Efficacy of drugs treatment in patients with endometrial hyperplasia with or without atypia: A systematic review and network meta-analysis

We searched the PubMed, ClinicalTrials.gov., and Embase databases for studies published from their inception to March 31, 2023. The methodological quality of each study was evaluated in accordance with the Cochrane Collaboration’s tool for assessing the risk of bias. The RevMan5.3 software provided by the Cochrane Collaboration was used for direct meta-analysis statistical analysis; and the relative risk and 95% confidence interval along with the mean difference and 95% confidence interval, were used as evaluation indexes.

We included 21 randomized controlled trials involving a total of 2276 women with EH, 6 studies were of high quality, and 15 were of moderate quality. The blinding of subjects and intervention providers was identified as the main source of potential bias. Six interventions were addressed in the network meta-analysis: medroxyprogesterone acetate (MPA), plus metformin, norethisterone (NET), levonorgestrel-releasing intrauterine system (LNG-IUD), megestrol acetate, and other drugs. In the direct meta-analysis, we found the probability of endometrial complete regression (CR) in the LNG-IUD group to be significantly higher than those in the NET. In the network meta-analysis, we found the probability of CR in the NET group to be significantly lower than those in the MPA and plus metformin groups, the probability of CR in the LNG-IUD group to be significantly higher than those in the NET, the probability of CR in the other drugs group to be significantly higher than those in the LNG-IUD. The NET group had the lowest incidences of endometrial complete regression, plus metformin could have a better outcome.

According to the 21 randomized controlled trials included in this study, MPA is the most effective for EH endometrial outcome when applied as a single agent, while the combination of metformin can achieve a more significant effect. 1. Introduction Endometrial hyperplasia (EH) is a hyperplastic endometrial lesion with irregular gland size, increased glands, and increased glandular interstitial ratio. It is divided into 2 categories: endometrial hyperplasia without atypia and atypical endometrial hyperplasia. This two-tier model, endorsed by the World Health Organization Classification of Female Reproductive Tumors in 2014,[1] represents an evolution of the four-tier approach proposed in 1994. Previous systems considered both cytological atypia and glandular complexity, and the results were divided into 4 categories: simple hyperplasia that is not atypical, simple hyperplasia that is atypical, complex hyperplasia that is not atypical, and complex hyperplasia that is atypical. This classification system has come under scrutiny in large part because the highest risk category, complex hyperplasia with atypia, fails to reflect an important subset of lesions associated with a high incidence of concurrent or future endometrioid cancers.[1–3] During follow-up, some EH progressed further to endometrial cancer (EC), and some patients diagnosed with EH experienced pathological escalation after hysterectomy (EC was found). EC, one of the major reproductive system tumors in women, is one of the sixth most common cancers in women, with 417,000 new cases worldwide in 2020.[4] Over the past 30 years, the overall incidence of EC has increased by 132%.[5] Most ECs occur after menopause, but as many as 14% occur before menopause (4% before age 40).[6] The standard treatment of EC requires hysterectomy, which is difficult to accept for premenopausal (young women), especially women with fertility needs, while progesterone therapy with fertility preservation function is only recommended for early-stage patients.[7] It is crucial to provide timely treatment for EH and improve the overall prognosis and reproductive outcomes of young patients. Results of a meta-analysis by Pierluigi Giampaolino suggest that conservative treatment may be an option for patients with stage IA, G2 EC who wish to preserve their fertility.[8] It is generally believed that abnormal stimulation of the endometrium by high estrogen is the major risk factor. Due to the continuous increase of exogenous or endogenous estrogen in the body, endometrial glands grow and proliferate, lacking the antagonistic effect of progesterone, the endometrial cannot be transformed from proliferative stage to secretory stage, resulting in endometrial hyperplasia.[9] The main reasons for endogenous estrogen increase or continuous effect include: polycystic ovary syndrome can inhibit ovulation and progesterone secretion; the level of estrogen in the obese was higher than that in the standard heavy body. Tumors secreting estrogen (e.g., granulosa cell tumor); endocrine system diseases (such as prolactinoma) can inhibit ovulation and progesterone secretion or promote the secretion of estrogen. An increase in exogenous estrogen is often seen with the irrational use of hormone replacement therapy.[10] Long-term use of hormone-regulating drugs can also lead to abnormal endometrial proliferation. Carthew study[11] showed a significant increase in the incidence of uterine adenocarcinoma at 24 to 35 months of tamoxifen treatment (26%) compared with the absence of any estrogen agonist in utero (9%). In addition, endometrial inflammation may also be a high-risk factor for endometrial hyperplasia and malignant changes in the endometrial.[12] Some related genes and proteins have been found to be associated with the transition of endometrial from benign to malignant, such as DNA error repair gene, PTEN gene, Bcl-2 gene, proliferating nuclear antigen, p53, etc. The vast majority of postmenopausal EH is symptomatic of postmenopausal uterine bleeding (abnormal uterine bleeding). However, for premenopausal or perimenopausal women, abnormal uterine bleeding is not as closely associated with EH as postmenopausal women.[13] For premenopausal women, although abnormal uterine bleeding is still a common clinical manifestation of EH, it is not as strongly associated as postmenopausal women. The proportion of abnormal uterine bleeding in EH in premenopausal women is very low, and abnormal uterine bleeding in premenopausal women cannot be used as a specific symptom of EH,[14,15] but only as a reference indicator. The gold standard for diagnosis of endometrial lesions is histological pathology, which is performed using Pipelle samplers, diagnostic curettage, or hysteroscopic procedures. Pathological examination of suspicious pathological tissues can be performed under direct vision. Besides improving the comprehensiveness of sampling, it can also provide endoscopic endometrial information, which is the only diagnostic method compared with pathological examination of total hysterectomy at present.[16,17] Progesterone is the main treatment for patients with endometrial hyperplasia without atypia. Progesterone therapy includes oral progesterone and levonorgestrel-releasing intrauterine system (LNG-IUD).[18] For patients with endometrial dysplasia who are willing to preserve fertility function, high-dose progesterone therapy may be the most suitable.[16,19,20] There are many kinds of progesterone, while no meta-analysis of the efficacy of various drugs against EH. This study will summarize the randomized controlled trials (RCTs) carried out in the past, and conduct network meta-analysis (NMA) on the blood pressure control of EH patients with various drugs, in order to provide new evidence, support for the medication strategy of clinical EH patients. 2. Methods This study followed the NMA extension of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline.[21] This network meta-analysis is registered with PROSPERO (Reference: CRD42023405198). 2.1. Search strategy We searched the PubMed, ClinicalTrials.gov., and Embase databases for relevant studies published from inception to March 31, 2023. Study retrieval involved a combination of subject-heading and keyword searches. Search terms included “endometrial hyperplasia,” “oral levonorgestrel,” “Levonorgestrel intrauterine sustained release system (LNS-IUS),” “metformin,” “medroxyprogesterone acetate,” “megestrol acetate,” “progesterone,” “norethisterone,” “dydrogesterone” and “endometrial electrocoagulation.” The publication type of retrieved studies was limited to RCTs, with no language or site restrictions. The diagnostic criteria for EH was in accordance with World Health Organization Classification of Female Reproductive Tumors.[1] And the specific diagnostic criteria were adjusted according to the year in which the study was conducted. 2.2. Inclusion and exclusion criteria Studies included in the NMA meta the following criteria: (1) patients were diagnosed with EH were histologically diagnosed; (2) the study was an RCT, and (3) types of interventions included LNS-IUS or endometrial electrocoagulation or oral progesterone or other oral drugs (e.g., metformin); (4) relevant endometrial regression outcome. The exclusion criteria were as follows: (1) the design of the study did not qualify it as a randomized controlled study (thus excluding reviews, letters, and others); (2) the study did not meet the diagnostic criteria for EH (such as endometrial cancer); (3) patients had comorbidities such as severe kidney disease, or liver disease. 2.3. Data extraction and quality evaluation Two evaluators independently search the database, identify the literature based on inclusion and exclusion criteria, and, for each study retrieved, record the name of the first author, the year of publication, the country in which the study was conducted, whether the blind method was used. Diagnostic criteria used in EH, interventions applied, dosage of medication used, demographics of subjects (sample size, mean body mass index, age), and outcomes (primary and secondary results). The methodological quality of the study was evaluated in accordance with the Cochrane Collaboration’s tool for assessing risk of bias.[22] The evaluation included: random sequence generation, hidden distribution hiding, subject and intervention provider blinding, outcome evaluation blinding, outcome data integrity, selective outcome reporting, and other sources of bias. Disagreement t was judged by public discussion. In accordance with the Cochrane Collaboration Group criteria, we divided the studies into 3 categories: (1) low bias risk (low bias risk in all key areas), (2) unclear bias risk (unclear bias risk in one or more key areas), and (3) high bias risk (high bias risk in one or more key areas). The Grading of Recommendations Assessment, Development, and Evaluation framework was used to assess the quality of evidence for the primary outcomes contributing to each network estimate.[23] All disagreements of quality evaluation were resolved through discussion between all authors. 2.4. Statistical analysis 2.4.1. Direct meta-analysis (DMA) RevMan5.3 software(https://revman.cochrane.org/) provided by the Cochrane Collaboration, was used for DMA statistical analysis, and the relative risk and 95% confidence interval (CI) and the mean difference and 95% CI were used as evaluation indices. First, the chi test was used to assess heterogeneity, and the existence of heterogeneity (I2) was quantitatively analyzed (I2 > 50%). Meta-analysis was performed without heterogeneity when statistical heterogeneity existed among study results, the source of heterogeneity was further analyzed, and the influence of obvious clinical heterogeneity was excluded and a random effects model was adopted. When there was no statistical heterogeneity among the results, a fixed effects model was applied. Funnel maps were created by STATA 17.0 (StataCorp, College Station, TX) software to detect publication bias. 2.4.2. Network meta-analysis We performed a frequentist NMA using STATA 17.0 software. NMA can combine direct and indirect comparisons to further analyze the effects of different treatment options on endometrial regression outcomes for EH women with or without atypical. The results of the comparisons were expressed as the relative risk and 95% CIs. Moreover, we built a network diagram using STATA 17.0 software, and calculated the surface under the cumulative ranking curve (SUCRA) to rank the different interventions.[24] If one intervention had a higher SUCRA value than the others, indicating the greater the treatment effect, the lower the incidence of adverse reactions. The assumption of consistency between direct and circumstantial evidence was evaluated using the node splitting method.[25] When the direct evidence and indirect evidence were consistent (P > .05), a consistency model was used, otherwise we used an inconsistency model. 3. Results 3.1. Retrieved results Following a predesigned literature retrieval strategy, 3940 articles were retrieved, but this included 894 duplicate articles. After reviewing the titles, abstracts and full texts, we included 21 RCTs involving a total of 2276 women with EH. The literature screening process and the results are shown in Figure 1. The basic features of the included studies are shown in Table 1. The included studies were published between 2011 and 2022, 6 studies[26–31] were of high quality and 15 studies[32–46] were of moderate quality. Table 1 - Characteristics of included studies. ID Author Publication year Recruitment year EH type Standard Age (years) Total number Randomization Withdrawal and dropouts GRADE 1 Ozlem Ozdegirmenci 2011 2006–2007 Simple EH without atypia WHO 1994 30–57 90 Computer-generated codes Lost to follow-up (n = 8) Moderate quality 2 M. Karimi-Zarchi 2013 NR Simple EH NR 22–47 40 NR 0 Moderate quality 3 A Ørbo 2013 2005–2011 EH WHO 1994 45–51 170 Computer-generated list of random numbers Withdrawal (n = 17) High quality 4 Mohamed Taha Ismail 2013 2010–2012 Simple EH WHO 1994 35–50 100 Computer-generated list of random numbers 0 Moderate quality 5 Hatem Abu Hashim 2013 2009–2011 Non-atypical EH NR 40–50 120 Computer-generated random numeric table Lost to follow-up (n = 7) High quality 6 Jessica L. Hubbs 2013 1999–2011 EH WHO 1994 22–92 123 NR Lost to follow-up (n = 9) Moderate quality 7 Weiwei Shan 2014 2012–2013 Atypical EH NR 26–43 22 NR Lost to follow-up (n = 3), withdrawal (n = 3) Moderate quality 8 Fariba Behnamfar 2014 2013 Non-atypical EH NR 38.4 ± 4.8 60 Random-maker software Withdrawal (n = 5) High quality 9 Manal M. El Behery 2015 2011–2012 Non-atypical EH NR 30–50 118 NR Lost to follow-up (n = 18) Moderate quality 10 A Ørbo 2015 2005–2011 EH WHO 1994 45–51 170 Computer-generated list of random numbers Withdrawal (n = 17) High quality 11 Fatemeh Sharifzadeh 2016 NR Simple EH without Atypia NR NR 43 NR Lost to follow-up (n = 1), withdrawal (n = 2) Moderate quality 12 Ahmed Mohamed Nooh 2016 2013–2015 Non-atypical EH WHO 1994 35–50 158 Computer-generated randomization sequence Lost to follow-up (n = 5), withdrawal (n = 7) High quality 13 Sanam Moradan 2017 2014–2015 Simple EH without atypia WHO 1994 20–42 50 Balanced (permuted) block randomization 0 Moderate quality 14 Gulsum Uysal 2017 2014–2016 Simple EH without atypia WHO 1994 35–55 120 Computerized database Lost to follow-up (n = 21) Moderate quality 15 B-Y Yang 2020 2013–2017 Atypia EH WHO 2014 18–45 123 Simple randomization Lost to follow-up (n = 11) Moderate quality 16 Mi Kyoung Kim 2020 2015–2018 EH NR 18–58 65 NR Lost to follow-up (n = 2), withdrawal (n = 19) Moderate quality 17 Ramya Dinnekere Ravi 2021 2016–2018 Non-atypical EH WHO 2014 44.4 ± 5.8 51 NR Lost to follow-up (n = 5) Moderate quality 18 Giovanni Campo 2021 2014–2018 Non-atypical EH WHO 2014 NR 215 NR 0 Moderate quality 19 Afsaneh Tehranian 2021 2016–2018 Non-atypical EH NR 18–75 60 Computer-generated randomization Lost to follow-up (n = 3), withdrawal (n = 1) High quality 20 Wei-ya Kong 2022 2016–2020 Complex EH NR NR 234 NR Lost to follow-up (n = 15) Moderate quality 21 Şener Gezer 2022 2019–2020 Non-atypical EH WHO 2014 18–55 144 Sequentially numbered envelopes Lost to follow-up (n = 6) Moderate quality For EH diagnosis, 12 studies the World Health Organization standards and 9 studies did not explicitly specify the diagnostic criteria applied. Six interventions were reported in the 21 studies: medroxyprogesterone acetate (MPA), plus metformin, norethisterone (NET), LNG-IUD, megestrol acetate, and other drugs. 3.3. Quality evaluation The quality of the included studies was evaluated, and the results showed that the blinding of subjects and intervention providers was the main source of potential bias (Fig. 2). This was because blinding was not possible in trials that used LNG-IUD, as LNG-IUD and oral drugs were administered by completely different routes. Figure 3A shows a network evidence diagram that includes the 21 interventions addressed in the NMA: MPA, plus metformin, NET, LNG-IUD, MA, and other drugs. In Figure 3A, the size of the circles is proportional to sample size, the lines between circles represents direct comparative evidence and the width of the lines is proportional to the number of trials. (A) Network plot of eligible comparisons between different strategies. Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. (B) Direct Meta-analysis results. Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. (C) Network meta-analysis results. Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. 3.5. Direct meta-analysis and network meta-analysis results Figure 3B and C shows the DMA and NMA results regarding endometrial complete regression (CR). Figure 4A shows the contribution of direct and indirect comparisons to final estimates. All 21 of the included studies reported the effects of different interventions on CR in EH women. (A) Contribution of DMA and NMA. Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. (B) The surface under the cumulative ranking curve (SUCRA). Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. (C) Comparison-adjusted funnel plot. Points with different colors represent different interventions. Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. (D) Loop-consistency plot. Interventions: (A) medroxyprogesterone acetate (MPA), (B) plus metformin, (C) norethisterone (NET), (D) levonorgestrel-releasing intrauterine system (LNG-IUD), (E) megestrol acetate (MA), and (F) other drugs. In the DMA, we found that the probability of CR in the LNG-IUD group to be significantly higher than those in the NET. No significant differences between the MPA, plus metformin, NET, MA and other drugs groups. In the NMA, we found that the probability of CR in the NET group to be significantly lower than those in the MPA (0.41, 95% CI 0.18–0.95) and plus metformin (0.21, 95% CI 0.06–0.75) groups, the probability of CR in the LNG-IUD group to be significantly higher than those in the NET (4.46, 95% CI 1.86–10.65), the probability of CR in the other drugs group to be significantly higher than those in the LNG-IUD (0.37, 95% CI 0.16–0.82). No significant differences were observed between the LNG-IUD, MA, and other drugs groups. 3.6. SUCRA NMA can evaluate the best effect of each intervention for different results and sort the interventions by SUCRA value, a higher SUCRA value indicates a better intervention or a lower incidence of adverse reactions. Figure 4B shows the detailed ranking results. According to Figure 4B, the NET group had the lowest incidences of endometrial complete regression, plus metformin could have a better outcome. 3.7. Publication bias Figure 4C shows a comparison-adjusted funnel diagram. All studies on the funnel maps are symmetrically distributed with respect to the vertical line X = 0, indicating that there were no significant small-sample effects or publication bias. Finally, Figure 4D shows that no loop inconsistency exists in this NMA. 4. Discussion In this study, NMA revealed that, high potency progesterone combined with metformin was found to have the best effect on EH endometrium CR, and MPA is the most effective single drug. High potency progesterone combined with metformin is preferentially used to treat patients with EH. MPA is a synthetic oral derivative of the naturally occurring steroid hormone progesterone. It is widely utilized in the endocrine therapy of hormone-related cancers and as supportive treatment for cachexic syndromes in oncology. Multi-center clinical trials have shown that MPA use is inversely associated with EC risk, and this association was independent of the tumor subtype.[47] But the side effects of drugs also need to be considered. Common adverse events include the development of peripheral edema and an increased incidence of thromboembolic complications, primarily deep vein thrombosis in the lower extremities; however, the latter is generally associated with relatively high doses of progesterone and is typically not severe.[48] Other adverse events may arise from glucocorticoid-like activity; indeed, metabolic syndromes such as diabetes and Cushing syndrome have been reported only occasionally.[49] Additional toxicities linked to corticosteroids, including myopathy, skin markings, opportunistic infections, femoral head necrosis, and peptic ulcer disease, are rare. Notably, patients receiving MPA are less likely to discontinue the medication due to adverse events.[48] The LNG-IUD was first introduced in Finland in 1990.[50] Mirena, the first commercially available LNG-IUD, contains 52 mg of levonorgestrel, which is released into the uterine cavity at a rate of 20 mg per day for 5 years. Following the launch of LNG-IUD 52 mg (Mirena), other types of LNG-IUD, Kyleena and Jaydess were introduced to the commercial market. Kyleena has 19.5 mg of levonorgestrel, and Jaydess has 13.5 mg. Recently updated guidelines recommend LNG-IUS as a first-line treatment for the absence of dysplastic endometrial hyperplasia.[20,51] In addition, LNG-IUS is especially recommended as a first-line treatment for women with atypical hyperplasia who wish to preserve their fertility.[20] Although many studies have demonstrated the effect of the LNG-IUD on endometrium CR, the reluctance or discomfort with using the LNG-IUD itself may affect its acceptance in many women of different ages.[52] There are some misconceptions about LNG-IUD, such as the possibility of infertility or pelvic inflammatory disease, and the relatively high incidence of device discharge in adolescents and non-childbearing women.[53] However, the recent guidelines support the safety of LNG-IUD in adolescents and nonpregnant women, as well as perimenopausal women.[54,55] NET (and similar nortestosterone acetate, NETA, and nortestosterone) is the most widely used progesterone in several European countries. It is a potent progesterone that has a strong effect on the endometrium.[56] Unlike other progesterone, NET is partially converted (about 0.4–1%) to ethinylestradiol (EE) in the liver and therefore also produces estrogen effects in the body.[57,58] Since previous estrogen action is required for progesterone activity, the resulting EE also enhances the progesterone properties of NET. However, given the thromboembolic risks associated with EE,[59] this conversion may be important with respect to the adverse effects NET(A) may have.[60] Metformin, a drug often used to treat diabetics, has been shown in some human studies to reverse EH. Previous results of a conventional meta-analysis suggest that there is insufficient evidence for the treatment of endometrial hyperplasia with metformin alone or in combination with standard therapy (especially megestrol acetate) and megestrol acetate alone.[61] However, this NMA found that combined metformin had a better effect on endometrial CR in EH patients (especially compared with NET). To address this clinical issue, reliable, well-powered randomized controlled trials need to be designed to obtain long-term outcome data. Despite its high heterogeneity, a meta-analysis conducted by Cinthia G. Meireles indicates that metformin-assisted therapy may facilitate the reversal of normal endometrial histology in cases of atypical endometrial hyperplasia, reduce biomarkers of cell proliferation linked to tumor progression, and enhance overall survival rates in endometrial cancer patients.[62] However, further prospective controlled trials are necessary to evaluate the impact of metformin as an adjuvant therapy on clinical outcomes. This study has the certain limitations that need to be considered. The total number of included studies and the number of sample cases were limited, and the representativeness of the results was limited. In this study, NMA was only conducted on the endometrium CR of EH patients with various drugs. The adverse reaction of the drug involves whether the patient can accept the full dose and full course of drug treatment, and only the standard use of the drug can play the best effect. The study did not summarize adverse reactions without drugs. Whether young women can achieve ideal pregnancy outcome after EH treatment is also a point of great clinical concern. Due the limited body of literature, this study did not conduct subgroup analysis on the subtype of EH, the way of administration and dose of the same drug. This study was limited by the time of inclusion and tracking, and no relevant outcome was reported. In the future, it is a good direction to study the side effects of treatment without drugs on EH patients and the pregnancy outcome after the completion of the course of treatment. 5. Conclusion According to the 21 RCTs included in this study, high potency progesterone combined with metformin is preferentially used to treat patients with EH. Oral sex hormone drugs should be taken strictly and regularly to achieve the target efficacy. For patients with difficulty in taking drugs regularly, LNG-IUD (plus metformin recommended) is an effective alternative treatment plan. Author contributions Conceptualization: Ruoan Jiang. Data curation: Yingsha Yao, Shuhang Xu, Ting Wang. Formal analysis: Yingsha Yao, Shuhang Xu. Methodology: Ruoan Jiang. Software: Yingsha Yao, Ting Wang. Supervision: Ruoan Jiang. Writing – original draft: Yingsha Yao, Shuhang Xu. Writing – review & editing: Ruoan Jiang. Abbreviations: CI confidence interval CR complete regression DMA direct meta-analysis EH endometrial hyperplasia LNG-IUD levonorgestrel-releasing intrauterine system MPA medroxyprogesterone acetate NET norethisterone NMA network meta-analysis RCTs randomized controlled trials

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