Endometrial cancer (EC), arising from the epithelial lining of the uterus, stands as the most prevalent malignant tumor in the female reproductive tract and ranks as the sixth most common cancer in women globally. The disease exhibits an escalating morbidity and mortality rate worldwide. In 2020 alone, there were 417,000 new cases of endometrial cancer, resulting in 97,000 related deaths. The cumulative risk of developing this cancer by the age of 75 is 1%, with a corresponding risk of death at 0.2%. Despite its widespread occurrence, endometrial cancer is generally associated with a favorable prognosis, primarily because, in the majority of cases, the disease is confined to the uterus. The overall 5-year survival rates for endometrial cancer differ by stage: stage I disease boasts an 80% survival rate, stage II at 60%, stage III at 30%, and stage IV at 5%. The incidence of endometrial cancer varies significantly across regions, with a tenfold difference observed globally. The highest incidence rates are documented in Northern America, Europe, Micronesia/Polynesia, and Australia/New Zealand, while the lowest rates are found in most African regions and South Central Asia. In terms of mortality rates, regional disparities are relatively modest. Eastern Europe, Micronesia/Polynesia, the Caribbean, and Northern America report the highest mortality rates (1–4), highlighting the need for increased awareness and targeted interventions in these regions.

Endometrioid neoplastic lesions of the endometrium follow a histological continuum, spanning from endometrial hyperplasia without atypia (EH) to endometrial hyperplasia with atypia (AEH) and well-differentiated endometrial cancer (EC) (5). Broadly categorized into type I and type II, endometrial cancer exhibits distinct characteristics. Type I cancers are primarily associated with obesity-related sequelae, marked by excessive proliferation of endometrial cells. Patients with type I cancer often suffer from hyperestrogenism, hyperlipidemia, diabetes, and anovulatory uterine bleeding-all linked to metabolic syndrome. These type I cancers, mainly highly to moderately differentiated endometrioid tumors, typically originate from atypical endometrial hyperplasia, with at least 90% expressing medium to high levels of estrogen receptors. Conversely, type II cancers are unrelated to metabolic or endocrine disorders and do not stem from endometrial hyperplasia, commonly appearing in non-obese women. This category includes more aggressive histological variants such as clear cell carcinoma, serous carcinoma, or uterine carcinosarcoma (6, 7). Several risk factors contribute to the likelihood of endometrial cancer, with age, race, metabolic syndrome, unopposed estrogen exposure, and genetic predispositions being significant. Unopposed estrogen replacement notably increases the risk of EC by up to 20-fold, with a higher risk associated with prolonged exposure. However, the combined use of progestin significantly reduces this risk (8). Given the dependence of endometrial proliferation on estrogen, well-differentiated tumors are inclined to retain their estrogen and progestin receptors. Additionally, progestin assumes an anti-estrogen role in the endometrium (9).

The standard treatment for endometrial cancer involves surgery, typically with total abdominal hysterectomy and bilateral salpingectomy. In cases with high-risk factors, lymph node dissection followed by individualized adjuvant therapy becomes necessary. Adjuvant treatment strategies for endometrial cancer encompass external-beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and the combination of chemotherapy and radiotherapy. Approximately 20% of endometrial cancers occur in premenopausal women, posing a significant concern for maintaining fertility. Surgical treatment, while standard, carries substantial risks for certain patients, particularly those who are morbidly obese or experiencing serious complications (9, 10). Progestin therapy stands as the primary fertility-preserving treatment for young women with atypical endometrial hyperplasia (AEH) and well-differentiated endometrial cancer (EC) (11). Enhancing the efficacy of progestin therapy has become a focal point in addressing the needs of this patient population. For women with AEH who do not intend to bear children, hysterectomy with adnexal removal is strongly recommended, given the approximately 30% risk of developing invasive carcinoma. Conversely, conservative treatment is an option for women who wish to preserve fertility or are at higher surgical risk. These individuals should receive relatively high-dosed progestin therapy, and the use of a progestin-containing intrauterine device is also a viable approach (12). As progestin therapy becomes more prevalent in clinical applications, adverse reactions, including progesterone resistance, thrombosis, and weight gain, are frequently observed, impacting therapeutic efficacy and patient compliance (13). Additionally, a potential consequence of progestin therapy is the reduction in progestin receptor concentration, leading to a shorter duration of response (14). Clinical trials have indicated that progestin combination therapy can mitigate the side effects of long-term progestin use while maintaining its therapeutic benefits. However, there is no consensus on the outcome of progestin combination therapy. For instance, the levonorgestrel-releasing intrauterine system (LNG-IUS) is a device placed in the uterus that increases the concentration of progestin in localized tissues. Fang et al. demonstrated that LNG-IUS combined with oral progestin therapy was more effective in improving menstrual status and endometrial thickness compared to the control group, reducing adverse effects (15). In a 3-year randomized controlled trial, Xu et al. found no difference in treatment efficacy between megestrol acetate (MA) alone, LNG-IUS alone, and MA combined with LNG-IUS (16). Despite these studies, there is still a lack of evidence-based consensus on the efficacy of progestin combination therapy, necessitating further exploration.

Network meta-analyses serve as a valuable tool by amalgamating evidence from both direct and indirect comparisons of different trials, constructing a comprehensive network of treatments. This approach enables researchers to assess the impact of multiple interventions simultaneously for the same condition. Commonly reported outcomes in network meta-analyses include mean ranks or the surface under the cumulative ranking curve (SUCRA), which provides a numerical summary of the distribution to establish hierarchies of treatment comparisons (17, 18). In this study, we employed a network meta-analysis to compare the effectiveness of various progestin combination regimens for patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH). The aim is to identify the optimal combination treatment regimen, offering a theoretical reference for the clinical management of AEH or EC patients.

In this investigation, we conducted a comprehensive comparison of the effectiveness of various progestin-based regimens for treating patients with endometrial cancer or endometrial atypia. A total of 5,323 patients diagnosed with endometrial cancer or atypical hyperplasia, sourced from 27 studies, were included, encompassing 19 different interventions. Among these interventions, 9 comprised progestin-based combination therapy programs. Our findings indicated that the Hydroxyprogesterone caproate (HC)+tamoxifen regimen demonstrated superior efficacy in extending overall survival (OS), while the mTOR inhibitor+megestrol acetate (MA)+tamoxifen regimen exhibited the best performance in prolonging progression-free survival (PFS). Regarding efficacy indicators, the LNG-IUS+medroxyprogesterone acetate (MPA) regimen emerged as the top choice for increasing the number of complete responses (CR). The MA+tamoxifen regimen proved to be the optimal treatment for enhancing the number of partial responses (PR). For the objective response rate (ORR), the LNG-IUS+MPA regimen stood out as the most effective combination therapy. In terms of stable disease (SD), the mTOR inhibitor+MA+tamoxifen regimen demonstrated superior efficacy. In the context of disease progression, the LNG-IUS+MPA regimen exhibited the lowest likelihood of causing disease progression. Additionally, the LNG-IUS+MA regimen emerged as the preferred combination therapy for improving pregnancy rates, and it was also the least likely to result in disease relapse. However, in terms of safety, mTOR inhibitor and mTOR inhibitor+MA+tamoxifen had the highest likelihood of adverse events, while LNG-IUS+MPA was the safest combination regimen. Overall, combination therapy based on mTOR inhibitors had advantages in improving certain indicators, but it also faced the risk of adverse events. The combination therapy based on tamoxifen had a lower risk of adverse events compared to mTOR inhibitor combination therapy, but the indicators it improves were limited. The LNG-IUS-based dual progestin regimen not only had an advantage in the number of indicators improved but was also the safest approach. Therefore, among all the combination regimens, the LNG-IUS-based dual progestin regimen may represent the most suitable approach for treating endometrial cancer or atypical endometrial hyperplasia.

In our investigation, tamoxifen featured prominently in optimal combination regimens associated with prolonged survival index, and it was also a key component in the optimal combination regimen employing PR and SD as outcome indicators. Existing studies have highlighted that estrogen replacement therapy without progestin supplementation leads to a substantial increase (4- to 14-fold) in the relative risk of endometrial cancer (48). Tamoxifen, classified as a selective estrogen receptor modulator (SERM), functions by obstructing estrogen binding to estrogen receptors in endometrial cancer (44, 49). Consequently, it holds potential beneficial effects in managing endometrial cancer or atypical endometrial hyperplasia. Hald et al. investigated tamoxifen’s efficacy in advanced endometrial cancer, reporting assessable disease remission (partial and complete) in 8 of 33 patients (50). Quinn et al. observed a 20% remission rate in 10 out of 49 patients with advanced/recurrent endometrial cancer treated with tamoxifen (51). However, the relationship between tamoxifen and an elevated risk of endometrial cancer is a subject of extensive discourse. Leeuwen et al. conducted a case-control study in the Netherlands, revealing a trend toward a significantly increased risk of endometrial cancer with longer duration of tamoxifen use and an escalating cumulative dose (52). In conclusion, the role of tamoxifen in endometrial cancer, along with its specific mechanisms, warrants further exploration.

High-frequency aberrations on the PI3K/Akt/mTOR pathway have been identified in endometrial cancer (31). Elevated activity of the PI3K/Akt/mTOR pathway is linked to resistance to progesterone treatment in endometrial cancer cell lines and mouse models, and inhibition of this pathway can reverse such resistance (53). Consequently, mTOR inhibitors demonstrate promise as targeted agents for endometrial cancer treatment. In our investigation, mTOR inhibitors emerged as crucial components in the optimal combination regimen for achieving positive outcomes in terms of progression-free survival (PFS) and stable disease (SD). First-generation mTOR inhibitors currently undergoing clinical trials for advanced or recurrent endometrial cancer include everolimus (RA001), temsirolimus (CCI779), and ridaforolimus (AP2357) (54). A phase II clinical trial of ridaforolimus (AP2357) in patients with advanced and recurrent endometrial cancer revealed a clinical benefit response (CBR) in 9 out of 27 patients with evaluable responses (55). Tsoref et al. conducted a phase II trial assessing the tolerability and activity of oral ridaforolimus (AP2357) in patients with metastatic or recurrent endometrial cancer, reporting that among the 31 evaluable patients, 3 achieved partial response (PR), and an additional 18 achieved stable disease (SD) (56). The application of mTOR inhibitors restrains the proliferation and progression of cancer cells, and when combined with progestins, they may exert synergistic effects.

Among the various optimal combination regimens, the LNG-IUS-based dual progestin regimen emerged prominently, underscoring the crucial role of LNG-IUS in treating endometrial cancer or atypical endometrial hyperplasia. LNG-IUS serves as a long-acting contraceptive option for women and is employed in the management of abnormal and heavy bleeding (heavy periods). Its mechanism involves the inhibition of endometrial proliferation, leading to endometrial atrophy through metaplasia and suppression of endometrial glands (57). This effect may stem from LNG-IUS inhibiting the synthesis of endometrial estrogen receptors, rendering the endometrium insensitive to circulating estrogen. Furthermore, the therapeutic efficacy relies significantly on local progestogen action within the uterine cavity, potentially making it preferable to other progestins (58). LNG-IUS demonstrates heightened effectiveness in reversing endometrial hyperplasia. For example, Varma et al. conducted a prospective study involving 105 women diagnosed with endometrial hyperplasia treated with LNG-IUS, revealing a remarkable 90% regression within 2 years, with 92% resolution of atypical endometrial hyperplasia (59). In another study, Hashim et al. conducted a randomized controlled trial involving 120 perimenopausal women with atypical endometrial hyperplasia, noting a significantly higher regression rate in the LNG-IUS group compared to the oral progestogen group, achieving regression within 1 year (60). Additionally, LNG-IUS plays a pivotal role in endometrial cancer treatment. Westin et al. conducted a phase II trial of LNG-IUS in 57 patients diagnosed with complicated atypical hyperplasia and early endometrial cancer, reporting an overall 83% 12-month remission rate (RR), with a 66.7% remission rate for grade 1 endometrial-looking endometrial cancer (61). However, it’s worth noting that LNG-IUS may face challenges in delivering a uniform progesterone dose to the entire endometrial cavity, potentially creating a ‘myometrial sanctuary’ for tumors (62).

In terms of progestin therapy for EC or AEH, relevant guidelines are also described, for example, for patients with grade 1, stage IA endometrial cancer who wish to preserve fertility, both the National Comprehensive Cancer Network (NCCN) and European guidelines recommend continuous progestin-based therapy, which includes MA, MPA, or LNG-IUS. In addition, for patients with disseminated metastases, who are unsuitable for local therapy, or who have further recurrence, both the NCCN and the European guidelines recommend hormonal therapy, with the European Society of Gynaecological Oncology (ESGO) guidelines recommending the use of MA and MPA (63). Treatment guidelines recommend that patients with atypical endometrial hyperplasia should be treated with hysterectomy. However there is still controversy over the use of progestins (64). Although some guidelines do not make a clear statement about progestin-based combination therapy regimens, this is the innovation we wanted to explore. The results of a meta-analysis showed that oral progestins still resulted in high CR rates and relapse rates within the accepted range for patients with AEH or EC who relapsed after receiving conservative treatment (65). Through this study, we want to find an efficacious and safe progestin-based combination therapy regimen, to raise awareness of progestin therapy for endometrial cancer, and to lay the foundation for subsequent research.

Notably, alterations occurring in the endometrium can link reproductive and oncological diseases. It has been shown that polycystic ovary syndrome (PCOS), a heterogeneous endocrine disease, causes dysregulation of endometrial sex hormone receptor and co-receptor expression, endometrial insulin resistance, impaired glucose transport and utilization, chronic inflammation, immune dysfunction, uterine vascular alterations, and even abnormal gene expression and cellular abnormalities of the endometrium, which make the endometrium dysfunctional (66). A national case-control study from Australia showed a four-fold increased risk of endometrial cancer in patients with PCOS compared to those without PCOS, and in addition, hirsutism and extremely irregular menstruation among the symptoms of PCOS were significantly associated with the risk of endometrial cancer (67). Results from another cohort study from Denmark showed a similar fourfold increase in endometrial risk (68). This is consistent with the results of a number of meta-analyses of which we are aware. For example a meta-analysis that included 10 studies showed that women with PCOS had a significantly increased risk of endometrial cancer compared to controls (69), with a further increase in risk when postmenopausal people were excluded from the meta-analysis. Similarly, adenomyosis is a benign gynaecological disease, whereas EC can originate from malignant transformation of ectopic endometrium within the adenomyosis lesion, leading to endometrial carcinoma arising in adenomyosis (EC-AIA). This disease is difficult to diagnose preoperatively, but differs from EC in postoperative histological features and prognosis (70). We therefore envisage that the combination of hysteroscopic surgery and progestins will yield beneficial results in the treatment of endometrial carcinoma and its rarer types.

Previous risk stratification of EC has been based on pathological features, and studies of The Cancer Genome Atlas (TCGA) may have changed our view. In TCGA, EC can be classified into four prognostically relevant groups based on mutation load and somatic copy number variation, namely POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP). Each group differs in pathological characteristics, prognosis, and response to different therapies, making the TGCA classification of great advantage for risk stratification and management of EC (71).

This study has certain advantages. Firstly, our study investigates the potential of progestin-based combination therapy regimens in treating endometrial cancer or atypical endometrial hyperplasia and finds the combination regimen with the best efficacy and the least number of adverse events, offering significant clinical implications. Secondly, the rigorous application of the network meta-analysis method ensures a high level of medical evidence, delivering crucial information for clinicians and policymakers. We also assessed the risk of bias for each of the included studies, and none found the presence of serious bias. Finally, the inclusion of randomized controlled trials and a rigorous data extraction process ensure the quality of the study. However, our study has some limitations. While we incorporated 27 studies and analyzed data from 5323 patients, the persuasiveness of our findings could be further strengthened with a more extensive literature review. Additionally, we acknowledge a lack of in-depth consideration of heterogeneity among the studies. Factors like patient age, weight, progesterone dosage, and administration route were not thoroughly addressed and may introduce confounding variables. For the EC and AEH patients involved in this study, we did not analyze them separately. Finally, although we chose multiple indicators to assess, the number of studies included in each indicator was not the same, which may have had some impact on the results.

In summary, our study indicates that while tamoxifen and mTOR inhibitors show efficacy in combined progestin-based regimens, a dual progestin-based approach utilizing LNG-IUS has better efficacy and safety and holds greater promise for treating endometrial cancer or endometrial atypical hyperplasia. This insight could be valuable for clinicians in selecting the most suitable progestin treatment for patients with endometrial cancer or atypical endometrial hyperplasia.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

JC: Conceptualization, Methodology, Writing – original draft. YZ: Data curation, Writing – review & editing. LS: Writing – review & editing. T-JW: Conceptualization, Writing – review & editing.