Metabolic syndrome is an independent risk factor for time to complete remission of fertility-sparing treatment in atypical endometrial hyperplasia and early endometrial carcinoma patients

Fertility-sparing treatment is usually applied for young patients with AEH and early EC who have a strong desire to retain future fertility potential. The administrations mainly include oral MPA or MA, GnRH-a, or Levonorgestrel Intrauterine device (LNG-IUD) [3, 4]. Although there is sufficient evidence of the efficacy and safety of fertility-sparing treatment, the selection of specific and appropriate patients is a problem that must be addressed.

Our previous studies suggested that the cumulative CR rates were 58.0%, 76.0% and 95.5% with the duration of treatment extending from 6 to 9 months to more than 9 months and sometimes longer, accompanied by the significantly increasing recurrence rate with 21.1%, 25.0% and 36.4% respectively [8]. This is consistent with the findings of Martin Koskas et al. Since CR rate increased over time but plateau, while recurrence rates don’t [6], blindly prolonging fertility-sparing treatment duration would increase the risk of recurrence. Our study focused on the factors that influenced the time to CR to identify patients suitable for extended conservative therapy.

We divided 106 patients with AEH or early EC into three groups based on the time intervals to achieve CR (< 6 m, 6-9 m, > 9 m). The basic characteristics of the three groups were roughly comparable, except for PCOS, which was more prevalent in groups with time to CR more than 9 months. Univariate analysis identified MetS, PCOS, and FBG as independent risk markers of prolonged time to CR and the effect of MetS was of particular concern. To further investigate the effect of MetS on time to CR, we performed a multivariate analysis. After adjusting for some basic confounding factors, such as age, BMI, gestation and parity, the risk effect of MetS on time to CR was still statistically significant. Additionally, the effect of MetS on time to CR was slightly elevated after adjusting for the other two risk factors PCOS and FBG. ROC curve analysis and DCA suggested that MetS significantly increased the predictive accuracy of longer time to CR after fertility-sparing management in AEH and early EC patients.

MetS is a cluster of components including IR, obesity, dyslipidemias, HBP and DM, with increasing incidence worldwide. Current viewpoints hold that MetS is closely associated with the occurrence and development of various cancers, which may be caused by the imbalance of estrogen and progesterone levels due to the status of metabolic imbalance. MetS is an independent prognostic factor of endometrial carcinoma and is closely related to tumor stage, grade, vascular invasion, tumor size, and lymph node metastasis [11]. The risk ratio of patients with three or more MetS symptoms increases around eightfold to diagnose EC, and is rising as the number of components increasing [12]. IR was usually indicated as the core symptom of MetS, which induced a chronic inflammatory state, manifested by excessive local expression of TNF-α, IL-6 and reactive oxygen species, resulting in persistent stimulation of endometrial cell hyperplasia [13]. Numerous studies have identified factors affecting CR rate in fertility-sparing therapy. In addition to the previously mentioned factors such as operative hysteroscopy, previous pregnancies, infertility, therapeutic regimens, longer menstrual cycles and infrequent menstrual bleeding [5,6,7], metabolism-related factors play a significant role in outcomes of these patients, such as PCOS, obesity and IR [14,15,16]. This is further supported by endometrial cancer association to hormone levels and metabolism [17]. Our results suggest that patients with MetS have longer time to CR. Therefore, AEH and early EC patients with MetS may be at risk of extended hormone treatment duration and require personalized fertility-sparing treatment.

To our knowledge, there are several diagnostic criteria for metabolic syndrome, such as the criteria proposed by World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and the International Diabetes Federation (IDF). The general principles in each definition are similar but the cutoffs and thresholds for the variables are somewhat different. There is no single unified diagnostic standard for MetS currently [18]. We referred to diagnostic criteria put forward by the Chinese medical association diabetes branch in 2004 [9]. However, different diagnostic standards for MetS can be applied for further study in the future.

A previous study indicated that the cumulative 16-week CR rate of early EC fertility-sparing treatment for PCOS patients was significantly lower compared to control group, while time to CR prolonged, and the relapse time after CR was shorter [14]. In our study, we found a significant increase in the proportion of PCOS patients who achieved CR with longer than 9 months therapy. Univariate analysis identified PCOS as a risk factor for time to CR, which indicated that a longer conservative therapy may be needed for PCOS patients to achieve CR. This phenomenon may be associated with progesterone resistance induced by low-grade chronic inflammation, insulin resistance and hyperandrogenemia in women with PCOS [14, 19].

After stratified analysis, we found that in women younger than 30 years old, MetS significantly prolonged the time to CR from fertility-sparing treatment, thus those patients may be at greater risk of relapse as the treatment continues. In overweight women with BMI ≥ 24.0 kg/m2, MetS was associated with 2.9-fold increased risk of prolonged time to CR. A previous study indicated that BMI ≥ 28.0 kg/m2 was an independent predictor of progesterone insensitivity [20], thus high BMI may be chosen as a risk marker for longer progestin treatment duration of AEH and early EC with MetS. In addition, MetS could predict longer time to CR in patients with AEH, but may not have a significant effect on time to CR in patients with early EC.

Interestingly, we noticed that patients with MetS who did not take metformin during conservative treatment were four times more likely to have a significantly longer time to reach CR. However, if they had ever taken metformin, the effect of MetS on prolonged time to CR would be reduced to 0.5 times. It was previously reported that metformin not only increased the early CR rate from 13.6% to 26.5% in patients with MetS during the fertility-sparing management of AEH and early EC, but also improved recurrence-free survival and overall survival for patients with early EC [21,22,23]. Mechanistically this may result from suppressed expression of Ki-67 via AMPK-dependent mTOR inhibition and extracellular signal-regulated kinase dephosphorylation by metformin [24, 25]. Alternatively, metformin may modulate inflammatory pathways and oxidative stress pathways by improving hyperglycemia and hyperinsulinemia, thereby reducing the stimulation of tumor cell growth [26]. Others may suggest that the MetS status probably has no impact on the efficacy of metformin together with MA for fertility-sparing treatment of AEH and early EC; but the implication was that regardless of the presence of MetS, treatment with metformin showed a higher CR rate than that with MA only, indicating the safety and efficacy of metformin [27]. Therefore, we suggest that treatment with metformin may shorten the time to CR in the course of fertility-sparing management for patients with MetS. This however required further validation with purpose-designed clinical trials.

We also observed an interaction between HDL levels and metabolic syndrome. In the middle HDL group, the risk of prolonged time to CR increased 24.3 times in the non-MetS group and 31.3 times in the MetS group. However, increase of HDL level, risk of MetS for time to CR was not significant. In other words, HDL could be regarded as a protective factor to alleviate the negative effect of MetS on time to CR. Many studies suggested that serum lipids were associated with EC, but the results were inconsistent. High HDL level had been shown to increase the risk of EC, primarily associated with non-endometrioid endometrial cancer [28], while other studies held the contrary view that HDL was unrelated to the elevated risk of EC [29]. Therefore, the specific role of HDL in the EC patients remains unclear, nor was it clear in fertility-sparing patients. In the general population, HDL levels represented as a J-type dose response manner associated with cancer mortality. It means that very high and very low HDL levels were related to elevated mortality [30]. This challenged the conventional view that the higher HDL level was better. As for our study, HDL levels in most of the patients were below 2.0 mmol/L, located on the descending part of the J-type curve, which may partially explain why high HDL levels improved outcomes of fertility-sparing treatment in the patients with MetS. Further research is needed to explore the protective mechanism of HDL on the outcome of fertility-sparing treatment of AEH and early EC patients.

To the best of our knowledge, this is the first study designed to screen risk factors for time to CR in AEH and early EC patients receiving fertility-sparing therapy, which is conducted with a large sample size and comprehensive analysis. However, there are some limitations in our study. This is a retrospective study and the factors which included in our analysis are mainly classic clinicopathologic factors. In recent years, novel molecular classification and molecular markers have become a hot research topic in endometrial cancer. But limited literature has explored their value in predicting the treatment response for fertility-sparing treatment in AEH and early EC patients. Loss of PTEN expression does not seem to predict the efficacy of fertility-sparing therapy [31]. Mismatch repair status could be used as a predictive biomarker for better treatment response of hormone treatment [32]. The identification of these biomarkers may improve clinical outcomes and promote the management of fertility-sparing treatment, with greater potential research value. Unfortunately, because of the retrospective nature of our data, the effect of molecular classification and other molecular markers on time to CR has not been clarified in our study. Future studies are needed to confirm the value of specific molecular predictors in fertility-sparing treatment. Therefore, a prospective and randomized controlled trial with large-sample size is required to validate the outcome of AEH and early EC patients with MetS undergoing fertility-sparing management, and to guide clinical decision-making.

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