Weight loss improve pregnancy and livebirth outcomes in young women with early-stage endometrial cancer and atypical hyperplasia:15 years’ experience

Background: To evaluate the effects of body weight loss on pregnancy and livebirth outcomes in young women with early-stage endometrial cancer (EC) and atypical hyperplasia (AH) with fertility-sparing therapy. Thus, improve the management of this patient group. Method: Patients with AH (n=36) and well-differentiated EC (n=8, FIGO stage IA) who achieved complete regression after conservative treatment were included in this retrospective study. A weight loss group (n=25) and a non-weight loss group (n=19) were divided; while subgroup analysis according to body mass index and stratication analysis according to weight loss proportion were performed to investigate the effect of weight loss on pregnancy and livebirth outcomes. A univariate and multivariate logistic regression analysis were undertaken to analysis the factors associated with pregnancy. Results: The mean body weight and body mass index at pretreatment of progestin and initiation of fertility treatment was 70.63±12.03 and 67.08±8.18 kg, respectively, and 27.06±4.44 and 25.73±3.15 kg/m 2 , respectively. 25 patients (56.82%) had weight loss; the median weight loss amount is 5.00kg (1.00-34.50), median weigh loss proportion was 6.70% (1.00-36.00) during median time interval of 12months (5.00-97.00). An impressive favorable pregnancy rate (65.91%) and live birth rate (50.00%) were achieved. The pregnancy and livebirth rate were meaningfully higher in the weight loss group than the non-weight loss group (88.00% vs.36.84%,P=0.000; 64.00% vs.31.58%,P=0.033, respectively); weight loss ≥ 5% signicantly increased pregnancy and live birth rate in patients with BMI ≥ 25. The risk ratios of weight loss ≥ 5% in multivariate logistic analysis for pregnancy was 0.096(0.010, 0.907). Conclusions: Weight loss could have a positive effect on pregnancy rates and seem to be useful for improving live birth rates in overweight or obese women with early-stage endometrial cancer and atypical hyperplasia during/after fertility-sparing therapy. weight loss ≥ 5% was protective factors of pregnancy in fertility-sparing patients with early-stage endometrial cancer and atypical hyperplasia. on a transvaginal ultrasound scan. Early pregnancy loss including loss of an intrauterine pregnancy < 12 weeks and biochemical pregnancy losses were included also in this study. biochemical pregnancy was diagnosed as Human chorionic gonadotropin ≥ 25 mIU/mL. Endometrial thickness was measured via transvaginal ultrasound.Follow-up period was initiated from the date of progestin withdrawal. All patients were followed till December 2020. The median follow-up period was 86.80 months (12.00-188.50).

Weight loss improve pregnancy and livebirth outcomes in young women with early-stage endometrial cancer and atypical hyperplasia: 15

Background
Endometrial carcinoma (EC) and its precursor atypical hyperplasia (AH) classically affect postmenopausal women. However, approximately 5% of cases of them occur in women aged 40 years or younger. The trend toward late childbearing has made fertility preservation a major issue for women who face EC and AH. Among the affected women, 70% are nulliparous [1]. NCCN guideline 2018 indicated fertility sparing management may be considered in selected patients and it is consistently recognized that progestin is safe and effective in conservative treatment [2]. Because the ultimate goal of fertility-sparing treatment is childbearing, following high dose progestin therapy and con rmation of the regression of cancer, a favorable pregnancy and livebirth rates in these patients are also clinical concerns. However, an unsatisfying pregnancy and livebirth rate reported recently in a systematic review and meta-analysis was 26.8% and 20.5%, respectively [3]. Meanwhile, few studies have evaluated the barriers to successful childbearing in these patients. It was known that obesity is a well-known disruptor of the female fertility but evidence is still lacking on whether weight loss interventions improve fertility in patients after fertility-sparing therapy.
In the current study, we focused on such subset patients, aim to verify the importance of weight loss to improve pregnancy and livebirth outcomes and provide some procedures in clinical practice and management of those who require fertility-sparing treatment diagnosed with EC or AH.

Methods
This retrospective study included women younger than 40 years diagnosed with EC or AH who desired fertility-sparing management from May 2005 to May 2019.
Approval was obtained from the Institutional Ethics Committee.
All patients were given full information regarding the risks and bene ts of conservative treatments,and all of the patients had signed consents.
Exclusion criteria: (1) Lynch/hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (2) lost to follow up/data not extractable/ with unavailable data for body weight and height pretreatment of progestin and at imitation of fertility treatment (3) patients achieved complete regression (CR) did not wish to conceive immediately (4) women without a partner when the data was collected.
All patients were pathologically diagnosed by endometrial biopsy through dilation and curettage (D&C) with hysteroscopy.
Pathologic diagnosis was reviewed by two experienced gynecological pathologists according to the World Health Organization pathological classi cation (2014).
Medical records were reviewed for demographic, clinicopathological parameters, oncologic and reproductive data. Blood samples were tested for cancer antigen (CA125), 75g oral glucose tolerance test (OGTT), while fasting blood glucose (FBG), fasting insulin (FINS) for patients with diabetes mellitus. Homeostasis model assessment of insulin resistance (HOMA-IR) index [FBG (mmol/L) × FINS (µU/mL)/22.5] ≥ 2.69 was de ned as insulin resistance (IR). Body weights pretreatment (body weight1) of progestin and at initiation of fertility treatment (body weight2) were collected to get body weight change; body mass index (BMI) was calculated and marked as BMI1 and BMI2 respectively.
Overweight was de ned as BMI ≥ 25 kg/m 2 .and Obesity as BMI ≥ 30 kg/m 2 Following con rmation of EC or AH, appropriately selected patients who desire fertility preservation were recommended to referred to a reproductive endocrinologist to assess reproductive fertility. In overweight or obesity women, health education was performed and weight loss was recommended.
Patients received a daily oral dose of 250-500 mg medroxyprogesterone acetate (MPA) or 160mg-320mg megestrol acetate (MA). Metformin 1500 mg/day was administered concurrently for patients with insulin resistance. Metformin therapy was continued after progestin administration until conception. Endometrial biopsy through dilation and curettage (D&C) with hysteroscopy was performed once 3 months after initiating progestin administration. CR was de ned as remission with the absence of evidence of hyperplasia or carcinoma.
Progestin was continued to the second negative biopsy.
We recommended that the patients undergo infertility treatment as soon as possible after progestin withdrawal. The parameters, which included infertility management, endometrial thickness during ovulation or embryo transfer date, the clinical pregnancy and live-birth outcomes were collected. Clinical pregnancy was de ned as observation of a gestational sac on a transvaginal ultrasound scan. Early pregnancy loss including loss of an intrauterine pregnancy < 12 weeks and biochemical pregnancy losses were included also in this study. biochemical pregnancy was diagnosed as Human chorionic gonadotropin ≥ 25 mIU/mL. Endometrial thickness was measured via transvaginal ultrasound.Follow-up period was initiated from the date of progestin withdrawal. All patients were followed till December 2020. The median follow-up period was 86.80 months (12.00-188.50).
Study end-points: weight loss and pregnancy and livebirth outcomes 3. Results

Patient characteristics
A total of 36 AH and 8 EC patients who met inclusion criteria were enrolled in. The total patients' characteristics are summarized in Table 1

Statistical analysis
All data were presented as means, medians, or proportions. The median values were compared using Mann-Whitney U-test. Frequency distributions were compared using the Chi-squared test or Fisher's exact test. Multivariate analysis was performed in the pregnancy and nonpregnancy groups using endometrial thickness, number of D&C, duration of progestin, age at diagnosis, hormone level and fasting plasma glucose as independent variables, using a logistic regression to determine the risk ratios. The difference was regarded as statistically signi cant when P-value 0.05 in two-sided test. All statistical analyses were performed using SPSS for Mac (version23.0; IBM).

Discussion
The prevalence of obesity is increasing worldwide, with a corresponding increase in overweight and obese patients referred with infertility. It is well established that obesity is not only the leading risk factor in the development of endometrial cancer and its precancerous lesions; but also, as disruptor of the female fertility, it affects ovulation, oocyte development, maturation and quality, endometrial receptivity, implantation, and even miscarriage [4][5][6]. But little is known about the impact of weight loss on pregnancy rate and livebirth outcomes in EC and AH patients who received fertility-preserving treatment. In current study it was demonstrated an impressive favorable pregnancy rate (65.91%) and live birth rate (50.00%) after weight loss in fertility-sparing treatment women, which were meaningfully higher than those reported in literature [3,7]. This study is the rst to show that the pregnancy and livebirth rate were signi cantly higher in weight loss group than non-weight loss one among young women with early-stage endometrial cancer (EC) and atypical hyperplasia (AH).
With the intervention of weight loss, the current study indeed demonstrated more cases of natural pregnancies or pregnancies by ovulation induction occurring soon after conservative treatment, but not In vitro fertilization (IVF) pregnancies. Most of these women in present study suffered from infertility or subfertility with underlying disorders related to overweight/obesity and PCOS, which conditions should be encouraged to seek assisted reproductive therapy (ART) for conception. Studies reported that ART might increase the likelihood of pregnancy than spontaneous way (39.4% VS 14.9%) and decreases the interval to conception [3,8,9]. But in this study, Non-ART patients achieved the same, even more favorable reproductive outcomes compared to ART group, pregnancy rate (71.43% vs 63.33%; P = 0.738) and live birth rate (50.00% vs 50.00%; P = 0.813) respectively. Moreover, only 16 out of 44 patients (patients at advanced age, primary ovarian insu ciency diagnosed, failed to be pregnant by ovulation induction.) required the aid of IVF, and only 9 of the 16 patients who received IVF in the study successfully got pregnant. So far, limited studies, mainly case reports and retrospective studies, have investigated the association between controlled ovarian hyperstimulation and cancer risk, which mainly refer to endometrial and ovarian cancer risk, the conclusions were inconsistent across trials, our understanding is inconclusive given the short follow-up terms and lack of information on important confounders [10][11][12]. Outcomes in this study indicated that the bene ts of weight reduction, including not only improvement in pregnancy rates, but also a reduced need for IVF. So, it is of paramount importance that overweight and obese women are given the necessary advice and support to achieve the weight loss before pregnancy during/after fertility-sparing treatment.
To date, only one research about the signi cance of weight change on pregnancy and livebirth outcomes in young EC women who undertook fertility preservation treatment is reported [13]. In this study, Park, J Y argued that pre and posttreatment of progestin, BMIs and weight change were not associated with pregnancy and live birth rates, which is not completely consistent with our results. It was demonstrated in our study that (the data not shown) BMI at pretreatment of progestin and at pretreatment of infertility and weight gain were not associated with pregnancy and live birth rate (additional Table 1), but an improved pregnancy and livebirth outcomes were shown resulting from weight loss.
Firstly, the difference may come from the higher weight loss composition with weight loss interventions in our study, the proportion of weight loss (56.82%). In Park' study, without weight loss interventions mentioned, a lower weight loss (33.1%) and higher weight gain (48.1%) proportion were shown, the BMI posttreatment was higher than pretreatment, i.e., BMIs were 25.99 ± 5.94 and 25.51 ± 5.99kg/m 2 (P = 0.034). Secondly, to accurately analyze the relationship between weight change and pregnancy and livebirth outcomes, a subgroup analysis according to BMI was done in current study, which was not included in Park'. A conclusion was drown in subgroup analysis that weight loss meaningfully increased the pregnancy and livebirth rate, especially in overweight and obese patients(BMI ≥ 25). Thirdly, a 5% weight loss proportion in ours according to perform strati cation analysis was different from the 10% proportion which according to in Park' study.
It is unknow what is the differences of weight loss proportion on fertility in patients with EC and AH after conservative treatment. In obese women with PCOS only 2-5% of total body weight loss from baseline is generally accepted as a "clinically meaningful amount" to improve ovulatory function and is more likely to result in spontaneous pregnancy. There is also evidence to support improved outcomes from ovulatory cycles and pregnancy at moderate weight loss (5-10%) of total body weight loss [14]. Reported for the rst time in current study, weigh loss ≥ 5% was associated with improved pregnancy and livebirth rate, and meanwhile was independent protective factors for pregnancy after adjust as age at diagnosis, duration of progestin, and endometrial thickness. But weigh loss seemed not to associate with decreased pregnancy loss, this may lie in the small cases of this study and it also raises another consideration, what amount of weight loss is necessary to achieve bene t with respect to different medical purposes. Although there are few studies has been done to demonstrate whether it is true that the greater level weight loss the even greater improvement on female fertility, clinicians in medical weight management should bear in mind that the target should be reproductive health improvement, rather than a large number on the scale, different tissues and individual patients respond differently to weight loss. Moreover, consistent with literatures, it was demonstrated that in this study, overweight and obesity before pregnancy increased the pregnancy loss and decreased livebirth rate (data not shown) [15][16][17]; it was also shown in our data that weight loss was unrelated to an increased risk of pregnancy loss. So, in this sense weight loss is crucial and safe for the clinical management of this patient group.
Progestin therapy is a widely accepted, effective treatment for EC and AH, but paradoxically, weight gain is a well-known side effect [18]. In this study, weight gain was not evident (15.91%) and made little in uence on reproductive outcomes. Otherwise, most patients achieved weight loss, it perhaps mainly affected by administration of metformin. 72.73% women in our study commonly used metformin because of insulin resistance. Metformin has been examined in multiple disease processes as a weight gain prevention tool. Metformin appears to impact appetite regulation both directly and indirectly due to its gastrointestinal side effects and a modi ed microbiome to decreased caloric intake versus increases in energy expenditure [19]. Moreover, health education related non-pharmacological Interventions may take some account of weight loss [20]. In overweight and obese patients in current study, health education was performed and the majority expressed interest in weight loss interventions in person; with a relatively long time to lose weight before pregnancy, 22 patients(73.3%) lost weight and 18 patients(60%) achieved ≥ 5% proportion, which may improve outcomes from ovulatory cycles and pregnancy rate [20]. Just as Ashley F' study about relationship between obesity and endometrial cancer arguing that "a lack of knowledge but opportunity for intervention" [21].
The study demonstrated a signi cant high incidence of cesarean delivery (22 among 25 pregnancies; 88%) among women after conservative treatment. To some extent, the increased cesarean rate in these women appears to be associated with hypertensive disorders, macrosomia related to gestational diabetes mellitus which may be associated with a higher BMI pre and during pregnancy,A proper weight loss amount pre-pregnancy and weight gain during pregnancy are crucial to improve obstetric outcomes. Meanwhile with misconception on delivery mode among neoplastic disease survivor, social factors increased the incidence of cesarean delivery. So, caring for these young cancer patients requires collaboration between a dedicated, adherent patient and her medical team of gynecological oncologist, reproductive endocrinologist and obstetric experts.
With the primary limitation of retrospective analysis conducted at a single center and small cases of patients, further large-scale welldesigned RCTs studies are necessary.

Conclusion
we have demonstrated weight loss may be an effective way to improve the pregnancy and livebirth outcomes in patients with early-stage endometrial cancer and atypical hyperplasia during/after fertility-sparing therapy, especially in overweighted or obese patients.

Declarations
Ethics approval and consent to participate    Figure 1 Infertility treatment after conservative treatment and reproductive outcomes. ART: assisted reproductive therapy; IVF: In vitro fertilization; ICSI: Intracytoplasmic Sperm Injection; OI: ovulation induction; IUI: Intrauterine insemination a: the pregnancy rate of Non-ART patients was not different from the ART patients (P=0.738); b: the livebirth rate of Non-ART patients was same as the ART patients (P=1.000).