐up: 3 months | 24 per 1000 | 22 per 1000 (1 to 275) | OR 0.91 (0.05 to 15.52) | 85 (2 RCTs) | ⊕⊝⊝⊝ Very lowa,b | Only one woman in each arm of the pooled results had a hysterectomy. |
| Abnormal uterine bleeding follow‐up: 3 months | 48 per 1000 | 44 per 1000 (2 to 437) | OR 0.91 (0.05 to 15.52) | 44 (1 RCT) | ⊕⊝⊝⊝ Very lowd,e | Only one woman experienced abnormal uterine bleeding in each arm of the study. |
| Health‐related quality of life (HRQoL) ‐ not measured | ‐ | ‐ | ‐ | ‐ | ‐ | No study in this comparison measured this outcome. |
| Adverse effects during treatment ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data for adverse effects during treatment were reported for this comparison. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_440700108855565380. | ||||||
a Downgraded two levels for very serious risk of bias. One study did not blind the investigators or participants to the interventions. One study did not describe the blinding process. b Downgraded two levels for very serious imprecision. Both studies have very small sample sizes. c Downgraded two levels for very serious imprecision. No events across two studies. d Downgraded two levels for very serious risk of bias. Single study; did not blind the investigators or participants to the interventions. e Downgraded two levels for very serious imprecision. One study with very small sample size.
Summary of findings 2. Summary of findings table ‐ Metformin + megestrol compared to megestrol for endometrial hyerplasia.
| Metformin + megestrol compared to megestrol for endometrial hyerplasia | ||||||
| Patient or population: endometrial hyerplasia Setting: hospital outpatient clinic Intervention: metformin and megestrol Comparison: megestrol | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with megestrol | Risk with metformin and megestrol | |||||
| Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium follow‐up: 3 months | 540 per 1000 | 794 per 1000 (660 to 884) | OR 3.27 (1.65 to 6.51) | 258 (4 RCTs) | ⊕⊕⊝⊝ Lowa,b | Metformin in addition to megestrol may improve regression of endometrial hyperplasia (with or without atypia) towards normal histology. |
| Recurrence of endometrial hyperplasia follow‐up: median 10.55 months | 0 per 1000 | 0 per 1000 (0 to 0) | Not estimable | 8 (1 RCT) | ⊕⊝⊝⊝ Very lowc,d | No recurrences reported in either arm of the included study. |
| Progression of endometrial hyperplasia to endometrial cancer follow‐up: range 3 months to 12 months | 0 per 1000 | 0 per 1000 (0 to 0) | OR 7.96 (0.16 to 402.02) | 156 (3 RCTs) | ⊕⊝⊝⊝ Very lowa,e | Only one event of progression to endometrial cancer (in a megestrol only group) in all three studies. |
| Hysterectomy rate | 0 per 1000 | 0 per 1000 (0 to 0) | OR 7.39 (0.15 to 372.38) | 72 (2 RCTs) | ⊕⊝⊝⊝ Very lowa,f | One hysterectomy was performed in the megestrol only arm of 1 included study. |
| Abnormal uterine bleeding ‐ not measured | ‐ | ‐ | ‐ | ‐ | ‐ | None of the studies measured this outcome. |
| Health‐related quality of life (HRQoL) ‐ not measured | ‐ | ‐ | ‐ | ‐ | ‐ | None of the studies measured this outcome. |
| Adverse effects during treatment follow‐up: 3 months | 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. | 8 (1 RCT) | ⊕⊝⊝⊝ Very lowc,g | The evidence is very uncertain about the effect of metformin in addition to megestrol on the risk of adverse effects. | ||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444756351503177282. | ||||||
a Downgraded one level for serious risk of bias. Two studies were open‐label trials and one study was a single‐blind clinical trial. One study had high attrition bias. b Downgraded one level for serious imprecision. Small sample sizes in all four studies. c Downgraded two levels for very serious risk of bias. One study was an open‐label trial. d Downgraded two levels for very serious imprecision. No events. e Downgraded two levels for very serious imprecision. Small sample sizes. Only one event across all three studies. f Downgraded two levels for very serious imprecision. Small sample sizes. Only two events across two studies. g Downgraded two levels for very serious imprecision. Small sample size in one study.
Summary of findings 3. Summary of findings table ‐ Metformin + levonorgestrel (intrauterine system) compared to levonorgestrel intrauterine system for endometrial hyperplasia.
| Metformin + levonorgestrel (intrauterine system) compared to levonorgestrel intrauterine system for endometrial hyperplasia | ||||||
| Patient or population: endometrial hyperplasia Setting: hospital outpatient clinic Intervention: metformin and levonorgestrel (intrauterine system) Comparison: levonorgestrel (intrauterine system) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with levonorgestrel (intrauterine system) | Risk with metformin and levonorgestrel (intrauterine system) | |||||
| Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium follow‐up: 6 months | 955 per 1000 | 986 per 1000 (732 to 999) | OR 3.42 (0.13 to 88.40) | 46 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | It is uncertain whether the addition of metformin to levonorgestrel results in increased regression of endometrial hyperplasia (with or without atypia) towards normal histology |
| Recurrence of endometrial hyperplasia ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No events of recurrence of endometrial hyperplasia. |
| Progression of endometrial hyperplasia to endometrial cancer follow‐up: 6 months | Not pooled | Not pooled | Not pooled | (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | No events of progression of endometrial hyperplasia to endometrial cancer. |
| Hysterectomy rate follow‐up: 6 months | 91 per 1000 | 12 per 1000 (1 to 163) | OR 0.12 (0.01 to 1.95) | 46 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | Only two events of hysterectomy in the levonorgestrel only arm. |
| Abnormal uterine bleeding follow‐up: 6 months | 292 per 1000 | 201 per 1000 (62 to 483) | OR 0.61 (0.16 to 2.27) | 49 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | It is uncertain whether the addition of metformin to levonorgestrel results in less abnormal uterine bleeding. |
| Adverse effects during treatment ‐ all effects follow‐up: 6 months | 500 per 1000 | 800 per 1000 (535 to 933) | OR 4.00 (1.15 to 13.90) | 51 (1 RCT) | ⊕⊝⊝⊝ Very lowb,c | It is uncertain whether the addition of metformin to levonorgestrel results in less adverse effects. No placebo was given to the levonorgestrel only group. |
| Adverse effects during treatment ‐ nausea follow‐up: 6 months | 115 per 1000 | 400 per 1000 (136 to 739) | OR 5.11 (1.21 to 21.68) | 51 (1 RCT) | ⊕⊝⊝⊝ Very lowb,c | It is uncertain whether the addition of metformin to levonorgestrel results in less adverse effects. No placebo was given to the levonorgestrel only group. |
| Adverse effects during treatment ‐ heaviness in lower abdomen follow‐up: 6 months | 154 per 1000 | 201 per 1000 (55 to 515) | OR 1.38 (0.32 to 5.85) | 51 (1 RCT) | ⊕⊝⊝⊝ Very lowb,c | It is uncertain whether the addition of metformin to levonorgestrel results in less adverse effects. No placebo was given to the levonorgestrel only group. |
| Adverse effects during treatment ‐ pain in abdomen follow‐up: 6 months | 231 per 1000 | 199 per 1000 (62 to 488) | OR 0.83 (0.22 to 3.18) | 51 (1 RCT) | ⊕⊝⊝⊝ Very lowb,c | It is uncertain whether the addition of metformin to levonorgestrel results in less adverse effects. No placebo was given to the levonorgestrel only group. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444825865034383704. | ||||||
a Downgraded one level for serious risk of bias. Single study did not blind the investigators or participants to the interventions. No placebo was given to the levonorgestrel only group. b Downgraded two levels for serious risk of imprecision. Single study with small sample size. c Downgraded two levels for serious risk of bias for adverse effects. Single study did not blind the investigators or participants to the interventions. No placebo was given to the levonorgestrel only group.
Background
Description of the condition
Endometrial hyperplasia is a precancerous endometrial lesion that commonly presents with abnormal uterine bleeding. It is thought to be due to unopposed, prolonged endometrium exposure to oestrogen, and if managed expectantly, can progress to endometrial carcinoma, although the condition may also resolve spontaneously. It is diagnosed histologically, and subsequently can be categorised into four subtypes: simple, simple with atypia, complex, and complex with atypia (Kurman 1985). The risk of progression to endometrial carcinoma is dependent on the type of endometrial hyperplasia, and progression rates vary widely across the literature. This discrepancy is likely due, in part, to the fact that many cases of endometrial hyperplasia, especially when atypia is present, are managed pre‐emptively, with a hysterectomy. However, atypia is thought to be a strong risk factor for progression to adenocarcinoma (Doherty 2020). As of 2014, the World Health Organization (WHO) classification for endometrial hyperplasia differentiates only two categories of endometrial hyperplasia, based on the presence of cytological atypia: hyperplasia without atypia, and atypical hyperplasia/endometrioid intraepithelial neoplasia (Nees 2022; RCOG/BSGE 2016). Progression rates have been reported as less than 5% for non‐atypical hyperplasia, but 28% for atypical hyperplasia cumulatively over 20 years (RCOG/BSGE 2016). This difference in progression risk has been seen at interval‐specific time points of four years, nine years, and 20 years post‐diagnosis (Lacey 2010). Predictably, risk factors for endometrial hyperplasia are very similar to those for endometrial carcinoma, and include obesity, diabetes mellitus, nulliparity, tamoxifen use, oestrogen therapy, and polycystic ovary syndrome (PCOS (Raglan 2019; Torres 2012)).
Polycystic ovary syndrome is a metabolically‐driven gynaecological disorder that is thought to affect as high as 26% of women of reproductive age (Deswal 2020). A diagnosis of PCOS must fulfil two or more of the following controversial, yet widely used, Rotterdam criteria, in the absence of another cause of chronic anovulation: hyperandrogenism (clinical, biochemical, or both), oligo or anovulation, and polycystic ovaries apparent on ultrasound (ESHRE/ASRM 2004). The prevalence of endometrial hyperplasia in women with PCOS varies greatly in the literature – between 5% and 10% (Holm 2012). But the risk of endometrial carcinoma appears to be well‐founded, as women with PCOS have an almost three‐fold increased risk of developing endometrial carcinoma when compared with the non‐PCOS population (Johnson 2023; Watter 2021).
The aim of endometrial hyperplasia treatment, regardless of whether PCOS is a comorbidity or not, is to control abnormal vaginal bleeding, while minimising the risk of progression to endometrial carcinoma (RCOG/BSGE 2016). Historically, endometrial hyperplasia without atypia has been treated medically with oral progestogens (alone or in combination with oestrogen in PCOS) or intrauterine progestogens, inhibiting oestrogen‐driven cell growth and inducing withdrawal bleeds, once reversible risk factors, such as obesity or the use of oestrogen therapy, have been addressed (Yang 2011). Medical treatment provides the benefit of preserving fertility and inducing regression, but is associated with side effects (RCOG/BSGE 2016); in the short term, women may experience headaches, mood changes, acne, or breast tenderness; over the longer term, there is the risk of a thromboembolic event or breast cancer (BNF 2022). The side effects of these medications have had the effect of potentially hindering compliance, consequently, producing a relatively high relapse rate. In one study, 28.3% of women treated with oral progestogens and 12.7% treated with intrauterine levonorgestrel had a relapse of their complex endometrial hyperplasia following an initial regression (Gallos 2013). Intrauterine progesterones, such as levonorgestrel‐releasing intrauterine systems (LNG‐IUS) are currently used as first‐line treatment in the UK because they have a higher disease regression rate (up to 100% in some reports involving cases without atypia), a more favourable bleeding pattern, and fewer systemic side effects (Nees 2022; RCOG/BSGE 2016). For women with atypia, and for those who are resistant to progestogens, surgical hysterectomy (preferably laparoscopically) is the treatment of choice, introducing the potential complications of major abdominal surgery (Nees 2022; RCOG/BSGE 2016).
Description of the intervention
Metformin, a biguanide that acts as an insulin sensitiser, is the oral hypoglycaemic agent most commonly used for the treatment of type 2 diabetes mellitus. It acts to inhibit hepatic gluconeogenesis, decreasing liver glucose production, and thereby, reducing levels of circulating glucose and insulin.
Metformin is also prescribed for women with PCOS to induce weight loss and improve menstrual regularity, both as monotherapy and in combination with a progestogen. It is frequently used to treat ovulatory dysfunction in women with PCOS who have shown resistance to treatment with clomiphene (Morley 2017). Despite the widespread use of metformin in women with PCOS, a systematic review comparing metformin with the oral contraceptive pill found no definitive improvement in clinical or biochemical features. Several randomised controlled trials published since the review by Fraison 2020 have also failed to demonstrate significant outcomes, although some have suggested it is as effective as the oral contraceptive pill in increasing menstrual regularity and improving hirsutism (Cetinkalp 2009; Meyer 2007; Wu 2009). This suggests a role for metformin in managing PCOS in women who wish to conceive, as well as those who have impaired glucose tolerance, or co‐existing type 2 diabetes mellitus (Morley 2017). Metformin has an established side effect profile that includes nausea and vomiting, diarrhoea, abdominal pain, and changes in taste, as well as rarer or less‐publicised effects, such as lactic acidosis or decreased B12 absorption, possibly leading to anaemia and potentially irreversible neuronal damage, if left unmonitored and uncorrected for prolonged periods (De Jager 2010).
How the intervention might work
Hyperinsulinaemia secondary to insulin resistance is thought to exhibit a mitogenic effect, inducing cell division via mitosis – a risk factor for hyperplasia – and ultimately, the development of carcinoma. This effect is likely due to its activity at the insulin‐like growth factor‐1 receptor, promoting proliferation and angiogenesis, which can be demonstrated by the positive correlation between diabetes and breast and gynaecological cancers (Vrachnis 2016). The insulin‐mediating effects of metformin show evidence of reducing the incidence of, and improving women's survival from these malignancies, although the evidence is mixed (Nevadunsky 2014). The link between insulin resistance and cell proliferation offers an intriguing potential therapeutic target for reversing hyperplasia and preventing endometrial carcinoma.
One systematic review summarised the known anticancer properties of metformin, highlighting it as an ideal anticancer therapy due to its well described safety profile, acceptable route of administration, and long history of use (Aljofan 2019). It summarised several studies that retrospectively audited cases of cancer in people with diabetes who were already on metformin, showing they had lower rates of multiple kinds of cancer compared to the background population, including endometrial cancer. The same review also summarised possible mechanisms of action of metformin, all of which relate to AMP‐activated protein kinase activation in cancer cells, a regulator of lipid and glucose metabolism. However, they stated that further work was needed to decipher the exact mechanism of anticancer activity of metformin (Aljofan 2019).
Why it is important to do this review
Medical therapy for endometrial hyperplasia currently involves multiple side effects and continued risk of recurrence. Therefore, a systematic review of a novel, alternative therapy is needed to collate the available evidence and to guide future clinical trials. The risk of progression from endometrial hyperplasia to carcinoma is significant; up to 28% of women with endometrial hyperplasia with atypia go on to develop carcinoma – the most common fatal gynaecological malignancy, which compromises 7% of all annual cancer diagnosis in women in the USA (Lacey 2010; RCOG/BSGE 2016; Ring 2022). Globally, this rate is expected to increase by up to 100% over the next 20 years (Dowling 2011). The biguanide insulin sensitiser, metformin, has been linked to the reversal of endometrial hyperplasia; if it can be used in this way, it may contribute to a decrease in the prevalence of endometrial carcinoma without the use of hormonal contraceptives, or irreversible infertility following a hysterectomy (Tabrizi 2014). Publications include in vitro studies, which report reversed endometrial hyperplasia in mice and cell lines, and some case reports; the results of treatment are relatively ambiguous, and the mode of action, effectiveness, and safety of metformin remain unclear (Aljofan 2019; Erdemoglu 2009; Rosato 2011; Session 2003). This review may help to clarify the role of metformin in the treatment of women with this disease. We are updating the review to consider new literature.
Objectives
To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs), both published and unpublished. We also planned to include cross‐over trials, but we planned to use only data from the first phase of these trials in the analysis.
Types of participants
We included women with histologically confirmed endometrial hyperplasia of any type.
Types of interventions
We included trials comparing metformin with placebo, no treatment, conventional medical treatment (typically progestogens, e.g. oral or intrauterine), or any other active intervention. We also included trials that provided co‐interventions (e.g. metformin plus progesterone versus progesterone). We analysed the results of these studies separately, so we could identify the effects of metformin separately from the co‐interventions.
Types of outcome measures
Primary outcomes
Regression of endometrial hyperplasia histology (with or without atypia) towards normal histology
Secondary outcomes
Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
Hysterectomy rate
Abnormal uterine bleeding
Health‐related quality of life, as reported in the included studies
Adverse effects during treatment, as reported in the included studies
Search methods for identification of studies
We searched for all published and unpublished RCTs of metformin for endometrial hyperplasia, without language restriction. Review authors liaised with the Cochrane Gynaecology and Fertility Group Information Specialist when conducting the search.
Electronic searches
In accordance with guidance from the Cochrane Gynaecology and Fertility Group, we searched the following electronic databases on 5 September 2022:
Cochrane Gynaecology and Fertility Specialised Register of controlled trials (Procite platform; searched 5 September 2022; Appendix 1);
Cochrane Central Register of Studies Online (CRSO; web platform; searched 5 September 2022; Appendix 2);
MEDLINE Ovid platform (1946 to 5 September 2022; Appendix 3);
Embase Ovid platform (1980 to 5 September 2022; Appendix 4);
PubMed (web platform; searched 5 September 2022; Appendix 5);
Google Scholar (web platform; searched 5 September 2022; Appendix 6).
We also searched the following trials registers and databases to identify ongoing and unpublished trials.
ClinicalTrials.gov (clinicaltrials.gov; searched 5 September 2022; Appendix 7)
World Health Organization International Trials Registry Platform (www.who.int/clinical-trials-registry-platform; searched 5 September 2022; Appendix 8)
OpenGrey (opengrey.eu/; searched 5 September 2022; Appendix 9)
LILACS (Latin American Caribbean Health Sciences Literature; lilacs.bvsalud.org/en/; searched 5 September 2022; Appendix 10)
For unpublished trials, we emailed the contact person to request further information to aid our assessment for inclusion.
Searching other resources
We handsearched the bibliographies of all included studies and relevant reviews on this topic, and contacted experts in the field.
Data collection and analysis
Selection of studies
We uploaded the titles and abstracts of all reports retrieved by electronic searches to Covidence, and removed duplicates. Two review authors (HS, NC) independently assessed titles and abstracts to identify studies for potential inclusion in the review. We sought full‐text reports for potentially relevant studies. Two review authors (HS, NC) then independently assessed each full‐text report against the inclusion criteria, and documented a justification for exclusion of each irrelevant study. Review authors resolved disagreements regarding trial suitability by discussion, or by consultation with a third review author.
We screened studies for duplicate publication by comparing study author names and study locations, dates, and durations. When uncertainty about study methods or the possibility of duplicate studies arose, we contacted the authors of relevant papers. We constructed a PRISMA flow chart to illustrate the selection of studies for this review (Figure 1; Moher 2009).
1.
PRISMA flowchart for 2022 study selection
Data extraction and management
Two review authors independently extracted data, using a data extraction form based on the checklist of items to consider in data collection or data extraction, provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). If, during study selection, we found a study that had multiple publications, we extracted and collated study data into a single file. We treated such studies as a single unit of interest for the review, and attributed multiple references to the single file. When necessary, we contacted study authors to request additional data on their methods or results.
Assessment of risk of bias in included studies
Two review authors (HS, NC) independently assessed each included study for risk of bias, using the Cochrane RoB 1 tool, described in the Cochrane Handbook (Higgins 2017). We assessed bias according to the following domains.
Selection bias (random sequence generation and allocation concealment)
Performance bias (blinding of participants and personnel)
Detection bias (blinding of outcome assessments)
Attrition bias (incomplete outcome data)
Reporting bias (selective reporting)
Other bias (other sources of bias)
We graded the risk of bias as low, high, or unclear for all domains listed above, using the criteria outlined in the Cochrane Handbook (Higgins 2017). We resolved disagreements by discussion, and when necessary, by consultation with a third review author. We provided justification for each judgement in the risk of bias table, and when possible, a quote from the study to support this judgement. We considered our risk of bias assessment when interpreting the findings of the review, for example, when performing the sensitivity analysis and GRADEing the certainty of the evidence. To minimise bias in selective reporting of trial outcomes, we planned, when possible, to compare published protocols against methods and outcomes described in the final report.
Measures of treatment effect
If we have sufficient data in future updates, we will calculate hazard ratios for survival outcomes. For this update, we calculated rates at a set time point, using the Mantel‐Haenszel odds ratio (OR) and the numbers of events in the control and intervention groups. If there were no events, or a rare number of events in an arm, we used the Peto odds ratio (OR).
If we have sufficient data in future updates, we will use means, standard deviations, and mean differences (MDs) for continuous data. We will treat ordinal data, such as side effect severity scoring systems and health‐related quality of life questionnaires, as continuous data for purposes of analysis. If different scales are used to report similar outcomes (e.g. change in endometrial thickness), we will calculate the standardised mean difference (SMD). We will express the SMD effect as small (0.2 to < 0.5), medium (0.5 to < 0.8), or large (≥ 0.8 (Cohen 1988)).
We provided 95% confidence intervals (CIs) for all outcomes.
We reported outcomes measured as short‐term (up to 6 months), medium‐term (6 to 12 months), and long‐term (more than 12 months).
Unit of analysis issues
We performed the primary analysis per woman. When a valid analysis was not possible, we briefly summarised the data, but did not include them in the meta‐analysis.
If we include cross‐over trials in future updates, we will only include first‐phase data in the analysis.
To calculate recurrence, we used the number of women who had experienced regression as the denominator.
Dealing with missing data
We analysed the data on an intention‐to‐treat basis when possible, and attempted to obtain missing data from the original trialists.
When contacting study authors for missing information, we sent a first reminder email 14 days after the initial email, and a second reminder email 7 days later. When we were unable to obtain data, we analysed only available data. We discussed the potential impact of missing data in the Discussion section of the review.
Assessment of heterogeneity
We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity using the I² statistic. We considered an I² greater than 50% to indicate substantial heterogeneity (Higgins 2022).
Assessment of reporting biases
Reporting bias is a potential issue for all reviews. We aimed to minimise reporting bias in our analysis by creating a comprehensive search strategy and searching a multitude of electronic databases, including those that record unpublished work and work prepared in languages other than English. This ensured that we maximised the yield of eligible studies included in the review, and were able to identify cases of data duplication.
For future updates, if we include 10 or more studies in a single analysis, we will use a funnel plot to explore the possibility of small‐study effects (i.e. the tendency for estimates of the intervention effect to be more beneficial in smaller studies).
Data synthesis
When the included studies were sufficiently similar, we combined the data in Review Manager software, using a fixed‐effect model, for the following comparisons (RevMan Web 2023).
Metformin versus placebo or no treatment
Metformin versus progestogens
Metformin versus another active intervention
Metformin plus co‐intervention versus co‐intervention alone
If we have sufficient data in future updates, we will stratify analyses by the dose of metformin (high, moderate, low).
We graphically displayed the results of these meta‐analyses in forest plots. Regardless of whether results were negative or positive, increasing odds are demonstrated by a marker right of the centre‐line, and decreasing odds by a marker left of the centre‐line.
Subgroup analysis and investigation of heterogeneity
If there are sufficient data in future updates, we will conduct subgroup analyses to obtain separate evidence for the following subgroups.
Women with PCOS
Women with atypical endometrial hyperplasia
In future updates, if pooled data demonstrate substantial heterogeneity (> 50%), we will consider additional subgroup analyses (e.g. by dose or route of metformin), or sensitivity analyses. We will acknowledge the degree of heterogeneity when interpreting the meta‐analysis.
Sensitivity analysis
We conducted sensitivity analyses for the primary outcome to determine whether conclusions were robust to our choice of study eligibility and analysis. Because of paucity of data, we were only able to explore whether the review conclusions would have been different if we removed studies with high risk of bias in one or more domains from the analysis for one comparison.
In future updates, if we have sufficient data, we will:
Remove studies with a high risk of bias in one or more domains from the analysis;
Re‐analyse the data using a random‐effects model;
Re‐analyse the data, expressing the effect estimate as a risk ratio (RR) rather than an OR.
Summary of findings and assessment of the certainty of the evidence
Two review authors independently assessed the quality (certainty) of the evidence. Three summary of findings tables were prepared using GRADEpro GDT software and Cochrane methods (Higgins 2022).
We presented a concise overview of the certainty of available evidence for these outcomes.
Regression of endometrial hyperplasia towards normal histology
Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
Hysterectomy rate
Abnormal uterine bleeding
Health‐related quality of life
Adverse effects during treatment
We prepared a separate summary of findings table for each of these three comparisons.
Metformin versus megestrol
Metformin plus megestrol versus megestrol monotherapy
Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy
Two review authors independently rated the certainty of the evidence as high, moderate, low, or very low, depending on how the evidence measured against the five GRADE criteria (study limitations, consistency of effect, imprecision, indirectness, and publication bias). We documented the justification for each GRADE awarded, and incorporated the overall GRADE into our final conclusions.
Results
Description of studies
Results of the search
All three studies that were analysed in the previous review were included in this review (Clement 2017). Through the 2022 search, we retrieved 352 records after duplications were removed; we excluded 325 on the basis of title and abstract review. We sought the full text of the remaining 27 articles. See Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies, and the PRISMA flow chart in Figure 1.
Included studies
Study design and setting
We included seven randomised controlled trials (RCTs) in this review. All seven were single‐centre studies, based in hospital outpatient clinics in China, India, or Iran (Ravi 2021; Sayyah Melli 2018; Shan 2014; Sharifzadeh 2016; Tabrizi 2014; Tehranian 2021; Yang 2020). Two studies took place within the same centre in Iran (Sayyah Melli 2018; Tabrizi 2014), and two studies took place within the same centre in China (Shan 2014; Yang 2020)
Participants
In total, investigators randomised 387 women with endometrial hyperplasia across the seven RCTs. All studies included histopathological diagnoses in all women, defined as endometrial hyperplasia with or without atypia.
One study randomised women with endometrioid endometrial carcinoma, disordered proliferative endometrium, and simple endometrial hyperplasia (Tabrizi 2014). We excluded data from the participants with endometrial carcinoma and disordered proliferative endometrium from our analyses, as per the exclusion criteria. Two studies restricted participants to those under 45 years of age (Shan 2014; Yang 2020). One study required that participants have at least one sign of metabolic syndrome (Shan 2014).
Interventions
Two studies compared metformin to megestrol acetate (Sharifzadeh 2016; Tabrizi 2014). Four studies compared metformin and megestrol acetate dual therapy to megestrol acetate monotherapy (Sayyah Melli 2018; Shan 2014; Tehranian 2021; Yang 2020). One study compared metformin and levonorgestrel (intrauterine system) dual therapy to levonorgestrel (intrauterine system) monotherapy (Ravi 2021).
Outcomes
One study measured outcomes at six months (Ravi 2021); the remaining six studies measured outcomes at three months. Thus, for all eligible studies, we were only able to analyse short‐term outcomes. All studies reported on the review's primary outcome, regression of endometrial hyperplasia towards normal histology.
Excluded studies
We excluded 23 full‐text reports for the following reasons.
nine included the wrong population
seven had the wrong study design
two used the wrong intervention
two measured the wrong outcomes
two used a wrong comparator
one was a commentary only
Ongoing studies
In the previous review, there were three ongoing studies.
IRCT201410275283N11 was published as Sayyah Melli 2018, and we included the results in our analysis.
NCT01968317 was published as Yang 2020, and we included the results in our analysis.
NCT01686126 is still ongoing.
In total, we identified six ongoing studies, four of which are due to be completed in 2023, one in 2025, and one in 2026. We have no interim preliminary results thus far.
Risk of bias in included studies
A summary of the risks of bias as judged by review authors for all domains is shown in Figure 2 and Figure 3.
2.
3.
Allocation
Sequence generation
We assessed all seven studies at low risk of bias related to sequence generation, as all participants were appropriately randomised.
Allocation concealment
We assessed five studies at low risk of bias for allocation concealment; allocation was conducted in a hidden randomised manner, they used sealed envelopes, or both (Ravi 2021; Sayyah Melli 2018; Sharifzadeh 2016; Tehranian 2021; Yang 2020). We assessed the other two studies as unclear risk of bias, as the study authors did not describe the method used.
Blinding
We assessed one study at low risk of bias, as the investigators and participants were blinded (Tehranian 2021).
We assessed five studies at high risk of bias, as investigators, participants, or both were not blinded (Ravi 2021; Sayyah Melli 2018; Shan 2014; Sharifzadeh 2016; Tehranian 2021; Yang 2020). However, in two of these studies, the analysing pathologists were blinded (Ravi 2021; Shan 2014).
The remaining study described no blinding process; therefore, we judged this trial as unclear risk of bias for this domain (Tabrizi 2014).
Incomplete outcome data
We judged six studies at low risk of attrition bias with minimal loss to follow‐up, reporting of all outcomes, or both (Ravi 2021; Sayyah Melli 2018; Sharifzadeh 2016; Tabrizi 2014; Tehranian 2021; Yang 2020).
We judged one study at high risk of bias in this domain, as only 16 of 30 participants completed 12 weeks of therapy and were included in the analysis (Shan 2014).
Selective reporting
We assessed five studies at low risk of reporting bias, as outcomes were reported as defined in a protocol published prior to the publication of the study (Ravi 2021; Sayyah Melli 2018; Sharifzadeh 2016; Tehranian 2021; Yang 2020).
We assessed the other two studies at high risk of bias, as no protocol was published prior to publication. However, the outcomes stated in the methods were reported appropriately (Shan 2014; Tabrizi 2014).
Other potential sources of bias
We judged that one study had potential sampling bias, as participants were not matched between the intervention and control groups by histology, age, features of metabolic syndrome, or PCOS diagnosis, and therefore, investigators did not control for these known risk factors for the development of endometrial hyperplasia (Tabrizi 2014). This study also had potential exclusion bias; although diagnosis of diabetes was an exclusion criterion, some pre‐intervention blood glucose values appeared to show some undiagnosed cases of diabetes, but were still included, showing an inconsistent exclusion of women with diabetes – again, a known effector of endometrial histology.
We judged one study as unclear risk of bias, as they combined the baseline characteristics of the atypical hyperplasia group and endometrial cancer group (Yang 2020). Therefore, we were unable to determine if the groups were appropriately matched for these characteristics.
We did not identify any potential sources of within‐study bias in the remaining five studies.
One study did not include a funding source, or potential author conflict of interest information (Ravi 2021). Funding sources that were declared included national research or local hospital/university grants. When declared, there were no author conflicts of interests. None of the studies declared the involvement of pharmaceutical companies.
Effects of interventions
See: Table 1; Table 2; Table 3
1. Metformin versus megestrol
We included two studies in this comparison; a total of 83 participants were analysed (Sharifzadeh 2016; Tabrizi 2014). The results are summarised in Table 1.
Primary outcome
Regression of endometrial hyperplasia histology (with or without atypia) towards normal histology
We are uncertain whether metformin increased regression of endometrial hyperplasia compared to 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; Analysis 1.1; Figure 4). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression in the metformin group would be between 71% and 96%.
1.1. Analysis.
Comparison 1: Metformin versus megestrol, Outcome 1: Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium
4.
Secondary outcomes
Recurrence of endometrial hyperplasia
No study in this comparison reported this outcome.
Progression of endometrial hyperplasia to endometrial cancer
Two studies provided data for this outcome (N = 83), but reported no events in either arm (Analysis 1.2).
1.2. Analysis.
Comparison 1: Metformin versus megestrol, Outcome 2: Progression of endometrial hyperplasia to endometrial cancer
Hysterectomy rate
The evidence is uncertain about the effect of metformin on hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52; 2 RCTs, 85 participants; very low‐certainty evidence; Analysis 1.3). This evidence suggests that if the rate of hysterectomy with megestrol is 2%, the rate of hysterectomy with metformin would be between 0% and 28%.
1.3. Analysis.
Comparison 1: Metformin versus megestrol, Outcome 3: Hysterectomy rate
Abnormal uterine bleeding
The evidence is uncertain about the effect of metformin on rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52; 1 RCT, 44 participants; very low‐certainty evidence; Analysis 1.4). The only study contributing data to this analysis reported only two events. This evidence suggests that if the rate of abnormal uterine bleeding with megestrol is 5%, the rate of abnormal uterine bleeding with metformin would be between 0% and 44%.
1.4. Analysis.
Comparison 1: Metformin versus megestrol, Outcome 4: Abnormal uterine bleeding
Health‐related quality of life
No study in this comparison measured this outcome.
Adverse events
No study in this comparison reported this outcome.
2. Metformin plus megestrol versus megestrol monotherapy
We included four studies in this comparison; a total of 258 participants were analysed (Sayyah Melli 2018; Shan 2014; Tehranian 2021; Yang 2020). The results are summarised in Table 2.
Primary outcome
Regression of endometrial hyperplasia histology (with or without atypia) towards normal histology
Metformin plus megestrol may increase regression of endometrial hyperplasia compared to megestrol monotherapy (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%; low‐certainty evidence; Analysis 2.1; Figure 5). This evidence 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%.
2.1. Analysis.
Comparison 2: Metformin plus megestrol versus megestrol, Outcome 1: Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
5.
Secondary outcomes
Recurrence of endometrial hyperplasia
Only one study provided data for this outcome (N = 8); it reported no events in either arm (Analysis 2.2).
2.2. Analysis.
Comparison 2: Metformin plus megestrol versus megestrol, Outcome 2: Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
The evidence is uncertain about the effect of metformin plus megestrol versus megestrol monotherapy on progression of endometrial hyperplasia to endometrial cancer (OR 7.96, 95% CI 0.16 to 402.02; 3 RCTs, 156 participants; very low‐certainty evidence; Analysis 2.3). There was only one event across the three studies.
2.3. Analysis.
Comparison 2: Metformin plus megestrol versus megestrol, Outcome 3: Progression of endometrial hyperplasia to endometrial cancer
Hysterectomy rate
The evidence is uncertain about the effect of metformin plus megestrol versus megestrol monotherapy on hysterectomy rates (OR 7.39, 95% CI 0.15 to 372.38; 2 RCTs, 156 participants; very low‐certainty evidence; Analysis 2.4). There was only one event across the two studies, reported in the megestrol monotherapy group.
2.4. Analysis.
Comparison 2: Metformin plus megestrol versus megestrol, Outcome 4: Hysterectomy rate
Abnormal uterine bleeding
No study in this comparison measured this outcome.
Health‐related quality of life
No study in this comparison measured this outcome.
Adverse events
In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment.
Sensitivity analysis
We carried out a sensitivity analysis to determine if removing a trial with high risk of bias in any domain would have an important impact on the primary outcome, regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium (Shan 2014).
After removing Shan 2014, the odds ratio of regression reduced slightly from 3.27 (95% CI 1.65 to 6.51) to 2.95 (95% CI 1.43 to 6.09).
3. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy
We included one study for this comparison; a total of 51 participants were randomised (Ravi 2021).
Primary outcome
Regression of endometrial hyperplasia histology (with or without atypia) towards normal histology
We are uncertain whether metformin plus levonorgestrel increased regression of endometrial hyperplasia compared to levonorgestrel monotherapy (OR 3.42, 95% CI 0.13 to 88.40; 1 RCT, 46 participants (only 46/51 participants were available for histopathological evaluation); very low‐certainty evidence; Analysis 3.1). In this study, there were high rates of women who reached the primary outcome (95% (21/22) of women receiving levonorgestrel monotherapy, and 100% (24/24) of women receiving metformin and levonorgestrel had regression of their endometrial hyperplasia). 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%.
3.1. Analysis.
Comparison 3: Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system), Outcome 1: Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium
Secondary outcomes
Recurrence of endometrial hyperplasia
No study in this comparison reported this outcome.
Progression of endometrial hyperplasia to endometrial cancer
The one study for this comparison reported no events in either arm (Analysis 3.2).
3.2. Analysis.
Comparison 3: Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system), Outcome 2: Progression of endometrial hyperplasia to endometrial cancer
Hysterectomy rate
We are uncertain whether metformin plus levonorgestrel had a different effect on hysterectomy rates than levonorgestrel monotherapy (OR 0.12, 95% CI 0.01 to 1.95; 1 RCT, 46 participants (only 46/51 participants were available to evaluate the clinical response); very low‐certainty evidence; Analysis 3.3). There were only two events, both in the levonorgestrel monotherapy group.
3.3. Analysis.
Comparison 3: Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system), Outcome 3: Hysterectomy rate
Abnormal uterine bleeding
We are uncertain whether metformin plus levonorgestrel had a different effect on abnormal uterine bleeding rates than levonorgestrel monotherapy (OR 0.61, 95% CI 0.16 to 2.27; 1 RCT, 49 participants (only 46/51 participants were available to evaluate the clinical response); very low‐certainty evidence; Analysis 3.4). This evidence suggests that if the rate of abnormal uterine bleeding with levonorgestrel monotherapy is 29%, the rate of abnormal uterine bleeding with the addition of metformin would be between 6% and 48%.
3.4. Analysis.
Comparison 3: Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system), Outcome 4: Abnormal uterine bleeding
Health‐related quality of life
No study in this comparison measured this outcome.
Adverse effects during treatment
Ravi 2021 provided data for this outcome. We are uncertain whether there is a difference between groups for the development of adverse effects during treatment (OR 4.00, 95% CI 1.15 to 13.90; P = 0.03; 1 RCT, 51 participants; very low‐certainty evidence; Analysis 3.5). This evidence suggests that if the rate of adverse effects during treatment with levonorgestrel monotherapy is 50%, the rate of adverse effects with the addition of metformin would be between 54% and 93%.
3.5. Analysis.
Comparison 3: Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system), Outcome 5: Adverse effects during treatment
Subgroup analysis
Described adverse effects included nausea, heaviness in the lower abdomen, and pain in the abdomen. In subgroup analysis, we only found a difference between groups for the presence of nausea (OR 5.11, 95% CI 1.21 to 21.68; P = 0.03; Analysis 3.5) with increased nausea in those taking metformin plus levonorgestrel. We found no clear differences between the groups in heaviness in the lower abdomen, or pain in the lower abdomen (Analysis 3.5). This evidence suggests that if the rate of nausea during treatment with levonorgestrel monotherapy is 12%, the rate of nausea with the addition of metformin would be between 14% and 74%.
Other analyses
Data were insufficient to undertake other sensitivity or subgroup analyses.
Discussion
Summary of main results
For this update, we included seven randomised controlled trials (RCTs) that randomised a total of 387 women.
Two included studies compared metformin with megestrol; four other studies compared metformin and megestrol with megestrol monotherapy; and one study compared metformin and levonorgestrel (intrauterine system) with levonorgestrel (intrauterine system) monotherapy. Both megestrol and levonorgestrel are mainstream treatment options for the management of endometrial hyperplasia.
No studies investigated metformin compared with placebo. This is important, as it is possible that endometrial hyperplasia may regress without the need for additional therapy.
Trial results provided no evidence to support or refute short‐term use of metformin, either alone or in combination with megestrol or levonorgestrel for the treatment of endometrial hyperplasia. The certainty of the evidence is low for metformin plus megestrol, and very low for metformin instead of megestrol or in addition to levonorgestrel (intrauterine system).
Overall completeness and applicability of evidence
We undertook a comprehensive search of a range of databases and trials registries, with no language restrictions, to identify published, unpublished, and ongoing studies. Thus, we are confident that we identified all potentially relevant RCTs. However, we only identified seven studies, conducted in three countries that met our inclusion criteria; all had small sample sizes, and consequently, overall applicability remains unclear. All studies had relatively short‐term follow‐up (three to six months) and long‐term effects of the therapy could not be established.
Quality of the evidence
Using GRADE, review authors determined that there was low‐certainty evidence supporting the results for metformin and megestrol compared to megestrol monotherapy, and very low‐certainty evidence supporting results for both metformin compared to megestrol, and metformin and levonorgestrel (intrauterine system) compared to levonorgestrel (intrauterine system) monotherapy. All studies had very small sample sizes, especially when assessing relatively rare events, such as progression of endometrial hyperplasia to endometrial cancer. Confidence intervals were compatible with a large effect in one or both groups, or with a null effect.
Potential biases in the review process
We conducted this review according to guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). Two review authors independently performed each step of the review process, thus reducing potential bias when subjective decisions were required. When the two review authors disagreed, we sought the opinions of a third review author. Furthermore, this review underwent peer review; thus, we are confident that the findings reported here are a true representation of the current evidence pertaining to this question.
Investigators excluded 6 of the 22 randomised participants from one study's final analysis (Shan 2014). The study authors provided no details of participants excluded owing to incomplete data, nor did they provide data previously collected for these participants. They also failed to provide data on participants who dropped out. This was reflected in our rating of attrition bias for the study.
We note that standard therapy doses for metformin compared to megestrol and metformin and megestrol compared to megestrol monotherapy differed, and we recognise the impact this may have had on the therapeutic response. However, we did not directly compare these studies, but included them in two separate comparisons.
We made the decision to include one study even though the authors of this study performed only subgroup analysis (Tabrizi 2014). We made this decision because the subgroup analysis was relevant to the study, and further evidence available in the literature was limited.
Agreements and disagreements with other studies or reviews
One other published systematic review examined the effect of metformin on endometrial hyperplasia (Chae‐Kim 2021). However, this review included data from both randomised and observational studies in the analysis.
Authors' conclusions
Implications for practice.
Review authors found insufficient evidence to either support or refute the use of metformin given alone or in combination with standard therapy, specifically megestrol, for the treatment of women with endometrial hyperplasia.
Implications for research.
Well‐designed randomised controlled clinical trials are required to investigate the effectiveness and safety of metformin for treating women with endometrial hyperplasia in comparison with other interventions, including oral or intrauterine progestogens. These trials should provide long‐term follow‐up of women with endometrial hyperplasia (both with and without atypia) in all arms of the trial, and include assessments of progression to endometrial carcinoma and health‐related quality of life.
What's new
| Date | Event | Description |
|---|---|---|
| 2 May 2024 | New citation required but conclusions have not changed | The addition of 4 new studies has not led to a change in the conclusions of this review. There is still insufficient evidence to suggest metformin, with or without progresterone therapy, is favourable compared to other progesterone therapies for the treatment of endometrial hyerplasia. |
| 2 May 2024 | New search has been performed | Since the initial review, there have been 4 further studies including a study comparing metformin to levonorgestrel (intrauterine system) (Ravi 2021; Sayyah Melli 2018; Tehranian 2021; Yang 2020) |
History
Protocol first published: Issue 5, 2016 Review first published: Issue 10, 2017
Acknowledgements
We would like to thank the Cochrane Gynaecology and Fertility Group (formerly the Menstrual Disorders and Subfertility Group) in Auckland, New Zealand, for help and support provided, especially Marian Showell for assistance with the search protocols, and Helen Nagels as the Managing Editor. We would like to thank Victoria Pennick of the Cochrane Central Production Service for her role as Copy Editor.
We also thank Dr Annika Strandell, Ms Katie Stocking, and Dr Andy Watson for providing referee comments on the draft update.
Appendices
Appendix 1. Gynaecology and Fertility Specialised Register of controlled trials search strategy
Searched 5 September 2022
Procite platform
Keywords CONTAINS "endometrial hyperplasia" or "endometrial proliferation" or "endometrial thickness" or "proliferation" or "hyperplasia" or Title CONTAINS "endometrial hyperplasia" or "endometrial proliferation" or "endometrial thickness" or "proliferation" or "hyperplasia"
AND
Keywords CONTAINS "metformin" or "glucophage" or Title CONTAINS "metformin" or "glucophage"
(34 records)
Appendix 2. CENTRAL Register of Studies Online (CRSO) search strategy
Searched 5 September 2022
Web platform
#1 MESH DESCRIPTOR Endometrial Hyperplasia EXPLODE ALL TREES 163
#2 (Endometr* adj5 Hyperplas*):TI,AB,KY 631
#3 (endometri* adj5?proliferat*):TI,AB,KY 180
#4 #1 OR #2 OR #3 759
#5 MESH DESCRIPTOR Metformin EXPLODE ALL TREES 4456
#6 metformin:TI,AB,KY 11476
#7 glucophage:TI,AB,KY 221
#8 (dimethylbiguanidine or dimethylguanylguanidine):TI,AB,KY 1
#9 (dimethylbiguanidium or glucovance):TI,AB,KY 11
#10 #5 OR #6 OR #7 OR #8 OR #9 11487
#11 #4 AND #10 53
Appendix 3. MEDLINE search strategy
Searched from 1946 to 5 September 2022
Ovid platform
1 exp Endometrial Hyperplasia/ (3744) 2 (endometri$ adj5 hyperplas$).tw. (5256) 3 (endometri$ adj3?proliferat$).tw. (3231) 4 or/1‐3 (9145) 5 exp Metformin/ (16776) 6 metformin.tw. (25285) 7 glucophage.tw. (125) 8 (dimethylbiguanidine or dimethylguanylguanidine).tw. (7) 9 (dimethylbiguanidium or glucovance).tw. (19) 10 or/5‐9 (27305) 11 4 and 10 (96) 12 randomized controlled trial.pt. (576263) 13 controlled clinical trial.pt. (95017) 14 randomized.ab. (574491) 15 randomised.ab. (113915) 16 placebo.tw. (237613) 17 clinical trials as topic.sh. (200338) 18 randomly.ab. (390496) 19 trial.ti. (269560) 20 (crossover or cross‐over or cross over).tw. (94809) 21 or/12‐20 (1547693) 22 exp animals/ not humans.sh. (5042039) 23 21 not 22 (1424560) 24 11 and 23 (21)
Appendix 4. Embase search strategy
Searched from 1980 to 5 September 2022
Ovid platform
1 exp endometrium hyperplasia/ (8170) 2 (endometri$ adj5 hyperplas$).tw. (7196) 3 (endometri$ adj3 proliferat$).tw. (4301) 4 or/1‐3 (13672) 5 exp metformin/ (77204) 6 metformin.tw. (42604) 7 glucophage.tw. (1697) 8 (dimethylbiguanidine or dimethylguanylguanidine).tw. (7) 9 (dimethylbiguanidium or glucovance).tw. (209) 10 or/5‐9 (80193) 11 4 and 10 (259) 12 Clinical Trial/ (1034391) 13 Randomized Controlled Trial/ (721579) 14 exp randomization/ (94946) 15 Single Blind Procedure/ (47288) 16 Double Blind Procedure/ (195502) 17 Crossover Procedure/ (71205) 18 Placebo/ (371385) 19 Randomi?ed controlled trial$.tw. (294090) 20 Rct.tw. (48223) 21 random allocation.tw. (2365) 22 randomly.tw. (512806) 23 randomly allocated.tw. (41958) 24 allocated randomly.tw. (2792) 25 (allocated adj2 random).tw. (846) 26 Single blind$.tw. (29131) 27 Double blind$.tw. (226211) 28 ((treble or triple) adj blind$).tw. (1611) 29 placebo$.tw. (341956) 30 prospective study/ (788817) 31 or/12‐30 (2842259) 32 case study/ (87684) 33 case report.tw. (485056) 34 abstract report/ or letter/ (1208809) 35 or/32‐34 (1768075) 36 31 not 35 (2779784) 37 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6466669) 38 36 not 37 (2592733) 39 11 and 38 (70)
Appendix 5. PubMed search strategy
Searched 5 September 2022
Web platform
1. Endometrial Hyperplasia[mh]
2. (endometri* and hyperplas*)[tw]
3. (endometri* and proliferat*)[tw]
4. or/1‐3
5. Metformin[mh]
6. metformin[tw]
7. glucophage[tw]
8. (dimethylbiguanidine or dimethylguanylguanidine)[tw]
9. (dimethylbiguanidium or glucovance)[tw]
10. or/5‐9
11. 4 and 10
12. randomized controlled trial[ptyp]
13. controlled clinical trial[ptyp]
14. randomized[tw]
15. randomized[tw]
16. placebo[tw]
17. randomly[tw]
18. trial[tw]
19. (crossover or cross‐over or cross over)[tw]
20. or/12‐20
21. animals[mh] not humans[mh]
22. 20 not 21
23. 11 and 22
Appendix 6. Google Scholar search strategy
Searched 5 September 2022
Web platform
Keywords include: "endometrium", "endometrial", "hyperplasia, "proliferation", "metformin"
Appendix 7. ClinicalTrials.gov search strategy
Searched 5 September 2022
Web platform
(endometrial OR endometrium) AND (hyperplasia OR proliferation) AND (metformin OR glucophage OR dimethylbiguanidine OR dimethylguanylguanidine OR glucovance OR dimethylbiguanidium)
Appendix 8. World Health Organization International Trials Registry Platform search strategy
Searched 5 September 2022
Web platform
(endometrial OR endometrium) AND (hyperplasia OR proliferation) AND (metformin OR glucophage OR dimethylbiguanidine OR dimethylguanylguanidine OR glucovance OR dimethylbiguanidium)
Appendix 9. OpenGrey search strategy
Searched 5 September 2022
Web platform
(endometrial OR endometrium) AND (hyperplasia OR proliferation) AND (metformin OR glucophage OR dimethylbiguanidine OR dimethylguanylguanidine OR glucovance OR dimethylbiguanidium)
Appendix 10. LILACS search strategy
Searched 5 September 2022
Web platform
(endometrial OR endometrium) AND (hyperplasia OR proliferation) AND (metformin OR glucophage OR dimethylbiguanidine OR dimethylguanylguanidine OR glucovance OR dimethylbiguanidium)
Data and analyses
Comparison 1. Metformin versus megestrol.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium | 2 | 83 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.89 [1.56, 15.32] |
| 1.2 Progression of endometrial hyperplasia to endometrial cancer | 2 | 83 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| 1.3 Hysterectomy rate | 2 | 85 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.91 [0.05, 15.09] |
| 1.4 Abnormal uterine bleeding | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only |
Comparison 2. Metformin plus megestrol versus megestrol.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2.1 Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium | 4 | 258 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.27 [1.65, 6.51] |
| 2.2 Recurrence of endometrial hyperplasia | 1 | 8 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| 2.3 Progression of endometrial hyperplasia to endometrial cancer | 3 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 7.96 [0.16, 402.02] |
| 2.4 Hysterectomy rate | 2 | 72 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 7.39 [0.15, 372.38] |
Comparison 3. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 3.1 Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2 Progression of endometrial hyperplasia to endometrial cancer | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Totals not selected | |
| 3.3 Hysterectomy rate | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Totals not selected | |
| 3.4 Abnormal uterine bleeding | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.5 Adverse effects during treatment | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.5.1 All effects | 1 | 51 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.00 [1.15, 13.90] |
| 3.5.2 Nausea | 1 | 51 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.11 [1.21, 21.68] |
| 3.5.3 Heaviness in lower abdomen | 1 | 51 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.32, 5.85] |
| 3.5.4 Pain in abdomen | 1 | 51 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.22, 3.18] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ravi 2021.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline characteristics Levonorgestrel (Intrauterine system)
Metformin and levonorgestrel (intrauterine system)
Overall
Included criteria: women with abnormal uterine bleeding and histopathological diagnosis of endometrial hyperplasia without atypia Excluded criteria: women on progestin therapy for more than 15 days, with uterine or extra uterine malignancy, with renal dysfunction, liver disease or diabetes mellitus, with history of hypersensitivity to metformin or discontinuation due to adverse effects, pregnancy or lactation, recent (< 4 weeks) or active documented Pelvic Inflammatory Disease (PID) or cervical infection, with immune‐suppression, abnormal Pap smear or contraindication to metformin or progestin or IUS Pretreatment: no differences in baseline demographics |
|
| Interventions |
Intervention characteristics Levonorgestrel (intrauterine system)
Metformin and levonorgestrel (intrauterine system)
|
|
| Outcomes |
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory, or atrophic endometrium
Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
Abnormal uterine bleeding
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: None declared Country: India Setting: Outpatient Author's name: Ramya Dinnekere Ravi Institution: Department of Obstetrics & Gynaecology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Email: drjasvinpgi3@gmail.com |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement comment: fifty‐one recruited participants were randomized by asking them to pick up an envelope from a set of similar looking pre‐sealed opaque envelopes prepared by a third party, into LNG‐IUS with metformin group (Group M) and LNG‐IUS alone group (Group L). |
| Allocation concealment (selection bias) | Low risk | Judgement comment: "Fifty‐one recruited patients were randomized by asking them to pick up an envelope from a set of similar looking pre‐sealed opaque envelopes prepared by a third party, into LNG‐IUS with metformin group (Group M) and LNG‐IUS alone group (Group L)." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement comment: participants and personnel were not blinded. No placebo was given to the LNG‐IUS only group. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Judgement comment: pathologists were unaware of the management that the patient had received |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | cudgement Comment: metformin and LNG‐IUS group ‐ 1 refused 6 month followup visitLNG‐IUS only group ‐ 2 refused post‐treatment endometrial biopsy. 1 expelled LNG‐IUS. 1 patient underwent hysterectomy at a different centre for persistent bleeding |
| Selective reporting (reporting bias) | Low risk | Judgement comment: metformin and LNG‐IUS group ‐ 1 refused 6 month followup visitLNG‐IUS only group ‐ 2 refused post‐treatment endometrial biopsy. 1 expelled LNG‐IUS. 1 patient underwent hysterectomy at a different centre for persistent bleeding |
| Other bias | Unclear risk | Judgement comment: lack of conflict of interest statement |
Sayyah Melli 2018.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline characteristics Megestrol
Metformin and megestrol
Included criteria: participants who had abnormal uterine bleeding with disordered proliferative or hyperplastic endometrium with or without atypical status were included in the study. Excluded criteria: participants who had allergy to metformin, and not taking medications of bi‐guanidinium group (metformin), those who had renal failure, nausea, vomiting, anorexia, anaemia, cutaneous lesions, severe hepatic dysfunction, uncontrolled hypertension, thromboembolic disorders, and genital cancers or not satisfied to participate in the study, were excluded. |
|
| Interventions |
Intervention characteristics Megestrol
Metformin and megestrol
|
|
| Outcomes |
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
Progression of endometrial hyperplasia to endometrial cancer
Recurrence of endometrial hyperplasia
Abnormal uterine bleeding
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: funded by a grant from the Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences Country: Iran Setting: Outpatient Author's name: Manizheh Sayyah‐Melli Institution: Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Email: manizheh.sayyahmelli@gmail.com Address: |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement comment: random sampling was used to allocate participants to the groups. RandList software (version 2.1, Germany with sequentially numbered containers) was used for randomisation and eligible women were randomly allocated to the intervention groups. |
| Allocation concealment (selection bias) | Low risk | Judgement comment: random sampling was used to allocate participants to the groups. RandList software (version 2.1, Germany with sequentially numbered containers) was used for randomisation and eligible women were randomly allocated to the intervention groups. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement comment: single‐blind clinical trial |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Judgement comment: single‐blind clinical trial |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Judgement comment: all outcomes were reported |
| Selective reporting (reporting bias) | Low risk | Judgement comment: outcomes described in pre‐published protocol were reported (IRCT201410275283N11) |
| Other bias | Low risk | Judgement comment: no suggestion of other sources of bias |
Shan 2014.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline Characteristics Megestrol
Metformin and megestrol
Included criteria: pathologically diagnosed with EAH, aged 45 years or less, desire to preserve fertility and at least one sign of metabolic syndrome Excluded criteria: alcoholism, pregnancy, severe infection, complicated clinical diseases (heart, liver, lung and kidney dysfunction), severe cardiovascular disease, allergy to MA or metformin, thrombosis, breast cancer history, other reproductive system malignancies (including EC), contraindications for treatment of either MA or metformin and previous hormonal treatment Pretreatment: the mean ages of the MA and MET group participants were 34 ± 7.1 and 36.4 ± 4.2 years, respectively. There was no statistically significant difference in age distribution between the two groups (P = 0.433). All participants were married, and 37.5% of the participants (6/16) had a history of infertility. Furthermore, 50% of the participants (8/16) met the MS criteria, and 50% of the participants (4/8) had MS in both the MA and MET groups. |
|
| Interventions |
Intervention Characteristics Megestrol
Metformin and megestrol
|
|
| Outcomes |
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
Progression of endometrial hyperplasia to endometrial cancer
Recurrence of endometrial hyperplasia
Abnormal uterine bleeding
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: National Natural Science Foundation of China (NSFC No: 81101953 and 81210108021), Shanghai Municipal Science Foundation 2011 and 2013 (Project No's: 11ZR1404300 and 134119a4500). Country: China Setting: Hospital (Obstetrics and Gynaecology Hospital of Fudan Hospital) Author's name: Xiaojun Chen Institution: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai and Shanghai Key Laboratory of Female Reproductive Endocrine Reated Diseases, Shanghai Email: cxjlh@hotmail.com Address: Department of Gynecology, Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, No.419 Fangxie Rd, Shanghai 200011, China |
|
| Notes | Naomi Clement on 25/12/2016 04:02 Outcomes Missing data = 0 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement comment: communication with authors: "Using computer, we got a randomized table with a total sample of 16. Actually, we used function "RAND" in excel to form the table and changed these randomized number to 0 or 1. When a subject was enrolled, she would get a number. 0 means MA only and 1 means MA + metformin." |
| Allocation concealment (selection bias) | Unclear risk | Judgement comment: communication with authors: "Using computer, we got a randomized table with a total sample of 16. Actually, we used function "RAND" in excel to form the table and changed these randomized number to 0 or 1. When a subject was enrolled, she would get a number. 0 means MA only and 1 means MA + metformin." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement comment: communication with authors: "This study was an open label study. However, when analysing the data, the analyser was kept unaware of the meaning of the number 0 or 1. And only the investigator or sponsor had the right of access to personal data of subjects." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Judgement comment: communication with authors: "This study was an open‐label study. However, when analysing the data, the analyser was unaware of the meaning of the number 0 or 1." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Judgement comment: of the 30 participants, 16 completed 12 weeks of therapy, and 14 were excluded, which consisted of eight participants who chose to undergo an operation and were remitted, three participants who were lost during follow‐up, and three participants who had incomplete data (no blood test results available). |
| Selective reporting (reporting bias) | High risk | Judgement comment: no protocol was published prior to publication of the study. Outcomes were appropriately reported. 3 participants died following the completion of the study. |
| Other bias | Low risk | Judgement comment: no suggestion of other sources of bias |
Sharifzadeh 2016.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline characteristics Metformin
Megestrol
Overall
Included criteria: simple endometrial hyperplasia without atypia confirmed with endometrial sampling Excluded criteria: hypersensitivity to metformin or intolerance to metformin or progesterone; using metformin during the previous six months; known liver or renal disorders; blood sugar of less than 60 mg/dL or more than 200 mg/dL; using simultaneous medications; using oral contraceptives or oestrogen or progesterone; having know genital neoplasia or atypical endometrial hyperplasia |
|
| Interventions |
Intervention Characteristics Metformin
Megestrol
|
|
| Outcomes |
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
Abnormal uterine bleeding
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: None declared Country: Iran Setting: Hospital outpatient clinic Comments: Iran Registry of Clinical Trials (IRCT201506252624N18) Author's name: Maryam Kashanian Institution: Iran University of Medical Sciences Email: maryamkashanian@yahoo.com Address: Iran University of Medical Sciences, Department of Obstetrics & Gynecology, Akbarabadi Teaching Hospital, No 9, Mostaghimi Alley, Khajeh Nasir Toosi Avenue, post code 16117, Tehran, Iran |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement comment: communication with authors: "Randomization was performed using sealed, sequentially distributed envelopes to which the letters A and B had been allocated: the letter A to the metformin group and the letter B to the megestrol group. The participants chose one of the envelopes which was opened by the investigator’s colleague and based on the letters, the groups of participants were determined." |
| Allocation concealment (selection bias) | Low risk | Judgement comment: communication with authors: "Randomization was performed using sealed, sequentially distributed envelopes to which the letters A and B had been allocated: the letter A to the metformine group and the letter B to the megestrol group. The participants chose one of the envelopes which was opened by the investigator’s colleague and based on the letters, the groups of participants were determined." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement comment: communication from authors: "The investigators and participants were not blind to the interventions" |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Judgement comment: communication from authors: "The investigators and participants, were not blind to the interventions" |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Judgement comment: 1 participant was lost to follow‐up and 2 discontinued intervention |
| Selective reporting (reporting bias) | Low risk | Judgement comment: 1 participant was lost to follow‐up and 2 discontinued intervention. These were excluded from the analysis. |
| Other bias | Low risk | Judgement comment: no suggestion of other sources of bias |
Tabrizi 2014.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline characteristics Metformin
Megestrol
Included criteria: women with abnormal uterine bleeding, and disordered proliferative or hyperplastic endometrium with or without atypia; consent to participate Excluded criteria: women with allergy to metformin; women with renal failure; nausea, vomiting, anorexia; anaemia; cutaneous lesions |
|
| Interventions |
Intervention characteristics Metformin
Megestrol
|
|
| Outcomes |
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
Abnormal uterine bleeding
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: none declared Country: Iran Setting: Hospital outpatient clinic Comments: Author's name: Manijeh Sayyah Melli Institution: Women ´s Reproductive Health Research Center Email: manizheh.sayyahmelli@gmail.com Address: Tabriz University of Medical Sciences, East Azerbaijan, Tabriz, University Main St, Iran |
|
| Notes | In this updated review, the authors felt that 24 participants with a diagnosis of disordered proliferative endometrium met the inclusion criteria for the study. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "43 patients who fit the including criteria were categorized in two groups in randomized fashion." Judgement comment: participants were randomised |
| Allocation concealment (selection bias) | Unclear risk | Judgement comment: no description of the allocation process provided |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Judgement comment: as above, no blinding process described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Judgement comment: as above, no explanation of the blinding process |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "Amongst 43 patients, 22 (51.16%) cases were treated with Metformin and 21(48.83%) patients with Megestrol acetate for the period of three months." Judgement comment: no loss of the 43 participants was mentioned; assumed all present and accounted for |
| Selective reporting (reporting bias) | High risk | Judgement comment: no protocol was published prior to publication, so it is difficult to establish whether there was selective outcome reporting. |
| Other bias | High risk | Judgement comment: 1) Potential sampling bias: not matched by histology, age, features of metabolic syndrome or PCOS. Study reports inclusion criteria to be histology of DPE or SH only, yet cases of CH and EEC were included in the metformin pre‐treatment group. 2) Exclusion bias as women with diabetes were excluded, yet, of the pre‐intervention blood glucose values we assumed to be fasting, it is likely some undiagnosed cases of diabetes were included. This is inconsistent exclusion of women with diabetes. |
Tehranian 2021.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline characteristics Megestrol
Metformin and Megestrol
Included criteria: women aged 18 to 75 years with simple endometrial hyperplasia without atypia, proved by pathological evaluation of endometrial specimens that may have been obtained by either outpatient office biopsy or curettage in the operative room. Excluded criteria: contraindication for metformin or megestrol acetate intake, using metformin during the last 6 months, heart and lung dysfunction, blood sugar level more than 200 mg/dL or less than 65 mg/dL, alcohol consumption, vitamin B12 malabsorption and body mass index < 25 kg/m2, history of thrombosis, breast cancer and other genital tract malignancies, pregnancy, impaired hepatic and renal function tests Pretreatment: the characteristics compared between the metformin and megestrol group and placebo and megestrol group patients were age, gravida, days of bleeding, and number of participants who had reached menopause. There were no statistically significant differences between all these metrics. |
|
| Interventions |
Intervention characteristics Megestrol
Metformin and Megestrol
|
|
| Outcomes |
Progression of endometrial hyperplasia to endometrial cancer
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
Abnormal uterine bleeding
Recurrence of endometrial hyperplasia
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: supported by the Tehran University of Medical Sciences Country: Iran Setting: Hospital outpatient Author's name: Afsaneh Tehranian Institution: Tehran University of Medical Sciences Email: afsanehtehranian@yahoo.com Address: Arash Women’s HospitalRashid AveResalat HighwayP.O Box: 1653915981TehranparsTehranIran |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "An epidemiologist in the research center did the computer‐generated randomization with permuted blocks of six without any contact with patients. The allocation process was sealed in opaque envelops. They were opened at the time of allocation." Judgement Comment: "An epidemiologist in the research center did the computer‐ generated randomization with permuted blocks of size six without any contact with patients. The allocation process was sealed in opaque envelops. They were opened at the time of allocation." |
| Allocation concealment (selection bias) | Low risk | Judgement comment: "An epidemiologist in the research center did the computer‐ generated randomization with permuted blocks of six without any contact with patients. The allocation process was sealed in opaque envelops. They were opened at the time of allocation." |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Judgement comment: "The investigators who were responsible for patient treatment were kept blinded to the type of drug. Both drug and placebo were administered to participants by a midwife. She did not know anything about the interventional assignment. Each drug package was labeled with the patient number and dosage instruction." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Judgement comment: participants and study staff (site investigator and trial co‐ordinating center staff) were blinded to study treatment group assignment. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Judgement comment: Metformin and megestrol ‐ Lost to follow‐up (n=1/30).Megestrol and placebo ‐ Lost to follow‐up (n=2/30). Non‐compliance (n=1/30) |
| Selective reporting (reporting bias) | Low risk | Quote: "IRCT20140820018866N6)." Judgement comment: all outcomes reported. Trial protocol published on the Iranian Registry of Clinical Trials. (IRCT20140820018866N6) |
| Other bias | Low risk | Judgement comment: no other biases noted |
Yang 2020.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial Study grouping: parallel group |
|
| Participants |
Baseline characteristics Megestrol
Metformin and megestrol
Overall
Included criteria: 18 to 45 years old, pathologically diagnosed with AEH or EEC (endometrioid, grade I, without myometrial invasion) for the first time; desire to preserve their fertility; no signs of suspicious myometrial invasion or extra uterine metastasis by enhanced magnetic resonance imaging, enhanced computed tomography, or transvaginal ultrasonography; no contraindication for metformin, MA, or pregnancy; no hormone or metformin treatment within 6 months before entering the trial; not pregnant when participating in the trial; willing to follow the trial arrangement after being fully informed of all the risks and inconveniences caused by the trial. Excluded criteria: allergy history or contraindications for MA or metformin, pregnant when initiating the study, alcoholism, severe infection, severe chronic diseases (dysfunction of heart, liver, lung or kidney), high risk of thrombosis, recurrent AEH or EC, other malignancy history |
|
| Interventions |
Intervention characteristics Megestrol
Metformin and megestrol
|
|
| Outcomes |
Regression of endometrial hyperplasia (with or without atypia) to proliferative, secretory or atrophic endometrium
Recurrence of endometrial hyperplasia
Progression of endometrial hyperplasia to endometrial cancer
Abnormal uterine bleeding
Hysterectomy rate
Adverse effects during treatment
|
|
| Identification |
Sponsorship source: National Key Technology R&D Program of China (Grant Nos 2019YFC1005200and 2019YFC1005204), National Natural Science Foundation of China (Grant Nos 81671417 and 81370688), Shang‐hai Medical Centre of Key Programmes for Female Reproductive Diseases (Grant No. 2017ZZ010616), Shang‐hai Science and Technology Development medical guide project (Grant No.17411961000, 134119a4500,19411960400), and Municipal Human Resources Development Programme for Outstanding Leaders in Medical Disciplines in Shanghai (Grant No. 2017BR035) Country: China Setting: outpatient Author's name: XJ Chen Institution: Department of Gynaecology, Obstetrics and Gynaecology Hospital of Fudan University Email: xiaojunchen2013@sina.com Address: 419 Fang‐Xie Road, Shanghai 200011, China |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Judgement comment: 'A computer‐based procedure of simple randomisation (SPSS forMac, version 20.0; IBM, Armonk, NY, USA) was used for participant enrolment and randomisation. Before a woman was successfully enroled, her treatment assignment remained concealed’ |
| Allocation concealment (selection bias) | Low risk | Judgement comment: 'A computer‐based procedure of simple randomisation (SPSS forMac, version 20.0; IBM, Armonk, NY, USA) was used for participant enrolment and randomisation. Before a woman was successfully enroled, her treatment assignment remained concealed’ |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement comment: 'This trial was open‐label: participants and study physicians were aware of treatment assignment.' |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Judgement comment: 'This trial was open‐label: participants and study physicians were aware of treatment assignment.' |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Judgement comment: all outcomes were reported |
| Selective reporting (reporting bias) | Low risk | Quote: "NCT01968317" Judgement comment: outcomes defined in the study protocol were reported |
| Other bias | Unclear risk | Judgement comment: baseline characteristics of the atypical hyperplasia group and endometrial cancer group were combined. We were unable to contact the authors for clarification. |
CH: complex hyperplasia
DPE: disordered proliferative endometrium
EEC: endometrioid endometrial cancer
MA: megestrol acetate
PCOS: polycystic ovary syndrome
SH: simple hyperplasia
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Acosta Torres 2019 | Wrong study design |
| Campagnoli 2013 | Wrong study design |
| Insin 2017 | Wrong population |
| Janda 2021 | Wrong population |
| Kim 2014 | Commentary only |
| Kitson 2018 | Wrong population |
| Legro 2007 | Wrong population |
| Lin 2016 | Wrong comparator |
| Mitsuhashi 2014 | Wrong comparator |
| Mitsuhashi 2014a | Wrong population |
| Mitsuhashi 2016 | Wrong study design |
| Mitsuhashi 2020 | Wrong intervention |
| O'Hara 2022 | Wrong intervention |
| Pino 2022 | Wrong population |
| Pérez‐López 2014 | Wrong population |
| Randall 2014 | Wrong study design |
| Seebacher 2016 | Wrong population |
| Shen 2008 | Wrong study design |
| Sivalingam 2015 | Wrong outcomes |
| Sivalingam 2016 | Wrong study design |
| Yates 2017 | Wrong outcomes |
| You 2016 | Wrong population |
| Zhou 2015 | Wrong study design |
EH: endometrial hyperplasia
PCOS: polycystic ovary syndrome
Characteristics of ongoing studies [ordered by study ID]
NCT01686126.
| Study name | Improving the treatment for women with early stage cancer of the uterus (feMMe) |
| Methods | Randomised parallel‐group open‐label trial |
| Participants |
|
| Interventions | 1. Levonorgestrel (Mirena) 52 mg intrauterine drug delivery system + metformin 2. Levonorgestrel (Mirena) 52 mg intrauterine drug delivery system 3. Levonorgestrel (Mirena) 52 mg intrauterine drug delivery system + weight loss |
| Outcomes | Primary outcome Pathological complete response Secondary outcomes 1. Predicted response to treatment 2. Predicted response to treatment through blood and tissue molecular biomarkers 3. Increased molecular understanding of the biological pathogenesis of "early" EAC |
| Starting date | October 2012 |
| Contact information | Vanessa L Taylor; vanessa.taylor3@health.qld.gov.au |
| Notes |
NCT02035787.
| Study name | Metformin with the levonorgestrel‐releasing intrauterine device for the treatment of complex atypical hyperplasia (CAH) and endometrial cancer (EC) in non‐surgical patients |
| Methods | open label, single‐arm, single‐center study of the addition of metformin to standard levonorgestrel‐releasing intrauterine device |
| Participants | Women over the age of 18 years, with biopsy‐proven CAH/EC, who are not candidates for surgical management, and therefore, have plans to start standard of care treatment with the LR‐IUD |
| Interventions | Drug: metformin Subjects will be given oral metformin therapy for 12 months, or until disease progression occurs (whichever occurs first), in addition to LR‐IUD treatment. Serial endometrial biopsies will be performed, as per standard of care, to assess disease status. |
| Outcomes | Primary Objective To compare the rate of CR at 6 months in non‐surgical grade 1 EC and CAH patients receiving metformin + LR‐IUD to 50% Secondary Objectives
Exploratory Objectives
This is an open‐label, single‐arm, single‐center study of the addition of metformin to standard levonorgestrel‐releasing intrauterine device (LR‐IUD) treatment of 30 evaluable non‐surgical women with either complex atypical hyperplasia (CAH; n = 15) or grade 1 endometrial adenocarcinoma (EC; n = 15). Women over the age of 18 years with biopsy‐proven CAH/EC who are not candidates for surgical management, and therefore are planning to start standard of care treatment with the LR‐IUD, will be given oral metformin therapy for 12 months, or until disease progression occurs (whichever occurs first), in addition to LR‐IUD treatment. Serial endometrial biopsies will be performed, as per standard of care, to assess disease status. We hypothesise that the addition of metformin to standard LR‐IUD treatment of CAH and grade 1 EC will result in a complete response (CR) rate at 6 months that is significantly higher than 50% in a population of non‐surgical candidates. In addition, we plan to estimate CR rate at 6 months in CAH and EC separately, and in the group as a whole, at 12 months. We will also document the rate of patient adherence to long‐term metformin therapy. |
| Starting date | 27 February 2014 |
| Contact information | Victoria Bae‐Jump, MD, PhD UNC Lineberger Comprehensive Cancer Center |
| Notes |
NCT04576104.
| Study name | Megestrol acetate compared with megestrol acetate and metformin to prevent endometrial cancer |
| Methods | Study type: interventional Primary purpose: prevention Study phase: phase 2 Interventional study model: parallel assignment Number of arms: 2 Masking: none (open‐label) Allocation: randomised Enrolment: 50 (anticipated) |
| Participants | Participants with endometrial intraepithelial neoplasia (EIN) on an endometrial biopsy or dilation and curettage specimen |
| Interventions | Active comparator: arm I (megestrol acetate) Prior to standard of care surgery, women receive megestrol acetate orally, twice a day for 4 weeks in the absence of disease progression or unacceptable toxicity. Experimental: arm II (megestrol acetate, metformin hydrochloride) Prior to standard of care surgery, women receive megestrol acetate orally, twice a day and metformin hydrochloride extended‐release orally, twice a day for 4 weeks in the absence of disease progression or unacceptable toxicity. |
| Outcomes | Primary objective: I. To compare the change in endometrial cell proliferation, as measured by the percentage (%) of Ki‐67 positive cells, in participants with endometrial intraepithelial neoplasia who underwent 4 weeks of treatment with megestrol acetate + metformin or megestrol acetate alone prior to hysterectomy. Secondary objective: I. To measure the changes in protein expression in the endometrial intraepithelial neoplasia lesion, using immunohistochemistry (i‐vi) in women treated with megestrol acetate + metformin compared to those treated with megestrol acetate alone. Exploratory objective: I. To explore whether baseline Ki‐67 expression and other clinical characteristics are associated with treatment response. |
| Starting date | 1 April 2021 |
| Contact information | Emma Barber Principal Investigator Northwestern University |
| Notes |
NCT05292573.
| Study name | Longitudinal follow‐up in women with endometrial hyperplasia without atypia |
| Methods | This study will prospectively enrol a total of 1000 women (200 per year) with simple hyperplasia/complex hyperplasia (SH/CH) without atypia. All women will receive education for exercise and weight control and be randomized 1:1 to groups with or without metformin intervention. At the end of this 3‐year project, an interim analysis will be performed. Since long‐term follow‐up is intended, for the 4th to 6th year, a new grant support will be looked for. The long‐term occurrence of endometrial cancer (up to 15 years) data will be acquired from the national cancer registry, permission for which is addressed in the informed consent. |
| Participants | Inclusion Criteria:
Exclusion Criteria:
|
| Interventions | No intervention: observation group Only exercise and weight control for all eligible participants Experimental: metformin group
|
| Outcomes | Primary outcome measures:
The primary endpoint of the randomised prospective study is to evaluate the ROC of the prediction miR panel of the 3 miRs. Secondary outcome measures:
Incidence of progression to endometrial cancer among groups, the proportion of participants with treatment‐related adverse events as assessed by CTCAE v4.0 |
| Starting date | 1 August 2018 |
| Contact information | CHYONG‐HUEY LAI, MD +88633281200 ext 8254 laich46@cgmh.org.tw |
| Notes |
NCT05316935.
| Study name | GnRHa + letrozole in progestin‐insensitive endometrial cancer and atypical hyperplasia patients |
| Methods | Treatment/intervention study Allocation: non‐randomized Interventional model: parallel assignment Masking: none (open‐label) Objectives To investigate the efficacy of GnRHa plus letrozole vs Diane‐35 plus metformin in non‐obese progestin‐insensitive early‐stage endometrial cancer (EEC) and atypical hyperplasia(EAH) patients asking for conservative treatment. To investigate the efficacy of GnRHa plus letrozole in obese progestin‐insensitive EEC and EAH patients. |
| Participants | Inclusion criteria:
Using progestin, any of the following therapies, as first‐line treatment:
Progestin‐insensitive:
Exclusion Criteria:
|
| Interventions |
|
| Outcomes | Primary outcome measures
Secondary outcome measures
|
| Starting date | 13 July 2022 |
| Contact information | Xiaojun Chen, PhD Phone Number: 8602133189900 ext 6429 Email Address: cxjlhjj@163.com |
| Notes |
PACTR201908498370196.
| Study name | Metformin versus levonorgestrel‐releasing intrauterine device (Mirena) in the management of endometrial hyperplasia |
| Methods | Study type: interventional Study design: factorial: participants randomly allocated to either no, one, some or all interventions simultaneously; simple randomisation using a randomisation table created by a computer software programme; sealed opaque envelopes |
| Participants | 1. Women between the ages of 18 and 75 years old 2. Women with a histological diagnosis of endometrial hyperplasia without atypia, confirmed by endometrial biopsy |
| Interventions | Control group: Mirena group Levonorgestrel intrauterine device will be inserted for women with endometrial hyperplasia for 6 months Experimental group: metformin group Metformin 850 mg orally for 6 months; once daily for 2 months, then twice daily for 4 months |
| Outcomes | Primary outcome Evaluation of hyperplasia resolution by comparison of pre‐ and post‐treatment endometrial biopsies Secondary outcome Intervention‐related side effects |
| Starting date | 25 August 2019 |
| Contact information |
Principal Investigator Mohammed Abdelgelil drmody1104@gmail.com 01223423685 |
| Notes |
BMI: body mass index
CT: computed tomography
D & C: dilation & curettage
EAC: esophageal adenocarcinoma
MRI: magnetic resonance imaging
Differences between protocol and review
In the protocol, we stated that for the outcomes (i) regression of endometrial hyperplasia, and (ii) progression to endometrial carcinoma, we would calculate Mantel‐Haenszel odds ratios. In the review, we added that if data were available, we planned to (in preference) calculate hazard ratios for the outcomes (i) regression of endometrial hyperplasia, (ii) recurrence of endometrial hyperplasia, and (iii) progression to endometrial carcinoma, as hazard ratios include participants who dropped out of the study, and therefore, provide the best way to analyse these outcomes.
In the protocol, our objective was 'To determine the efficacy and safety of metformin in treating women with endometrial hyperplasia'. Upon editorial recommendation, we changed this to, 'To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia'.
Contributions of authors
WA, HS and NC initiated the review; HS and NC drafted and finalised the background and objectives; HS, NC, WA drafted and finalised the methods sections. WA reviewed the final protocol.
For this update, HS and NC performed all the searches. HS and NC then screened titles and abstracts for potential inclusion. HS and NC assessed each paper for potential inclusion. HS performed searches of unpublished trials and contacted relevant authors. HS and NC extracted data from included studies, with WA providing clinical interpretation of data. HS, NC, JD and WA drafted the review, and all authors reviewed the final draft.
Sources of support
Internal sources
-
No source of support, UK
No source of support
External sources
-
No sources of support, UK
No source of support
Declarations of interest
Declarations at March 2024 are as made for the first published verison of this review in October 2017.
WA is a Professor of Obstetrics and Gynaecology at Mohamed Bin Rashid University of Medicine and Health Sciences in Dubai, United Arab Emirates. He was previously a Clinical Associate Professor and a Consultant Gynaecologist at Queen's Medical Centre, at Nottingham, in the UK. He previously submitted an application to the Nottingham Clinical Trials Unit (in the process of developing a research grant application to the UK NIHR) to conduct a clinical trial comparing metformin with progesterone for treatment of endometrial hyperplasia. A systematic review was suggested to support the trial.
HS, NC and JD have no interests to declare.
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
Ravi 2021 {published data only}
- Ravi RD, Kalra J, Srinivasan R, Bagga R, Jain V, Suri V, et al. A randomized clinical trial of levonorgestrel intrauterine system with or without metformin for treatment of endometrial hyperplasia without atypia in indian women. Asian Pacific Journal of Cancer Prevention : APJCP 2021;22(3):983-9. [DOI: 10.31557/APJCP.2021.22.3.983] [DOI] [PMC free article] [PubMed] [Google Scholar]
Sayyah Melli 2018 {published data only}
- Sayyah-Melli M, Mostafa-Gharabaghi P, Rahmani V. Comparison of metformin + megestrol acetate and megestrol alone on endometrial abnormal histology. International Journal of Obstetrics and Gynecology 2018;143(Supplement 3):739. [DOI: 10.1002/ijgo.12583] [DOI] [Google Scholar]
- Sayyah-Melli M, Pourazad S, Gharebaghi PM, Ouladsahebmadarek E, Jafari-Shobeiri M, Rahmani V. The comparative effect of combination of metformin and megestrol acetate with megestrol acetate alone on endometrial growth disorders. International Journal of Women's Health and Reproduction Sciences 2018;6(2):211-5. [DOI: 10.15296/ijwhr.2018.35] [DOI] [Google Scholar]
Shan 2014 {published data only}
- Shan W, Wang C, Zhang Z, Gu C, Ning C, Luo X, et al. Conservative therapy using metformin plus megestrol acetate for endometrial atypical hyperplasia: preliminary results of a pilot study. International Journal of Gynecological Cancer 2014;24(9 Suppl 4):1306-7. [DOI: 10.1097/01.IGC.0000457075.08973.89] [DOI] [Google Scholar]
- Shan W, Wang C, Zhang Z, Gu C, Ning C, Luo X, et al. Conservative therapy with metformin plus megestrol acetate for endometrial atypical hyperplasia. Journal of Gynecologic Oncology 2014;25(3):214-20. [DOI: 10.3802/jgo.2014.25.3.214] [DOI] [PMC free article] [PubMed] [Google Scholar]
Sharifzadeh 2016 {published data only}
- Sharifzadeh F, Aminimoghaddam S, Kashanian M, Fazaeli M, Sheikhansari N. A comparison between the effects of metformin and megestrol on simple endometrial hyperplasia. Gynecological Endocrinology 2016;33(2):1-4. [DOI] [PubMed] [Google Scholar]
- Sharifzadeh F, Aminimoghaddam S, Kashanian M, Fazaeli M, Sheikhansari N. A comparison between the effects of metformin and megestrol on simple endometrial hyperplasia. Gynecological Endocrinology 2017;33(2):152-5. [DOI: 10.1080/09513590.2016.1223285] [DOI] [PubMed] [Google Scholar]
Tabrizi 2014 {published data only}
- Tabrizi AD, Melli MS, Foroughi M, Ghojazadeh M, Bidadi S. Antiproliferative effect of metformin on the endometrium − a clinical trial. Asian Pacific Journal of Cancer Prevention 2014;15(23):10067-70. [DOI] [PubMed] [Google Scholar]
Tehranian 2021 {published data only}
- Tehranian A, Ghahghaei-Nezamabadi A, Arab M, Khalagi K, Aghajani R, Sadeghi S. The impact of adjunctive metformin to progesterone for the treatment of non-atypical endometrial hyperplasia in a randomized fashion, a placebo-controlled, double blind clinical trial. Journal of Gynecology Obstetrics and Human Reproduction 2021;50(6):101863. [DOI: 10.1016/j.jogoh.2020.101863] [DOI] [PubMed] [Google Scholar]
Yang 2020 {published data only}
- Yang B, Yierfulati G, Guan J, Chen X. Effect of megestrol acetate plus metformin as fertility-sparing treatment for patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer. A randomized controlled trial. International Journal of Gynecological Cancer 2019;29(Suppl 3):A4-5. [DOI: 10.1136/ijgc-2019-IGCS.7] [DOI] [Google Scholar]
- Yang BY, Gulinazi Y, Du Y, Ning CC, Cheng YL, Shan WW, et al. Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial. BJOG: An International Journal of Obstetrics & Gynaecology 2020;127(7):848-57. [DOI: 10.1111/1471-0528.16108] [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Acosta Torres 2019 {published data only}
- Acosta-Torres S, Doglioli M, Varghese A, Tanner EJ, Stone RL, Levinson KL, et al. Efficacy of combined metformin and progestin therapy for complex atypical hyperplasia and well-differentiated endometrial cancer in patients desiring fertility. Gynecologic Oncology 2019;154(Suppl 1):267. [DOI: 10.1016/j.ygyno.2019.04.620] [DOI] [Google Scholar]
Campagnoli 2013 {published data only}
- Campagnoli C, Abbà C, Ambroggio S, Brucato T, Pasanisi P. Life-style and metformin for the prevention of endometrial pathology in postmenopausal women. Gynecological Endocrinology 2013;29(2):119-24. [DOI] [PubMed] [Google Scholar]
Insin 2017 {published data only}
- Insin P, Prueksaritanond N. Therapeutic use of metformin in diabetes and survival outcomes in endometrial cancer patients with diabetes. Asian Pacific Journal of Cancer Prevention 2018;19(5):1295–1302. [DOI: 10.22034/APJCP.2018.19.5.1295] [DOI] [PMC free article] [PubMed] [Google Scholar]
Janda 2021 {published data only}
- Janda M, Robledo KP, Gebski V, Armes JE, Alizart M, Cummings M, et al. Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial. Gynecologic Oncology 2021;161(1):143-51. [DOI] [PubMed] [Google Scholar]
Kim 2014 {published data only}
- Kim MK, Seong SJ. Conservative treatment for atypical endometrial hyperplasia: what is the most effective therapeutic method? Journal of Gynecologic Oncology 2014;25(3):164-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kitson 2018 {published data only}
- Kitson S, Maskell Z, Sivalingam V, Slade R, Ali S, Burns S, et al. Pre-surgical metformin in uterine malignancy: results of the PREMIUM randomised controlled trial. BJOG: An International Journal of Obstetrics and Gynaecology 2018;125(8):e29. [DOI: 10.1111/1471-0528.15256] [DOI] [Google Scholar]
- Kitson SJ, Maskell Z, Sivalingam VN, Allen JL, Ali S, Burns S, et al. Pre-surgical metformin in uterine malignancy (premium): a multi-center, randomized double-blind, placebo-controlled phase III trial. Clinical Cancer Research 2019;25(8):2424-32. [DOI: 10.1158/1078-0432.CCR-18-3339] [DOI] [PMC free article] [PubMed] [Google Scholar]
Legro 2007 {published data only}
- Legro RS, Zaino RJ, Demers LM, Kunselman AR, Gnatuk CL, Williams NI, et al. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. American Journal of Obstetrics and Gynecology 2007;196(4):402.e1-402.e11. [DOI: 10.1016/j.ajog.2006.12.025] [DOI] [PubMed] [Google Scholar]
Lin 2016 {published data only}
- Lin J, Su C. Combination of Diane-35 with metformin to reverse of endometrial atypical hyperplasia and early endometrial carcinoma with polycystic ovarian syndrome. BJOG: An International Journal of Obstetrics and Gynaecology 2016;123(Suppl 2):188. [DOI: 10.1111/1471-0528.14109] [DOI] [Google Scholar]
- Lin J. Combination of Diane-35 with metformin to reverse of endometrial atypical hyperplasia and early endometrial carcinoma with polycystic ovarian syndrome. Gynecological Endocrinology 2016;32(Suppl 1):109. [DOI: 10.3109/09513590.2016.1150635] [DOI] [Google Scholar]
Mitsuhashi 2014 {published data only}
- Mitsuhashi A, Usui H, Satoh Y, Kiyokawa T, Shozu M. A phase II study of medroxyprogesterone acetate plus metformin as fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer. Journal of Clinical Oncology 2014;32(15 Suppl 1):32. [DOI] [PubMed] [Google Scholar]
Mitsuhashi 2014a {published data only}
- Mitsuhashi A, Kiyokawa T, Sato Y, Shozu M. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer 2014;120(19):2986-95. [DOI: 10.1002/cncr.28853] [DOI] [PubMed] [Google Scholar]
Mitsuhashi 2016 {published data only}
- Mitsuhashi A, Sato Y, Kiyokawa T, Koshizaka M, Hanaoka H, Shozu M. Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer. Annals of Oncology 2016;27(2):262-6. [DOI] [PubMed] [Google Scholar]
Mitsuhashi 2020 {published data only}
- Mitsuhashi A, Kawasaki Y, Hori M, Fujiwara T, Hanaoka H, Shozu M. Medroxyprogesterone acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and endometrial carcinoma: trial protocol for a prospective, randomised, open, blinded-endpoint design, dose-response trial (FELICIA trial). BMJ Open 2020;10(2):e035416. [DOI: 10.1136/bmjopen-2019-035416] [DOI] [PMC free article] [PubMed] [Google Scholar]
O'Hara 2022 {published data only}
- O'Hara M, Janda M, McCarthy AL, Nicklin J, Walker G, Obermair A. Patient experiences of conservative treatment for early stage endometrial cancer and endometrial hyperplasia with atypia using levonorgestrel intrauterine device: a qualitative study. Gynecologic Oncology Reports 2022;39:100914. [DOI: 10.1016/j.gore.2021.100914] [DOI] [PMC free article] [PubMed] [Google Scholar]
Pérez‐López 2014 {published data only}
- Pérez-López FR. Metformin treatment and evolution of endometrial cancer. Climacteric 2014;17(2):207-9. [PubMed] [Google Scholar]
Pino 2022 {published data only}
- Pino I, Iacobone AD, Vidal Urbinati AM, Di Giminiani M, Radice D, Guerrieri ME, et al. Fertility-sparing treatment for endometrial cancer: oncological and obstetric outcomes in combined therapies with levonorgestrel intrauterine device. Cancers 2022;14(9):2170. [DOI: 10.3390/cancers14092170] [DOI] [PMC free article] [PubMed] [Google Scholar]
Randall 2014 {published data only}
- Randall LM, Gibson SJ, Monk BJ. The American Society of Clinical Oncology 50th Annual Meeting 2014: an overview and summary of selected abstracts. Gynecologic Oncology 2014;134(2):222-7. [DOI: 10.1016/j.ygyno.2014.07.086] [DOI] [PubMed] [Google Scholar]
Seebacher 2016 {published data only}
- Seebacher V, Bergmeister B, Grimm C, Koelbl H, Reinthaller A, Polterauer S. The prognostic role of metformin in patients with endometrial cancer: a retrospective study. European Journal of Obstetrics & Gynecology & Reproductive Biology 2016;203:291-6. [DOI: 10.1016/j.ejogrb.2016.06.013] [DOI] [PubMed] [Google Scholar]
Shen 2008 {published data only}
- Shen ZQ, Zhu HT, Lin JF. Reverse of progestin-resistant atypical endometrial hyperplasia by metformin and oral contraceptives. Obstetrics & Gynecology 2008;112(2):465-7. [DOI] [PubMed] [Google Scholar]
Sivalingam 2015 {published data only}
- Sivalingam VN, McVey R, Kitson S, Gilmour K, Ali S, Roberts C, et al. Pre-surgical window study of metformin in obesity-driven endometrial cancer. Gynecologic Oncology 2015;137:18. [DOI: 10.1016/j.ygyno.2015.01.042] [DOI] [Google Scholar]
Sivalingam 2016 {published data only}
- Sivalingam VN, Kitson S, McVey R, Roberts C, Pemberton P, Gilmour K, et al. Measuring the biological effect of presurgical metformin treatment in endometrial cancer. British Journal of Cancer 2016;114(3):281-9. [DOI: 10.1038/bjc.2015.453] [DOI] [PMC free article] [PubMed] [Google Scholar]
Yates 2017 {published data only}
- Yates MS, Basen-Engquist K, Zhang Q, Schmandt R, Medepalli M, Nebgen DR, et al. Prospective randomized biomarker study of metformin and lifestyle intervention for prevention in obese postmenopausal women at increased risk for endometrial cancer. Journal of Clinical Oncology 2017;35(15 Suppl 1):1551. [Google Scholar]
- Yates MS, Coletta AM, Zhang Q, Schmandt RE, Medepalli M, Nebgen D, et al. Prospective randomized biomarker study of metformin and lifestyle intervention for prevention in obese women at increased risk for endometrial cancer. Cancer Prevention Research (Philadelphia, Pa.) 2018;11(8):477-90. [DOI: 10.1158/1940-6207.CAPR-17-0398] [DOI] [PMC free article] [PubMed] [Google Scholar]
You 2016 {published data only}
- You B, Dugue A, Leary A, Rodrigues M, Follana P, Maucort-Boulch D, et al. ENDOLA: a GINECO-GINEGEPS French NCI sponsored phase I/II trial to assess the safety and efficacy of metronomic cyclophosphamide, metformin and OLAparib in recurrent advanced/metastatic endometrial cancer patients. Annals of Oncology 2016;27:vi311. [DOI: 10.1093/annonc/mdw374.49] [DOI] [Google Scholar]
Zhou 2015 {published data only}
- Zhou R, Yang Y, Lu Q, Wang J, Miao Y, Wang S, et al. Prognostic factors of oncological and reproductive outcomes in fertility-sparing treatment of complex atypical hyperplasia and low-grade endometrial cancer using oral progestin in Chinese patients. Gynecological Oncology 2015;139(3):424-8. [DOI] [PubMed] [Google Scholar]
References to ongoing studies
NCT01686126 {published data only}
- NCT01686126. Improving the treatment for women with early stage cancer of the uterus (feMMe) [A phase II randomised clinical trial of Mirena® ± metformin ± weight loss intervention in patients with early stage cancer of the endometrium]. clinicaltrials.gov/study/NCT01686126 (first received 12 September 2012).
NCT02035787 {published data only}
- NCT02035787. Metformin with the levonorgestrel-releasing intrauterine device for the treatment of complex atypical hyperplasia (CAH) and endometrial cancer (EC) in non-surgical patients. clinicaltrials.gov/study/NCT02035787 (first received 10 January 2014).
NCT04576104 {published data only}
- NCT04576104. Megestrol acetate compared with megestrol acetate and metformin to prevent endometrial cancer [Surgical window of opportunity study of megestrol acetate compared with megestrol acetate and metformin for endometrial intraepithelial neoplasia]. clinicaltrials.gov/study/NCT04576104 (first received 3 October 2020).
NCT05292573 {published data only}
- NCT05292573. Longitudinal follow-up in women with endometrial hyperplasia without atypia [MicroRNAs as biomarkers of predicting future endometrial malignancy and longitudinal follow-up with randomized intervention in women with endometrial hyperplasia without atypia]. clinicaltrials.gov/study/NCT05292573 (first received 4 August 2021).
NCT05316935 {published data only}
- NCT05316935. GnRHa + letrozole in progestin-insensitive endometrial cancer and atypical hyperplasia patients [Gonadotropin-releasing hormone agonist (GnRHa) plus letrozole in progestin-insensitive early-stage endometrial cancer and atypical hyperplasia patients with conservative treatment]. www.clinicaltrials.gov/study/NCT05316935 (first received 29 March 2022).
PACTR201908498370196 {published data only}
- PACTR201908498370196. Metformin versus levonorgestrel-releasing intrauterine device (Mirena) in the management of endometrial hyperplasia. pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9335 (first received 22 August 2019).
Additional references
Aljofan 2019
- Aljofan M, Riethmacher D. Anticancer activity of metformin: a systematic review of the literature. Future Science OA 2019;5(8):FSO410. [DOI] [PMC free article] [PubMed] [Google Scholar]
BNF 2022
- Joint Formulary Committee. British National Formulary. 83rd edition. London: BMJ Group and Pharmaceutical Press, 2022. [Google Scholar]
Cetinkalp 2009
- Cetinkalp S, Karadeniz M, Erdogan M, Zengi A, Cetintas V, Tetik A, et al. Apolipoprotein E gene polymorphism and polycystic ovary syndrome patients in Western Anatolia, Turkey. Journal of Assisted Reproduction and Genetics January 2009;26:1-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chae‐Kim 2021
- Chae-Kim J, Garg G, Gavrilova-Jordan L, Blake LE, Wu Q, Hayslip CC. Outcomes of women treated with progestin and metformin for atypical endometrial hyperplasia and early endometrial cancer: a systematic review and meta-analysis. International Journal of Gynecologic Cancer 2021;31(12):1499-505. [DOI: 10.1136/ijgc-2021-002699] [DOI] [PubMed] [Google Scholar]
Cohen 1988
- Cohen J. Statistical Power Analysis for the Behavioural Sciences. 2nd edition. Hillsdale, NJ: Lawrence Eribaum, 1988. [Google Scholar]
Covidence [Computer program]
- Covidence. Version 7.1.2. Melbourne: Veritas Health Innovation. Available at www.covidence.org.
De Jager 2010
- Jager J, Kooy A, Lehert P, Wulffele MG, Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ (Clinical Research ed) 2010;340:c2181. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Deswal 2020
- Deswal R, Narwal V, Dang A, Pundir CS. The prevalence of polycystic ovary syndrome: a brief systematic review. Journal of Human Reproductive Sciences 2020;13(4):261. [DOI] [PMC free article] [PubMed] [Google Scholar]
Doherty 2020
- Doherty MT, Sanni OB, Coleman HG, Cardwell CR, McCluggage WG, Quinn D, et al. Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis. PLoS One 2020;15(4):e0232231. [DOI] [PMC free article] [PubMed] [Google Scholar]
Dowling 2011
- Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Medicine 2011;9:33. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Erdemoglu 2009
- Erdemoglu E, Güney M, Giray SG, Take G, Mungan T. Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia. European Journal of Obstetrics & Gynecology and Reproductive Biology 2009;145(2):195-9. [DOI] [PubMed] [Google Scholar]
ESHRE/ASRM 2004
- Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility 2004;81(1):19-25. [PMID: ] [DOI] [PubMed] [Google Scholar]
Fraison 2020
- Fraison E, Kostova E, Moran LJ, Bilal S, Ee CC, Venetis C, et al. Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2020, Issue 1. Art. No: CD005552. [DOI: 10.1002/14651858.CD005552.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
Gallos 2013
- Gallos ID, Krishan P, Shehmar M, Ganesan R, Gupta JK. Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up. Human Reproduction (Oxford, England) 2013;28(5):1231-6. [PMID: ] [DOI] [PubMed] [Google Scholar]
GRADEpro GDT [Computer program]
- GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), Accessed 19 April 2023. Available at gradepro.org.
Higgins 2017
- Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.2.0 (updated June 2017). The Cochrane Collaboration, 2017. Available from training.cochrane.org/handbook/archive/v5.2/.
Higgins 2022
- Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3 (updated February 2022). Cochrane, 2022. Available from training.cochrane.org/handbook/archive/v6.3.
Holm 2012
- Holm NS, Glintborg D, Andersen MS, Schledermann D, Ravn P. The prevalence of endometrial hyperplasia and endometrial cancer in women with polycystic ovary syndrome or hyperandrogenism. Acta Obstetricia et Gynecologica Scandinavica 2012;91(10):1173-6. [PMID: ] [DOI] [PubMed] [Google Scholar]
IRCT201410275283N11
- Comparison of metformin‐megestrol acetate combination and megestrol acetate alone on endometrial histology in patients with disordered proliferative or hyperplastic endometrium. www.irct.ir/searchen.php?keyword=IRCT201410275283N11&field=a&lang=en 2018.
Johnson 2023
- Johnson JE, Daley D, Tarta C, Stanciu PI. Risk of endometrial cancer in patients with polycystic ovarian syndrome: a meta‑analysis. Oncology Letters 2023;25(4):1-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kurman 1985
- Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985;56(2):403-12. [PMID: ] [DOI] [PubMed] [Google Scholar]
Lacey 2010
- Lacey JV Jr, Sherman ME, Rush BB, Ronnett BM, Ioffe OB, Duggan MA, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. Journal of Clinical Oncology 2010;28:788-92. [DOI: 10.1200/JCO.2009.24.1315] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Meyer 2007
- Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome. Diabetes Care 2007;30(3):471-8. [DOI] [PubMed] [Google Scholar]
Moher 2009
- Moher D, Liberati A, Tetzlaff J, Altman D G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. [DOI: 10.1136/bmj.b2535] [DOI] [PMC free article] [PubMed] [Google Scholar]
Morley 2017
- Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin‐sensitising drugs (metformin, rosiglitazone, pioglitazone, D‐chiro‐inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No: CD003053. [DOI: 10.1002/14651858.CD003053.pub6] [DOI] [PMC free article] [PubMed] [Google Scholar]
NCT01968317
- Megestrol acetate plus metformin to megestrol acetate in patients with endometrial atypical hyperplasia or early stage endometrial adenocarcinoma. clinicaltrials.gov/study/NCT01968317 (first received 16 October 2013).
Nees 2022
- Nees LK, Heublein S, Steinmacher S, Juhasz‐Böss I, Brucker S, Tempfer CB, et al. Endometrial hyperplasia as a risk factor of endometrial cancer. Archives of Gynecology and Obstetrics January 2022;306:407-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nevadunsky 2014
- Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, Frimer M, et al. Metformin use and endometrial cancer survival. Gynecologic Oncology 2014;132(1):236-40. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Raglan 2019
- Raglan O, Kalliala I, Markozannes G, Cividini S, Gunter MJ, Nautiyal J, et al. Risk factors for endometrial cancer: an umbrella review of the literature. International Journal of Cancer 2019;145(7):1719-30. [DOI] [PubMed] [Google Scholar]
RCOG/BSGE 2016
- Royal College of Obstetrics & Gynaecology and British Society for Gynaecological Endoscopy (RCOG/BSGE). Management of endometrial hyperplasia. Green-top guideline no. 67. RCOG/BSGE joint guideline [No GT. Management of Endometrial Hyperplasia]. RCOG BSGE Joint Guideline 2016;67(30):125-9.
RevMan Web 2023 [Computer program]
- Review Manager Web. Version 7.1.2. Copenhagen: Cochrane, 2023. Available at revman.cochrane.org.
Ring 2022
- Ring KL, Mills AM, Modesitt SC. Endometrial hyperplasia. American Journal of Obstetrics & Gynaecology 2022;140(6):1061-75. [DOI] [PubMed] [Google Scholar]
Rosato 2011
- Rosato V, Zucchetto A, Bosetti C, Dal Maso L, Montella M, Pelucchi C, et al. Metabolic syndrome and endometrial cancer risk. Annals of Oncology 2011;22(4):884-9. [PMID: ] [DOI] [PubMed] [Google Scholar]
Session 2003
- Session DR, Kalli KR, Tummon IS, Damario MA, Dumesic DA. Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent. Gynecological Endocrinology 2003;17(5):405-7. [DOI: 10.1080/09513590312331290298] [DOI] [PubMed] [Google Scholar]
Torres 2012
- Torres ML, Weaver AL, Kumar S, Uccella S, Famuyide AO, Cliby WA, et al. Risk factors for developing endometrial cancer after benign endometrial sampling. Obstetrics and Gynecology 2012;120(5):998-1004. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
Vrachnis 2016
- Vrachnis N, Lavazzo C, Iliodromiti Z, Sifakis S, Alexandrou A, Siristatidis C, et al. Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives. Archives of Gynaecology and Obstetrics 2016;293(2):239-46. [DOI] [PubMed] [Google Scholar]
Watter 2021
- Wattar BH, Fisher M, Bevington L, Talaulikar V, Davies M, Conway G, et al. Clinical practice guidelines on the diagnosis and management of polycystic ovary syndrome: a systematic review and quality assessment study. Journal of Clinical Endocrinolology & Metabolism August 2021;106(8):2436-2446. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wu 2009
- Wu J, Zhu Y, Jiang Y, Cao Y. Effects of metformin and ethinyl estradiol-cyproterone acetate on clinical, endocrine and metabolic factors in women with polycystic ovary syndrome. Gynecological Endocrinology 2008 Jan;24(7):392-8. [DOI] [PubMed] [Google Scholar]
Yang 2011
- Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. Trends in Endocrinology and Metabolism 2011;22(4):145-52. [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
References to other published versions of this review
Clement 2016
- Clement NS, Oliver TRW, Shiwani H, Sanner JRF, Mulvaney CA, Atiomo W. Metformin for endometrial hyperplasia. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No: CD012214. [DOI: 10.1002/14651858.CD012214.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Clement 2017
- Clement NS, Oliver TRW, Shiwani H, Sanner JRF, Mulvaney CA, Atiomo W. Metformin for endometrial hyperplasia. Cochrane Database of Systematic Reviews 2017, Issue 10. Art. No: CD012214. [DOI: 10.1002/14651858.CD012214.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]