Fertility-preserving treatment of endometrial cancer and endometrial atypical hyperplasia for patients with metabolic abnormalities: Challenge or opportunity?

Abstract

Background:

There is a growing demand for fertility-sparing treatment among young patients with early-stage endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). This study aims to evaluate the efficacy of a regimen that combines anti-estrogen therapy with treatments targeting glucose, lipid, and calcium metabolism in EC and EAH patients.

Methods:

We conducted a retrospective analysis of patients with EC and EAH who were treated at Peking University People’s Hospital between January 2018 and November 2023. The study investigated the clinical profiles of the patients and assessed the efficacy of different treatment strategies.

Results:

A total of 285 patients were enrolled in the study, with 149 receiving anti-estrogen monotherapy and 136 receiving a combination therapy (including metformin, statins, calcium channel blockers [CCBs]). The combination therapy group showed a significantly higher proportion of patients with elevated body mass index, insulin resistance, diabetes, and hypertension compared to anti-estrogen group (P <0.05), and both groups had similar complete response (CR) time and CR rate. Pathological type of EAH and metformin regimen were protective factors for shorter complete response time (P <0.05). Subsequent stratified analysis revealed that combination therapy with metformin significantly benefited patients with insulin resistance (hazard ratio [HR] = 1.888, 95% confidence interval [CI]: 1.313–2.713) and diabetes mellitus (HR = 2.749, 95% CI: 1.046–7.299).

Conclusions:

Fertility-sparing treatments for patients with metabolic risk factors may have poor efficacy. However, the integration of anti-estrogen therapy with the metabolic-targeting interventions, like metformin, appears to improve the outcomes of fertility-preserving strategies in this patient population.

Introduction

Endometrial cancer (EC) is one of the most common gynecologic malignancies worldwide, and there were approximately 77,700 new EC cases reported in China in 2022. In some developed countries and regions, EC has become the most prevalent malignancy of the female reproductive system.^[1] In recent years, the incidence of EC has exhibited a trend toward younger age at diagnosis. The incidence of EC in younger patients increased by 1.5-fold between 1995 and 2018. Notably over 12% of cases occurring in women under 50 years of age.^[2] The standard therapeutic approach for EC and its precancerous lesions, atypical endometrial hyperplasia (EAH), was hysterectomy combined with bilateral adnexectomy with or without lymph node resection. While this approach would result in the permanent loss of fertility in young EC patients. Furthermore, the possible accompanying hormonal fluctuations, sexual dysfunction, and pelvic floor structural and functional alterations impose substantial physical and psychological burdens. These issues compounded by the social and self-evaluation challenges following surgery, significantly affect treatment compliance and quality of life. Consequently, there is a growing demand for organ-preserving and fertility-sparing treatments among patients with EC and EAH.

High-dose progestin therapy is the preferred option for fertility-preserving treatment in EC. Previous studies have shown that 52.6%, 18.5%, 7.5% and 13.6% of patients with endometrial cancer exhibit insulin resistance (IR), diabetes mellitus (DM), hypertension and metabolic syndrome, and these metabolic abnormalities are significant risk factors for progestin resistance, affecting both the time to achieve complete response (CR) and recurrence rates.^[3,4] Accumulating the results of clinical cohort studies with large sample sizes over more than a decade, we developed anti-estrogen combined with metabolic-targeting therapy including glucose-lowering, lipid-lowering and calcium-lowering therapy. The preliminary research findings suggest that improving glucose metabolism is conducive to enhancing the therapeutic effect of preserving fertility.^[5]

This study included EC and EAH patients undergoing fertility-preserving treatment in Peking University People’s Hospital and analyzed the relationship between different treatment regimens and clinical outcomes, with a particular focus on those with metabolic disturbance. The aim was to identify the optimal treatment approach for patients with metabolic abnormalities.

Methods

Ethical approval

This study was approved by the Ethics Review Committee of Peking University People’s Hospital (Ethics No: 2022PHB380-001). All patients signed informed consent.

Clinical data collection

Retrospective data from patients who received fertility-preserving treatment at the Department of Obstetrics and Gynecology, Peking University People’s Hospital between January 2018 and November 2023 were collected. And the patient’s follow-up was completed by December 2023. The inclusion criteria were as follows: (1) Histopathological diagnosis of the endometrioid carcinoma, classified as either highly differentiated or moderately differentiated; (2) Imaging confirmed that the tumor was limited to the endometrium or less than 50% myometrial invasion; (3) No contraindications to high-dose progestin therapy; (4) A strong desire for fertility with no other identified barriers to fertility as assessed; (5) Signed informed consent and satisfactory follow-up conditions. The exclusion criteria were: (1) Lack of baseline clinical data; (2) Failure to adhere to treatment protocols; (3) Loss to follow-up.

Basic clinical information, such as age, height, weight, comorbidities, pathological type, blood lipids, fasting blood glucose, fasting insulin, and glycated hemoglobin, as well as treatment plans, maintenance therapy, recurrence, and pregnancy outcomes, were collected. IR was assessed using the Homeostasis Model Assessment Insulin Resistance Index (HOMA-IR), calculated as fasting blood glucose (mmol/L) × fasting insulin (mU/L)/22.5. HOMA-IR >2.5 was defined as IR.^[6] Triglyceride (TG)≥1.7 mmol/L and/or high-density lipoprotein cholesterol (HDL-C) <1.0 mmol/L was regarded as dyslipidemia.^[7]

Treatment regimen

For newly diagnosed patients without contraindications, high-dose progestin therapy was the first-line treatment, including medroxyprogesterone acetate (MPA, 250–500 mg/day) or megestrol acetate (MA, 160–320 mg/day). For patients who did not achieve CR after two cycles of first-line therapy or those who experienced recurrence, the treatment was either switched to or combined with gonadotropin-releasing hormone agonists (GnRH-a), a levonorgestrel intrauterine system (LNG-IUS) or letrozole.^[8]

For patients with DM, IR, or obesity, adjunctive hypoglycemic agent such as metformin (500 mg three times daily), was recommended. For patients with dyslipidemia, statins were recommended. For patients with hypertension, calcium channel blockers (CCBs) were selected as antihypertensive agent.

Response evaluation

Hysteroscopy and image examinations including ultrasound and/or magnetic resonance imaging (MRI) were performed every three months. Therapeutic responses were classified into CR, partial response (PR), stable disease (SD), and progressive disease (PD) based on the hysteroscopic pathological diagnosis. CR was defined as the absence of atypical hyperplasia or carcinoma. PR was defined as a reduction in the degree of glandular structural and cellular atypia or a significant reduction in the extent of the lesion after treatment. SD was defined as no change in the lesion on pathology compared to pre-treatment or existence of the initial disease. PD was defined as progression to a higher grade or advancement of the lesion.

Follow-up

Follow-up was conducted through outpatient visits and telephone interviews. Patients were followed up every three months within the first two years after initial treatment, and every six months within the following years. Follow-up assessments included symptoms, transvaginal ultrasound, tumor marker testing, and pelvic MRI or hysteroscopy if necessary. The primary outcome was CR, while secondary outcomes include recurrence, hysterectomy, pregnancy, live birth, and mortality.

Statistical analysis

Statistical analysis was performed using SPSS (version 26.0; Chicago, IL, USA) and R software (version 4.4.1; R Foundation, Vienna, Austria). Categorical data was analyzed using the chi-square test (χ² test). Continuous data was assessed for normality; normally distributed data were presented as mean ± standard deviation, while non-normally distributed data were presented as median (interquartile range). Factors influencing time to achieve CR were analyzed using Kaplan–Meier analysis and multivariate cox regression models. P <0.05 was considered statistically significant.

Results

General information

A total of 358 patients had accepted fertility-sparing treatment during January 2018 to November 2023. And 285 patients were included, with 182 EC patients and 103 EAH patients. Their average age was 33.5 ± 5.8 years old. Among them, 170 patients (59.6%) were assessed as IR, and 32 patients (11.2%) were diagnosed with DM. Additionally, 102 patients (35.8%) presented with dyslipidemia, and 12 patients (4.2%) had hypertension.

Treatment regimens

All patients undergoing fertility-preserving treatment received MPA-based regimen, with 136 (47.7%) patients additionally receiving glucose-lowering, lipid-lowering, or calcium-lowering medications as the metabolic-targeting treatment. In addition, 47 patients had their regimens changed to combined regimen with metabolic-targeting [Figure 1].

Figure 1.

Study flowchart of patients with endometrial cancer and endometrial atypical hyperplasia who received fertility-preserving treatment. CR: Complete response; PR: Partial response; SD: Stable disease.

Treatment outcomes

A total of 220 patients (77.2%) achieved CR, and the median time to CR was 6 (4, 12) months. Five patients underwent surgery due to persistent or progressive lesions. The median follow-up duration was 23.5 (11.0, 40.3) months. During the follow-up period, 23 patients experienced recurrence (8.1%), of whom 10 achieved CR once more following treatment. One EAH patient who achieved CR and completed childbirth, experienced recurrence after 41 months. She underwent total hysterectomy + bilateral salpingectomy + sentinel lymph node dissection + pelvic lymphadenectomy, with postoperative pathology indicating EAH. Among the 220 patients who achieved complete remission, 126 patients had no fertility plan temporarily and received maintenance therapy with LNG-IUS or oral progestin. And 94 patients who had active fertility need sought assisted reproductive treatment or expected natural pregnancy. A total of 36 (38.3%) patients became pregnant, and 27 (28.7%) successfully delivered live births.

Patients were divided into two groups according to whether they received monotherapy of anti-estrogen or combined therapy of targeting metabolism at baseline [Table 1]. Compared to patients receiving anti-estrogen regimen, those in the combination therapy group had a significantly higher frequency of elevated body mass index (BMI) (P = 0.017), retreatment after relapse (P = 0.025), IR (P = 0.004), DM (P = 0.011), and hypertension (P = 0.012). There were no statistically significant differences in the CR rate and CR time among the two groups. Also, both groups had similar recurrence rates and time to recurrence (P >0.05).

Table 1.

Comparison of clinical characteristics of patients with EC or EAH treated with different regimens.

Characteristics	Total (n = 285)	Anti-estrogen regimen (n = 149)	Combination regimen (n = 136)	Statistics	P values
Pathological types				2.306*	0.129
EAH	103 (36.1)	60 (40.3)	43 (31.6)
EC	182 (63.9)	89 (59.7)	93 (68.4)
Age (years)	33.5 ± 5.8	33.1 ± 6.0	33.9 ± 5.5	–1.160†	0.247
BMI (kg/m2)	27.7 ± 5.4	27.0 ± 5.5	28.5 ± 5.2	–2.394†	0.017
Status of diseases				5.047*	0.025
Initial treatment	257 (90.2)	140 (94.0)	117 (86.0)
Post-relapse treatmen§	28 (9.8)	9 (6.0)	19 (14.0)
Complication
IR	170 (59.6)	77 (51.7)	93 (68.4)	8.243*	0.004
DM	32 (11.2)	10 (6.7)	22 (16.2)	6.391*	0.011
Dyslipidemia	102 (35.8)	50 (33.6)	52 (38.2)	0.677*	0.411
Hypertension	12 (4.2)	2 (1.3)	10 (7.4)	6.369*	0.012
CR	220 (77.2)	121 (81.2)	99 (72.8)	2.859*	0.091
Time to CR (months)	6 (4, 12)	7 (4, 12)	6 (4, 11)	0.810‡	0.418
Recurrence	23 (8.1)	11/121 (9.1)	12/99 (12.1)	0.534*	0.465
Time to recurrence (months)	6.0 (4.0, 12.0)	6.0 (4.0, 10.0)	5.0 (4.0, 19.5)	–0.345‡	0.730

Data shown as n (%), mean ± standard deviation or median (P₂₅, P₇₅). BMI: Body mass index; CR: Complete response; DM: Diabetes mellitus; EAH: Endometrial atypical hyperplasia; EC: Endometrial cancer; IR: Insulin resistance. *χ² values; ^†t values; ^‡Z Values. ^§Patients who were recurrent cases when included in this study and received a retreatment, compared to those who received the initial treatment.

Impact of treatment regimes on the efficacy of fertility-preserving treatment

Cox regression analysis indicated that pahtological type of EAH (compared with EC) (P <0.001) and the use of metformin at baseline (P = 0.046) were the independent protective factors influencing the time to CR. For patients receiving CCBs regimen, the CR time tended to be shorter but without statistically significant difference (P = 0.067) [Table 2].

Table 2.

Multivariate Cox regression analysis of characteristics affecting CR time.

Characteristics	Total (n)	CR, n (%)	P values	HR (95% CI)
Pathological types			<0.001	1.835 (1.381, 2.439)
EAH	103	95 (82.2)
EC	182	125 (68.7)
Age	285		0.767	0.996 (0.973, 1.021)
BMI	285		0.182	0.980 (0.952, 1.009)
DM	285		0.170	0.719 (0.449, 1.151)
Yes	32	22 (68.8)
No	253	198 (78.6)
IR	285		0.200	0.827 (0.617, 1.106)
Yes	170	124 (72.9)
No	115	96 (83.5)
Hypertension	285		0.200	1.604 (0.779, 3.304)
Yes	12	11 (91.7)
No	273	209 (76.6)
Dyslipidemia	285		0.113	1.282 (0.943, 1.744)
Yes	102	73 (71.6)
No	183	147 (80.3)
Metformin usage	285		0.046	1.337 (1.005, 1.779)
Yes	112	88 (78.6)
No	173	132 (76.3)
Statins usage	285		0.791	0.931 (0.549, 1.579)
Yes	42	17 (40.5)
No	243	203 (83.5)
CCBs usage	285		0.067	2.234 (0.945, 5.284)
Yes	10	8 (80)
No	275	212 (77.2)

BMI: Body mass index; CCBs: Calcium channel blockers; CR: Complete response; DM: Diabetes mellitus; EAH: Endometrial atypical hyperplasia; EC: Endometrial cancer; HR: Hazard ratio; IR: Insulin resistance.

We retrospectively investigated the influence of metformin in subgroups correlated with clinicopathologic and metabolic status. Cox regression analysis showed that metformin addition benefited those patients with IR (P = 0.001) and DM (P = 0.040) [Figure 2]. In DM patients, those treated with a combination of metformin are 2.749 times more likely to achieve CR during the same time compared to those receiving anti-estrogen treatment. Similarly, those receiving a combination of metformin have a 1.888 times CR rate higher than the monotherapy group in IR patients. Also, metformin showed a slight benefit for overweight patients (P = 0.073).

Figure 2.

Subgroup analyses of influence of metformin regimen on CR according to clinicopathologic and metabolic characteristics. Overweight means BMI ≥25 kg/m². CI: Confidence interval; CR: Complete response; DM: Diabetes mellitus; EAH: Endometrial atypical hyperplasia; EC: Endometrial cancer; HR: Hazard ratio; IR: Insulin resistance.

Furthermore, Kaplan–Meier survival analysis demonstrated that patients with IR and DM who received metformin treatment achieved a significantly higher CR rate compared to those who received anti-estrogen therapy alone (P <0.001, P = 0.027). In patients with hypertension, those treated with a combination of CCBs exhibited a trend toward a higher CR rate; however, the difference did not reach statistical significance (P = 0.071) [Figure 3].

Figure 3.

Subgroup analysis according to clinical characteristics. (A) The CR time of IR patients in the anti-estrogen group and the anti-estrogen combined with metformin group. (B) The CR time of DM patients in the anti-estrogen group and the anti-estrogen combined with metformin group. (C) The CR time of dyslipidemia patients in the anti-estrogen group and the anti-estrogen combined with statins group. (D) The CR time of hypertension patients in the anti-estrogen group and the anti-estrogen combined with CCBs group. CCBs: Calcium channel blockers; CR: Complete response; DM: Diabetes mellitus; IR: Insulin resistance.

Discussion

Previous studies have demonstrated that the majority of EC are estrogen-dependent neoplasms. Obesity, diabetes mellitus, and hypertension constitute the characteristic triad of EC, with metabolic disorders playing a pivotal role in tumorigenesis and disease progression. In our cohort, metabolic comorbidities were prevalent: insulin resistance was identified in 170 patients (59.6%), dyslipidemia in 102 patients (35.8%), and hypertension in 12 patients (4.2%). Our research team found that high glucose levels led to glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation in endometrial cancer. These alterations are significant contributors to progestin resistance.^[9] Besides, lipid metabolic disturbance could prolong the treatment duration of endometrial cancer.^[10] Calcium channel blockers (CCBs), as the first line treatment for the treatment of hypertension, has been demonstrated to counteract the progression of EC induced by elevated calcium levels.^[11] Based on the research, our team proposed the “Anti-Estrogen with Tri-Lowering Therapy”, which integrates glucose-lowering, lipid-lowering, and calcium-regulating.

This combination therapy aims to regulate glucose and lipid metabolism, as well as calcium homeostasis, which act synergistically with anti-estrogen therapy in the treatment of EC.

More than 80% of early-stage endometrial cancer are type I estrogen-dependent tumors, with high expression of estrogen receptors. Estrogen promotes the development of EC by binding to estrogen receptor α and β subtypes and their variants, exerting dual receptor regulation through transcriptional and non-transcriptional pathways.^[12] LNG-IUS and high-dose oral progestins bind to the progesterone receptor and competitively inhibit the action of estrogen receptors, inhibiting and reversing endometrial cancer cell proliferation, regulating several cell cycle proteins and promoting apoptosis. Numerous of clinical studies have demonstrated the effectiveness of traditional oral progestins and LNG-IUS in the treatment of endometrial cancer, with CR rates ranging from 72% to 89%,^[5,13] and they have been designated as first-line treatment options by multiple guidelines. GnRH-a reduces ovarian estrogen secretion by inhibiting the hypothalamic-pituitary-ovarian axis, while letrozole decreases the synthesis of peripheral estrogen. Chen conducted a retrospective analysis of 179 patients with EC and EAH patients who received treatment with GnRH-a combined with LNG-IUS/letrozole, achieving a complete response rate of 94.4%.^[14] In this study, all patients received treatment based on anti-estrogen therapy, achieving a complete response rate of 77.2%. This demonstrates the effectiveness of anti-estrogen therapy.

However, a number of patients are not sensitive to progestins, resulting in prolonged therapy durations. Five patients underwent hysterectomy due to persistent, progressive, or recurrent lesions. Previous studies have reported that 48.3–62.9% of patients underwent treatment for more than six months, and 41–76% of patients with EC relapsed during follow-up.^[15,16,17] Prolonged anti-estrogen treatment can cause side effects such as increased appetite, weight gain, and bone mineral density loss in patients. Additionally, extending the treatment duration and recurrence may impact future fertility plans. Consequently, how to enhance the sensitivity of anti-estrogen therapy and reduce the recurrence rate is a topic worth further investigation. Several clinical trials are currently investigating these issues to improve patient outcomes.

Application of glucose-lowering therapy in fertility-preserving treatment. Insulin resistance, a common pathophysiological condition in obesity, DM, and hypertension, can enhance estrogen-mediated endometrial proliferation by upregulating estrogen receptor expression and results in progestin resistance.^[18] In our previous studies, IR was identified as an independent risk factor for poor efficacy and recurrence in fertility-preserving treatment.^[4] And metformin combined with pyruvate dehydrogenase kinase 1 (PDK1) inhibitors could improve progestin treatment sensitivity and promote EC cell apoptosis by targeting metabolic reprogramming.^[9] Yang et al^[5,19] reported that EAH patients who received metformin in combination therapy achieve better outcomes and lower recurrence rates. In this study, we found that patients with IR and DM who used metformin in combination with anti-estrogen therapy had shorter CR time compared to those who received anti-estrogen therapy alone. Therefore, it is recommended to use metformin in combination therapy for patients with DM and IR.

Application of lipid-lowering therapy in fertility-preserving treatment. Dyslipidemia is closely associated with the development of various tumors. Cholesterol can activate transcriptional activity in EC cells via endoplasmic reticulum-dependent pathway, promoting the proliferation of EC. Previous studies have shown that metabolic syndrome is positively correlated with the grade, stage, and lymph node metastasis of EC, while low HDL-C is closely linked to an increased risk of mortality in EC patients.^[20] Increased expression of genes involved in fatty acid biosynthetic processes, lipid metabolic processes, lipid translocation and regulation of lipid metabolic process related genes may contribute to progestin resistance in endometrial cancer.^[21] Clinical research has shown that active weight management helps promote weight loss and improve lipid metabolism, increasing the complete response rates of fertility-preserving treatment.^[22]

In this study, 42 patients received combined lipid-lowering therapy, with 17 achieving CR within six months (40.5%). However, the limited efficacy observed may be attributed to the short follow-up period and small sample size. An ongoing RCT at our hospital (NCT06102863) is evaluating the combination of progesterone therapy with statins in young women with early-stage EC or EAH. Targeted lipid metabolism regulation may represent a promising approach to enhancing fertility-preserving treatment sensitivity in the future.

Application of calcium-lowering therapy in fertility-preserving treatment. Estrogen has been shown to mediate extracellular calcium influx and influence calcium-related protein expression in normal endometrial epithelial cells.^[23] Elevated calcium levels are also associated with advanced tumor stages, higher grades, lymph node metastasis, and lymphovascular space invasion (LVSI).^[24] Dysregulation of intracellular calcium homeostasis is a key mechanism through which estrogen promotes the development of EC. CCBs have been shown to modulate estrogen-induced increases in intracellular calcium, inhibiting tumor cell proliferation, inducing apoptosis, and suppressing invasion.^[11,25] Ten patients received CCBs at the initial treatment stage, and 8 of them (80%) achieved CR after treatment, and the CR time tended to be shorter in patients with combined use of CCBs. Therefore, in EC patients with hypertension, it is recommended to use CCBs after thorough evaluation.

Patients with EC and EAH often present with an imbalance of estrogens and progestins, as well as metabolic disorders. In response, our team proposed the anti-estrogen combined with triple lowering therapy to address glucose, lipid, and calcium metabolism. Our findings suggest that this approach holds significant promise in enhancing fertility-preserving treatment outcomes and also fit with the idea of individualized therapy. Specifically, we proved the treatment efficacy of metformin for fertility-sparing patients and identify who will benefit most from metformin use. However, this study has certain limitations. Firstly, the follow-up period was relatively short in this study, which may introduce potential biases into the findings. Further investigation into its long-term efficacy, safety, pregnancy and recurrence conditions is in demand. Additionally, this is a single-center retrospective study. More rigorously designed, multicenter, and prospectively conducted clinical trials with standardized protocols are warranted. To address these gaps, we are planning to conduct a multicenter, randomized controlled trial and sincerely invite both domestic and international research teams to collaborate on advancing this therapeutic strategy, with the goal of improving long-term outcomes for patients with EC and EAH.

Funding

This work was supported by grants from the National Key Technology Research and Developmental Program of China (Nos. 2022YFC2704400 and 2022YFC2704405) and Chinese Maternal and Child Health Research Association Program (No. 2023CAMCHS0402).

Conflicts of interest

None.