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Clinical outcomes of levonorgestrel-releasing intrauterine device present during controlled ovarian stimulation in patients with early stage endometrioid adenocarcinoma and atypical endometrial hyperplasia after fertility-sparing treatments: 10-year experience in one tertiary hospital in China

  • Author Footnotes
    2 Co-first author.
    Jie Yin
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    2 Co-first author.
    Affiliations
    Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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  • Author Footnotes
    2 Co-first author.
    Yan Li
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    2 Co-first author.
    Affiliations
    Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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    2 Co-first author.
    Hanbi Wang
    Footnotes
    2 Co-first author.
    Affiliations
    Gynecological Endocrine and Assisted Reproduction Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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  • Wei Wang
    Affiliations
    Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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  • Yu Gu
    Affiliations
    Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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  • Ying Jin
    Affiliations
    Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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  • Author Footnotes
    1 Authors contributed equally to this work.
    Chengyan Deng
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    1 Authors contributed equally to this work.
    Affiliations
    Gynecological Endocrine and Assisted Reproduction Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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    1 Authors contributed equally to this work.
    Lingya Pan
    Correspondence
    Corresponding author at: Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College (CAMS & PUMC), 1 Shuai Fu Yuan, Beijing, China.
    Footnotes
    1 Authors contributed equally to this work.
    Affiliations
    Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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  • Author Footnotes
    1 Authors contributed equally to this work.
    2 Co-first author.
Open AccessPublished:November 10, 2022DOI:https://doi.org/10.1016/j.ejogrb.2022.11.009

      Abstract

      Background

      To evaluate the oncologic and pregnancy outcomes of patients with early stage endometrioid adenocarcinoma (EMC) and atypical endometrial hyperplasia (AEH) treated with controlled ovarian stimulation (COS) with or without levonorgestrel-releasing intrauterine device (LNG-IUD) after fertility-sparing treatment (FSTs).

      Methods

      A total of 67 patients with EMC or AEH who achieved complete response after FSTs and underwent COS between January 2010 and December 2019 were retrospectively reviewed. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for recurrence after COS.

      Results

      The average age was 32.9 ± 3.46 years. 23.9 % of these patients relapsed after COS during the follow-up period. The 2-year cumulative recurrence rate was 14.9 % (9.1 % and 20.6 % in the LNG-IUD and control groups, respectively). Compared with the control group, the recurrence rate was lower in patients with LNG-IUDs present during COS (12.1 % vs 35.5 %, p = 0.027). The clinical pregnancy (42.4 % vs 52.9 %, p = 0.392) and live birth (21.2 % vs 29.4 %, p = 0.444) rates were similar between the LNG-IUD and control groups. Age, body mass index (BMI), histology, FST type and time to complete response were not related to prognosis after COS. After adjusting for age and BMI in a multivariate Cox regression model, the use of LNG-IUD during COS was a favorable factor for better oncologic outcomes after COS (HR 0.263, 95 %CI 0.084–0.822, p = 0.022).

      Conclusions

      Patients with early stage EMC and AEH treated with assisted reproductive technology after FSTs might benefit from LNG-IUDs present during COS.

      Keywords

      Introduction

      Endometrial cancer (EC) is the second most common gynecological malignant cancer. A trend of increasing incidence of EC in young patients has emerged, with approximately 5 % of cases occurring in women younger than 40 years of age [
      • Gao J.
      • Yang G.
      • Wen W.
      • Cai Q.Y.
      • Zheng W.
      • Shu X.O.
      • et al.
      Impact of known risk factors on endometrial cancer burden in Chinese women.
      ,
      • Wright J.D.
      • Barrena Medel N.I.
      • Sehouli J.
      • Fujiwara K.
      • Herzog T.J.
      Contemporary management of endometrial cancer.
      ]. Endometrioid adenocarcinoma (EMC) is the main pathological and histological type of EC, and atypical endometrial hyperplasia (AEH) is considered a precursor of EMC. Hysterectomy is the standard treatment for EMC and AEH. Bilateral salpingo-oophorectomy with or without regional lymphadenectomy is also required for EMC. Early stage EMC and AEH have favorable oncological prognoses. Fertility-sparing treatments (FSTs) are appropriate for young patients with stage Ia, Grade1 (G1), EMC [
      • Gallo A.
      • Catena U.
      • Saccone G.
      • Di Spiezio S.A.
      Conservative surgery in endometrial cancer.
      ,

      NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). National Comprehensive Cancer Network; Plymouth, PA, USA: 2021 Uterine Neoplasmas, Version 3 2021. 2021.

      ,
      • Gullo G.
      • Etrusco A.
      • Cucinella G.
      • Perino A.
      • Chiantera V.
      • Lagana A.S.
      • et al.
      Fertility-sparing approach in women affected by stage i and low-grade endometrial carcinoma: an updated overview.
      ]. High-dose progestins have been used as FSTs for AEH and early stage EMC since 1985 [
      • Bokhman J.V.
      • Chepick O.F.
      • Volkova A.T.
      • Vishnevsky A.S.
      Can primary endometrial carcinoma stage I be cured without surgery and radiation therapy?.
      ]. In general, there are several different types of treatments, including high doses of medroxyprogesterone acetate (MPA), megestrol acetate (MA), and gonadotropin-releasing hormone agonists (GnRHa) [
      • Ramirez P.T.
      • Frumovitz M.
      • Bodurka D.C.
      • Sun C.C.
      • Levenback C.
      Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review.
      ,
      • Jadoul P.
      • Donnez J.
      Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma.
      ]. A levonorgestrel-releasing intrauterine device (LNG-IUD) is also used to treat AEH and EMC, alone or in combination with oral progestins and GnRHa. “Three steps” hysteroscopic technique followed by progestin was first described by Mazzon et al. [
      • Mazzon I.
      • Corrado G.
      • Morricone D.
      • Scambia G.
      Reproductive preservation for treatment of stage IA endometrial cancer in a young woman: hysteroscopic resection.
      ]. In addition, letrozole combined with GnRHa is also used in young patients with early stage EMC and AEH [
      • Zhou H.
      • Cao D.
      • Yang J.
      • Shen K.
      • Lang J.
      Gonadotropin-releasing hormone agonist combined with a levonorgestrel-releasing intrauterine system or letrozole for fertility-preserving treatment of endometrial carcinoma and complex atypical hyperplasia in young women.
      ].
      Nearly 75–85 % of patients with AEH and 50–75 % of those with EMC achieve complete response (CR) [
      • Gunderson C.C.
      • Fader A.N.
      • Carson K.A.
      • Bristow R.E.
      Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review.
      ]. The CR rate varies with different FSTs. The CR rates of oral progestins alone, LNG-IUD alone, and hysteroscopic resection followed by progestin therapy were reported to be 76.3 %, 72.9 %, and 95.3 %, respectively [
      • Fan Z.
      • Li H.
      • Hu R.
      • Liu Y.
      • Liu X.
      • Gu L.
      Fertility-preserving treatment in young women with grade 1 presumed stage IA endometrial adenocarcinoma: a meta-analysis.
      ]. High disease recurrence after FSTs is the primary clinical problem. A meta-analysis found that 12- and 24-month recurrence probabilities were 9.6 % and 29.2 %, respectively [
      • Koskas M.
      • Uzan J.
      • Luton D.
      • Rouzier R.
      • Darai E.
      Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis.
      ]. In another prospective study, recurrence rates were 26 % and 36 % for AEH and EC, respectively. The recurrence rates in women taking oral progestins alone, using LNG-IUDs alone, and hysteroscopic resection followed by progestin therapy were 30.7 %, 11.0 %, and 14.4 %, respectively [
      • Fan Z.
      • Li H.
      • Hu R.
      • Liu Y.
      • Liu X.
      • Gu L.
      Fertility-preserving treatment in young women with grade 1 presumed stage IA endometrial adenocarcinoma: a meta-analysis.
      ].
      Pregnancy should be encouraged as early as possible after FSTs. The pregnancy rate has been reported to be approximately 18–34 %. More encouraging pregnancy rates in women taking LNG-IUDs (56 %), oral progestins alone (52.1 %), and hysteroscopic resection combined with progestins (47.8 %) have also been reported [
      • Gallo A.
      • Catena U.
      • Saccone G.
      • Di Spiezio S.A.
      Conservative surgery in endometrial cancer.
      ,
      • Fan Z.
      • Li H.
      • Hu R.
      • Liu Y.
      • Liu X.
      • Gu L.
      Fertility-preserving treatment in young women with grade 1 presumed stage IA endometrial adenocarcinoma: a meta-analysis.
      ]. The pregnancy and live birth rates of those treated with assisted reproductive technologies were 75 % and 50 %, respectively [
      • Elizur S.E.
      • Beiner M.E.
      • Korach J.
      • Weiser A.
      • Ben-Baruch G.
      • Dor J.
      Outcome of in vitro fertilization treatment in infertile women conservatively treated for endometrial adenocarcinoma.
      ]. However, the effect of controlled ovarian stimulation on oncologic outcomes in patients with EMC or AEH is still unknown.
      LNG-IUDs provide local release of high-dose LNG with few systemic side effects and do not affect cycle performance (including total oocytes, mature oocytes, clinical pregnancy rate, and live birth rate) in women undergoing ovarian stimulation cycles [
      • Adeleye A.J.
      • Aghajanova L.
      • Kao C.N.
      • Cedars M.I.
      • Sauer M.V.
      Impact of the levonorgestrel-releasing intrauterine device on controlled ovarian stimulation outcomes.
      ]. LNG-IUDs, placed as maintenance therapy after CR in patients with EMC or AEH, could decrease the recurrence rate [
      • Yin J.
      • Ma S.
      • Shan Y.
      • Wang Y.
      • Li Y.
      • Jin Y.
      • et al.
      Risk factors for recurrence in patients with atypical endometrial hyperplasia and endometrioid adenocarcinoma after fertility-sparing treatments.
      ]. Therefore, during the past 10 years, some patients were encouraged to receive controlled ovarian stimulation (COS) with LNG-IUDs (as a maintenance therapy after FSTs) as soon as possible. The intrauterine device was then removed, and the endometrium was evaluated when sufficient blastocysts were collected and/or decisions on frozen embryo transplantations were made. If no pathological EMC or AEH was diagnosed, frozen embryo transfer (FET) was performed.
      In this study, the clinical records of patients who received COS with or without LNG-IUDs after FSTs in our hospital were reviewed, and the oncologic and pregnancy outcomes were reported.

      Methods

      Study design and patients

      This retrospective cohort study followed the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Peking Union Medical College Hospital (PUMCH, Beijing, China, No. I-22PJ002, approval date: 26th May 2022). There was no conflict of interests for the patients, and this work did not involve personal privacy; therefore, the requirement for written informed consent was waived. The medical records of patients with early stage EMC and AEH who underwent FSTs between January 2010 and December 2019 were reviewed. Pathologic diagnosis for all patients was performed by two experienced gynecologic pathologists. The inclusion criteria were as follows: (i) age ≤40 years; (ii) curettage was performed under hysteroscopy and Grade 1-phase, EMC or atypical endometrial hyperplasia (AEH) was diagnosed by histopathological examination; and (iii) EMC patients who were all presumed to be in the early stage (Stage Ia, according to the 2009 staging system of the International Federation of Gynecology and Obstetrics) through imaging. Diseases limited to the endometrium were diagnosed using transvaginal ultrasound or MRI. The absence of suspicious or metastatic distance was evaluated using CT; (iv) patients who had been treated with MA, MPA, or GnRHa. Some patients received oral progestins or GnRHa combined with Letrozole [
      • Zhou H.
      • Cao D.
      • Yang J.
      • Shen K.
      • Lang J.
      Gonadotropin-releasing hormone agonist combined with a levonorgestrel-releasing intrauterine system or letrozole for fertility-preserving treatment of endometrial carcinoma and complex atypical hyperplasia in young women.
      ] or LNG-IUDs at a certain time point during the treatment process. The choice of treatment and use of letrozole or LNG-IUDs was based on the advice given by the professors in charge. Curettage under hysteroscopy was performed every 3 months to evaluate the disease. Patients who were diagnosed with pathological CR received consolidation therapy for 3 months, then underwent COS in the IVF unit; (v) patients who received COS through the administration of gonadotropin (Gn) and/or GnRHa, which are gonadotropin-releasing hormone agonist and gonadotropin-releasing hormone antagonist, respectively, in the IVF unit after FSTs; and (vi) patients who were regularly followed up in the outpatient department or by telephone. The oncologic and pregnancy outcomes were assessed. Maintenance therapies, such as regular oral progestins and LNG-IUDs, were supplied until pregnancy or frozen embryo transfer was ready. Maintenance therapies were also suggested after the pregnancy was complete. Transvaginal ultrasound was performed every 3 months, endometrial biopsy was performed every 6 months after CR and pregnancy was completed. CR was defined as the absence of atypia on pathological examination. Disease recurrence was diagnosed on the basis of pathology.
      Patients with LNG-IUDs present during COS were placed into the LNG-IUD group, and the others into the control group. The primary endpoint was disease recurrence after COS or at the end of the follow-up period. The secondary endpoints were clinical pregnancy and live birth. Progression-free survival (PFS) was defined as the time (months) from the date of the first treatment to the date of recurrence or the final follow-up. Disease-free survival (DFS) since COS started was defined as the time (months) from the beginning of COS to the date of recurrence or final follow-up. According to the guidelines for the prevention and control of overweight and obesity in Chinese adults approved by the Division of Disease Control, Ministry of Health of the People’s Republic of China, BMI ≥28 kg/m2 and 24–27 kg/m2 are defined as obese and overweight, respectively, and <24 kg/m2 is normal [
      • DODC
      • MOH
      • PRC
      The guideline for prevention and control of overweight and obesity in Chinese adults.
      ]. Clinical pregnancy was defined by fetal heart activity documented on ultrasound examination–5–6 weeks after embryo transfer. The time to live birth was defined as the interval between the beginning of COS and live births.

      Statistical analysis

      Categorical variables are presented as n (%). Continuous variables are described as mean ± SD or median ± SD. The chi-squared and Fisher’s exact tests were used to assess categorical data. A t-test was used to compare continuous data that conformed to a normal distribution. Univariate and multivariate Cox regression analyses were used to detect risk factors of recurrence since COS started. Hazard ratios (HR) were calculated.

      Results

      Comparations of general clinical characteristics between LNG-IUD group and control group

      A total of 156 patients with AEH and early stage EMC who underwent FSTs achieved CR between January 2010 and December 2019. Among them, 94 patients had pregnancy plans, including 23 with natural conception, 4 with clomiphene or letrozole. Ultimately, 67 patients received COS through administration of Gn and/or GnRHa in the IVF units. Thirty-three patients were divided into the LNG-IUD group and 34 into the control group, as described in the methods section. The classification tree of all patients is shown in the Supplementary Fig. 1. The general clinical characteristics of the patients are presented in Table 1. Among them, 62 patients received COS in our PUMCH IVF unit, and their COS details were collected. Five patients who were treated in other IVF units were followed up by telephone. The median follow-up time was 49.4 months (range: 24–87 months; Table 1).
      Table 1Comparisons of general clinical features of LNG-IUD group and control group.
      VariableTotalLNG-IUD group (n = 33)Control group (n = 34)P value
      (n = 67)
      Age (mean ± SD, year)32.9 ± 3.4632.6 ± 3.5533.2 ± 3.390.46
      Follow-up time49.5 ± 15.9448.0 ± 12.34 (25-71)56.5 ± 18.11 (16-87)0.946
       (median ± SD, range, months)(24–87)
      Body mass index (BMI, kg/m2)0.796
       <2421(31.3%)11(33.3%)10(29.4%)
       ≥2446(68.7%)22(66.7%)24(70.6%)
      Histology0.022
       AEH33(49.3%)11(33.3%)22(64.7%)
       EMC34(50.7%)22(66.7%)12(35.3%)
      Type of FSTs0.26
       MA33(49.3%)14(42.4%)19(55.9%)
       MPA6(9.0%)2(6.1%)4(11.8%)
       GnRH agonist28(41.8%)17(51.5%)11(32.4%)
      Time to CR (months)0.399
       311(16.4%)7(21.2%)4(11.8%)
       625(37.3%)10(30.3%)15(44.1%)
       >631(46.3%)16(48.5%)15(44.1%)
      Interval between CR to COS starting (months)0.09
       ≤627(40.3%)18(54.5%)9(26.5%)
       07-Dec22(32.8%)10(30.3%)12(35.3%)
       >1218(26.9%)5(15.2%)13(38.2%)
      Cycles of COS*0.721
       Mean ± SD1.58 ± 0.991.72 ± 1.081.44 ± 0.89
       <353(67.1%)26(83.9%)27(87.1%)
       ≥39(11.4%)5(16.1%)4(12.9%)
      COS protocol0.843
       GnRH agonist long-protocol53(52.5%)29(53.7%)24(51.1%)
       GnRH antagonist protocol48(47.5%)26(46.3%)23(48.9%)
      E2 peak during COS2751.0 ± 1849.42540.2 ± 1696.52998.4 ± 2004.80.219
      (mean ± SD, pg/ml)
      Endometrial thickness at HCG day (mean ± SD, mm)8.1 ± 2.56.5 ± 1.59.9 ± 2.30
      *Five patients underwent COS in other IVF units. Oncologic and pregnancy outcomes were obtained via telephone. The distributions of age and follow-up time in the two groups were normal and t-tests were used. Abbreviations: AEH, atypical endometrial hyperplasia; EMC, endometrioid adenocarcinoma; COS, controlled ovarian stimulation; MA, megestrol acetate; MPA, medroxyprogesterone acetate; GnRH, gonadotropin-releasing hormone; SD, standard deviation; CR, complete response; HCG, human chorionic gonadotropin.
      Thirty-four of the 67 patients were diagnosed with EMC; 22 were placed in the LNG-IUD group, and 12 in the control group. The proportion of EMC in the LNG-IUD group was higher than that in the control group (66.7 % vs 35.3 %, p = 0.022, Table 1). There were no significant differences between the two groups in other general clinical features, including age, BMI, follow-up time, type of FSTs, time to CR, interval between CR and COS initiation, cycles of COS, COS protocol, and E2 peak during COS (Table 1). The thickness of the endometrium on HCG day was also monitored, and there was a significant difference between the two groups (p = 0.000, Table 1).

      Comparison of oncologic and pregnancy outcomes between LNG-IUD group and control group

      The median PFS and DFS after COS initiation for all 67 patients were 46 and 29 months, respectively. 16 of 67 patients (23.9 %) experienced disease recurrence during the follow-up period. The 2-year cumulative recurrence rate after initiation of COS was 14.9 % (Table 2). Compared with the control group, the recurrence rate (12.1 % vs 35.3 %) was lower in the LNG-IUD group during the follow-up period, although more patients with EC were involved. This difference was significant (p = 0.027, Table 2). The 2-year cumulative recurrence rate since COS was started in the two groups was 9.1 % (3 of 33 patients, LNG-IUD group) and 20.6 % (7 of 34 patients in the control group), respectively, but there was no significant difference (p = 0.305, Table 2). The log-rank test was used to analyze PFS and DFS since COS initiation. The median PFS and DFS since COS started in the LNG-IUD group were not reached. There was no difference in PFS between the two groups. The DFS since COS started varied significantly depending on the use of LNG-IUD during COS (p = 0.016).
      Table 2Comparison of oncologic and pregnancy outcomes between the LNG-IUD group and control group.
      Total

      n (%, 67 patients)
      LNG-IUD group

      n (%, 33 patients)
      Control group

      n (%, 34 patients)
      P value
      Oncologic outcome
       Disease recurrence16(23.9%)4(12.1%)12(35.3%)0.027
       2-year cumulative recurrence rate since COS started10(14.9%)3(9.1%)7(20.6%)0.305
      Fisher test was used. #Log-rank test was performed PFS, progression-free survival; DFS, disease-free survival.
      PFS (months)0.077#
       Median (range)46(16–82)Not been reached75(22–82)
       Mean ± SD46.6 ± 15.0(18–71)

      65.2 ± 2.674
      62.0 ± 4.171
      DFS since COS started (months)
       Median (range)29(2–51)Not been reachedNot been reached
       Mean ± SD28.1 ± 13.349(3–51)

      46.0 ± 2.352
      (8–50)

      36.4 ± 3.002
      0.016#
      Pregnancy outcome
       Clinical pregnancy32(47.8%)14(42.4%)18(52.9%)0.392
       Live birth17(25.4%)7(21.2%)10(29.4%)0.444
      Time to live birth (months)0.219#
       Median (range)15(10–48)22(12–48)12(10-28)
       Mean ± SD17.5 ± 10.23724 ± 1.78917 ± 6.828
      * Fisher test was used. #Log-rank test was performed PFS, progression-free survival; DFS, disease-free survival.
      In total, 32 of 67 patients (47.8 %) successfully reached clinical pregnancy and 25.4 % (17 of 67 patients) had live births. The median time to live birth was 15 months (Table 2). In the LNG-IUD group, an artificial cycle of estradiol valerate tablets and progesterone injection was used for the FET. Up to the end of the follow-up period, 22 of the 33 patients underwent FET. The median time between the egg retrieval date and FET start date was 4.5 months (range, 1–32 months). In the control group, 25 (73.5 %) patients underwent fresh embryo transfer. The reasons for delayed embryo transfer were OHSS (17.6 %), adenomyosis (5.9 %), and a thin endometrium (3.0 %). 15 of the 34 patients underwent FET to improve pregnancy. At the final follow-up, the clinical pregnancy rate (42.4 % vs 52.9 %, p = 0.392) and live birth rate (21.2 % vs 29.4 %, p = 0.444) during the follow-up period were similar between the LNG-IUD and control groups.

      Risk factors for recurrence after COS

      Several probable high-risk factors for disease recurrence were further analyzed through univariate regression, such as age, BMI, histology, type of FSTs, time to CR, interval between CR and COS initiation, cycles of COS, use of LNG-IUD during COS, clinical pregnancy, and live birth (Table 3). Age, BMI, histology (AEH vs EMC), type of FSTs, time to CR, and the interval between CR and COS were unrelated to disease recurrence after COS (Table 3, Fig. 1A and B, Supplementary Table 1). Use of LNG-IUDs during COS might improve oncologic outcomes after COS (HR 3.662, 95 %CI 1.178–11.384, p = 0.025, Table 3). When LNG-IUDs were used during COS, the disease recurrence HR after COS was 0.273 (95 %CI 0.088–0.849, p = 0.025) (Fig. 1B).
      Table 3Univariate Cox regression analyses of risk factors for recurrence since COS started.
      VariableHR (95 %CI)P value
      Age1.051 (0.906–1.220)0.510
      BMI2.227 (0.828–5.990)0.113
      Histology0.842 (0.315–2.247)0.731
      Type of FSTs1.106 (0.662–1.846)0.701
      Time to CR1.100 (0.582–2.080)0.768
      Interval between CR to COS started1.643 (0.869–3.108)0.127
      Cycles of COS0.387 (0.050–2.983)0.362
      LNG-IUD present during COS3.662 (1.178–11.384)0.025
      Clinical pregnancy0.926(0.347–2.476)0.879
      Live birth1.766 (0.499–6.245)0.378
      Abbreviations: HR, hazard ratio; CI, confidence interval; BMI, body mass index; CR, complete response; COS, controlled ovarian stimulation; LNG-IUD, levonorgestrel-releasing intrauterine device.
      Figure thumbnail gr1
      Fig. 1Univariate Cox regression analysis of risk factors (including age, BMI and LNG-IUD) for PFS and DFS since COS started. A, age (<35 years vs ≥35 years), BMI (<24 kg/m2 vs ≥24 kg/m2) and LNG-IUD present during COS (yes vs no) were not correlated with PFS. B, LNG-IUD present during COS might significantly improve prognosis after COS starting (HR 0.273, 95 %CI 0.088–0.849), compared with control group. Age (<35 years vs ≥35 years), BMI (<24 kg/m2 vs ≥24 kg/m2) were not risk factors for DFS since COS started.
      In a multivariable model (Table 4), when age and BMI were adjusted, the use of LNG-IUD during COS was still a favorable factor for improving oncologic outcomes after COS (HR 0.263, 95 %CI 0.084–0.822, p = 0.022).
      Table 4Multivariate Cox regression model analyses of risk factors for prognosis since COS started.
      VariableΒ estimateHR (95 % CI)P value
      Age
       <35 years0.1441.154 (0.369–3.616)0.805
       ≥35 yearsreference
      BMI
       <24−0.8740.417 (0.155–1.125)0.084
       ≥24reference
      LNG-IUD present during COS
       Yes−1.3350.263 (0.084–0.822)0.022
       Noreference
      HR was mutually adjusted for the other variables in the table. Difference was considered statistically significant at p < 0.05. Abbreviations: HR, hazard ratio; CI, confidence interval.

      Discussion

      In this study, we present a retrospective cohort study to evaluate the clinical outcomes of the use of LNG-IUDs during COS in patients with early stage EMC or AEH after fertility-sparing treatments, and the risk factors for disease recurrence after COS. The oncologic outcome was the primary endpoint of this study. The recurrence rate significantly decreased when LNG-IUDs were present during COS. The use of LNG-IUDs during COS might be a favorable factor for improving prognosis after COS initiation. Based on our results, age, BMI, histology (AEH vs EMC), type of FSTs, and number of cycles of COS were not correlated with recurrence after COS.
      Fertility-sparing treatment in young patients with early stage endometrioid adenocarcinoma or atypical endometrial hyperplasia who desire to preserve their fertility is an accepted concept today. The disease can be completely relieved by progestin or GnRHa treatment. The response rates of endometrial cancer to LNG-IUDs are consistent with the response rates reported for oral progestins [
      • Gunderson C.C.
      • Fader A.N.
      • Carson K.A.
      • Bristow R.E.
      Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review.
      ,
      • Pal N.
      • Broaddus R.R.
      • Urbauer D.L.
      • Balakrishnan N.
      • Milbourne A.
      • Schmeler K.M.
      • et al.
      Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device.
      ]. However, the disease recurrence rate of FSTs is relatively high (nearly 25 %), and its probability increases continually with time [
      • Koskas M.
      • Uzan J.
      • Luton D.
      • Rouzier R.
      • Darai E.
      Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis.
      ,
      • Perri T.
      • Korach J.
      • Gotlieb W.H.
      • Beiner M.
      • Meirow D.
      • Friedman E.
      • et al.
      Prolonged conservative treatment of endometrial cancer patients: more than 1 pregnancy can be achieved.
      ,
      • Yu M.
      • Yang J.X.
      • Wu M.
      • Lang J.H.
      • Huo Z.
      • Shen K.
      Fertility-preserving treatment in young women with well-differentiated endometrial carcinoma and severe atypical hyperplasia of endometrium.
      ,
      • Ushijima K.
      • Yahata H.
      • Yoshikawa H.
      • Konishi I.
      • Yasugi T.
      • Saito T.
      • et al.
      Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women.
      ]. Long-term monitoring and regular evaluation are crucial. Regular administration of oral progestin or use of LNG-IUDs after FSTs and birth can significantly improve prognosis [
      • Yin J.
      • Ma S.
      • Shan Y.
      • Wang Y.
      • Li Y.
      • Jin Y.
      • et al.
      Risk factors for recurrence in patients with atypical endometrial hyperplasia and endometrioid adenocarcinoma after fertility-sparing treatments.
      ,
      • Novikova O.V.
      • Nosov V.B.
      • Panov V.A.
      • Novikova E.G.
      • Krasnopolskaya K.V.
      • Andreeva Y.Y.
      • et al.
      Live births and maintenance with levonorgestrel IUD improve disease-free survival after fertility-sparing treatment of atypical hyperplasia and early endometrial cancer.
      ]. In addition, lower recurrence rates (<10 %) have also been reported in patients with the three-step hysteroscopic resection technique followed by progestins [
      • Yang B.
      • Xu Y.
      • Zhu Q.
      • Xie L.
      • Shan W.
      • Ning C.
      • et al.
      Treatment efficiency of comprehensive hysteroscopic evaluation and lesion resection combined with progestin therapy in young women with endometrial atypical hyperplasia and endometrial cancer.
      ,
      • Giampaolino P.
      • Di Spiezio S.A.
      • Mollo A.
      • Raffone A.
      • Travaglino A.
      • Boccellino A.
      • et al.
      Hysteroscopic endometrial focal resection followed by levonorgestrel intrauterine device insertion as a fertility-sparing treatment of atypical endometrial hyperplasia and early endometrial cancer: a retrospective study.
      ]. Extension of treatment time by 3–6 months can decrease recurrence, and is safe and reasonable [
      • Pal N.
      • Broaddus R.R.
      • Urbauer D.L.
      • Balakrishnan N.
      • Milbourne A.
      • Schmeler K.M.
      • et al.
      Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device.
      ]. In this study, hysteroscopic resection was not used routinely, but all patients received 3-month consolidation therapy and maintenance treatments with LNG-IUDs or regular oral progestin to prevent disease recurrence after CR.
      Pregnancy and live births are the final goals of FSTs. Although the CR rates of fertility-sparing treatments are above 85 %, the pregnancy and live birth rates are still far from satisfactory (approximately 54 % and 42 %, respectively) [
      • Pal N.
      • Broaddus R.R.
      • Urbauer D.L.
      • Balakrishnan N.
      • Milbourne A.
      • Schmeler K.M.
      • et al.
      Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device.
      ,
      • Yang B.
      • Xu Y.
      • Zhu Q.
      • Xie L.
      • Shan W.
      • Ning C.
      • et al.
      Treatment efficiency of comprehensive hysteroscopic evaluation and lesion resection combined with progestin therapy in young women with endometrial atypical hyperplasia and endometrial cancer.
      ,
      • Giampaolino P.
      • Di Spiezio S.A.
      • Mollo A.
      • Raffone A.
      • Travaglino A.
      • Boccellino A.
      • et al.
      Hysteroscopic endometrial focal resection followed by levonorgestrel intrauterine device insertion as a fertility-sparing treatment of atypical endometrial hyperplasia and early endometrial cancer: a retrospective study.
      ,
      • Yang B.Y.
      • Gulinazi Y.
      • Du Y.
      • Ning C.C.
      • Cheng Y.L.
      • Shan W.W.
      • et al.
      Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial.
      ]. Some studies reported improved birth rate with assistant reproduction treatments (ARTs) [
      • Wang Y.
      • Zhou R.
      • Wang H.
      • Liu H.
      • Wang J.
      Impact of treatment duration in fertility-preserving management of endometrial cancer or atypical endometrial hyperplasia.
      ,
      • Park J.Y.
      • Seong S.J.
      • Kim T.J.
      • Kim J.W.
      • Kim S.M.
      • Bae D.S.
      • et al.
      Pregnancy outcomes after fertility-sparing management in young women with early endometrial cancer.
      ]. In our hospital, patients are encouraged to receive ARTs to conceive as soon as possible after FSTs. The effects of ARTs on oncologic outcomes were not mentioned in these studies. There are doubts about ARTs’ risk of long-term recurrence because of few clinical case reports [
      • Elizur S.E.
      • Beiner M.E.
      • Korach J.
      • Weiser A.
      • Ben-Baruch G.
      • Dor J.
      Outcome of in vitro fertilization treatment in infertile women conservatively treated for endometrial adenocarcinoma.
      ,
      • Rasool N.
      • Rose P.G.
      Fertility-preserving surgical procedures for patients with gynecologic malignancies.
      ]. Estrogen elevation during ovulation induction is presumed to be a probable risk factor for EC progression or recurrence. The use of letrozole in conjunction with Gn for COS was reported to prevent high estrogen levels [
      • Azim A.
      • Oktay K.
      Letrozole for ovulation induction and fertility preservation by embryo cryopreservation in young women with endometrial carcinoma.
      ], and ARTs did not result in increased disease recurrence [
      • Fan Y.
      • Li X.
      • Wang J.
      • Wang Y.
      • Tian L.
      • Wang J.
      Analysis of pregnancy-associated factors after fertility-sparing therapy in young women with early stage endometrial cancer or atypical endometrial hyperplasia.
      ]. Some retrospective cohort studies have also reported that LNG-IUDs did not affect cycle performance in women undergoing ovarian stimulation cycles [
      • Adeleye A.J.
      • Aghajanova L.
      • Kao C.N.
      • Cedars M.I.
      • Sauer M.V.
      Impact of the levonorgestrel-releasing intrauterine device on controlled ovarian stimulation outcomes.
      ]. Furthermore, clinical pregnancy and live birth rates are not affected by the presence of LNG-IUDs [
      • Cakmak H.
      • Katz A.
      • Cedars M.I.
      • Rosen M.P.
      Effective method for emergency fertility preservation: random-start controlled ovarian stimulation.
      ,
      • Soderstrom-Anttila V.
      • Tiitinen A.
      • Hovatta O.
      Levonorgestrel-releasing intrauterine device can be used in oocyte donors during ovarian stimulation.
      ]. Based on these findings, we suggest that patients who chose LNG-IUDs as maintenance therapy after FSTs to retain the IUD during COS. Reasonable endometrial thickness during COS illustrates the local effectiveness of LNG-IUDs in the uterus. Here, common COS protocols were used, and the mean E2 peak was lower than 3000 pg/ml in both the LNG-IUD and control groups. Among the 67 patients, the total recurrence rate (23.9 %) was similar to that reported in other published studies. However, the total live birth rate (25.4 %) in the present study was low. The small sample size and short follow-up time may be the main reasons for this finding. If new cycles of COS followed by fresh embryo transfer or FET are continued, the pregnancy outcomes might be improved. LNG-IUDs present during COS do not affect both clinical pregnancy and live birth rates but might prolong the time to live birth based on the results in this study. Removal of IUDs and pathological evaluation of endometrium after COS may delay FETs. So, use of LNG-IUD during COS might be a potential factor for longer time to live birth.
      It is worth noting that LNG-IUDs used during COS could significantly decrease recurrence. In our opinion, effective oncology monitoring by transvaginal ultrasound during COS and opportune pathological evaluation of the endometrium before frozen embryo transplantation are also the advantages of the use of LNG-IUDs during COS. However, a longer time to live birth is the main limitation of LNG-IUDs during COS.
      To our knowledge, this is the first single-center study to report the oncologic outcomes of early stage EMC and AEH with the use of LNG-IUDs during COS after fertility-sparing treatments with the largest sample thus far. This study has demonstrated that the use of LNG-IUDs during COS is a favorable factor for the prognosis of patients with EMC or AEH after COS in clinical settings, which is a novel finding. Here, we reported 10-years’ experience of fertility preservation in patients with EMC and AEH in our center.
      Our study also has some limitations, including its retrospective study design, single-center design, small sample size, and short follow-up time. In addition, the median DFS since COS started in the LNG-IUD and control groups was not reached during the follow-up period. Moreover, several questions remain unanswered. These include: Is it necessary for all patients to wear LNG-IUDs during COS? The patients should be layered based on a larger sample size. After pregnancy is completed with ART, how can the endometrium, ultrasound, MRI, or diagnostic curettage be monitored every 6 months? Should different COS protocols be used for different patients? More clinical experience is needed, and a cohort study with a larger sample size should be designed to answer these questions.
      LNG-IUDs can be used during COS to improve the oncologic outcomes of patients with EMC and AEH after FSTs.

      Conclusion

      Early stage EMC and AEH patients treated with assisted reproductive technology after FSTs might benefit from the use of LNG-IUDs during COS.

      Author contributions

      Conception: Lingya Pan, Chengyan Deng
      Data curation: Jie Yin, Hanbi Wang, Chengyan Deng
      Formal analysis: Jie Yin
      Funding acquisition: Lingya Pan, Chengyan Deng
      Investigation: Jie Yin, Yan Li, Hanbi Wang
      Methodology: Lingya Pan, Yan Li, Hanbi Wang, Chengyan Deng, Wei Wang, Yu Gu, Ying Jin
      Project administration: Lingya pan, Chengyan Deng
      Supervision: Lingya Pan, Chengyan Deng
      Validation: Yan Li, Hanbi Wang
      Visualization: Yan Li, Hanbi Wang
      Roles/Writing – original draft: Jie Yin
      Writing – review & editing: Lingya Pan

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We thank all patients who contributed to this study. The work is not supported by any funding.

      References

        • Gao J.
        • Yang G.
        • Wen W.
        • Cai Q.Y.
        • Zheng W.
        • Shu X.O.
        • et al.
        Impact of known risk factors on endometrial cancer burden in Chinese women.
        Eur J Cancer Prev. 2016; 25: 329-334
        • Wright J.D.
        • Barrena Medel N.I.
        • Sehouli J.
        • Fujiwara K.
        • Herzog T.J.
        Contemporary management of endometrial cancer.
        Lancet. 2012; 379: 1352-1360
        • Gallo A.
        • Catena U.
        • Saccone G.
        • Di Spiezio S.A.
        Conservative surgery in endometrial cancer.
        J Clin Med. 2021; 11
      1. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). National Comprehensive Cancer Network; Plymouth, PA, USA: 2021 Uterine Neoplasmas, Version 3 2021. 2021.

        • Gullo G.
        • Etrusco A.
        • Cucinella G.
        • Perino A.
        • Chiantera V.
        • Lagana A.S.
        • et al.
        Fertility-sparing approach in women affected by stage i and low-grade endometrial carcinoma: an updated overview.
        Int J Mol Sci. 2021; 22
        • Bokhman J.V.
        • Chepick O.F.
        • Volkova A.T.
        • Vishnevsky A.S.
        Can primary endometrial carcinoma stage I be cured without surgery and radiation therapy?.
        Gynecol Oncol. 1985; 20: 139-155
        • Ramirez P.T.
        • Frumovitz M.
        • Bodurka D.C.
        • Sun C.C.
        • Levenback C.
        Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review.
        Gynecol Oncol. 2004; 95: 133-138
        • Jadoul P.
        • Donnez J.
        Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma.
        Fertil Steril. 2003; 80: 1315-1324
        • Mazzon I.
        • Corrado G.
        • Morricone D.
        • Scambia G.
        Reproductive preservation for treatment of stage IA endometrial cancer in a young woman: hysteroscopic resection.
        Int J Gynecol Cancer. 2005; 15: 974-978
        • Zhou H.
        • Cao D.
        • Yang J.
        • Shen K.
        • Lang J.
        Gonadotropin-releasing hormone agonist combined with a levonorgestrel-releasing intrauterine system or letrozole for fertility-preserving treatment of endometrial carcinoma and complex atypical hyperplasia in young women.
        Int J Gynecol Cancer. 2017; 27: 1178-1182
        • Gunderson C.C.
        • Fader A.N.
        • Carson K.A.
        • Bristow R.E.
        Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review.
        Gynecol Oncol. 2012; 125: 477-482
        • Fan Z.
        • Li H.
        • Hu R.
        • Liu Y.
        • Liu X.
        • Gu L.
        Fertility-preserving treatment in young women with grade 1 presumed stage IA endometrial adenocarcinoma: a meta-analysis.
        Int J Gynecol Cancer. 2018; 28: 385-393
        • Koskas M.
        • Uzan J.
        • Luton D.
        • Rouzier R.
        • Darai E.
        Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis.
        Fertil Steril. 2014; 101: 785-794
        • Elizur S.E.
        • Beiner M.E.
        • Korach J.
        • Weiser A.
        • Ben-Baruch G.
        • Dor J.
        Outcome of in vitro fertilization treatment in infertile women conservatively treated for endometrial adenocarcinoma.
        Fertil Steril. 2007; 88: 1562-1567
        • Adeleye A.J.
        • Aghajanova L.
        • Kao C.N.
        • Cedars M.I.
        • Sauer M.V.
        Impact of the levonorgestrel-releasing intrauterine device on controlled ovarian stimulation outcomes.
        Fertil Steril. 2018; 110: 83-88
        • Yin J.
        • Ma S.
        • Shan Y.
        • Wang Y.
        • Li Y.
        • Jin Y.
        • et al.
        Risk factors for recurrence in patients with atypical endometrial hyperplasia and endometrioid adenocarcinoma after fertility-sparing treatments.
        Cancer Prev Res (Phila). 2020; 13: 403-410
        • DODC
        • MOH
        • PRC
        The guideline for prevention and control of overweight and obesity in Chinese adults.
        Acta Nutrienta Sinica. 2004; 26 (Article in Chinese): 1-4
        • Pal N.
        • Broaddus R.R.
        • Urbauer D.L.
        • Balakrishnan N.
        • Milbourne A.
        • Schmeler K.M.
        • et al.
        Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device.
        Obstet Gynecol. 2018; 131: 109-116
        • Perri T.
        • Korach J.
        • Gotlieb W.H.
        • Beiner M.
        • Meirow D.
        • Friedman E.
        • et al.
        Prolonged conservative treatment of endometrial cancer patients: more than 1 pregnancy can be achieved.
        Int J Gynecol Cancer. 2011; 21: 72-78
        • Yu M.
        • Yang J.X.
        • Wu M.
        • Lang J.H.
        • Huo Z.
        • Shen K.
        Fertility-preserving treatment in young women with well-differentiated endometrial carcinoma and severe atypical hyperplasia of endometrium.
        Fertil Steril. 2009; 92: 2122-2124
        • Ushijima K.
        • Yahata H.
        • Yoshikawa H.
        • Konishi I.
        • Yasugi T.
        • Saito T.
        • et al.
        Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women.
        J Clin Oncol. 2007; 25: 2798-2803
        • Novikova O.V.
        • Nosov V.B.
        • Panov V.A.
        • Novikova E.G.
        • Krasnopolskaya K.V.
        • Andreeva Y.Y.
        • et al.
        Live births and maintenance with levonorgestrel IUD improve disease-free survival after fertility-sparing treatment of atypical hyperplasia and early endometrial cancer.
        Gynecol Oncol. 2021; 161: 152-159
        • Yang B.
        • Xu Y.
        • Zhu Q.
        • Xie L.
        • Shan W.
        • Ning C.
        • et al.
        Treatment efficiency of comprehensive hysteroscopic evaluation and lesion resection combined with progestin therapy in young women with endometrial atypical hyperplasia and endometrial cancer.
        Gynecol Oncol. 2019; 153: 55-62
        • Giampaolino P.
        • Di Spiezio S.A.
        • Mollo A.
        • Raffone A.
        • Travaglino A.
        • Boccellino A.
        • et al.
        Hysteroscopic endometrial focal resection followed by levonorgestrel intrauterine device insertion as a fertility-sparing treatment of atypical endometrial hyperplasia and early endometrial cancer: a retrospective study.
        J Minim Invasive Gynecol. 2019; 26: 648-656
        • Yang B.Y.
        • Gulinazi Y.
        • Du Y.
        • Ning C.C.
        • Cheng Y.L.
        • Shan W.W.
        • et al.
        Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial.
        BJOG. 2020; 127: 848-857
        • Wang Y.
        • Zhou R.
        • Wang H.
        • Liu H.
        • Wang J.
        Impact of treatment duration in fertility-preserving management of endometrial cancer or atypical endometrial hyperplasia.
        Int J Gynecol Cancer. 2019; 29: 699-704
        • Park J.Y.
        • Seong S.J.
        • Kim T.J.
        • Kim J.W.
        • Kim S.M.
        • Bae D.S.
        • et al.
        Pregnancy outcomes after fertility-sparing management in young women with early endometrial cancer.
        Obstet Gynecol. 2013; 121: 136-142
        • Rasool N.
        • Rose P.G.
        Fertility-preserving surgical procedures for patients with gynecologic malignancies.
        Clin Obstet Gynecol. 2010; 53: 804-814
        • Azim A.
        • Oktay K.
        Letrozole for ovulation induction and fertility preservation by embryo cryopreservation in young women with endometrial carcinoma.
        Fertil Steril. 2007; 88: 657-664
        • Fan Y.
        • Li X.
        • Wang J.
        • Wang Y.
        • Tian L.
        • Wang J.
        Analysis of pregnancy-associated factors after fertility-sparing therapy in young women with early stage endometrial cancer or atypical endometrial hyperplasia.
        Reprod Biol Endocrinol. 2021; 19: 118
        • Cakmak H.
        • Katz A.
        • Cedars M.I.
        • Rosen M.P.
        Effective method for emergency fertility preservation: random-start controlled ovarian stimulation.
        Fertil Steril. 2013; 100: 1673-1680
        • Soderstrom-Anttila V.
        • Tiitinen A.
        • Hovatta O.
        Levonorgestrel-releasing intrauterine device can be used in oocyte donors during ovarian stimulation.
        Hum Reprod. 1997; 12: 491-495