Endometrial cancer (EC) is one of the most common and an increasingly problematic gynecological cancer, whose incidence has gradually risen in recent years (1). With the significant increase in the proportion of the obese population, the number of premenopausal EC patients of childbearing age increased (2). The standard treatment requires, at a minimum, a hysterectomy with bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy, if indicated. However, this standard treatment results in a permanent loss of fertility while young patients have a strong desire to bear children. Therefore, fertility-sparing treatment should be discussed in young patients who wish to preserve their fertility. To date, conservative management for young patients has been applied and showed encouraging results on treatment and reproductive outcomes (3–5). Factors such as obesity might be associated with the oncologic and reproductive outcomes (6). Many researchers have shown that weight gain increases the risk of developing endometrial cancer (7). The risk of endometrial cancer increases by 6 times when the body mass index (BMI) is over 40 kg/m², and morbid obesity was associated with higher mortality and disease recurrence (8). Also, weight loss in obese women was associated with lower EC risk (9). Although EC is the cancer most strongly associated with obesity (10, 11), data on the effective application of conservative treatment for obese patients were relatively limited. Therefore, this study aimed to investigate the efficacy and safety of fertility-preserving therapy in obese EC or AEH patients.

As the major risk factor for EC, obesity has become a global public health problem (13, 14). According to the World Health Organization, obesity is defined as BMI ≥30 kg/m² (15). Women with obesity have about a 2.6- to 4.7-fold increase in the risk for EC compared with women of normal weight (16). With the number of obese populations increasing significantly, the proportion of EC in patients of childbearing age has increased accordingly. Fertility-sparing treatments have been applied to young women with EC/AEH to preserve their uterus with a high remission rate (17–22). Conservative therapy such as progestin therapy is widely accepted as the main method with satisfactory results. Also, it is possible to manage young patients using not only medical therapy but also hysteroscopic resection (23). However, progestin therapy is associated with a significant increase in body weight (3–5). For obese patients, further weight gain may lead to a higher risk of treatment failure, a high relapse rate, and a low possibility of live birth. Therefore, it is a big challenge for us to manage patients with obesity and select the most effective methods for these obese women. However, only a few studies have reported the outcomes of conservative management for obese patients or only as part of their report until now (24, 25). The effect of weight change during treatment on oncologic and reproductive outcomes are yet to be well assessed. This study aimed to investigate the oncological and reproductive outcomes of fertility-preserving treatment for EC and AEH patients with BMI ≥30. We also compared the efficacy and safety of different regimens as well as evaluated the influence of weight change during treatment on CR, recurrence, and pregnancy.

In our cohort, over 90% AEH and 80% EC patients achieved CR with 6 months of median CR time, proving that fertility preservation was feasible for obese women. Both GnRHa and progestin regimens showed great therapeutic effects, whereas a higher remission rate was found in GnRHa-based regimen with CR rate up to 93.4%. In previous studies for fertility-sparing progestin therapy, overweight or obesity was significantly associated with a poor response to progestin therapy (26, 27), this is consistent with our results. In our research, progestin therapy was associated with a significant increase in body weight. Although weight control was recommended for all patients, about 43.9% of the patients gained weight, and 26.8% gained more than 5% of their weight. Among the patients who received progestin therapy but failed to achieve CR, 9 women were transferred to receive GnRHa based therapy and finally got complete remission after 1–2 courses. Our previous studies proved that GnRHa combination treatment in patients who failed oral progestin therapy produced good treatment and reproductive outcomes (28). Also, a low recurrence rate was found in GnRHa-based therapy compared with progestin.

Consequently, progesterone alone therapy may not be the most efficient treatment regimen, and the GnRHa combination regimen could be an alternative for obese patients. Nevertheless, the long-term adverse effect of GnRHa and its influence on fertility by repeated curettage need to be noted owing to the low pregnancy rate of the GnRHa regimen. It has been documented that 2–3% of bone mass will be lost with 6 months of GnRHa use. In addition, it is unclear what is the maximal duration of GnRHa therapy, whether the add-back therapy should be performed, whether the bone mineral density should be monitored, and whether calcium and bisphosphonates should be added. Therefore, the long-term side effect of GnRHa such as osteoporosis and cardiovascular complications should be considered in future studies.

Weight loss is crucial in the clinical management of young patients undergoing fertility-sparing therapy. A previous study suggested that weight change has little influence on complete response and recurrence rates during treatment, while obesity was a significant predictor for low response rates and high recurrence rates (25). However, the correlation between treatment outcome and weight change has rarely been mentioned, especially for obese patients. In this study, obese patients who lost less than 10% of their weight had a poor response and pregnancy outcomes, as well as a higher rate of recurrence, consistent with previous studies (6). Besides, the more weight patients lost, the higher the CR rate observed. Thus, weight control and health consulting are crucial in the whole-lifespan management of fertility-sparing treatment. GnRHa-based therapy has an advantage on weight control since it is well known that weight gain is the main side effect of high-dose oral progestin. Further research concerning the correlation between weight loss and pregnancy loss is still needed.

The Cancer Genome Atlas (TCGA)-based molecular classification system and MMR testing have been proposed in young women desiring fertility-sparing treatment, but the association is still unclear (29). Some researches revealed a 100% recurrence rate in MMR-deficient patients and suggested that patients with Lynch syndrome and P53 mutations should not be treated conservatively (30, 31). Owing to data limitations in our study, we failed to conduct further research in this aspect, Still, we believe that the TCGA classification system can contribute to selecting populations who suit fertility-sparing treatment and help to predict the oncologic outcomes (32, 33).

Previous studies revealed a high rate of relapse of fertility-sparing treatment in EC patients (17, 18). In our research, about 20% of women had developed recurrence with 26 months of median recurrence time, in accordance with former research. However, some of the recurrences occurred as early as 8 months after a CR. Another study reported that some recurrence occurred at 3–4 months after CR, which mandates the follow-up to be started early (34). The longest recurrence in our research took place at 52 months, and recurrence occurring at 13 years was also reported in other previous studies (35, 36). Therefore, long-term monitoring and regular follow-up are essential. Additionally, hormonal maintenance therapy is crucial for women who have no birth plan immediately after completion of treatment (34, 37). Moreover, a low recurrence rate was also found in patients with pregnancy. Herein, maintenance therapy and conception immediately were encouraged to reduce the risk of recurrence. For recurrent patients, fertility-sparing re-treatment could be considered after complete evaluation. Over 60% of recurrent patients achieved CR again in our research. In our previous study, the CR rate was about 90% in BMI normal patients. However, with increased treatment times, the recurrence time shortened, and no patients got pregnant after the third-round treatment (12). Patients were supposed to be informed of treatment failure and conceive before the re-treatment. Given the limited number of patients and several patients still being treated, whose therapeutic efficacy is yet to be assessed, we assumed that a future study with a larger samples size should be performed to evaluate the effect.

Conception is the ultimate goal of uterine preservation for most patients. However, the pregnancy and live birth rates in our research are still somewhat suboptimal, lower than previous studies (27, 38). However, the miscarriage rate at the first or second trimester is in accordance with the ordinary population (39). This might be due to patients included in our studies being obese women, which was associated with a lower probability of pregnancy. Moreover, the follow-up time in our study was relatively short; if longer follow-up times were performed, a high rate of relapse and live birth might be observed (40). The correlation between weight loss and reproductive outcomes has not been well evaluated and reported before. Some studies believed that the weight loss was not related to pregnancy and live birth rates in EC patients who received fertility-preserving treatment. In contrast, our current results showed that patients who lost weight more than 10% had a higher pregnancy rate. So, we concluded that weight loss could positively affect the pregnancy and live birth rate in obese women. It has been reported that weight loss ≥5% could also improve the pregnancy rate as an independent positive factor (41). Therefore, weight loss or recovery patients’ normal BMIs during therapy as well as the ART time is of great significance. Despite our expectations, ART did not significantly improve the live birth rate, women who chose IVF-ET had relatively better results, and some studies did report improved birth rate with ART (42, 43). Hence, once CR has been achieved, getting pregnant should be considered as soon as possible, and IVF-ET is recommended.

Firstly, our study was a single-center retrospective study, and the choice of individual regimens was essentially a matter of physician preference. Multi-center prospective clinical trials are supposed to be conducted to verify the efficacy. Secondly, some patients were still under treatment until the last contact, which may influence the research results. Thirdly, the follow-up time of our study is relatively limited, and long-term follow-up was recommended to verify high pregnancy and recurrence rates.

In conclusion, the findings of our study confirm that fertility-sparing treatment for obese women with EC/AEH appears to be an acceptable method. The combination of GnRHa with LNG-IUS/letrozole is an alternative regimen with a higher regression rate and low rate of recurrence, as well as fewer side effects such as weight gain compared with progestin. Besides, weight loss of more than 10% positively influences CR, recurrence, and pregnancy rates. Therefore, weight control and health consulting are crucial in the whole-lifespan management of fertility-sparing treatment, especially for obese patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Conceptualization: JC and DC. Data curation: JC, DC, JY, MY, HZ, JW, YZ, NC, PP, and KS. Formal analysis: JC and DC. Software: JC. Writing—original draft: JC and DC. Writing—review and editing: JY, MY, HZ, JW, YZ, NC, PP, and KS. All authors contributed to the article and approved the submitted version.

This work was supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-PT320-003).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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