FST relies primarily on progestin therapy, administered via oral or intrauterine routes. The most commonly prescribed oral agents are megestrol acetate (MA) and medroxyprogesterone acetate (MPA), while the NCCN guidelines designate the levonorgestrel-releasing intrauterine system (LNG IUS) as the preferred option. Combination therapy with LNG-IUS and oral progestins may also be considered in selected patients [2][19].

Oral progestin dosing varies widely across FST protocols. MPA is typically 400 - 600 mg/day, with reported ranges from 80 - 1000 mg/day, while MA is used at 160 - 320 mg/day with ranges of 40 and 800 mg/day [19][20].

LNG-IUS delivers approximately 20 mcg/day of levonorgestrel directly to the endometrium. A 2020 Cochrane review comparing LNG-IUS with oral progestins for endometrial hyperplasia found LNG-IUS to be associated with higher regression rates (RR 1.21, 95% CI 1.01 - 1.46), though the certainty of evidence was low [21]. The American College of Obstetricians and Gynecologists (ACOG) similarly notes that intrauterine progestins may achieve higher regression rates compared with oral therapy [22]. A 2025 Cochrane review further suggests that combining LNG-IUS with oral progestins improves complete response rates over oral therapy alone, though definitive evidence remains limited [23]. Compared with oral agents, LNG-IUS is associated with fewer systemic side effects, including weight gain, and depression, and it may improve patient adherence to treatment [21][22].

Beyond progestin therapy, several adjunctive strategies have been investigated. Hysteroscopic resection followed by progestin therapy has demonstrated CR rates exceeding 90% with lower recurrence rates [24]. Metformin combined with progestins has been shown to improve response rates, with particular benefit in patients with insulin resistance or metabolic syndrome [23][25]. Gonadotropin-releasing hormone agonists (GnRH-a) represent an additional option, particularly in obese patients, with some studies reporting longer progression free survival compared with oral progestins alone [26].

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising adjunct to progestin-based FST. Originally developed for type 2 diabetes, GLP-1 Ras have attracted growing interest in EC research given that GLP-1 receptors are expressed in both benign and malignant endometrial tissue. These agents activate cAMP-PKA and AMPK-mTOR pathways, exerting antiproliferative and proapoptotic effects [27]. Kanda et al. (2018) demonstrated that liraglutide inhibits tumor growth and induces autophagy via AMPK, with high GLP-1R expression correlating with positive ER/PR status and improved survival [28]. Hagemann et al. (2025) reported that semaglutide combined with levonorgestrel reduces tumor viability in organoid models, and semaglutide has also been shown to upregulate progesterone receptors, a mechanism that may help overcome progestin resistance [27][29].

Clinical evidence for GLP-1RAs in EC is growing but remains mixed. Dai et al. (2025) reported an association between GLP-1RA use and reduced EC risk in obese adults [30]. In the FST setting, Hsieh et al. (2026) demonstrated that GLP-1RA combined with progestin significantly reduced hysterectomy rates compared with progestin alone at 18 months (10.2% vs. 23.4%; HR 0.41, 95% CI 0.29 - 0.58) [31] and Yen et al. (2026) similarly confirmed a reduced EC risk with this combination [32]. Conversely, a meta-analysis by Ko et al. (2025) found little effect on EC risk [33]. Prospective trials are warranted to define the role of GLP-1Ras in FST [27].

Reported CR rates vary by treatment modality and patient characteristics. Pooled analyses report CR rates of 76% - 85% for early stage EC [34]-[36], with even higher rates in AEH patients, where pooled CR rate of 85.6% has been reported [35]. Notably, CR probability continues to increase up to 24 months, suggesting that longer treatment duration may be appropriate in selected patients [37].

Median time to CR ranges from 6 to 12 months, though some patients require extended treatment [22][37][38]. Peng et al. (2024) demonstrated that time to CR varies significantly by molecular subtype, with POLEmut tumors achieving CR most rapidly (median 3.0 months) and MMRd tumors requiring the longest duration (median 7.9 months) [39].

Despite its potential benefits, FST carries inherent risks that must be addressed with patients. Although CR rates are high in selected candidates, response varies by histology, molecular subtype, and treatment approach [5][38]. About 10% - 30% of patients fail to achieve CR with initial therapy [37][38].

Recurrence after CR remains a major concern, with reported rates ranging from 20% to 40% [35][38][40]. Gallos et al. reported relapse rates between 26% and 41%, varying by initial diagnosis (AEH vs EC) [35]. Even among patients receiving progestin maintenance therapy, recurrence rates at 24 months can reach 31.3% [37].

Table 2 summarizes the risk factors for recurrence.

Table 2. Risk factors for recurrence.

Disease progression during FST requires strict surveillance, with reported rates ranging from 1.9% to 16.6%. Higher progression rates are observed in patients with grade 2 tumors or superficial myometrial invasion [20][40], and pre-treatment tumor size ≥ 2 cm has been independently associated with risk of disease progression (HR 5.456; 95% CI 1.34 - 22.14) [40].

Although progestin-based FST is generally well tolerated, adverse events should be discussed when counseling patients. Weight gain is the most common grade 3-4 event associated with oral progestin therapy [21][23], while LNG-IUS is associated with higher rates of irregular bleeding or spotting but lower rates of nausea and weight gain compared with oral progestins [21][23]. Thromboembolic events are rare but are of particular concern in obese patients or those with additional thrombotic risk factors [22][38]. Other common reported effects include mood changes, headache, and breast tenderness [21][22].

Given these risks, FST patients require intensive surveillance in accordance with current clinical guidelines. Endometrial evaluation should be performed every 3-6 months via hysteroscopy with directed biopsy, dilation and curettage (D&C), or office endometrial biopsy [2][12][22]. Magnetic resonance imaging (MRI) or transvaginal ultrasound (TVUS) is used to assess myometrial invasion and disease extent at baseline and during follow-up [38][41]-[44]. If disease persists after 6 months, escalation to dual-progestin therapy or alternative regimens should be considered [2]. Failure to achieve CR within 9 - 12 months, or evidence of disease progression at any time, warrants definitive surgical management [2][13].

Following CR, patients should be encouraged to pursue conception, with continued sampling every 3 - 6 months [2][13][22]. Referral to assisted reproductive technology (ART) centers is recommended to maximize pregnancy outcomes, as live birth rates are higher with ART (39.4%) than with spontaneous conception (14.9%) [22]. For patients who do not wish to conceive, maintenance progestin-based therapy is associated with improved disease-free survival, with LNG-IUS representing the preferred option [2][42].

After completing childbearing, TH/BSO and surgical staging is strongly recommended [2][38][45], as completion hysterectomy has been associated with improved oncologic outcomes, including one study reporting 0% recurrence with surgery vs. 22.4% without (p = 0.055) [45]. Ovarian preservation may be considered in carefully selected premenopausal patients with stage IA grade 1 endometrioid carcinoma, normal-appearing ovaries, no family history of ovarian cancer or Lynch syndrome, and absence of high-risk features such as p53 abnormality, MMRd, lymphovascular space invasion (LVSI), or positive cytology [2]. Patients who decline hysterectomy require lifelong surveillance with endometrial sampling every 6 - 12 months [2][22].

POLE-mutated tumors represent a small subset of early-stage EC, with reported prevalence ranging from 7% to 12% and a pooled prevalence of 5.8% [9][39][46]. Several studies include few or no POLEmut cases within FST cohorts, and these tumors demonstrate paradoxical outcomes in the FST setting, contrasting sharply with their excellent prognosis following definitive surgical management [47][48].

Figure 3. Distribution of TCGA molecular groups according to FST candidates (low-grade endometrioid tumors). Adapted from [14].

Table 3. Molecular subtypes and FST outcomes.

The largest meta-analysis to date (Ferrari et al., 2025; n = 363) reported a CR rate of 66.6% and a recurrence rate of 14.3% among POLEmut tumors treated with FST [9]. Outcomes across Individual studies are highly variable; small cohorts report CR rates of 100% (n = 5), while others describe progression rates of up to 50% during treatment [46][49]. Peng et al. (2024) similarly reported a 100% CR rate in POLEmut tumors, though this finding was based on only five patients; notably, this subgroup also demonstrated the shortest median time to CR at 3 months [12].

In the Ferrari meta-analysis, POLEmut tumors did not demonstrate superior treatment outcomes compared with other molecular subgroups. This paradox, excellent surgical prognosis alongside inconsistent hormonal response, suggests that these tumors may not be as hormone-sensitive as previously hypothesized. ESGO/ESHRE/ESGE guidelines acknowledge that the role of FST in POLEmut tumors remains uncertain, and that additional evidence is required before firm recommendations can be established [13].

MMRd tumors account for 9% - 25% of ECs in FST cohorts and are characterized by deficiencies in the DNA mismatch repair system. Emerging evidence suggests that MMRd status may be a potent predictor for progestin resistance with these tumors demonstrating lower CR rates at 33-71%, a longer median time to CR of 7.9 months, and high recurrence rates from 42% to 100% [1][5][9][14][39][50][51].

A 2024 meta-analysis by Zhang et al., evaluating MSI-H/MMRd tumors (66 patients from 10 studies), confirmed these findings reporting a CR rate of 61.8% and recurrence rate of 41.2%. Among 12 patients with Lynch syndrome, 75% achieved CR; however, 77.8% subsequently experienced disease recurrence [51]. Chung et al. (2020) were among the first to demonstrate the influence of MMR status on FST outcomes, reporting significantly lower CR rates at 6 months in MMRd tumors compared with p53 wild-type tumors (11.1% vs. 53.3%; p = 0.010); four of nine MMRd patients required immediate hysterectomy due to treatment failure, and three had upstaged disease at surgery [50]. The Ferrari meta-analysis (2025; n = 363 patients) further confirmed lower CR rates and higher recurrence rates in MMRd tumors compared with NSMP tumors (p < 0.001 and p = 0.01, respectively) [9].

The mechanisms underlying poor MMRd response to FST remain incompletely understood. MMRd tumors frequently exhibit low estrogen and progesterone receptor expression, which limits hormone therapy [50][52][53]. Some studies suggest that mismatch repair deficiency may interact with ARID1A loss, a tumor suppressor gene alteration that may contribute to progestin resistance [7][52]. It was also hypothesized that the elevated mutational burden of these tumors may activate alternative oncogenic pathways that are less dependent on hormone receptor signaling [6][53][54].

Lynch syndrome patients warrant focused consideration, as germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) confer distinct clinical behavior. Catena et al. (2022) highlighted prognostic differences between sporadic MMRd and Lynch syndrome-associated tumors, noting that while all Lynch syndrome patients in their cohort responded to FST, none achieved pregnancy and all experienced recurrence [43]. These findings support the potential benefit of universal MMR screening in EC patients and underscore the importance of genetic counseling and enhanced surveillance in this population [2].

In light of these findings, ESGO/ESTRO/ESP guidelines recommend caution when offering FST to MMRd patients, limiting its use to carefully selected cases with close monitoring given the elevated risk of disease progression [13].

MMRd tumors also exhibit the highest rates of PD-L1 positivity among EC molecular subtypes [55]. Although immune checkpoint inhibitors are not currently part of standard fertility-sparing management, they represent a promising therapeutic strategy for progestin-resistant MMRd cases [50]. The impact of these agents on fertility preservation and subsequent pregnancy outcomes remains an important area of research [54].

The p53abn subtype is characterized by a high copy-number genomic profile and aggressive clinical behavior [56], with a prevalence of 2% - 8% in FST cohorts [5][9][14][39][57]. Abnormal p53 expression is associated with the worst oncologic outcomes among EC molecular subtypes, including high recurrence rates and increased progestin resistance [1][58], with reported CR rates of 33%-55% and recurrence rates from 30% - 100% [1][5][9][57].

Peng et al. (2024) reported a median time to CR of 3.5 months in patients with p53abn tumors, shorter than the 7.9 months observed in MMRd tumors, though small sample sizes limit the interpretation of this finding [39].

Clinical data in this subtype remains limited given its rarity in fertility-sparing cohorts. Due to the aggressive tumor biology and elevated risk of disease progression, FST is generally not recommended for p53abn tumors, a position reflected in ESGO/ESTRO/ESP, NCCN, and ESMO guidelines, which uniformly classify p53abn as the highest-risk molecular group [2][6][11][13].

The p53 wild-type (p53wt), also referred to as the no specific molecular profile (NSMP) group, represents the majority of low-grade endometrioid carcinomas, accounting for 64-86.7% of FST cases. This subtype demonstrates the highest CR rates and lowest recurrence rates among all molecular subtypes with the Ferrari meta-analysis (2025) reporting a CR rate of 78.4% and a recurrence rate of 18.4% [9], consistent with other studies reporting CR rates of 72% to 92% and recurrence rates of 14% to 20% [1][5][39][50][57][59].

Although response variation within this subgroup likely reflects its underlying biological heterogeneity [6], the consistently high CR and low recurrence rates support current FST protocols and establish p53wt/NSMP tumors as the most suitable candidates for fertility preservation [1][9]. However, the conclusions on NSMP as the best FST group and p53abn should be viewed cautiously, as the current studies are small, and mainly retrospective cohorts.

Emerging data support extending FST consideration to selected patients with superficial myometrial invasion or grade 2 histology under strict surveillance. The GORILLA-2001 study Lee et al. (2023) demonstrated feasibility in stage I grade 2 EC without myometrial invasion, and in grade 1 - 2 tumors with superficial myometrial invasion [40] and Centini et al. (2025) further discussed potential expansion of FST eligibility criteria to these categories [3].

NSMP tumors typically harbor mutations in PTEN, PIK3CA, KRAS, and CTNNB1 [49][60][61] and present as low-grade, endometrioid, hormone receptor-positive tumors well-suited to progestin-based FST [14][62]. However, their biological heterogeneity has prompted ongoing research into refining biomarkers, including CTNNB1 mutations or L1CAM expression, to improve risk stratification and treatment outcomes [6][44][60].

PTEN

PTEN is a tumor suppressor gene whose inactivation is a key driver of endometrioid EC, with somatic mutations occurring in 70 to 80% of these tumors [63]-[65]. Through its role in the PI3K/AKT signaling pathway, PTEN loss has been associated with progestin resistance [52].

The impact of PTEN mutations on FST outcomes remains unclear, with existing studies reporting mixed results. A 2018 meta-analysis by Travaglino et al. found that PTEN loss did not significantly affect therapy failure (RR = 1.24, 95% CI 0.88 - 1.76; p = 0.21) [66], while Xu et al. (2023) reported an association between PTEN mutation and lower CR rates (HR 0.61, 95% CI 0.38 - 0.98; p = 0.046) [49]. Hirano et al. (2025) further reported longer times to CR in patients harboring these mutations [60].

PIK3CA

PIK3CA is among the most frequently mutated genes in EC, with TCGA data reporting a prevalence of 52% [67]. PIK3CA and PTEN mutations commonly co-occur, reflecting their shared involvement in the PI3K/AKT signaling pathway [68]. In the FST setting, PIK3CA mutations have been associated with prolonged time to CR and potentially lower CR rates [49][60], though further studies are needed to confirm these findings.

KRAS

KRAS mutations occur in 16% - 20% of endometrioid EC and have been implicated in tumor initiation, progression, and invasion [61][69][70]. While KRAS mutations do not appear to significantly influence CR rates, recent studies have reported a meaningful association with increased risk of disease progression during FST [49][61].

CTNNB1

CTNNB1 mutations occur in up to 50% of grade 1 - 2 ECs and are particularly prevalent in the NSMP molecular subgroup [6]. These mutations may cooperate with PTEN and KRAS alterations and have been associated with increased tumor proliferation and disease progression [61].

Ruz-Caracuel et al. (2021) demonstrated that CTNNB1 exon 3 mutations were independently associated with reduced disease-free survival in low-grade, early-stage tumors (p = 0.010), regardless of FIGO stage, tumor grade, MMR status, or LVSI [71]. Although the role of CTNNB1 mutations in FST has not yet been fully established, they represent a promising tool for refining risk stratification within the biologically heterogeneous NSMP subgroup [6].

ARID1A

ARID1A is a tumor suppressor gene mutated in approximately 40% of endometrioid EC cases, and its loss of function has been associated with MLH1 epigenetic silencing and microsatellite instability (MSI) [72][73].

Recent studies have demonstrated a potential relationship between ARID1A alterations and reduced progesterone receptor (PR) expression. Asaka et al. (2023) reported significantly lower PR expression in ARID1A-deficient tumors compared with ARID1A-intact tumors (p = 0.0002) and Xing et al. (2023) further demonstrated that ARID1A knockout reduced both PR and MLH1 expression while increasing MSI in experimental models [74][75]. Collectively, these findings suggest that ARID1A mutations may impair hormonal therapy sensitivity through downregulation of progesterone receptor expression.