INTRODUCTION — Endometrial hyperplasia (EH) is categorized into two groups: EH without atypia and EH with atypia (also referred to as endometrial intraepithelial neoplasia [EIN]). EH with atypia is neoplastic and may progress or coexist with endometrial carcinoma. Early diagnosis and treatment of EH (with or without atypia) can prevent progression to endometrial carcinoma.
Terminology of EH varies widely (table 1). This topic will utilize the 2014 World Health Organization classification criteria [1]. However, supporting studies cited in this topic may use other classification systems, which will be documented where appropriate. In addition, as there is significant overlap of EH with atypia and EIN, recommendations made in this topic for patients with EH with atypia can be applied to patients with EIN.
Management of EH is reviewed here. Related topics can be found separately:
●(See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis".)
●(See "Overview of resectable endometrial carcinoma".)
●(See "Abnormal uterine bleeding and uterine pathology in patients on tamoxifen therapy".)
GOAL OF MANAGEMENT — When managing patients with EH, the goal is to identify coexisting, and prevent progression to, endometrial carcinoma.
Management is guided by the following clinical factors:
●Type of EH (ie, with or without atypia)
●Menopausal status
●Desire for fertility in premenopausal patients
●Contraceptive needs in premenopausal patients
●Risk factors for disease recurrence or progression, including:
•Age >50 years [2]
•Body mass index (BMI) >25 kg/m2 [2]
•Nulliparity [3]
•Diabetes mellitus [2]
•EH with atypia [2]
•Uterine size ≥9 cm [4]
•Endometrial lesion size >2 cm [5]
•Lack of adequate progestin therapy [3]
These risk factors are similar to those for the development of EH and endometrial carcinoma (table 2). However, one confounder is the inability to distinguish progression of EH from a missed concurrent endometrial carcinoma. In addition, these risk factors vary in degree of risk, and the clinician must decide with the patient whether a particular factor is clinically significant and how it impacts management decisions. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Risk factors'.)
EH WITHOUT ATYPIA
Natural history — The risk of progression of EH without atypia to endometrial carcinoma has not been well studied but appears to be less than 10 percent, based on studies with up to 20 years of follow-up [6-10]. Representative studies of EH without atypia in the absence of treatment are rare but include:
●In a review of 35 patients (mean age 46 years) with simple hyperplasia (ie, EH without atypia) managed expectantly for six months, approximately 74 percent of cases spontaneously regressed, 17 percent persisted, and 9 percent progressed to atypical hyperplasia; endometrial carcinoma was diagnosed in one patient (2.9 percent) [6].
●In an often-cited case series including 122 patients with simple and complex hyperplasia without atypia (ie, EH without atypia), the majority (approximately 90 percent) of whom were not treated with progestin therapy, two patients (1.6 percent) developed endometrial carcinoma after a mean duration of 10 years [7].
●A higher progression rate to endometrial carcinoma (five-year cumulative rate of approximately 10 percent) was noted in a cohort study including 164 patients with complex hyperplasia (ie, EH without atypia) who did not receive progestin therapy [8].
Preferred: Medical or surgical treatment — We recommend medical or surgical treatment rather than observation for most patients with a diagnosis of EH without atypia. The choice of treatment depends on menopausal status, desire for fertility, contraceptive needs, and patient-specific risk factors for progression (table 2).
●Premenopausal patients not meeting the criteria for low risk of progression detailed below (see 'Alternate for patients at low risk of progression: Observation' below) are treated with progestin therapy (algorithm 1). Progestin therapy includes intrauterine and oral progestins and combined estrogen and progestin oral contraceptives (COCs). Our approach to prescribing these therapies is described in detail below. (See 'Progestin therapy' below.)
Premenopausal patients with the inability to tolerate, or more rarely with contraindications to, progestins may undergo observation rather than treatment and are followed closely, as described below. (See 'EH without atypia: Premenopausal patients' below.)
●Postmenopausal patients are treated with either progestin therapy or hysterectomy (algorithm 2); the choice depends on the perceived risk of developing endometrial carcinoma based on their personal risk factors (eg, chronic ovulatory dysfunction, obesity, early menarche, late menopause, increasing age, tamoxifen therapy, Lynch syndrome, Cowden syndrome (table 2)). (See 'Goal of management' above.)
•Most postmenopausal patients are appropriate candidates for progestin therapy, which may be intrauterine or oral; COCs are not used in postmenopausal patients to avoid unnecessary exposure to estrogen, which may result in further risk (eg, venous thromboembolism). Our approach to therapy is described in detail below. (See 'Progestin therapy' below.)
•Hysterectomy is curative for EH and is performed in postmenopausal patients in whom progestin therapy is declined or contraindicated, in those with bothersome bleeding, in those at highest risk of developing endometrial carcinoma, or in those who desire definitive therapy. (See 'Hysterectomy' below.)
Alternate for patients at low risk of progression: Observation — We recommend observation rather than treatment for patients with a diagnosis of EH without atypia in whom the risk of progression to endometrial carcinoma is low. These patients are premenopausal and have one or more of the following (algorithm 1):
●The inciting factor that resulted in endometrial proliferation has been eliminated (eg, patient with anovulation, now corrected).
●Other risk factors for endometrial carcinoma are not present (table 2).
●Resumption of normal menses; ovulation and formation of a corpus luteum exposes the endometrium to high endogenous progesterone levels that are often sufficient to cause regression of EH without atypia.
Our approach to following these patients is discussed below. (See 'EH without atypia: Premenopausal patients' below.)
Evidence of the efficacy of progestin therapy — Data suggest that progestin therapy is an effective treatment for EH without atypia [9-17]; representative studies are as follows:
●In a nested case control study from a managed care organization including 63 patients with a diagnosis of EH without atypia of whom the majority (over 80 percent) received medical therapy and developed endometrial carcinoma, cumulative rates of progression to endometrial carcinoma were 1.2, 1.9, and 4.6 percent at 4, 9, and 19 years, respectively [9,10]. In the cohort study described above (see 'Natural history' above), of the 1037 patients with a diagnosis of EH without atypia treated with progestin therapy, the rate of progression to endometrial carcinoma was approximately 2 percent at 10 years [8].
●In a meta-analysis of 24 observational studies including over 1000 patients with simple and complex hyperplasia (ie, EH without atypia), regression rates with oral progestin therapy were between 66 and 89 percent, with the degree of glandular crowding being inversely related to regression rate [11]. Regression rates were even higher with the levonorgestrel (LNG)-releasing intrauterine device (IUD [LNG 52 mg; 92 to 96 percent; total of 174 patients]).
●A subsequent meta-analysis of seven randomized trials also demonstrated that the LNG 52 mg was more effective than oral progestins for the treatment of EH without atypia; the LNG 52 mg had a higher response rate at six months in four trials (88 versus 69 percent, odds ratio [OR] 3.16, 95% CI 1.84-5.45) and a lower hysterectomy rate (OR 0.26, 95% CI 0.15-0.45) [13]. (See 'Progestin therapy' below.)
●Relapse rates may also be lower after treatment with LNG 52 mg compared with oral progestins. One cohort study including over 200 patients with complex EH (ie, EH without atypia) and long-term follow-up (>5 years) after treatment with either the LNG 52 mg or oral progestin therapy showed a relapse rate of approximately 13 and 28 percent, respectively [17].
EH WITH ATYPIA (EIN)
Natural history — The risk of progression of EH with atypia (endometrial intraepithelial neoplasia [EIN]) to endometrial carcinoma is higher than that of EH without atypia and is between 15 and 40 percent, based on studies with up to 20 years of follow-up [7-9,18].
●In a case series including 48 patients with EH with atypia, 83 percent of whom were not treated with progestin therapy, eleven patients (23 percent) developed endometrial carcinoma after a mean duration of approximately five years [7].
●A higher progression rate to endometrial carcinoma (five-year cumulative rate of approximately 40 percent) was noted in a cohort study including 62 patients with EH with atypia who did not receive treatment [8].
Coexistent endometrial carcinoma may be present in up to 40 percent of patients with EH with atypia [19,20]; risk factors for concomitant endometrial carcinoma include increased age, obesity, diabetes mellitus, and postmenopausal patients with a transvaginal ultrasound showing an endometrial thickness ≥20 mm [21-23]. This is discussed in more detail elsewhere. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Natural history'.)
Preferred treatment: Hysterectomy — Given the high risk of concurrent, or progression to, endometrial carcinoma, for most postmenopausal patients and premenopausal patients who have completed childbearing, we recommend definitive treatment with hysterectomy for treatment of EH with atypia (algorithm 3 and algorithm 4). In a longitudinal study of patients with hyperplasia (with and without atypia), the only EH-related deaths were in patients with endometrial carcinoma at the time of surgery [8]. (See 'Hysterectomy' below.)
It is also important to address any underlying conditions that may have led to the development of EH. For example, patients with obesity may benefit from referral for medical and/or surgical weight loss [24].
Patients that are at high risk for surgical complications may be managed with progestin therapy rather than surgery, as discussed below. (See 'Alternate treatment: Progestin therapy' below.)
Alternate treatment: Progestin therapy — Historically, the recommendation for treatment of EH with atypia was with hysterectomy, and few exceptions were made. However, with increasing data regarding efficacy of pharmacologic therapy, and after the introduction of the levonorgestrel (LNG)-releasing intrauterine device (IUD [LNG 52 mg]), progestins became an alternative treatment for some patients, though long-term surveillance and medical therapy are required and treatment may not be curative, as with hysterectomy [11,14-17,25-35]. We consider progestin therapy a reasonable alternative to hysterectomy for the following (algorithm 3 and algorithm 4):
●Premenopausal patients who desire future fertility
●Patients of any reproductive status who decline hysterectomy
●Patients at high risk of surgical complications
These patients must be able to comply with medical therapy and follow-up endometrial sampling.
Progestin therapy includes intrauterine and oral progestins. Combined estrogen and progestin oral contraceptives (COCs) are not used for the treatment of EH with atypia. Our approach to prescribing these therapies is described in detail below. (See 'Progestin therapy' below.)
Evidence of the efficacy of progestin therapy — The efficacy of progestins for treatment of EH with atypia is supported by the following evidence:
●In a cohort study including over 240 patients who had EH with atypia, patients treated with progestin (180 patients) compared with untreated patients (62 patients) had lower rates of endometrial carcinoma (20.5 versus 101.4 per 1000 person-years) and hysterectomy (61 versus 297 per 1000 person-years) [8]. However, disease persistence and recurrence remain high after treatment. In this study, of the 180 patients with EH with atypia treated with progestin therapy, 27 patients (15 percent) developed endometrial carcinoma by 10 years [8]. Similarly, in one systematic review including 111 patients with EH with atypia treated with progestin therapy (median age 31.7 years), persistent disease and disease recurrence were noted in 14 and 23 percent of patients, respectively [31].
●In the nested case control study from a managed care organization of patients with EH described above (see 'Evidence of the efficacy of progestin therapy' above), among those who had EH with atypia and developed endometrial carcinoma (42 patients; 86 to 92 percent of whom received progestin treatment), rates of progression to endometrial carcinoma were 8.2, 12.4, and 27.5 percent at 4, 9, and 19 years, respectively [9,10]. Subjects were diagnosed with carcinoma an average of six years after initial diagnosis (range 1 to 24 years).
While various oral progestin therapies are effective for this indication (see 'Oral progestins' below), the LNG 52 mg IUD (Mirena, Liletta) is the most effective first-line therapy [11,17,26-30]. Studies of patients who have EH with atypia have consistently demonstrated that the LNG 52 mg compared with oral progestins is associated with higher regression rates (90 versus 69 percent [11]), lower relapse rates (27 versus 50 percent [17]), and fewer subsequent hysterectomies (23 versus 36 percent [36]). In addition, patients with a higher body mass index (BMI) may derive a greater relative benefit from the LNG 52 mg than those with lower BMIs [30]; however, further study is needed to support this finding.
TREATMENT ADMINISTRATION
Progestin therapy
General considerations — Various progestin preparations have been used for treatment of EH (table 3), although none have received US Food and Drug Administration-approval for this indication. However, some have received approval for prevention of EH, and megestrol acetate and depot medroxyprogesterone acetate (DMPA) are approved for treatment of endometrial carcinoma.
●Pharmacology – Progestins reverse EH by activation of progesterone receptors, which results in stromal decidualization and subsequent thinning of the endometrium. Progestin exposure also activates hydroxylase enzymes to convert estradiol to its less active metabolite estrone [37].
●Contraindications – Some data suggest that high-dose oral progestins (ie, medroxyprogesterone acetate, norethindrone acetate) and DMPA increase the risk of venous thromboembolism (VTE) [38]. Other progestins (eg, oral norethindrone, micronized progesterone) appear to pose minimal or no increased VTE risk; megestrol acetate was not included in this study. Thus, consultation with a hematologist may be appropriate for patients in whom high-dose oral progestins or DMPA are being recommended. This is discussed in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Other progestin-only therapies' and "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Cardiovascular and thromboembolic risk'.)
Contraindications to the levonorgestrel (LNG)-releasing intrauterine device (IUD [LNG 52 mg; Mirena, Liletta]; also referred to as an intrauterine system) are discussed in detail elsewhere. It is important to note that the LNG 52 mg administers progestins locally to the uterus and results in minimal systemic absorption; these devices are not associated with an increased risk of VTE [38]. Thus, the LNG 52 mg is often preferred over high-dose oral progestins and DMPA. (See "Intrauterine contraception: Candidates and device selection", section on 'Contraindications' and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'How to choose'.)
●Continuous versus cyclic regimens – In terms of dosing, continuous progestins (daily dosing oral progestins or progestin IUDs) are superior in efficacy compared with cyclic progestin regimens (dosing varies; medication is typically taken for at least 12 to 14 days and then the patient receives no medication for the remainder of the month) [27,39]. Thus, a continuous dosing regimen is preferred over a cyclic regimen if amenorrhea can be achieved. Cyclic regimens may be used in patients who cannot tolerate, or do not want to use, a continuous regimen.
●Side effects – Some patients experience bothersome progestin side effects (eg, irregular vaginal bleeding, bloating, irritability, depression, headaches) and may require an adjustment in dose or a switch to a different progestin formulation. Side effects are more likely with oral progestins, and in these situations, we advise changing to the LNG 52 mg, which has a more favorable side effect profile.
Choice of progestin — The LNG 52 mg (Mirena, Liletta) is our choice for first-line progestin therapy in patients with EH (with and without atypia) [11-13,16,17,26-30,34,35,40-42], although historically, the most common treatments were oral medroxyprogesterone acetate (MPA) or megestrol acetate. Studies have consistently demonstrated that the LNG 52 mg compared with oral progestins for the treatment of EH is associated with higher regression rates and lower relapse rates for the treatment of EH with (see 'Evidence of the efficacy of progestin therapy' above) and without (see 'Evidence of the efficacy of progestin therapy' above) atypia. In addition to higher efficacy, these devices may be used in patients with relative contraindications to progestins, offer long-acting contraception, and do not require daily dosing [16,18,34]. They are also typically better tolerated than oral progestins, although the meta-analysis of randomized trials discussed above found no significant difference in rates of irregular vaginal bleeding with the LNG 52 mg compared with oral progestins [13].
Oral progestins are an acceptable alternative for patients who decline, cannot tolerate (eg, difficult insertion, repetitive expulsions), or are not candidates for an LNG IUD. (See "Intrauterine contraception: Candidates and device selection", section on 'Contraindications'.)
When oral agents are used for treatment of EH with atypia, megestrol acetate is preferred because it is more potent than other progestins, such as MPA [32,33] (table 3). Other oral progestin treatment options are similar to those for EH without atypia, although oral norethisterone and micronized progesterone have not been adequately studied in patients who have EH with atypia. Often, higher progestin doses are used for EH with atypia compared with doses recommended for EH without atypia, although there are minimal data to support this approach. (See 'Oral progestins' below.)
Levonorgestrel-releasing IUD (LNG 52 mg) — The initial LNG 52 mg dose is 20 mcg/day; by five years the daily dose is approximately 10 mcg/day. While the LNG 52 mg is approved for six (Liletta) or seven (Mirena) years of use as a contraceptive, we remove and replace the IUD at five years when treating EH. Lower dose LNG-releasing IUDs are also available (13.5, 17.5, and 18.6 mcg/day) and vary from three- to five-year formulations, but these have not been studied in patients with EH to determine whether the lower progestin dose is as effective as the LNG 52 mg. We do not use them for this indication in our practice. Detailed general information about use of the LNG IUD can be found separately.(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD' and "Intrauterine contraception: Insertion and removal" and "Intrauterine contraception: Management of side effects and complications".)
Oral progestins — Oral progestins may be given as progestins alone (eg, megestrol acetate, MPA); in premenopausal patients without atypia, combined estrogen and progestin oral contraceptives (COCs) may also be used [43]. Patients are usually treated for three to six months with continuous dosing [44]. Studies comparing higher-dose progestins with the doses listed below have found no significant difference [14,45].
For patients with EH (with or without atypia) who are treated with noncontraceptive oral progestins, medications, doses, and regimens that have been reported are, in order of our preference:
●Megestrol acetate 40 to 160 mg daily [32,46]; however, no standard dose is routinely prescribed and higher doses have been reported [11]. One contributor's (BG) practice is to use 40 mg twice daily for patients with EH without atypia and 80 mg twice daily for patients with EH with atypia. This medication is considered a "chemotherapeutic agent," but it is best classified as a strong progestin [15]. As megestrol acetate is an appetite stimulant and associated with weight gain, particularly at higher doses, we dose based on shared decision making and tolerance of side effects.
●Medroxyprogesterone acetate (MPA) 10 to 20 mg daily [27,47]; however, no standard dose is routinely prescribed and higher doses have been reported [11,26,45]. MPA was one of the first-line therapies for EH before the LNG 52 mg was studied for this indication.
●Norethindrone acetate (NETA, also known as norethisterone acetate; eg, Aygestin) 5 to 15 mg daily; however, this has not been well studied. Studies with small numbers of patients taking NETA suggest similar efficacy to oral MPA [14,48,49] but lower efficacy than DMPA [50]. (See 'Depot medroxyprogesterone acetate' below.)
●Micronized progesterone 200 to 300 mg daily was beneficial in a single study of patients with EH [51]. However, this is a relatively weak progestin, and we do not consider it for first-line progestin treatment. In our practice, we use it only for EH without atypia (because these patients are at low risk for progression to endometrial carcinoma) and in those who cannot tolerate stronger synthetic progestins or refuse the LNG 52 mg.
For patients who require contraception, medications, doses, and regimens that have been reported are:
●Norethindrone (progestin-only contraceptive pill; eg, Micronor) 0.35 mg twice or three times daily; however, this has not been well studied. In addition, norethindrone, when given daily, has lower contraceptive efficacy than the LNG 52 mg or COCs.
●Combined estrogen and progestin contraceptives (COCs); although COCs (available in pills, patches, and rings) have not been studied for treatment of EH progestin, the dose of progestin is, in theory, sufficient to reverse the majority of cases of EH without atypia [52,53]. In addition, COCs are associated with a lower risk of developing endometrial cancer [54]. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Use of hormonal contraception'.)
Depot medroxyprogesterone acetate — Progestin injections have not been well studied for the treatment of EH [50,55]. One of the authors uses DMPA, a long-acting progestin contraceptive requiring only four injections per year, as subsequent-line therapy for premenopausal patients with EH without atypia who are intolerant of oral progestins or the LNG 52 mg.
One study found that the intramuscular DMPA (150 mg every three months) was more successful than NETA (15 mg daily for 14 days per cycle) in the treatment of EH without atypia [50]. In this six-month randomized trial including 146 patients ages 35 to 50 years with EH without atypia, rates of regression to normal endometrium were higher with DMPA compared with NETA (91 versus 67 percent, relative risk [RR] 1.4, 95% CI 1.2-1.6). Side effects were present with both medications, with more nausea and breast discomfort with NETA and more amenorrhea with DMPA.
Other preparations — Progestin implants (ie, etonogestrel; Nexplanon) and vaginal micronized progesterone [56,57] have not been well studied for the treatment of EH, and we do not typically use these in our practice.
A small study of infertility patients found that vaginal micronized progesterone had similar effects on the endometrium as intramuscular progesterone, with no EH seen [57]. In theory, this progestin could be used as maintenance treatment, as its local effect achieves high endometrial concentrations.
Hysterectomy — Total extrafascial hysterectomy is the definitive treatment for EH. Supracervical hysterectomy is not performed, in part because of the potential for local extension of endometrial neoplasia into the cervix [25].
All measures should be taken to detect endometrial carcinoma before or during hysterectomy. Because of variations in interpretation of EH, if hysterectomy is planned based on a single endometrial specimen, we have the slides reviewed by a second pathologist to confirm the classification [58]. In addition, if the diagnosis of EH with atypia is based on an office endometrial biopsy, we advise further evaluation with D&C (with or without hysteroscopy) prior to proceeding with hysterectomy to exclude coexistent endometrial carcinoma [59]. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Subsequent evaluation of EH with atypia' and "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Postmenopausal patients with bleeding'.)
During hysterectomy, gross inspection, and frozen section when appropriate, are typically performed to evaluate for endometrial carcinoma. Reports of the sensitivity of frozen section to detect endometrial carcinoma mostly range from 73 to 88 percent [60-62], although one study reported a sensitivity of 27 percent [63]. Thus, some patients will have endometrial carcinoma detected only on final pathology evaluation.
Patients with endometrial carcinoma detected at surgery should undergo full staging and be treated as appropriate. (See "Endometrial carcinoma: Staging and surgical treatment".)
Lymph node assessment at the time of hysterectomy for EH may be performed [64], and sentinel lymph node mapping for such patients has been described [65]. The discussion of when to perform such procedures can be done in consultation with a gynecologic oncologist.
Role of oophorectomy and salpingectomy — For most patients undergoing hysterectomy, we suggest hysterectomy with bilateral salpingectomy with or without bilateral oophorectomy; professional societies have not issued guidelines regarding removal or retention of ovaries in patients with EH. Patients with a hereditary ovarian cancer syndrome (eg, Lynch syndrome, Cowden syndrome) may be managed differently. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer".)
Salpingectomy alone provides possible prevention of ovarian, fallopian tube, and peritoneal carcinomas. This is discussed in more detail elsewhere. (See "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction".)
The choice of oophorectomy depends on immediate and long-term negative health effects (eg, increased risk of cardiovascular disease, cognitive decline) and possible benefits (eg, avoiding the need for a subsequent oophorectomy, breast cancer risk reduction) of surgical menopause. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Consequences of elective oophorectomy'.)
Even in cases of endometrial carcinoma, the ovaries have metastatic disease in only 5 percent of cases [66,67]. In addition, patients with concurrent endometrial carcinoma are likely to have low-risk disease, and the likelihood of an impact on survival with retaining the ovaries in a patient with stage I, grade 1 endometrial carcinoma is low [68,69]. However, some experts still perform bilateral salpingo-oophorectomy (BSO) in all cases of EH with atypia because of the high risk of concomitant endometrial carcinoma and because BSO is a standard part of staging (table 4 and table 5) [19,70].
For patients who do undergo oophorectomy, menopausal symptoms may be treated with postmenopausal estrogen therapy, if there are no contraindications. This is based on the safety of postmenopausal estrogen therapy in patients with early-stage endometrial carcinoma. (See "Overview of approach to endometrial cancer survivors", section on 'Menopausal symptoms'.)
Investigational therapies — Treatment with nonprogestin medications or uterine-sparing surgeries are not standard clinical practice, but have been described [71,72].
●Nonprogestin medications
•Gonadotropin-releasing hormone agonists were used in combination with an LNG 52 mg (Mirena, Liletta) to successfully treat 24 premenopausal patients with either EH with atypia or early-stage endometrial carcinoma [73].
•Ovulation induction (eg, with clomiphene or aromatase inhibitors) in reproductive-age patients will result in formation of a corpus luteum, exposure to endogenous progesterone, and resolution of EH in some patients [74]. Administration of these therapies should be under the supervision of a reproductive endocrinology and infertility specialist along with consultation from gynecologic oncology. Pregnancy is highly unlikely in the setting of ongoing EH. Careful surveillance is needed to assure EH regression. This approach is favored for patients with EH without atypia who desire pregnancy.
•Metformin has been shown to have both antiproliferative effects and to reduce insulin resistance, which may play a role in the development of endometrial carcinoma in patients with obesity [75]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
In a meta-analysis of observational studies and randomized trials including a subset of 472 patients with EH with atypia, those treated with progestin plus metformin compared with progestin alone had lower rates of disease relapse (pooled odds ratio 0.46, 95% CI 0.24-0.91; three studies) but similar rates of disease remission (six studies) [76]. One limitation of this analysis is that patients with endometrial carcinoma were also included and outcomes were not distinguished between groups. Further research, including larger randomized trials, are needed before metformin can be recommended for routine use as an adjunct therapy with progestin in these patients [77].
●Other surgical treatments
•Hysteroscopic resection of EH was reported to be effective in 68 of 73 treated patients, but the long-term consequence of this treatment remains to be determined [78]. A review of 36 patients treated with hysteroscopic tumor resection combined with hormone therapy reported an 89 percent response rate, with an 11 percent recurrence rate [79].
•Bariatric surgery may show promise [80,81]. In a retrospective study including over 1400 female patients with obesity, patients who underwent bariatric surgery had lower rates of cancer compared with patients who did not undergo bariatric surgery (3.5 versus 5.8 percent) [82]. The most frequent cancer in the group who had bariatric surgery was breast (28.3 percent), followed by endometrial (17 percent). In the control group, the most common cancer was endometrial (62.3 percent).
FOLLOW-UP
General considerations after hysterectomy — Following total hysterectomy, if there is no endometrial carcinoma in the specimen, no further surveillance related to EH is necessary. Vaginal cytology is not required for most patients, regardless of whether there is EH or endometrial carcinoma in the surgical specimen. Vaginal cancer is rare. Cytology of the vaginal cuff should be performed only if there is an indication based on the patient's history (eg, cervical intraepithelial neoplasia, in utero exposure to diethylstilbestrol), and not based on the history of EH. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Vaginal cytology'.)
General considerations for patients managed with observation or progestins — For patients with EH (with or without atypia) managed with observation or progestin therapy:
●Careful follow-up is needed to assess for disease persistence, progression, or recurrence. If endometrial carcinoma is found at any time, the patient should be managed as appropriate. (See "Overview of resectable endometrial carcinoma".)
●In patients with exposure to unopposed estrogen, the source should be corrected (if possible), if not already done. Examples include encouraging weight loss, discontinuing unopposed estrogen therapy (including nonprescription medications or topical products) or adding a progestin, correcting ovulatory dysfunction, or, rarely, removing an estrogen-producing neoplasm.
●Median time for regression to normal endometrium on progestin therapy appears to be three (EH without atypia) to nine (EH with atypia) months [14,31-33]; hormone receptor status does not appear to affect the response or relapse rates [83-85].
●The mainstay of follow-up is repeat endometrial sampling, although some postmenopausal patients may be followed with transvaginal ultrasound once endometrial sampling has normalized (see 'EH with atypia: Postmenopausal patients' below). Some experts advise discontinuing oral progestins and waiting for a withdrawal bleed before endometrial sampling is performed, while others sample the endometrium while the patient is on oral progestin therapy [25]; the decidual reaction that occurs with progestin therapy may make it more difficult to interpret pathologic findings. In our practice, we do not discontinue oral progestin therapy prior to sampling.
In patients with an intrauterine device (IUD), an endometrial biopsy may be performed with the device in place.
●Recurrence of EH is usually symptomatic (ie, abnormal uterine bleeding) and requires endometrial sampling.
●Some patients may have persistent or recurrent abnormal uterine bleeding, despite no disease progression on serial endometrial sampling. In such cases, patients may choose hysterectomy to address these bothersome symptoms, but the indication is the symptoms, not EH.
Endometrial surveillance
EH without atypia: Premenopausal patients — For premenopausal patients with a diagnosis of EH without atypia initially managed with observation or progestin therapy, we repeat endometrial biopsy every three to six months for one year (algorithm 1). If endometrial carcinoma is found at any point, hysterectomy is standard therapy; however, select patients are candidates for fertility preservation. (See "Overview of resectable endometrial carcinoma".)
If biopsy results show:
●Normal endometrium and:
•The patient desires pregnancy (and there are no medical contraindications), the patient can try to conceive. (See 'Fertility and pregnancy after treatment' below.)
•If the menstrual pattern normalizes (table 6), repeat endometrial biopsy is not required. With a normal menstrual pattern, it is highly likely that the desired outcome of a balanced endometrium has been achieved.
•If the bleeding pattern does not normalize, progestin therapy or combined estrogen and progestin contraceptives (COCs) is prescribed indefinitely. (See 'Maintenance therapy' below.)
●Persistent EH without atypia, we perform a dilation and curettage (D&C) and hysteroscopy to exclude more severe EH or endometrial carcinoma (algorithm 5). Focal lesions may be missed with office endometrial biopsy, and hysteroscopy allows inspection of the entire uterine cavity. If endometrial curettage results show:
•Normal endometrium, we continue progestin therapy and repeat the endometrial biopsy in three to six months (see 'Maintenance therapy' below). If the biopsy shows:
-Normal endometrium, we treat based on desire for pregnancy and menstrual pattern, as detailed above.
-Persistent EH without atypia, options include one, or a combination, of the following: request a second pathology review, continue progestin therapy and repeat endometrial biopsy in three to six months, reduce modifiable risk factors and repeat endometrial biopsy in three to six months (table 2), consult a gynecologic oncologist.
-EH with atypia, we follow the algorithm for premenopausal patients with a diagnosis of EH with atypia (algorithm 4), which is detailed below. (See 'EH with atypia: Premenopausal patients' below.)
•Persistent EH without atypia, we increase the progestin dose (see 'Maintenance therapy' below) and repeat the endometrial biopsy in three to six months. If the biopsy shows normal endometrium, we treat based on desire for pregnancy and menstrual pattern, as detailed above.
If any EH is found, we discuss the option of definitive surgical management with hysterectomy. Progestin therapy may be continued in select patients who are strongly motivated to preserve fertility, and in those patients willing to accept the risk of early or advanced endometrial carcinoma. Referral to a gynecologic oncologist is also appropriate.
●EH with atypia, we follow the algorithm for premenopausal patients with a diagnosis of EH with atypia (algorithm 4), which is detailed below. (See 'EH with atypia: Premenopausal patients' below.)
EH without atypia: Postmenopausal patients — For postmenopausal patients with a diagnosis of EH without atypia who are treated with progestins, we repeat the endometrial biopsy every three to six months for up to one year (algorithm 2).
If biopsy results show:
●Normal endometrium and:
•The patient has no further bleeding, the need for maintenance therapy is based on the presence or absence of risk factors (see 'Goal of management' above). If no risk factors are present, expectant management is reasonable. Endometrial biopsy is advised if abnormal uterine bleeding recurs.
If risk factors are present, progestin therapy (including combined estrogen-progestin contraceptives [COC]) is prescribed indefinitely. (See 'Maintenance therapy' below.)
•The patient continues to have postmenopausal bleeding, we perform D&C with hysteroscopy to exclude focal pathology. If the biopsy shows normal endometrium, maintenance progestin therapy is initiated and repeat endometrial biopsy is performed every three to six months for up to one year. (See 'Maintenance therapy' below.)
If any EH (with or without atypia) recurs, hysterectomy is performed.
●Persistent EH without atypia, we perform D&C with hysteroscopy to exclude more severe EH or endometrial carcinoma.
•If EH without atypia is found, a consultation with a gynecologic oncologist and/or a second pathology review to confirm the classification is often warranted. The patient may be treated with hysterectomy or a higher total progestin dose (see 'Maintenance therapy' below). If progestin therapy is chosen, repeat endometrial biopsy is performed every three to six months for up to one to two years.
●EH with atypia or endometrial carcinoma, hysterectomy is performed.
EH with atypia: Premenopausal patients — For premenopausal patients with a diagnosis of EH with atypia initially managed with progestin therapy, we repeat endometrial biopsy every three to six months for up to two years (algorithm 4). If endometrial carcinoma is found at any point, hysterectomy is standard therapy; however, select patients are candidates for fertility preservation. (See "Overview of resectable endometrial carcinoma".)
If biopsy results show:
●Normal endometrium – It is reasonable to perform an additional one to two biopsies to confirm the absence of EH or concomitant carcinoma [86]. If normal endometrium is confirmed and the patient desires pregnancy (and there are no medical contraindications), the patient can try to conceive (see 'Fertility and pregnancy after treatment' below). If the patient does not desire pregnancy, maintenance progestin therapy is continued. (See 'Maintenance therapy' below.)
●EH without atypia – We follow the algorithm for premenopausal patients with a diagnosis of EH without atypia (algorithm 1), which is detailed above. (See 'EH without atypia: Premenopausal patients' above.)
●Persistent EH with atypia – We perform D&C with hysteroscopy to exclude endometrial carcinoma (algorithm 6). If the biopsy shows:
•Normal endometrium, we treat based on desire for pregnancy and menstrual pattern, as detailed above.
•EH without atypia, we continue progestin therapy at the same dose (see 'Maintenance therapy' below) and repeat endometrial biopsy is performed in three months. Further follow-up of these patients is detailed in the algorithm (algorithm 6).
•Persistent EH with atypia, we recommend a second pathology review and a consultation with a gynecologic oncologist to discuss management options.
EH with atypia: Postmenopausal patients — Most postmenopausal patients with a diagnosis of EH with atypia are treated with hysterectomy (see 'Preferred treatment: Hysterectomy' above); however, for those patients in whom progestin is prescribed, we perform endometrial sampling every three to six months for two years (algorithm 3).
●If endometrial sampling shows EH, hysteroscopy and D&C should be performed, and stronger consideration is given to hysterectomy. If the patient cannot undergo surgical management, subsequent evaluations should be tailored to the individual patient's current and future risk for endometrial carcinoma, the presence or absence of abnormal uterine bleeding, and/or the severity of medical comorbidities precluding surgical management [87]. Referral to a gynecologic oncologist is appropriate.
●If complete regression of EH is achieved over one to two years and the patient has no bleeding, transvaginal ultrasound may be performed annually. Maintenance progestin therapy is often appropriate and may be continued indefinitely in patients with risk factors for endometrial carcinoma (eg, chronic ovulatory dysfunction, obesity, early menarche, late menopause, increasing age, tamoxifen therapy, Lynch syndrome, Cowden syndrome (table 2)) or in patients with recurrent postmenopausal bleeding [88]. This is discussed in detail below (see 'Postmenopausal patients' below). If transvaginal ultrasound is abnormal (eg, >4 mm endometrial thickness), D&C with or without hysteroscopy should be performed.
MAINTENANCE THERAPY — Following initial progestin treatment, maintenance therapy is often appropriate and may be continued indefinitely in patients with ongoing risk factors for endometrial carcinoma (eg, chronic ovulatory dysfunction, obesity, early menarche, late menopause, increasing age, tamoxifen therapy, Lynch syndrome, Cowden syndrome (table 2)) or persistent postmenopausal bleeding.
In our practice, we prefer the use of the levonorgestrel (LNG)-releasing intrauterine device (IUD [LNG 52 mg]) rather than oral progestins for maintenance therapy in both premenopausal and postmenopausal patients.
Premenopausal patients
●For patients with chronic ovulatory dysfunction that cannot be corrected (eg, polycystic ovary syndrome), a combined estrogen and progestin oral contraceptive (COC) is a good option in those who do not desire pregnancy and prefer not to use an IUD. Progestin therapy may be continued as long as chronic anovulation is present and there are risk factors for the development of EH. (See "Treatment of polycystic ovary syndrome in adults", section on 'Menstrual dysfunction'.)
●For those who cannot or prefer not to take a progestin-containing contraceptive, alternative options for endometrial protection include cyclic or continuous progestins not approved for contraception (table 3).
Postmenopausal patients
●In the absence of hot flashes, we treat with progestin only and prefer the LNG 52 mg.
●For patients with hot flashes, we offer a trial of progestin-only medication. Oral progestins may reduce hot flashes and have not been associated with increased breast cancer risk, although safety data are limited [89-92]. We also encourage behavioral modification (eg, dressing in layers of clothing that can be easily shed, avoiding triggers [such as spicy foods and stressful situations]) to reduce the number of hot flashes. (See "Menopausal hot flashes", section on 'Women with mild hot flashes'.)
●For patients with bothersome hot flashes that do not respond to the above measures and who are candidates for postmenopausal estrogen therapy: For EH at high risk of progression, we use the LNG 52 mg combined with low-dose postmenopausal estrogen, and for low-risk EH, we use a continuous estrogen-progestin regimen. Breast cancer risk with hormonal medication and nonhormonal pharmacotherapy for the treatment of hot flashes are discussed separately. (See "Menopausal hormone therapy: Benefits and risks", section on 'Breast cancer' and "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy'.)
Management of persistence or progression on maintenance therapy — An increase in maintenance therapy is needed when there is progression or persistence of EH. Options include:
●If the patient has the LNG 52 mg, add an oral progestin.
●If the patient is on an oral progestin, the LNG 52 mg can be added, the oral dose increased, or a more potent progestin can be used. (See 'Progestin therapy' above.)
SPECIAL CONSIDERATIONS
Patients on tamoxifen — Tamoxifen, a nonsteroidal selective estrogen receptor modulator (SERM), may be used as adjuvant treatment for patients with estrogen receptor-positive breast cancer or chemoprevention in those at increased risk for breast cancer. However, its use is associated with an increased risk of uterine pathology. The risk of endometrial hyperplasia, as well as management of endometrial hyperplasia in such patients, is discussed in detail separately. (See "Abnormal uterine bleeding and uterine pathology in patients on tamoxifen therapy".)
Proliferative endometrium — Proliferative endometrium is not a form of EH but suggests active estradiol secretion, akin to that seen in the proliferative phase of the menstrual cycle. However, proliferative patterns observed in anovulatory premenopausal patients or in postmenopausal patients, if not corrected, signify an excess of estrogen that may place them at higher risk of developing EH [93,94]. In one retrospective series including over 1800 postmenopausal patients (age ≥55 years) undergoing endometrial biopsy, patients with proliferative endometrium (16 percent) compared with atrophic endometrium had a fourfold increased risk of developing EH (6.2 versus 1.2 percent) or endometrial carcinoma (5.8 versus 1.8 percent) [95]. Of the patients who developed EH or endometrial carcinoma, more than one-half did so five or more years after their initial diagnosis of proliferative endometrium. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis".)
Treatment of proliferative endometrium should be solely based on the nature of the patient's symptoms that prompted the biopsy and the effect of such symptoms on quality of life. In our practice, we favor the levonorgestrel (LNG)-releasing intrauterine device (IUD [LNG 52 mg; Mirena, Liletta]) for premenopausal patients. For postmenopausal patients, consideration can be given to either the LNG 52 mg or oral progestins; however, the LNG 52 is favored in postmenopausal patients with a history of EH.
The frequency and duration of follow-up for such patients is uncertain. For postmenopausal patients, some experts perform endometrial sampling every three to six months for one year [96]; this is consistent with our practice. For premenopausal patients, additional sampling is typically not indicated if their bleeding patterns return to baseline. For premenopausal patients in whom their bleeding does not return to baseline, or with risk factors for endometrial cancer (table 2), we perform endometrial sampling every three to six months for one year.
Fertility and pregnancy after treatment — Many premenopausal patients who choose progestin therapy for treatment of EH may successfully conceive a pregnancy after regression. In two meta-analyses, both evaluating reproductive outcomes following fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma, 30 to 34 percent of patients achieved one or more pregnancies after treatment [97,98]; the live birth rate was between 14 and 35 percent in one study [98].
Patients who choose to try to conceive after regression of EH should stop progestin therapy as some of these medications may prevent ovulation and are not recommended during pregnancy. If the patient does not become pregnant within a year, we repeat an endometrial biopsy annually or more frequently if menses are irregular [99]; consultation with a reproductive endocrinology and infertility specialist is also appropriate.
Following pregnancy, maintenance progestin therapy and/or surveillance with endometrial biopsy is not required if the patient has regular cycles. If regular cycles do not resume, we perform a repeat endometrial biopsy. If contraception is desired, we recommend the LNG 52 mg or continuous combined oral contraceptives (COCs).
Hysterectomy is not recommended after birth in the absence of recurrent EH for most patients. In the case of recurrent EH with atypia in patients who desire further fertility, retreatment with progestins has been utilized [100]. However, a patient's risk factors for EH should be readdressed, and hysterectomy should be considered after the patient has completed childbearing. Patients with a hereditary endometrial cancer syndrome (eg, Lynch syndrome, Cowden syndrome) may be managed differently. (See "Fertility preservation in patients with endometrial carcinoma" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer", section on 'Risk-reducing hysterectomy with delayed or no BSO'.)
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
●Choice of treatment – Endometrial hyperplasia (EH) is categorized into two groups: EH without atypia and EH with atypia (also referred to as endometrial intraepithelial neoplasia [EIN]). EH may progress to, or coexist with, endometrial carcinoma. The choice of treatment (observation, progestin therapy, or hysterectomy) is based on several factors: type of EH (with or without atypia), menopausal status, desire for fertility, contraceptive needs, and risk factors present (table 2). (See 'Introduction' above and 'Goal of management' above.)
●EH without atypia – Untreated EH without atypia has a risk of progression to malignancy of approximately 10 percent or less over 20 years. (See 'Natural history' above.)
•For most patients with EH without atypia, we suggest progestin therapy with endometrial sampling rather than hysterectomy (Grade 2C) (algorithm 1 and algorithm 2). Treatment with progestin therapy reduces the risk of progression to endometrial carcinoma to approximately 2 percent at 10 years. Observation is a reasonable alternative for premenopausal patients who have no risk factors for endometrial carcinoma (table 2) and/or who have contraindications to progestins. For postmenopausal patients with endometrial carcinoma risk factors and/or contraindications to progestins, we discuss surgical management with hysterectomy for definitive management. (See 'Alternate for patients at low risk of progression: Observation' above and 'Preferred: Medical or surgical treatment' above.)
●EH with atypia – Untreated EH with atypia has a risk of progression to endometrial carcinoma of up to 40 percent over 20 years, and coexistent endometrial carcinoma may be present in up to 40 percent of these patients. (See 'Natural history' above.)
•For patients with EH with atypia who are postmenopausal or who are premenopausal and have completed childbearing, we recommend hysterectomy rather than progestin therapy with endometrial sampling (Grade 1B) (algorithm 4 and algorithm 3).
•For premenopausal patients with EH with atypia who wish to preserve fertility, we suggest progestin therapy with endometrial sampling rather than hysterectomy (Grade 2B) (algorithm 4). (See 'Preferred treatment: Hysterectomy' above and 'Alternate treatment: Progestin therapy' above.)
•For most patients undergoing hysterectomy as treatment for EH with atypia, we suggest hysterectomy without bilateral oophorectomy rather than with bilateral oophorectomy (Grade 2C). (See 'Role of oophorectomy and salpingectomy' above.)
●Progestin therapy – Common progestin treatments for EH (any type) include the levonorgestrel (LNG)-releasing intrauterine device (IUD [LNG 52 mg; Mirena, Liletta]), oral megestrol acetate, or oral medroxyprogesterone acetate (MPA (table 3)). Combined oral estrogen-progestin contraceptives (COCs) have not been well studied for EH treatment but are an option for some premenopausal patients. (See 'Progestin therapy' above.)
•For most patients with EH (with or without atypia) undergoing medical management, we suggest the LNG 52 mg rather than systemic progestins (oral, intramural, subcutaneous, or transdermal (Grade 2B)). Studies have demonstrated that the LNG 52 mg compared with oral progestins for the treatment of EH is associated with higher regression rates and lower relapse rates. (See 'Evidence of the efficacy of progestin therapy' above and 'Evidence of the efficacy of progestin therapy' above and 'Choice of progestin' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Giuntoli, II, MD, and Howard Zacur, MD, PhD, who contributed to earlier versions of this topic review.
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