Fertility preservation in patients with endometrial carcinoma

INTRODUCTION — Uterine cancer is the most common gynecologic malignancy in resource-abundant countries and is the second most common in resource-limited countries (cervical cancer is more common). The incidence of endometrial carcinoma (EC) is increasing in resource-abundant countries due to increased obesity and longer life expectancy.

The standard initial treatment of EC is hysterectomy, bilateral salpingo-oophorectomy, and assessment of retroperitoneal lymph nodes. This is an acceptable option for the majority of patients with EC, most of whom are postmenopausal. However, younger patients may desire fertility-sparing treatment options. For patients who are candidates for fertility preservation, the most common approach is progestin therapy and deferral of surgical staging until after completion of childbearing. Use of this approach is limited to patients with low-risk disease, and with fertility preservation the risk of recurrent or persistent disease is higher than with hysterectomy.

Fertility preservation in patients with EC is reviewed here. Related topics are discussed in detail separately, including:

●Overview (see "Overview of resectable endometrial carcinoma")

●Histopathology and pathogenesis (see "Endometrial cancer: Pathology and classification")

●Epidemiology and risk factors (see "Endometrial carcinoma: Epidemiology, risk factors, and prevention")

●Clinical features, diagnosis, and screening for high-risk patients (see "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening")

●Staging and surgical treatment (see "Endometrial carcinoma: Staging and surgical treatment")

●Adjuvant therapy (see "Overview of resectable endometrial carcinoma", section on 'Role of adjuvant therapy')

INCIDENCE IN REPRODUCTIVE-AGE PATIENTS — The majority of patients with EC are postmenopausal, but many young people also develop this disease.

The average age of diagnosis of uterine cancer in the United States is 63 years old [1]. The frequency of new cases diagnosed in patients ages 55 to 64 years, 35 to 44 years, and 20 to 34 years were 33.5, 4.9, and 1.5 percent, respectively.

Studies of EC incidence in young patients include:

●A review of over 50,000 patients with uterine cancer from the Surveillance, Epidemiology, and End Results (SEER) database reported that 4 percent were younger than 40 years of age [2].

●A tumor registry review over an 18-year period calculated a 4.5 percent incidence of EC in patients ages 40 or younger [3].

RISKS OF FERTILITY PRESERVATION — For patients undergoing fertility-preserving treatment of EC, the major concerns, apart from oncologic efficacy, which is covered below, include whether an undetected advanced endometrial cancer is present. Even in patients with clinical stage I disease, there is a moderate risk of extrauterine disease with grade >1 tumors. There is also a risk of an undetected synchronous ovarian cancer, and the lack of a tumor specimen may limit detection of Lynch syndrome.

The risk of a synchronous ovarian cancer may be as high as 25 percent in young patients, though the data to inform risk are sparse. For example, in one study of 102 patients younger than 45 years of age with EC who were presumed early stage, 26 patients (25 percent) had a coexisting ovarian malignancy upon surgical staging [4]. Nearly half of these patients had well-differentiated tumors with less than 50 percent myometrial invasion, suggesting that lower risk endometrial cancer does not preclude a coexisting ovarian malignancy. A study of premenopausal patients 45 years of age or younger with endometrioid endometrial cancer reported an incidence of coexisting malignant ovarian neoplasm of 4 percent [5].

Young patients who are diagnosed with EC may have Lynch syndrome as the underlying etiology of their cancer. Patients with EC should undergo molecular screening for Lynch syndrome when feasible [6]. Lynch syndrome is an inherited autosomal dominant genetic mutation in mismatch repair (MMR) genes. Patients with Lynch syndrome are at an increased risk of colorectal, endometrial, and ovarian cancer. Fertility-sparing therapy may limit the identification of patients with Lynch syndrome since molecular screening of tumor specimens is another important way patients with Lynch syndrome are identified. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Tumor MSI/IHC testing'.)

PRETREATMENT CONSIDERATIONS

Selection criteria — Selection criteria for fertility-sparing treatment of EC are discussed elsewhere. (See "Treatment of low-risk endometrial cancer", section on 'Fertility preservation as alternative in selected patients'.)

Counseling — Patients with EC who are interested in fertility-sparing therapy should be advised that such treatment represents a deviation from the recommended standard of care, which is complete surgical staging with total hysterectomy and bilateral salpingo-oophorectomy. Patients should be counseled to consider the strength of their desire for future childbearing versus the additional oncologic risks. This discussion should be documented in the medical record. (See 'Risks of fertility preservation' above.)

Patients should be counseled preoperatively regarding their potential future reproductive outcomes. Some data suggest that appropriate preoperative counseling for patients with gynecologic malignancies and fertility-sparing surgery are associated with a decreased risk of posttreatment regret [7].

Pretreatment evaluation — Pretreatment evaluation consists of clinical determination of stage and grade as well as evaluation for a synchronous primary malignancy. The pretreatment evaluation for patients considering fertility-sparing therapy includes:

●Medical history.

●Physical examination to assess uterus (size, mobility) and for metastatic disease.

●Endometrial sampling.

●Pelvic and abdominal imaging – In our practice, we order a transvaginal ultrasound (to assess uterus and adnexa) and magnetic resonance imaging (MRI) to assess depth of myometrial invasion.

The general pretreatment evaluation of patients with EC is discussed in detail separately. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Clinical findings'.)

Endometrial sampling is a key part of the evaluation to determine histology and grade. For patients who desire fertility-sparing treatment for EC, we suggest endometrial sampling by dilation and curettage (D&C) rather than by office endometrial biopsy alone. Office endometrial biopsy is an effective method for diagnosing EC (sensitivity, 99.6 percent in postmenopausal and 91 percent in premenopausal patients with the Pipelle device in a meta-analysis of 39 studies [8]), but some observational data suggest that D&C is associated with a better diagnostic performance for grade of disease and a lower rate of residual disease on subsequent hysterectomy. This may be because office endometrial biopsy is less effective at sampling focal rather than global lesions; thus, areas of pathology may be missed. In patients who desire fertility preservation, the detection of grade 2 disease or higher is of the utmost importance. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Endometrial sampling procedures'.)

The diagnostic performance of D&C compared with office endometrial biopsy was illustrated in a retrospective study (n = 490) of patients with a preoperative grade 1 EC who underwent hysterectomy and found that final pathology was upgraded in significantly more patients with an initial office endometrial biopsy compared with D&C (17.4 versus 8.7 percent) [9]. In addition, fewer patients in the office biopsy group had no residual tumor at hysterectomy (3.7 versus 14.8 percent), but the study did not report tests of statistical significance for this outcome. High-risk histologies (eg, serous, clear cell) were identified after hysterectomy in approximately 1 percent of patients in each sampling method group.

After confirming low-grade endometrioid EC with D&C, pelvic imaging should be performed to evaluate for myometrial invasion. In our practice, we use MRI for this evaluation. MRI is an effective modality for detection of myometrial invasion. As an example, in one study (n = 101), MRI detected myometrial invasion and cervical invasion with a sensitivity of 89 and specificity of 100 percent [10]. In another study (n = 65), for detection of superficial myometrial invasion, MRI had both a sensitivity and specificity of 74 percent [11].

Studies have been inconsistent regarding whether MRI is superior to ultrasound in detecting myometrial invasion [12,13]; however, MRI is generally recognized as the preferred imaging modality for endometrial cancer in part because it can also be used to assess locoregional disease spread [14-18], including cervical extension and deep myometrial invasion [19]. MRI has been demonstrated to be superior to computed tomography (CT) in that regard [20]. A finding on MRI of enlarged lymph nodes and those with central necrosis should be considered suspicious for metastatic disease.

FERTILITY-SPARING THERAPY OPTIONS — Progestin therapy is the mainstay of fertility preservation in EC. Other types of medications, such as gonadotropin-releasing hormone agonists or aromatase inhibitors, have been proposed, but there are few data regarding their efficacy [21-23]. Hysteroscopic resection of the endometrium prior to progestin therapy has been reported, but further studies are needed to determine its safety, efficacy, and feasibility before recommending it as a front-line treatment option [18,24,25].

Progestin therapy — Several different types of progestins, doses, and regimens may be used for treatment of EC. Progestins are typically given orally (medroxyprogesterone acetate [MPA], megestrol acetate [MA]) or via an intrauterine device (IUD). Historically, the most commonly used oral agents have been MPA or MA [26,27]. There are few high-quality data to establish the optimal type of progestin, route of administration, or dose.

The data regarding the efficacy and toxicity of progestin therapy are limited. Available data include a prospective, multicenter phase II study; meta-analyses of observational studies (mostly retrospective); a large national database study; and small series or case reports [28]. Outcomes relative to hysterectomy are discussed elsewhere. (See "Treatment of low-risk endometrial cancer", section on 'Efficacy relative to surgery'.)

Studies have included different doses, agents, and regimens. Most of the studies have evaluated oral progestins, and there are no studies that directly compare oral progestins with a progestin-releasing IUD for EC. Another limitation is that many studies include both patients with EC and those with endometrial hyperplasia. In addition, definitions of response, progression, and recurrence and the duration of follow-up vary across studies. The data supporting the choice of route of administration, agent, and dose are reviewed in detail below.

Oral agents — The two oral progestins used for treatment of EC are MPA or MA. There are no high-quality data regarding whether one is more effective than the other, and observational data show conflicting results. In addition, various doses have been used. The lowest doses that have been reported to be effective are: MPA (10 mg) and MA (160 mg).

Oral progestins should be administered daily based on evidence that continuous treatment is more effective than cyclic (eg, a cycle of dosing for two weeks, then no medication for two weeks) [29,30].

The data regarding oral progestin agents for fertility-sparing therapy for EC are mainly from meta-analyses of observational data, case series, and case reports. The best available data are reviewed here.

Efficacy, agent, and dose

●Overall results for oral progestins – Meta-analyses or reviews of the efficacy of oral progestins for EC treatment include:

•A meta-analysis of 25 observational cohort studies including 445 patients with early-stage EC treated with an oral progestin [31]. The regression rate was 82.4 percent; among patients with disease regression, 96.5 percent achieved complete response. The relapse rate was 25.0 percent. Regarding reproductive outcomes, 56 of 129 (53.1 percent) patients who tried to become pregnant succeeded.

•A meta-analysis of 45 studies included 280 patients with grade 1 EC treated with progestins (74 percent were treated with either MPA or MA) [26]. The complete response rate was 48 percent with a median time to response of six months. The rate of recurrence after complete response was 35 percent. Persistent or progressive disease was found in 25 percent of subjects. The rate of pregnancy after treatment was 35 percent and, for pregnancies in patients with either EC or atypical endometrial hyperplasia, the live birth rate was 117 of 114 pregnancies.

•A meta-analysis of 34 studies included 408 patients with presumed stage I EC managed with fertility-sparing treatment (mostly MPA or MA, but some patients were treated with other medications and/or endometrial resection) [32]. The regression rate was 76 percent, and recurrence after regression occurred in 41 percent. Following treatment, stage II or higher endometrial cancer was diagnosed in 1.8 percent of patients. Of note, 3.6 percent of patients were diagnosed with ovarian cancer after treatment, but it was unclear whether these were primary ovarian cancers or ovarian metastases of endometrial cancer. In terms of fertility, 28 percent of patients had a live birth after treatment.

•A literature review of 27 articles included 81 patients with grade 1 EC treated with hormonal therapy (the majority received MPA or MA) [27]. The response rate was 76 percent and recurrence rate was 24 percent.

While the inconsistencies in these results may in part represent overlap and redundancy of analyzed studies and reporting bias, it appears to be that oral progestin therapy is associated with a consistently moderate to high response rate and acceptable recurrence rate [33,34].

●MPA – Treatment of low-risk EC with oral MPA in a range of doses of has been reported, from 2.5 to 1500 mg daily [34,35]. There are few data to guide the selection of dose, and representative studies include:

•In a small retrospective study, 12 patients with presumed EC invading <50 percent of the myometrium were treated with MPA at a dose of 200 to 800 mg/day for 2 to 14 months (most commonly used dose was 600 mg daily) [33]. Nine (75 percent) of 12 patients had an initial response (eight complete responses and one partial response) to MPA.

•The study cited above [33] served as the basis for a multicenter, prospective phase II study including 22 patients with EC, presumed EC invading <50 percent of the myometrium (patients with atypical endometrial hyperplasia were also in the study); treatment was MPA (600 mg once daily) for 26 weeks [28]. In patients with EC, there was a 56 percent complete response rate (defined as the absence of any hyperplastic or cancerous lesions) and a 32 percent partial response rate (defined as a residual lesion with degeneration and atrophy of endometrial glands). Recurrences occurred in 47 percent of patients between 7 and 36 months. Two participants had severe adverse reactions (one weight gain, one liver dysfunction). At three years, there were 12 pregnancies and seven full-term births.

●MA – A range of doses of MA has been reported, from 10 to 400 mg daily [31]. There are few data to guide the selection of dose. MA at 160 mg, once daily, is commonly used [26,34]. As an example, a prospective study of patients with well-differentiated EC treated initially with MA (160 mg, once daily), and then increased to 320 mg daily for initial nonresponders, reported an 86 percent response rate [36]. No serious adverse effects were observed.

●MPA versus MA – The data regarding the efficacy of MPA compared with MA are limited because there are only a few small studies, and the results have been inconsistent:

•MPA was associated with a lower risk of recurrence in a study in patients with EC (n = 148) [34]. There was no significant difference in complete response rate with MPA compared with MA (79 versus 77 percent). The average time to achieve complete response was 18 weeks. There was a significant difference in recurrence rate with MPA (21 versus 44 percent; odds ratio [OR] 0.44, 95% CI 0.22-0.88) at an average of 66 months of follow-up. However, the dose of MPA (median dose, 500 mg/day; range, 30 to 1500 mg/day) was higher than that of MA (median dose, 160 mg/day; range, 40 to 240 mg/day).

•By contrast, MA was associated with a higher response rate than MPA in a meta-analysis of 24 observational studies (most retrospective) including 370 patients with atypical endometrial hyperplasia (AH) or EC (67 percent had EC) [37]. There was a significantly higher rate of remission with MA compared with MPA in an analysis of 161 patients (87 versus 76 percent; OR 2.70, 95% CI 1.20-6.02) at an average of 47 months of follow-up; among patients with EC, 77 percent achieved remission. No significant difference in recurrence rate was found between MA and MPA in an analysis of 100 patients (31 versus 38 percent; OR 1.48, 95% CI 0.64-3.42); among patients with EC, 35 percent recurred. However, the study lacked sufficient statistical power to detect a difference in recurrence. A limitation of the study was that only myoinvasive EC was classified as progression and not evolution from AH to EC. In addition, the study did not evaluate dose or duration of therapy.

•A small retrospective study also found MPA to be associated with better outcomes than MA. The study group included 3 patients with EC and 20 with AH; response rates were higher for patients treated with MPA versus MA (100 versus 43 percent) [35].

Based on the available data, there is no evidence that either MA or MPA is more effective. MA and MPA are both 17α-Hydroxyprogesterone derivatives, with nearly 100 percent bioavailability and similar biologic effects [38]. However, MA has been used effectively at lower doses than MPA.

The choice of dose is based on a need to balance efficacy with toxicity, as orally administered progestins have potential side effects, including thrombus formation, mood alterations, headaches, weight gain, and breast pain and/or tenderness [38,39]. Thus, the lowest effective dose should be used.

Some data suggest that lower doses are as or more effective than higher doses [40] (eg, MPA 10 mg daily [35] or MA 160 mg daily [36]). As an example, some data suggest that lower dose may be more effective. In a prospective randomized trial of patients with advanced or recurrent EC treated with MPA, the lower dose (200 mg/day) was actually more effective than the higher dose (1000 mg/day) [39].

Predictors of response — Progestin therapy is successful in most, but not all, appropriately selected patients with EC, based on the available data. The success rate is due to the progestin sensitivity of well-differentiated, early-stage EC and depends on careful selection and monitoring of EC patients treated with hormonal therapy.

Investigators have attempted to identify factors predictive of a response, including:

●In the phase II study cited above, at eight weeks of treatment, patients with a thinner compared with thicker endometrial stripe after eight weeks of treatment had a higher response rate (6.5 versus 14.7 mm; 73 versus 25 percent) [28]. (See 'Efficacy, agent, and dose' above.)

●In a meta-analysis of 24 observational studies, including patients with EC or endometrial hyperplasia, an increased likelihood of response to hormonal therapy was found in those with the following characteristics: younger age at diagnosis, prior pregnancy, infertility, and treatment with MA [37].

●Progesterone receptor B (PRB) may be a predictor of response in young patients with endometrial cancer treated with uterine-preserving resection and hormonal therapy [41]. Additional research is needed to determine the clinical utility of PRB as a biomarker for progesterone response in endometrial cancer.

●Body mass index (BMI) has variably been reported to be [34] and not be [28] correlated with response to progestin therapy.

●The tumor suppressor protein, phosphatase and tensin homolog (PTEN), has not been shown to be predictive of response to hormonal therapy [42].

In general, clinical application of predictive factors is limited because a majority of patients will respond to progestin therapy. Other limitations include the combination of data from both EC and endometrial hyperplasia, and the limitations of observational studies.

Time interval to response — The reported median time to response has ranged from eight weeks to nine months [26-28,33,40,43]. Calculating the average time interval from initiation of therapy to histologic response is difficult due to the variations in study design and methodology. Most commonly, patients undergo repeat endometrial sampling at three months [26].

In the prospective phase II study of MPA 600 mg orally daily, endometrial sampling was done at 8, 16, and 26 weeks [28]. Among patients who eventually had a complete response, half did so at eight weeks and 92 percent did so by 26 weeks. Those who ultimately had a complete response had at least a partial histologic response at eight weeks.

In a prospective, observational trial of patients treated with both levonorgestrel-releasing intrauterine device (LNG IUD) and oral MPA, the average time to complete remission was 10 months (range, 3 to 35 months), with 25 percent demonstrating a complete response at three months and half demonstrating a complete response by six months [44].

Risk and timing of recurrence — The exact duration of therapeutic benefit from hormonal therapy is unknown. Even patients who initially respond are at significant risk for recurrence. This risk ranges from 24 to 41 percent [26-28,32,34,37], with a mean time to recurrence between 15 and 35 months [27,28,34]. There is evidence that patients with recurrent disease can be retreated with progestin therapy, but these data are limited [45].

Progestin intrauterine device — Treatment of EC with a progestin-releasing IUD has been less well investigated than oral progestins. Studies of patients with endometrial hyperplasia have consistently demonstrated that progestin IUDs compared with oral progestins have higher regression rates and lower relapse rates, but this is not always seen in patients with EC. (See "Endometrial hyperplasia: Management and prognosis", section on 'Progestin therapy'.)

There are several progestin-releasing IUDs, but LNG IUD that releases 20 mcg/day (LNG 52; Mirena, Liletta) is most frequently studied. Progestin IUDs may be used for treatment alone or in combination with an oral progestin; we use a combination of LNG IUD and oral progestin rather than the IUD alone.

Studies of EC treatment with a LNG IUD, with and without additional oral hormonal agents, have reported complete response rates ranging from 63 to 96 percent [21,44,46-49]. The relatively impressive results seen with progestin-releasing IUDs may be secondary to an ability to generate higher and persistent concentrations of levonorgestrel within the endometrium [29,50]. An advantage of the IUD is that it does not require daily administration and serves as an effective contraceptive while in place.

Studies in patients with EC of reproductive age include:

●In a prospective study including 190 patients with EC (grade 1 to 2 with no or minimal myometrial invasion), those who had an LNG IUD, GnRH agonist, and three dilation and curettages (at 0, 3, and 6 months) had a higher complete response rate compared with patients treated with other combinations (96 versus 71 to 89 percent) [48]. Patients receiving MPA 500 mg daily in addition to other treatments had the lowest CR rates, leading to discontinuation in one treatment arm. Limitations of this study include that 20 patients (10.6 percent) had grade 2 disease, which is typically not treated with fertility-sparing approaches. In addition, it is unclear whether the third D&C was necessary as a majority of patients (67 percent) achieved a complete response before it was performed.

●In a prospective study of 16 participants (mean age 35 years) with grade 1 endometrioid adenocarcinoma confined to the endometrium, patients were treated with an LNG IUD combined with oral MPA (500 mg daily) and had an overall complete remission rate of 87.5 percent, with an average time to remission of 9.8 months [44]. There were no cases of progressive disease.

●A prospective study that included 32 participants (mean age 33 years) with grade 1 EC treated with LNG 52 in combination with a gonadotropin-releasing hormone agonist reported complete remission in 63 percent of patients at six months and a cumulative rate of 72 percent with a longer duration of therapy [46]. Two patients had a recurrence and 7 of 32 had persistent disease.

●A case series included three patients with EC treated with the LNG 52 and nine with a combination of the LNG 52 and an oral progestin, of whom one of three in the IUD-alone group and seven of nine in the combination therapy group responded. However, it should be noted that three of those deemed not to have responded actually underwent definitive management (ie, hysterectomy or radiation therapy) before follow-up curettage to evaluate response [51].

Clinical protocol — Fertility-sparing treatment with progestins may be offered to patients who meet the selection criteria described above. In this section, we present our treatment approach, based on the available evidence.

Treatment regimen — For patients with EC who meet the criteria for fertility preservation, we suggest treatment with the LNG 52 in combination with MA (80 mg, oral, daily) rather than a progestin-releasing IUD or oral progestin alone.

For conservative management to be considered a viable alternative to hysterectomy, attempts must be made to approximate the very high disease-specific survival seen in patients with early-stage endometrial cancer treated with the standard approach of total abdominal hysterectomy and bilateral salpingo-oophorectomy [52]. In deciding on the ideal progestin regimen, one must consider not only choice of agent, but also route of administration, frequency, and dose.

The LNG IUD allows for continuous exposure of the endometrium to progestin and does not require daily dosing. However, there is insufficient evidence to support use of the LNG 52 alone. However, based on the limited available observational data, it appears that the combination of the LNG 52 and an oral progestin may achieve a response rate in the 80 percent range, while oral progestins alone are associated with response rates in the 70 percent range [28,44,53]. Meta-analyses of patients with endometrial cancer, treated primarily with oral progestins, demonstrated that although a majority of patients responded, the cure rates are not equivalent to hysterectomy, as a significant proportion of patients either did not respond initially or recurred after an initial response, allowing for room for improvement in outcomes.

Follow-up — After progestin therapy is initiated, an office endometrial biopsy is performed in three months [8,54]. This can be performed with an IUD in place.

●For patients who have a complete response, we repeat an office endometrial biopsy in three months. After two consecutive negative biopsies, we encourage the patient to pursue pregnancy as soon as possible. If the patient does not wish to immediately conceive a pregnancy and risk factors for excess endogenous estrogen (eg, obesity) persist, the IUD should be left in place.

●For patients with persistence of disease (EC or atypical endometrial hyperplasia) at three months, including lack of any pathologic demonstration of progestin effect, we increase the dose of the oral progestin (eg, MA 160 mg/day). If a patient was treated initially with an LNG IUD alone, an oral progestin should be added.

●An office endometrial biopsy is performed again after three months of the change in therapy. Patients with persistence and/or progression after nine to twelve months of progestin therapy are unlikely to respond and should be counseled regarding the potentially nonhormonally responsive nature of their cancer and need to consider definitive treatment, and most experts advise hysterectomy. Although one retrospective study suggested that patients with persistent disease after nine months may subsequently achieve complete response after longer intervals, the trial was small, limiting confidence in this approach [55]. History of polycystic ovarian syndrome, histologic grade 2, and not achieving partial response until 12 months were all associated with the inability to achieve a complete response.

For patients treated successfully with progestins who have completed childbearing, there are no high-quality data regarding whether hysterectomy is required. Patients with a history of endometrial cancer treated with hormonal therapy should be counseled regarding risk factors, likelihood of recurrence based on persistence of risk factors, and symptoms warranting further evaluation (eg, abnormal vaginal bleeding).

Reproductive outcomes — Assessing reproductive outcomes depends upon the denominator used. That is, not all patients with EC treated with progestins will achieve a response, and among those who do, not all will attempt pregnancy. In addition, the measure of a successful outcome varies (eg, any pregnancy, spontaneous pregnancy, live birth, full-term birth).

Systemic reviews of relevant studies have reported pregnancy rates of 35 percent [26] and live birth rates of 28 percent [32] and 47 percent [56]. These patients often have infertility issues related to obesity, polycystic ovarian syndrome, and chronic anovulation. A majority will require assisted reproductive technology (ART) to become pregnant [23,28,40,57-59]. As an example, in a literature review of 27 studies of patients treated with a variety of hormonal agents, 62 of 81 responded to therapy; among the responders, documentation of pregnancy was available for 20 [27]. This included: full-term births (16 patients who delivered 21 singletons and 1 set of twins) at term; preterm births (a singleton at 32 weeks, twins at 35 weeks, and triplets at 30 weeks). Twelve of the 20 patients required fertility treatment to achieve pregnancy.

Although rare, there are cases of EC during pregnancy. The diagnosis is usually made in the first trimester with dilation and curettage (D&C) for pregnancy loss or termination [60,61]. EC cancer has also been reported in the postpartum period. However, it is difficult to comment on the timeline of the development of the cancer as there is generally no prepregnancy endometrial biopsy, and several cases reported were diagnosed two or more years postpartum.

Hysteroscopic resection — Hysteroscopic resection of early-stage EC has been described, including in patients who did not respond to initial hormonal therapy [62-65]. Hysteroscopic resection may serve a therapeutic role by removing tumor and potentially increasing the efficacy of and/or decreasing the duration of progesterone therapy required for a pathologic response [66]. There may also be a diagnostic role by allowing for assessment of any myometrial invasion. In combination with hormonal therapy, hysteroscopic resection was associated with favorable outcomes. However, data regarding safety and efficacy are limited to small case series, only patients with unifocal lesions may be candidates, and there is the risk of peritoneal dissemination of tumor cells (although of dubious clinical significance) [67,68].

Other options — Some patients with EC are candidates for ovarian preservation at the time of hysterectomy and may be candidates for oocyte retrieval and use of a gestational carrier [69,70]. Patients should be counseled about reproductive options based upon their EC disease status and prognosis and their reproductive function. (See "Overview of infertility and pregnancy outcome in cancer survivors".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●The standard initial treatment of endometrial carcinoma (EC) is hysterectomy, bilateral salpingo-oophorectomy, and assessment of retroperitoneal lymph nodes. This is an acceptable option for the majority of patients with EC, most of whom are postmenopausal. However, younger patients may desire fertility-sparing treatment options. (See 'Introduction' above.)

●Patients must be carefully selected for fertility-sparing treatment of EC. Optimal candidates include patients with the following characteristics (see 'Selection criteria' above):

•Well-differentiated (grade 1) endometrial adenocarcinoma with histology and grade confirmed on dilation and curettage (D&C)

•Tumor confined to the endometrium

•Reproductive-age and desirous of future childbearing

•No contraindications to hormonal therapy

•Understanding of the nonstandard nature of treatment, including risk of occult cancer, risk of recurrent and/or persistent cancer

●The pretreatment evaluation for patients considering fertility-sparing therapy includes medical history, physical examination to assess uterus (size, mobility) and for metastatic disease, endometrial sampling, and pelvic and abdominal imaging. For patients who desire fertility-sparing treatment of EC, we suggest endometrial sampling by D&C rather than by office endometrial biopsy alone. (See 'Pretreatment evaluation' above.)

●Progestin therapy is the mainstay of fertility preservation in EC. Other types of medications, such as gonadotropin-releasing hormone agonists or aromatase inhibitors, have been proposed, but there are few data regarding their efficacy. Surgical resection of the endometrium has also been proposed as part of a fertility preservation approach, but this approach is investigational. (See 'Fertility-sparing therapy options' above.)

●Complete response rates with progestin therapy range from 63 to 96 percent. There is no consensus regarding the optimal progestin agent or dose. For patients with EC who meet the criteria for fertility preservation, we suggest treatment with the LNG 52 in combination with megestrol acetate (MA; we use 80 mg, oral, daily) rather than a progestin-releasing intrauterine device (IUD) or oral progestin alone (Grade 2C). (See 'Progestin therapy' above.)

●After progestin therapy is initiated, an office endometrial biopsy is performed in three months. (See 'Clinical protocol' above.)

•For patients who have a complete response, we repeat an office endometrial biopsy in three months. After two consecutive negative biopsies, we encourage the patient to pursue pregnancy as soon as possible.

•For patients with persistence of disease at three months, we increase the dose of the oral progestin (eg, MA 160 mg/day). If a patient was treated initially with a levonorgestrel-releasing IUD alone, an oral progestin should be added. An office endometrial biopsy is performed again after three months of the change in therapy. Patients with persistence and/or progression after nine to twelve months of progestin therapy are unlikely to respond and should be counseled appropriately, including being offered a hysterectomy.