Uterine-Conserving Treatment Options for Atypical Endometrial Hyperplasia and Early Endometrial Cancer.

The NCCN guidelines endorse universal molecular testing for EC depending on resource availability [ 9 ], due to its importance for treatment selection and prognostication. In 2013, The Cancer Genome Atlas (TCGA) published an analysis of molecular profiling of 373 EC cases and identified four categories: POLE -mutant, microsatellite-instable, copy-number low, and copy-number high [ 75 , 92 – 94 ]. The Proactive Molecular Risk Classifier for Endometrial Carcinoma (ProMisE), an algorithm based on TCGA-identified categories, is encouraged by the ESGO/ESHRE/ESGE guidelines for all young patients with low-grade EC who wish to preserve fertility [ 24 ]. However, current data on clinical applicability of ProMisE is limited. Response to progestin has not been correlated with EC molecular subtype [ 24 ], and molecular profiling of AEH in patients undergoing uterine-conserving treatment is not well established [ 2 ]. Britton et al. (2019) found the ProMisE molecular classification to be prognostic in individuals <50 years old with EC, based on strong associations with overall, disease-specific, and progression-free survival (p<0.0001 for all) [ 95 ]. In addition, ProMisE subtypes were associated with differences in measured clinicopathological parameters (race/ethnicity, grade, histotype, stage, and chemotherapy or radiation treatment) except for the presence of synchronous ovarian tumors and fertility [ 95 ]. Of note, progesterone therapies were used in only 16% (42/257) of the cohort and were given across all molecular subgroups except p53-abnormal EC [ 95 ]. Moreover, the microsatellite-instable subtype may have lower likelihood of response to progestin: in a case series of 84 patients with AEH or grade 1 EC, those with deficient mismatch repair protein expression had poorer response to progesterone [ 96 ]. Larger studies assessing progestin response across molecular subtypes are necessary. Molecular biomarkers that may correlate with resistance to progesterone therapy have been identified. In a prospective phase II trial, LNG-IUD non-responders had higher baseline proliferation (Ki-67) and lower dickkopf WNT signaling pathway inhibitor 3 ( DKK3 ) gene expression than responders (p=0.023 and 0.030, respectively) [ 14 ]. Non-responders also significantly differed in secreted frizzled-related protein 1 ( SFRP1 ), frizzled class receptor 8 ( FZD8 ), and retinaldehyde dehydrogenase 1 family member A2 ( RALDH2 ) expression levels at 3 months of treatment relative to baseline compared to responders [ 14 ]. A systematic review of 27 studies including 1,360 patients with EC treated with HT showed that ER and PR expression correlated with response to progesterone therapy [ 97 ]. Loss of PTEN expression in combination with low phosphorylated AKT expression conferred poor response [ 98 ]. Other identified biomarkers of response to progesterone therapy include dual-specificity phosphatase (DUSP6) and endoplasmic reticulum stress glucose-regulated protein 78 (GRP78) [ 99 ]. Further studies are needed to determine the best biomarkers for HT selection and predicting response in patients with AEH or early EC.

There is no consensus regarding clinical and pathologic factors that influence response to uterine-conserving treatment, given conflicting results [ 13 , 14 , 24 , 75 ]. Uterine size has been inversely related to response to progestin in AEH and early EC; however, this factor has not had a consistent impact across all studies [ 13 ]. In a phase II trial of patients treated with an LNG-IUD, Westin et al. (2021) found that the absence of an effect from exogenous progesterone in pathology specimens at 3 months was associated with a lack of response at 12 months of treatment [ 14 ]. Similarly, a retrospective analysis of LNG-IUD for treatment of AEH and early EC showed 100% of responders demonstrated pathologic evidence of an exogenous progesterone effect in contrast to only 50% of non-responders [ 13 ]. As a known risk factor for EC, obesity has also been implicated in treatment response and subsequent recurrence. Severe obesity (BMI > 40 kg/m 2 ) was associated with a 1.7-fold (1.02–3.07, p=0.042) increased risk of recurrence of EC compared to a BMI < 40 kg/m 2 in a retrospective multivariate analysis of 520 patients with EC followed between January 1996 and December 2018 [ 76 ]. Although baseline BMI was not predictive of response in the feMMe trial, LNG-IUD + weight loss demonstrated the highest CR at 6 months compared to LNG-IUD + observation or LNG-IUD + metformin (67% vs. 61% vs. 57%, respectively), though the study was not powered for statistical comparisons between arms [ 64 ]. Of note, all patients enrolled in the trial lost weight from baseline, with those in the weight loss arm losing the most weight (average 8.2 kg) [ 64 ]. Similarly, baseline BMI was not predictive of response to LNG-IUD at 12 months in the MIRENA trial, a prospective nonrandomized study of 71 patients with AEH or early EC with an average BMI of 48 kg/m 2 treated with LNG-IUD with or without bariatric surgery [ 77 ]. However, patients who lost more than 10% of their total body weight were more likely to respond to LNG-IUD (adjusted odds ratio 3.95, 95% CI 1.3–12.5, p=0.02) [ 77 ]. Interestingly, patients who lost weight either via bariatric surgery or calorie restriction demonstrated enhanced response to progestin therapy, suggesting that any weight loss is beneficial [ 77 ]. Aberrant progesterone receptor (PR) signaling, metabolic-immune-tumor microenvironment, and EC stem cells have been associated with progestin resistance [ 78 ]. PR expression is positively correlated with progestin response and prognosis of AEH and EC [ 78 , 79 ]. Overall response rates to progestin therapy were 72% vs. 12% among patients with high vs. low PR expression, respectively [ 80 ]. Progestin resistance has also been associated with overexpression of growth factors, including transforming growth factor (TGF) α/epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), and EGFR tyrosine kinase (EGFR-TK), as well as activation of the PI3K/AKT/mTOR pathway [ 81 – 83 ], all of which are involved in EC cell proliferation [ 78 ]. In addition, excessive estrogen production and imbalance of estrogen receptor (ER) subtypes have been implicated in progestin resistance [ 84 ]. The imbalance of estrogen and progesterone levels seen in obesity and PCOS could explain the higher risk of progestin resistance in these conditions [ 85 ]. In fact, a prospective study involving at least 12 weeks of oral MA at 160 mg/day reported significantly increased recurrence among patients with PCOS (p=0.015) [ 57 ]. Other clinical factors likely to be predictors of progestin response are under investigation [ 78 , 86 ].

Despite advances in conservative treatment of early EC, there are several unanswered questions regarding optimal dosing of progestins, alternative conservative options for non-responders to progestin, and the clinical applicability of molecular biomarkers for response to progestin [ 109 ]. Current ongoing clinical trials aim to address some of these unanswered questions. In particular, the role of weight loss in the response to conservative treatment of AEH and EC is under study. NCT04008563 is a trial investigating bariatric surgery as a weight loss intervention among obese young patients with AEH or EC [ 110 ]. Additionally, the ongoing LEVER Trial is investigating if everolimus (an mTOR inhibitor) is necessary to overcome progesterone resistance in patients with AEH and stage IA, grade 1 EC treated with the LNG-IUD ( NCT02397083 ). A comprehensive list of ongoing clinical trials is synthesized in Table 1 .

Indications for uterine-conserving treatment of AEH and early EC include the desire for childbearing, patient preference, severe obesity, and significant medical comorbidities resulting in poor surgical candidacy (e.g., advanced age, poor performance status, severe cardiopulmonary disease, etc.). The National Comprehensive Cancer Network (NCCN) guidelines recommend the following criteria for patient selection for uterine-conserving treatment: (1) grade 1 endometrioid EC with histology and grade confirmed on dilation and curettage (D&C), (2) tumor confined to the endometrium on imaging studies (magnetic resonance imaging [MRI] preferred), (3) no contraindications to HT, and (4) patient acceptance of non–standard of care management of EC [ 9 ]. Per the European Society of Gynaecological Oncology (ESGO), the European Society of Human Reproduction and Embryology (ESHRE), and the European Society for Gynaecological Endoscopy (ESGE) guidelines, patient selection for fertility-sparing treatment should factor in patients’ reproductive potential (e.g. age, markers of ovarian reserve, weight, and presence of PCOS), Lynch syndrome (LS) status, and clinicopathological characteristics of the tumor (e.g. stage, histology, myometrial invasion, and nodal involvement) [ 24 ]. The committee recommends a second opinion by an experienced histopathologist when fertility-sparing treatment is being considered [ 24 ]. Conservative treatment can be considered in patients with stage IA (by imaging), grade 1 endometrioid EC without myometrial invasion [ 9 , 24 – 27 ]. Fertility-sparing treatment in patients with grade 2 endometrioid EC should be discussed on an individual basis [ 24 , 28 , 29 ]. For patients with stage IB EC, worse survival outcomes have been reported for patients treated with HT compared to those treated with hysterectomy [ 25 ]. Patients with high-grade EC and myometrial invasion are ineligible for uterine preservation [ 30 ].

Diagnostic evaluation for AEH and EC includes a complete personal and family history, physical examination, imaging, and endometrial sampling. Imaging modalities often include transvaginal ultrasonography and MRI to assess endometrial thickness, myometrial invasion, cervical involvement, and adnexal involvement [ 31 – 33 ]. Prognostic factors of EC, including stage, grade, myometrial invasion, lymphovascular space invasion, and lymph node metastasis, are best evaluated surgically and pathologically after hysterectomy [ 2 , 34 ]. However, individuals considering uterine conservation should be evaluated for these prognostic factors using physical examination, MRI, and endometrial sampling [ 10 , 11 ]. The NCCN guidelines recommend endometrial sampling with either office-based Pipelle endometrial aspiration biopsy or D&C [ 9 ]. Although prior studies demonstrated that Pipelle endometrial biopsy has a sensitivity and specificity >90% for AEH and EC, newer data suggest that D&C has higher diagnostic accuracy for grade, with fewer grade 1 EC cases upgraded on hysterectomy after D&C compared with Pipelle biopsy (8.7% vs. 17.7%, respectively; p=0.007) [ 35 , 36 ]. Further, Kim et al. (2019) reported that endometrial aspiration biopsy had only moderate diagnostic concordance of 53.3% (8/15) compared to D&C [ 37 ]. Thus, patients considering uterine conservation should have a D&C for more accurate diagnosis [ 2 ]. Of note, the American College of Obstetricians and Gynecologists recently released a clinical consensus recommending hysteroscopic examination with D&C as the most accurate method for detecting a concurrent carcinoma among patients diagnosed with AEH [ 38 ]. ESGO/ESHRE/ESGE guidelines similarly state that confirmation of diagnosis using hysteroscopic-guided endometrial sampling is preferred [ 24 ]. However, hysteroscopy is currently not standard of care [ 39 ].

Uterine-conserving therapy can be safe and effective in appropriately selected patients with early endometrial neoplasia. Given the variability in reported oncologic and fertility outcomes, patients should be thoroughly counseled by a multidisciplinary team involving gynecologic oncologists, as well as reproductive endocrinology and fertility specialists if future childbearing is desired. Counseling should emphasize the balance between oncologic and fertility outcomes or surgical risk depending on the indication for uterine conservation. An individualized, shared-decision-making discussion involving patients and physicians should focus on the indication(s) for uterine conservation, risks for treatment failure, potential adverse effects of progestins, treatment alternatives, and a plan for surveillance. Adherence to treatment and close surveillance are key factors for ensuring patient safety. Further data are needed to enhance our understanding of the role of clinical factors, such as obesity, as well as molecular biomarkers in response to uterine-conserving treatment for patients with AEH or EC. Lastly, high-quality prospective studies and randomized controlled clinical trials are needed to address progestin resistance and strategies for optimizing progestin response.

The most accepted conservative treatment approach for AEH and early EC is HT. As hyperestrogenic signaling is a major driver for the development of AEH and endometrioid EC, progesterone therapy, which counteracts estrogen signaling, has been the focus of conservative management for AEH and early EC [ 2 , 19 , 40 , 41 ]. Commonly used progestins (synthetic progesterone-mimicking drugs) include medroxyprogesterone acetate (MPA), megestrol acetate (MA), and progestin-releasing intrauterine device (IUD) [ 9 ]. The optimal duration, dosing, and formulation of progestins and subsequent disease surveillance are under evaluation [ 8 , 10 ]. Evidence regarding clinical response rates and toxic effects associated with HT for AEH and early EC will be reviewed in the subsequent sections. MA and MPA are the recommended oral progestins for uterine-limited disease not suitable for primary surgery [ 9 ]. Typical dosing ranges from 10–400 mg/day for MA and 20–1500 mg/day for MPA, with MA at 160–320 mg/day and MPA at 400–600 mg/day frequently reported [ 42 ]. ESGO/ESHRE/ESGE’s recommended formulations for treatment of AEH and early EC are MA at 160–320 mg/day or MPA at 400–600 mg/day for 6–12 months, after which complete response (CR) should be achieved [ 24 ], defined by two consecutive endometrial biopsies at least 3 months apart with no evidence of disease [ 24 ]. There are limited data on the use of hydroxyprogesterone caproate, norethisterone acetate, natural progesterone, or combined oral contraceptives [ 24 ]. Contraindications to systemic progestins include venous thromboembolism, myocardial infarction, active smoking status, and breast cancer [ 9 ]. Oral progestin adherence rates are variable and influenced by toxic effects, including increased appetite, weight gain, abnormal uterine bleeding, hypertension, headaches, liver enzyme elevation, and nausea [ 39 , 43 – 46 ]. Progestins have been associated with higher response rates, lower recurrence rates, and lower rates of persistent disease in patients with initial diagnoses of AEH compared to EC [ 40 , 47 ]. Data on the efficacy of oral progestins are largely based on small studies with varying response rates of 75%−85% in AEH [ 10 , 40 , 43 , 47 – 50 ] and 50%−75% in EC [ 19 , 40 , 42 , 43 , 47 ]. Systematic reviews have shown MA to achieve higher remission rates compared to MPA and other HT, likely due to higher bioavailability [ 51 – 53 ]. Progestins yielded similar 5-year survival outcomes to those of hysterectomy among patients with stage IA EC in an analysis of 18,497 individuals <50 years old from the National Cancer Database during 2004–2014 [ 25 ]. Despite initial responses to progestins after a median of 4–6 months, recurrence rates of 23.2% and 35.4% have been reported for AEH and grade 1 EC, respectively, in a systematic review [ 40 ]. Similar results have been reported in prospective studies [ 43 , 54 – 56 ]. Ushijima et al (2007) reported CR rates of 82% (14/17) and 55% (12/22) following 26 weeks of treatment with MPA at 600 mg and low-dose aspirin daily for AEH and grade 1, stage IA EC, respectively [ 43 ]. Among those who demonstrated CR at 26 weeks, response was achieved by 8 weeks in 64% of AEH and 50% of EC, and by 16 weeks in 86% of AEH and 92% of EC. However, recurrence rates were 38% and 57% among patients with AEH and EC, respectively, with median progression-free intervals of 44.2 months in AEH and 34.6 months in EC [ 43 ]. In another prospective study utilizing hysteroscopy with endometrial curettage and at least 12 weeks of oral MA at 160 mg/day, 80.8% (21/26) of patients with AEH or EC responded to treatment after a median of 12 weeks, and 23% (6/26) experienced relapse [ 57 ]. For patients with residual cancer or residual AEH, the optimal duration of treatment remains unclear [ 10 ]. Longer duration of systemic progestin therapy in non-responders may contribute to further delay in performing hysterectomy, which may lead to worse prognosis [ 58 , 59 ]. Due to a localized effect and more tolerable toxicity profile compared to systemic progestins, the 52 mg levonorgestrel (LNG)-releasing IUD is in many cases a preferred uterine-conserving regimen for AEH and early EC [ 9 , 13 , 14 , 56 , 60 , 61 ]. Among several formulations of the LNG-IUD [ 62 ], the most investigated for AEH and EC has been the 52-mg LNG-IUD, which releases LNG at 21 μg/day after 24 days and decreases progressively to 11 μg/day after 5 years and 7 μg/day after 8 years [ 63 ]. Despite being approved to treat heavy menstrual bleeding for up to 5 years and for contraception for up to 8 years by the U.S. Food and Drug Administration [ 63 ], the optimal use of LNG-IUDs for treatment of AEH and early EC is unknown. Whereas the ESGO/ESHRE/ESGE guidelines recommend a treatment duration of 6–12 months, after which CR should be achieved [ 24 ], the NCCN guidelines encourage consideration of maintenance progestin-based therapy for longer durations in patients who demonstrate CR by 6 months and do not actively try to conceive [ 9 ]. The LNG-IUD has favorable outcomes for treatment of AEH and early EC either as monotherapy or in combination with other progestins [ 14 , 37 , 55 , 60 , 61 , 64 ]. In a single-institution, single-arm, prospective phase II trial of LNG-IUDs for treatment of AEH and grade 1 endometrioid EC, 12-month response rates of 91% (29/32) and 54% (8/15), respectively, were reported [ 14 ]. Notably, four patients (9.5%) had a relapse after the initial response. Adverse events related to the LNG-IUD were mild and mostly included irregular bleeding and cramping. Other prospective studies assessed the efficacy of LNG-IUDs with MPA at 500 mg/day among patients with early EC and showed 37.1% (13/35) CR and 25.7% (9/35) partial response rates at 6 months, as well as a CR rate of 87.9% at 9 months, with no reported treatment-related toxic effects [ 37 , 55 ]. Similar results have been demonstrated in retrospective studies [ 13 , 65 , 66 ]. It is, however, unclear if the combination therapy provides additional benefit compared to LNG-IUD alone. The feMMe trial evaluated the efficacy of an LNG-IUD with and without either metformin (500 mg twice daily) or weight loss among obese patients with AEH or EC [ 64 , 67 ]. For the 3-arm study within this phase II randomized controlled trial, patients were randomized to LNG-IUD + observation (n=35), LNG-IUD + weight loss (n=36), or LNG-IUD + metformin (n=47; 10 patients withdrew) [ 64 ]. The majority of patients were postmenopausal with an average age of 53 years and body mass index (BMI) of 48 kg/m 2 . CR rates at 6 months were 82% for patients with AEH and 43% for patients with stage I, grade 1 EC. Overall response rates were 61% for LNG-IUD alone, 67% for LNG-IUD + weight loss, and 57% for LNG-IUD + metformin. These response rates are likely lower than those of other studies because of the trial’s 6-month timepoint, as well as the inclusion of only complete responders in the analysis. The progression rates at 6 months were higher in the LNG-IUD + metformin arm (17%) compared to the LNG-IUD + weight loss arm (3%) and the LNG-IUD + observation arm (9%). Of note, the trial was not powered to compare outcomes between the different treatment arms. The use of regimens including metformin, gonadotropin-releasing hormone agonist (GnRHa), tamoxifen, letrozole, and anastrozole have been reported. Some studies have assessed the efficacy of agents that interfere with hormonal signaling such as GnRHa alone or in combination with an LNG-IUD, selective estrogen receptor modulators (e.g., tamoxifen), and aromatase inhibitors (e.g., letrozole, anastrozole) in the treatment of AEH and early EC [ 24 , 68 ]. Given inconsistent results from the use of tamoxifen in advanced-stage and recurrent EC, its use in early EC has been limited [ 24 ]. As previously mentioned, metformin has been used in combination with HT to treat AEH and early EC, given evidence of its effects on enhancing sensitivity to progesterone, improving insulin resistance, decreasing gluconeogenesis and circulating insulin levels, and inhibiting EC cell proliferation [ 15 , 69 – 72 ]. In a phase II randomized controlled trial, at the 36-month follow-up, metformin + MPA achieved a CR of 81% and recurrence rate of 10% among patients with AEH and stage IA, grade 1 EC [ 15 ]. Metformin + MA achieved a higher CR rate compared to MA alone at 16 weeks among patients with AEH (39.6% vs. 20.4%, p=0.032), though not for patients with stage IA, grade 1 EC (14.3% vs. 22.2%, p=0.63) [ 16 ]. Interestingly, the addition of metformin was beneficial in non-obese (CR 51.4% vs. 24.3%, p=0.02) and insulin-sensitive (CR 54.8% vs. 28.6%, p=0.04) patients with AEH, though not for those with obesity or insulin insensitivity [ 16 ]. Grade 1–2 gastrointestinal adverse events (e.g. diarrhea) were more common in the metformin + MA arm than in the MA-only arm (15.8% vs. 4.1%; p=0.03) [ 16 ]. Similarly, in the fEMMe trial, gastrointestinal adverse events of any grade were more common in the LNG-IUD + metformin arm compared to the other arms [ 64 ]. Gastrointestinal adverse events can limit metformin adherence. Lastly, GnRHa has been shown to achieve satisfactory response rates both as monotherapy and in combination with LNG-IUD or letrozole [ 60 , 68 , 73 , 74 ]. In a prospective observational study, the combination of LNG-IUD for 1 year and GnRHa for 6 months yielded CR rates of 95% (19/20) and 57.1% (8/14) among women ≤40 years old with AEH or early EC, respectively [ 60 ]. One patient (5%) with AEH and four patients (28%) with EC had disease progression [ 60 ]. Recurrence rates were 20% (4/20) for those with AEH and 14% (2/14) for those with EC, with an average relapse time of 36 months (range 16–62 months) [ 60 ]. Of note, patients included in this study were younger compared to other prospective studies involving the use of HT to treat AEH or early EC [ 14 , 60 , 64 ]. Another study retrospectively assessed patients with AEH or early EC who received monthly GnRHa injection plus LNG-IUD or letrozole at 2.5 mg/day. After a median follow-up of 18.7 months, 12/12 patients (100%) with AEH and 15/17 patients (88.2%) with early EC achieved CR [ 68 ]. Following CR, one patient with AEH had disease recurrence after 8.8 months, and one patient with early EC had disease recurrence after 28.9 months. Overall, the average time to remission was 3.3±0.9 months and 4.1±1.4 months in the AEH and early EC group, respectively, and the average time to CR was 4.5±1.9 months in the AEH group and 5.0±2.9 months in the EC group. The use of GnRHa was limited by bone-related adverse events.

Endometrial cancer (EC) is the only gynecologic malignancy with a rising incidence rate in the United States with 67,880 new cases and 13,250 deaths estimated in the U.S. in 2024 [ 1 ]. The median age at diagnosis of EC is 63 years, and because 67% of cases are localized to the uterus at diagnosis, patients experience a 5-year survival rate greater than 95% [ 2 ]. Atypical endometrial hyperplasia (AEH) is a precursor to endometrioid EC, the most common histologic subtype [ 3 ]. Twenty-nine percent of untreated AEH will progress to EC, and it is often a marker of malignancy, as more than 40% of women with AEH on biopsy had a diagnosis of EC on their subsequent hysterectomy specimen [ 4 ]. Risk factors for AEH and EC include obesity, unopposed estrogen exposure, polycystic ovary syndrome (PCOS)/chronic anovulation, tamoxifen exposure, and hyperinsulinemia, often secondary to insulin resistance [ 5 , 6 ]. The standard of care for both AEH and early EC is definitive surgical management: hysterectomy with or without bilateral salpingo-oophorectomy and staging [ 7 – 11 ]. Surgery, however, is not the optimal choice for certain patients: those who desire future childbearing, as well as those with severe obesity and/or multiple medical comorbidities, which may lead to high surgical risk [ 8 ]. Progestins, aromatase inhibitors (e.g., letrozole), and metformin in combination with other hormonal therapies (HT) have been explored as uterine-conserving treatment options for AEH and early EC [ 12 – 16 ]. However, the decision to pursue uterine conservation must be carefully considered since AEH and EC have high recurrence rates [ 17 – 19 ]. In reproductive-age individuals, the pursuit of future childbearing must be weighed against optimizing oncologic outcomes. Given this tension between definitive surgical management and fertility preservation, several scientific societies have emphasized carefully counseling patients about limitations of fertility preservation, including the need for future hysterectomy [ 20 – 22 ]. The American Society of Clinical Oncology (ASCO) recommends discussion of the risk of infertility, fertility preservation, and referral to a fertility specialist if indicated soon after cancer diagnosis [ 23 ]. This review critically evaluates published literature and guidelines on uterine-conserving management of AEH and early EC by discussing patient selection, efficacy and safety of current treatment options, surveillance, and the role of molecular profiling. We will also summarize current evidence on oncologic and fertility outcomes.

AEH and EC in reproductive-age individuals can present a dilemma, as most of these patients carry risk factors for endometrial neoplasia that are also associated with infertility. As such, ESGO/ESHRE/ESGE guidelines recommend the consideration of patients’ reproductive potential (e.g., age, markers of ovarian reserve) when discussing fertility-sparing treatment [ 24 ]. Similarly, the ASCO clinical practice guidelines emphasize referral to fertility specialists for patients who express desire for childbearing and those who are ambivalent, as well as referral to psychological providers for those distressed about potential infertility [ 23 ]. Patients with AEH or EC who opt for uterine-conserving treatment to pursue childbearing have several options for achieving pregnancy. Patients without other risk factors for infertility can attempt spontaneous conception, while patients with risk factors for infertility such as obesity, PCOS, and endometriosis can pursue assisted reproductive technologies [ 24 ]. Oocyte cryopreservation, embryo cryopreservation, in vitro maturation, and gestational surrogacy are available options in the U.S., though limited by cost, with varying pregnancy and live birth rates [ 2 ]. There is a paucity of data regarding reproductive outcomes following uterine-conserving therapy for AEH or EC. Several retrospective studies and systematic reviews have been published [ 40 , 47 , 87 – 89 ]. In a systematic review by Gunderson et al. (2012), following progestin therapy, 41.2% of patients with AEH and 34.8% with EC achieved pregnancy (p=0.39) [ 40 ]. Wei et al. (2017) reported live birth rates of 20%, 14%, and 35% after treatment with oral progestins (MPA or MA), LNG-IUD, and oral progestin + LNG-IUD, respectively, in a meta-analysis of 1,038 patients with AEH or early EC [ 89 ]. A large cohort study by Harrison et al. (2019), which included 421 patients with AEH or EC, demonstrated a live birth rate of only 11.6%, of which 50% resulted from assisted reproductive technologies [ 88 ]. While the previous studies lacked information on fertility outcomes among only patients who attempted to conceive, the largest prospective study with fertility outcome data for patients with stage IA, grade 1–2 EC (n=28) treated with hysteroscopic resection plus MA or LNG-IUD reported a pregnancy rate of 93% with an 86% live birth rate among those who attempted to conceive [ 54 ]. In a smaller prospective study involving treatment of AEH and EC with MA, only 8/26 patients attempted to conceive after CR; two spontaneous conceptions and one live birth resulted [ 57 ]. Although the possibility has been raised, any adverse impact of fertility treatments on recurrence remains to be demonstrated. Patients who received fertility treatments demonstrated a similar 5-year disease-free survival rate compared to those who did not [ 90 ]. In fact, among patients who received assisted reproductive technologies, those who had a live birth demonstrated lower risk of recurrence compared to those who did not achieve a live birth [ 90 , 91 ]. The optimal timing for progestin therapy and attempting pregnancy to enhance live birth rate while minimizing risk of recurrence is unclear. Importantly, the role of inequitable access to infertility treatments needs to be further explored.

Surveillance for AEH and early EC managed conservatively should include interval endometrial sampling to monitor response to therapy and progression of disease or recurrence [ 2 ]. The NCCN guidelines recommend endometrial sampling every 3–6 months with either office-based Pipelle endometrial biopsy or D&C [ 9 ]. At our institution, patients with AEH or early EC who desire conservative management receive progesterone therapy until negative endometrial biopsies are achieved for a duration of 6–12 months. Treatment is then discontinued with close follow-up for those who desire to attempt pregnancy [ 13 ]. Patients who achieve a CR and desire childbearing should be encouraged to not delay attempting pregnancy [ 9 , 31 ]. Following childbearing, patients and physicians have a shared-decision-making discussion about whether to perform hysterectomy. Patients are then followed with surveillance for symptoms indicative of recurrence [ 13 ]. Maintenance therapy with systemic progestin or LNG-IUD is encouraged for patients who do not pursue childbearing [ 31 ]. Repeat pelvic MRI to exclude myometrial invasion and nodal involvement is recommended for patients who do not experience a response to HT after 6 months [ 9 ]. If AEH or early EC persists after 6–12 months of progesterone therapy, hysterectomy with surgical staging is recommended [ 9 ]. Ovarian preservation can be considered in selected premenopausal patients who have normal-appearing ovaries and no history of hereditary breast and ovarian cancer syndrome or LS [ 9 ]. For patients experiencing non-response, disease progression/recurrence, inability to conceive, or after childbearing regardless of response, ESGO/ESHRE/ESGE guidelines recommend definitive surgical management [ 24 ]. Responders can continue conservative treatment, though duration has not been specified given the substantial recurrence rates reported. Surveillance should include clinical pelvic examination, pelvic ultrasonography, and endometrial sampling every 3–6 months [ 24 ].

Although EC often arises from sporadic mutations, 5%−9% of cases in patients <50 years old are due to LS-associated mutations [ 100 , 101 ]. Patients with LS tend to be diagnosed with EC at a younger age (mean age 47–49 years) [ 102 , 103 ]. Due to the earlier onset of EC in patients with LS, fertility preservation is particularly relevant. However, the efficacy of uterine-conserving therapies in this patient population is unclear, and current knowledge is based mainly on case reports and retrospective studies [ 104 ]. Among women with LS, use of hormonal contraceptives conferred decreased risk for EC compared with never use (incidence rate 0.22 vs. 0.45 per 100 person-years, p<0.001), suggesting the utility for progestins as risk reduction against EC for women with LS [ 105 ]. Further, a prospective multicenter trial of 51 women with LS found that progestin alone, regardless of route of administration, demonstrated a protective effect on the endometrium by reducing endometrial epithelial proliferation [ 106 ]. Germline genetic testing and genetic counseling are recommended for individuals with risk factors for LS, including a strong family history of endometrial and/or colorectal cancer and a personal diagnosis of cancer (especially endometrial, colon, or ovarian) before age 50 years [ 107 , 108 ]. Per ESGO/ESHRE/ESGE guidelines, among patients with LS, (1) the presence of any concurrent cancer should be determined, (2) patients should be informed about their higher risk of disease persistence/recurrence, and (3) fertility-sparing treatment should be discussed on a case-by-case basis [ 24 ].