Endometrial hyperplasia

Authors

Howard A Zacur, MD, PhD

Robert L Giuntoli, II, MD

Marcus Jurema, MD Section Editor

Barbara Goff, MD Deputy Editor

Sandy J Falk, MD

Last literature review version 17.1: January 2009 | This topic last updated: December 29, 2008 (More)

INTRODUCTION — Endometrial hyperplasia is a histological diagnosis. It is characterized by proliferation of endometrial glands resulting in a greater gland-to-stroma ratio than observed in normal endometrium [1] . The proliferating glands vary in size and shape and may show cytological atypia, which may progress to or coexist with endometrial cancer. Endometrial hyperplasia virtually always results from chronic estrogen stimulation unopposed by the counterbalancing effects of progesterone.

CLASSIFICATION — The World Health Organization classification of endometrial hyperplasia is based upon two factors:

(1) The glandular/stromal architectural pattern, which is either simple or complex

(2) The presence or absence of nuclear atypia

Simple versus complex — Normal proliferative and secretory endometrium are shown in the micrograph (show histology 1A-B). In simple hyperplasia, the glands are cystically dilated with only occasional outpouching; mitoses of the glandular cells may or may not be present (show histology 2). Complex hyperplasia consists of endometrial glands that are back-to-back with luminal outpouching and minimal intervening stroma; mitoses may or may not be seen (show histology 3). Also, the gland-to-stroma ratio is higher in complex compared to simple hyperplasia.

Atypia — Simple atypical hyperplasia is characterized by atypical cells lining glands that are separated by significant amounts of normal stroma. By comparison, complex atypical hyperplasia consists of back-to-back crowding of glands lined by atypical cells (show histology 4 and show histology 5). Lipid laden "foam" cells may be noted in the intervening stroma.

Discussion — This classification system is useful, in part, because it correlates well with the risk of developing malignancy. The presence of nuclear atypia is the most worrisome finding. Women with simple hyperplasia without atypia are least likely to develop endometrial carcinoma, whereas women with complex hyperplasia with atypia are most likely to develop carcinoma.

In a classic study, endometrial carcinoma at hysterectomy was more than 10-fold higher in women with a history of atypical hyperplasia (simple or complex) than in women with no atypia (23 and 1.6 percent, respectively) [2] . Cancer occurred after a diagnosis of simple, complex, simple atypical, and complex atypical hyperplasia in 1, 3, 8, and 29 percent of cases, respectively. However, many of these women had some intervention between biopsy and hysterectomy, which was performed 1 to 27 years after initial diagnosis. Others reported that as many as 43 percent of women with atypical hyperplasia had coexistent endometrial cancer when hysterectomy was performed within 12 weeks of diagnosis [3,4] . A literature review noted the frequency of concurrent carcinoma among patients with atypical endometrial hyperplasia ranged from 17 to 52 percent across studies [4] . Unfortunately, few studies were designed to follow large numbers of patients with different types of endometrial hyperplasia over time without intervention [5] .

Most pathologists use the International Society of Gynecologic Pathologists and World Health Organization classification schemes for interpretation of endometrial hyperplasia. Despite this effort to create a prognostic classification scheme using glandular/stromal architecture and the presence or absence of atypical cells, significant interobserver variability among pathologists reviewing the same slides is well described [3,6-8] .

The difficulty of consistent classification of endometrial biopsy specimens was illustrated in a study of five pathologists working within one institution [6] . The authors reported only 69 percent interobserver agreement for the diagnoses of proliferative endometrium, hyperplasia without atypia, atypical hyperplasia, and well-differentiated endometrioid carcinoma. The diagnosis of atypical hyperplasia has the lowest level of agreement: in three large well-designed studies concordance for this diagnosis was only 38 to 47 percent [3,4,6] . Thus, distinguishing simple from complex hyperplasia and, in particular, distinguishing atypical complex hyperplasia from well differentiated endometrial carcinoma remains problematic.

One recommendation for simplifying the classification system is to combine simple and complex hyperplasia into one diagnostic category (endometrial hyperplasia) and to combine complex atypical hyperplasia with well differentiated adenocarcinoma into another (endometrioid neoplasia) [7,9] . This system increases the likelihood that histology from endometrial sampling and from hysterectomy will be concordant for the presence or absence of endometrial carcinoma.

The Endometrial Collaborative Group proposed another alternative using the terms endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), and adenocarcinoma to define distinctive subgroups relevant to clinical management of patients with endometrial disease [10] . EH would apply to the diffuse changes typically observed with anovulation, while EIN would refer to endometrial precancers. These new categories are based on concepts that can be confirmed morphometrically by the semiquantitative determination of the stromal volume in relation to total tissue volume (stroma+epithelium+gland lumen) [11] . Measurements that reflect glandular volume, architectural complexity, and cytologic atypia are used to calculate the D-score (DS). EIN is diagnosed if DS is <1 while a DS ≥ 1 suggests a very low risk of progression to malignancy. The EIN classification system has demonstrated high interobserver reproducibility [12] .

A retrospective multicenter study attempted to evaluate the accuracy of EIN for predicting progression of endometrial hyperplasia [13] . In this study, the performance of the 1994 World Health Organization (WHO94) classification system was compared to the EIN classification system. The authors found that the EIN system was better able to determine lesions most likely to progress to malignancy and those most likely to remain benign. Samples diagnosed as non-EIN were very low risk for progression to malignancy (2 of 359 patients [0.6 percent]). The presence of EIN significantly increased the risk of cancer: 22 of 118 patients (19 percent) with EIN developed malignancy.

By comparison, when the WHO94 system was used, 8 of 354 patients (2 percent) with non-atypical hyperplasia and 16 of 123 patients (13 percent) with atypical hyperplasia developed malignancy. If

EIN was noted in simple atypical hyperplasia, complex hyperplasia without atypia, or complex atypical hyperplasia samples, there was a significant risk of progression to malignancy: 17, 22, and 38 percent, respectively. This suggests that hysterectomy should be considered for such patients. Management of patients with simple hyperplasia with EIN is more uncertain since it is associated with only a 3 percent incidence of progression [13] .

Despite several advantages, the EIN classification system has not gained widespread acceptance.

RISK FACTORS — The risk factors for endometrial hyperplasia are the same as those for endometrial cancer (show table 1). In particular, the risk for both disorders is increased 10-fold in women who use unopposed estrogen replacement therapy (and have not undergone hysterectomy). Similarly, in women who are overweight (body mass index ≥ 25 kg/m2), the risk of endometrial hyperplasia increases with the degree of obesity [14] . (See "Endometrial cancer: clinical features, diagnosis, and screening", section on Risk factors).

ETIOLOGY — Exposure of the endometrium to continuous estrogen unopposed by progesterone can lead to endometrial hyperplasia. This effect appears to be both time and dose dependent for some, but not all, individuals and may be due to endogenous or exogenous hormone.

Endogenous estrogen — The most common source of endogenous unopposed estrogen is chronic anovulation, which can be accompanied by either continued ovarian secretion of estradiol or conversion of the androgens androstenedione and testosterone to estrone and estradiol, respectively, by aromatase in adipocytes. Chronic anovulation is a feature of both the polycystic ovary syndrome (PCOS) and the perimenopausal period (see individual topic reviews).

Secretion of excessive estradiol from an ovarian tumor (eg, granulosa cell tumor) may also result in endometrial hyperplasia. (See "Sex cord-stromal tumors of the ovary").

Obese women have high levels of endogenous estrogen due to the conversion of androstenedione to estrone and the aromatization of androgens to estradiol, both of which occur in peripheral adipose tissue. Obese women also have lower circulating levels of sex hormone binding globulin [15] .

Exogenous estrogen — The risk of unopposed estrogen therapy was illustrated in the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) [16] . Continuous exposure to unopposed estrogen (0.625 mg of conjugated equine estrogens orally daily) resulted in an increased proportion of women being diagnosed with some type of endometrial hyperplasia over the three years of the study. During this period, 62 percent of women who received only estrogen developed endometrial hyperplasia: 21, 24, and 17 percent in the first, second, and third years, respectively, and one-third of these women had complex hyperplasia with or without atypia. By comparison, endometrial hyperplasia developed in only 2 percent of women taking placebo.

The frequency of endometrial hyperplasia appears to be less and the time to onset of the histological change is delayed with lower dose estrogen. In one report, esterified estrogens (0.3 mg orally daily) for two years did not increase the incidence of endometrial hyperplasia compared to controls (1.7 percent in both), while doses of 0.625 and 1.25 mg were associated with a high rate of disease, 28 and 53 percent, respectively [17] .

However, even low dose therapy may not be safe if given for a prolonged period of time. This was demonstrated in a study in which 0.3 mg per day of conjugated equine estrogens given for longer than eight years caused a ninefold increased risk of endometrial cancer [18] . The risk of endometrial hyperplasia was not determined.

The risk of endometrial hyperplasia is not reduced by cyclic unopposed estrogen administration [19,20] . This was illustrated in a study in which 25 women were randomly assigned to receive either continuous or cyclic estrogen therapy and followed with serial endometrial biopsies [20] . The incidence of endometrial hyperplasia was almost 50 percent at one year in both groups (show figure 1) and the excess risk persisted five or more years after cessation of therapy. (See "Postmenopausal hormone therapy: Benefits and risks").

PATHOGENESIS — The ability of estrogen to function as a mitogen is clear, while its ability to act as a mutagen in simulating cellular division and organ growth is controversial. The former effects appear to occur via stimulation of the transcription of genes for cyclin D, protooncogenes, growth factors, and growth factor receptors.

Estrogen may affect the expression of genes leading to altered regulation of cellular signals in the development of endometrial hyperplasia. Additional genetic mutations, which may arise through mechanisms other than those mediated by estrogen, may have a delayed appearance along the

pathway from endometrial hyperplasia to carcinoma. Some genetic mutations are infrequently found in endometrial hyperplasia, but are often noted in endometrial cancer. As an example, mutation of the p53 tumor suppressor gene is not found in endometrial hyperplasia, but can be detected in 20 percent of cases of endometrioid carcinoma [21] and in more than 90 percent of serous tumors of the endometrium, which are estrogen-independent and arise from atrophic, rather than hyperplastic, endometrium [22] .

Knowledge of molecular genetics has led to additional theories of the development of endometrial hyperplasia and cancer [23-25] . Endometrioid adenocarcinomas, which are estrogen-dependent, account for 80 percent of all endometrial cancers and contain K-ras mutations (20 percent of cases), microsatellite instability (20 to 30 percent), and mutations in the PTEN (MMAC1) gene (83 percent) [23-26] . Endometrioid adenocarcinoma appears to arise from endometrial hyperplasia with atypical hyperplasia as an intermediate step. A PTEN gene mutation with loss of expression of the PTEN protein is an early event in this progression [25] , while mutations of ras and mismatch repair genes occur later. In contrast to endometrioid tumors, serous tumors of the endometrium arise from atrophic endometrium and these tumors are unresponsive to estrogen and progestins. Furthermore, almost all of these lesions possess p53 gene mutations, which are rarely seen in endometrioid cancers. (See "Endometrial cancer: clinical features, diagnosis, and screening").

CLINICAL MANIFESTATIONS — The diagnosis of endometrial hyperplasia should be suspected in women with heavy, prolonged, frequent (ie, less than 21 days), or irregular uterine bleeding. Abnormal uterine bleeding in perimenopausal or postmenopausal women is the most common clinical symptom of endometrial neoplasia, although such bleeding is usually (80 percent) due to a benign condition [27] . However, given the real risk of endometrial hyperplasia or carcinoma, all postmenopausal bleeding requires evaluation. (See "Terminology and evaluation of abnormal uterine bleeding in premenopausal women" and see "The evaluation and management of uterine bleeding in postmenopausal women").

SCREENING

General population of women — Screening for endometrial hyperplasia/cancer is generally not warranted in asymptomatic women without familial cancer syndromes. This recommendation is supported by a study in which transvaginal ultrasound examination and endometrial biopsy was performed on 1926 asymptomatic postmenopausal women who had not taken oral or vaginal ERT for six months [28] . The investigators detected one case of endometrial carcinoma and four cases of atypical hyperplasia among 1833 women with an endometrial stripe thickness ≤ 6 mm (ie, normal ultrasound study) (5/1833 or 0.27 percent). They concluded that vaginal ultrasonography

was not an effective screening procedure for the detection of endometrial cancer in asymptomatic women since the risk of missing an endometrial carcinoma using the ≤ 6 mm criteria was comparable to the baseline population risk of endometrial cancer in asymptomatic postmenopausal women reported elsewhere [29] .

Women on tamoxifen — Women taking tamoxifen are at increased risk of developing endometrial hyperplasia, endometrial polyps and microcysts, endometrial cancer, and sarcoma [30] , although the increase in risk is statistically significant only in postmenopausal women [31,32] . Evaluation for endometrial abnormalities in these women is primarily based upon the presence of symptoms (abnormal vaginal bleeding, bloody vaginal discharge, staining, spotting); most investigators do not recommend sonographic screening and routine endometrial biopsy in asymptomatic women [30,33-35] . However, this is a controversial area; some investigators have proposed that patients embarking on tamoxifen therapy should have pretreatment sonographic screening to determine if they have underlying endometrial abnormalities or other characteristics that place them at high risk of developing atypical hyperplasia. As an example, women with endometrial polyps before initiating tamoxifen therapy appear to be at higher risk of developing atypical hyperplasia [36] . This was confirmed in the only study that prospectively evaluated the endometrium of women who were begun on tamoxifen and were known to have preexisting endometrial hyperplasia of various severities [37] . The rate of progression to a more severe degree of endometrial hyperplasia was higher than expected: 5 of 24 patients showed progression.

Hysterectomy is appropriate in women with atypical hyperplasia who must continue on tamoxifen [33] . As these women are not typically considered candidates for systemic progestin therapy, patients with endometrial hyperplasia without atypia can be offered hysterectomy or they can be resampled every six months to be sure there is no progression. Consideration of medical therapy (progestins) should be done in consultation with the patient's medical oncologist. (See "Use of selective estrogen receptor modulators in postmenopausal women" section on Screening for uterine tumors and see "Saline infusion sonohysterography", section on Tamoxifen).

Women with hereditary nonpolyposis colorectal cancer — Screening is indicated in women who are at risk for hereditary nonpolyposis colorectal cancer because of the high risk of endometrial cancer in this population. Specific screening recommendations are provided separately. (See "Endometrial cancer: clinical features, diagnosis, and screening", section on Screening)

DIAGNOSTIC EVALUATION — Endometrial hyperplasia is a histological diagnosis; therefore, an endometrial tissue sample is required for diagnosis. Indications for diagnostic evaluation are listed below.

Indications for endometrial biopsy Abnormal uterine bleeding — An endometrial biopsy should be performed in all women with abnormal uterine bleeding in whom endometrial hyperplasia or carcinoma is a possibility (show table 2). There is an excellent correlation between the histopathology of endometrial specimens taken by Novak or Pipelle biopsy instruments and curettage [38-40] . As an example, one study of women undergoing hysterectomy found failure to diagnose endometrial pathology following preoperative biopsy with the Pipelle, Novak curette, and curettage occurred in approximately 5, 4, and 6 percent of women, respectively [40] . (See "Endometrial sampling procedures").

Ultrasonography has been used for selecting postmenopausal patients most likely to have an abnormal biopsy as an alternative to performing a biopsy on all symptomatic women. We do not suggest this approach because endometrial hyperplasia can be missed. This was illustrated by a clinical study of pelvic sonography and subsequent curettage in over 1100 women with postmenopausal bleeding that found six cases of endometrial hyperplasia (type not specified) in 518 women (1.1 percent) with an endometrial stripe ≤ 4 mm (ie, normal or negative test result) [41] . Focal endometrial hyperplasia has also been observed with a thin endometrial stripe [42] . A detailed discussion of the use of invasive and noninvasive methods of endometrial evaluation can be found separately. (See "Evaluation of the endometrium for malignant or premalignant disease"). Atypical glandular cells — Atypical glandular cells detected by cervical cytology should be investigated with an endometrial biopsy to determine whether endometrial hyperplasia or carcinoma is the cause. (See "Management of atypical and malignant glandular cells on cervical cytology"). Endometrial cells — Asymptomatic women with benign appearing endometrial cells noted on cervical cytology should undergo endometrial biopsy if they are at increased risk of endometrial cancer (eg, >40 years old; family or personal history of ovarian, breast, colon, or endometrial cancer; tamoxifen use; chronic anovulation; obesity; estrogen therapy; prior endometrial hyperplasia; diabetes). (See "Cervical cytology report", section on Benign appearing endometrial cells).

Indications for additional diagnostic evaluation — Indications for additional diagnostic evaluation include. Endometrial hyperplasia with atypia — If endometrial hyperplasia with atypia is diagnosed by office biopsy, further evaluation is needed to exclude a coexistent endometrial adenocarcinoma, which is present in approximately 25 percent of these patients. Dilation and curettage (D & C) can be performed to rule out endometrial cancer. Hysteroscopy with directed biopsies carries a theoretical risk of spreading endometrial cancer cells into the peritoneal cavity if endometrial cancer is present, especially if a fluid distending media is used. Given a risk of endometrial cancer of 35 to 43 percent in these women, hysterectomy should be seriously considered, especially in postmenopausal women or those no longer considering future fertility

(See "Overview of hysteroscopy", section on Dissemination of tumor). Nondiagnostic office biopsy — Endometrial hyperplasia/cancer needs to be excluded in women with a nondiagnostic office biopsy. We suggest dilatation and curettage or hysteroscopy with directed biopsy to determine the cause of bleeding. (See "Evaluation of the endometrium for malignant or premalignant disease"). Persistent bleeding — Endometrial hyperplasia/cancer needs to be excluded if abnormal uterine bleeding persists after a benign endometrial biopsy or treatment of endometrial pathology. Benign endometrial histology includes: atrophy (absence of a hormonal effect), proliferative endometrium (estrogen effect), secretory endometrium (progestin effect), disordered or dyssynchronous endometrium (implies irregular shedding of the endometrium secondary to unopposed estrogen), and endometritis. Transvaginal sonography with or without hysteroscopy/directed biopsy should be performed to determine the cause of bleeding. (See "Evaluation of the endometrium for malignant or premalignant disease").

The possibility of missing endometrial hyperplasia despite a negative blind biopsy was illustrated in a systematic review that determined the accuracy of outpatient endometrial biopsy in diagnosing endometrial hyperplasia in women with abnormal uterine bleeding [43] . Outpatient biopsy results were compared with endometrial histology obtained in the same patient by tissue sampling under anesthesia. A positive test result diagnosed endometrial hyperplasia with a pooled likelihood ratio (LR) of 12.0 (95% CI 7.8-18.6) while a negative test result had a pooled LR of 0.2 (95% CI 0.1-0.3). The posttest probability of endometrial hyperplasia with a positive test result was 57.7 percent (95% CI 41.1-72.7), with a negative test it was 2.2 percent (95% CI 0.9-4.1). Postmenopausal women — In general, further diagnostic evaluation of simple or complex endometrial hyperplasia without atypia is unnecessary in pre- or peri-menopausal women. Obesity, with conversion of androgens to estrogens in adipocytes, or hormone replacement therapy can be considered the probable etiology of endometrial hyperplasia in menopausal women with these risk factors. Clinical concern is greatest when endometrial hyperplasia is diagnosed in a postmenopausal woman in the absence of hormone replacement therapy or obesity. Development of endometrial hyperplasia with or without atypia in a woman who should be estrogen deficient requires an explanation.

Therefore, in the absence of hormone replacement therapy or obesity, we obtain serum estradiol and estrone concentrations in menopausal women with endometrial hyperplasia to exclude the presence of ovarian estrogen producing tumors (normal unconjugated estradiol ≤ 20 pg/mL [73 pmol/L], normal estrone ≤ 5.5 ng/dL [204 pmol/L] in postmenopausal women, may vary by laboratory). If estrogen levels are elevated, we obtain imaging studies of the adrenals and ovaries via sonography (with computed tomography or magnetic resonance imaging as needed).

In the unlikely event that a menopausal woman who is not obese and is not taking hormone replacement has endometrial hyperplasia and no elevation of her serum estradiol or estrone level, we would attempt to determine if other estrogenic drugs or medications or creams had been used by the patient. As an example, unopposed ethinyl estradiol may cause endometrial hyperplasia, but this would not be detected in an estradiol or estrone assay because the antibodies used in these immunoassays would not cross react with the ethinyl estradiol molecule. This is also true for some of the estrogens that are contained in topical creams. Endometrial cancer — Endometrial biopsy may show endometrial cancer. Consultation with a gynecologic oncologist is warranted for these patients. (See "Endometrial cancer: Staging, treatment, and follow-up").

TREATMENT — The purpose of treating simple or complex endometrial hyperplasia without atypia is to control abnormal uterine bleeding, which is the most common presentation of the disorder, and to prevent progression to cancer, although this risk is very low (<1 to 3 percent) and controversial [44] . Atypical endometrial hyperplasia also requires therapy, but due to the significant risk of endometrial cancer (17 to 53 percent), treatment recommendations typically include surgery.

Studies have consistently shown that progestins are an effective treatment of endometrial hyperplasia [45-56] . The response rate is highest in women without atypia and with therapy of at least 12 to 14 days per month. In a representative example, a series of 376 women with varying degrees of endometrial hyperplasia treated with a progestin for 7, 10, or 13 days each month for three to six months reported complete regression in 81, 98, and 100 percent of patients, respectively [47] .

Progestins reverse endometrial hyperplasia by activation of progesterone receptors, which results in stromal decidualization and subsequent thinning of the endometrium. Progestin exposure also decreases estrogen and progesterone receptors and activates hydroxylase enzymes to convert estradiol to its less active metabolite estrone [57] . Although the efficacy of progestins for reversing endometrial hyperplasia is proven, whether endometrial hyperplasia without atypia needs to be treated and whether endometrial cancer can be prevented in patients who discontinue therapy is controversial [58] .

The type of progestin, dose, and duration of treatment for endometrial hyperplasia varies widely. We recommend different treatment options depending upon the presence or absence of atypia and the menopausal status of the patient. Whether hyperplasia is simple or complex is not a factor. If regression is achieved on progestins, recurrences can be prevented by administering preventive progestin therapy (see "Prevention" below).

Premenopausal women No atypia — We typically suggest a course of treatment with progestins with follow-up sampling to document regression. We prescribe medroxyprogesterone acetate (MPA) 10 mg daily for 12 to 14 days each month for three to six months. Regression has been noted in 52 of 65 patients (80 percent) with hyperplasia without atypia treated with MPA [48] . Continuous progestin administration for three to six months may also be pursued. Micronized progesterone (100 to 200 mg) in a vaginal cream is an alternative to MPA. It resulted in regression of endometrial hyperplasia without atypia to normal endometrium in 91 percent of women treated from the 10th to the 25th day of the menstrual cycle for three to six months, with a relapse rate of 6 percent six months posttreatment [49] .

Ovulation induction is another option for younger women with endometrial hyperplasia without atypia who desire pregnancy.

Insertion of a levonorgestrel containing intrauterine contraception (IUC) is also effective, especially in women who desire this type of contraceptive [50-52] . Endometrial biopsy can be performed with an IUC in place. (See "Approach to intrauterine contraception").

Given the high rate of regression, conservative management of asymptomatic women with endometrial hyperplasia without atypia is also an option.

After treatment, we suggest initiating preventative treatment if the patient has not resumed normal cyclic menstrual function (see "Prevention" below). We rebiopsy if abnormal uterine bleeding recurs. With atypia — Endometrial hyperplasia with atypia on initial endometrial biopsy is further evaluated by D & C (see "Diagnostic evaluation" above). If the diagnosis is confirmed and there is no coexistent adenocarcinoma, treatment with continuous oral megestrol acetate 40 mg twice per day every day is initiated in women who wish to preserve childbearing potential, and may be increased to four times per day [53,59] .

Alternatively, resolution of atypical hyperplasia has been described in patients treated with a levonorgestrel-releasing intrauterine system and in women given a daily oral dose of 600 mg of MPA with low-dose aspirin [59-61] .

A repeat endometrial biopsy should be performed in three months, although one group reported that the median time for regression on progestin therapy was nine months [53] . A follow-up study suggested that persistent disease at seven to nine months was predictive of treatment failure [59] . Hysterectomy is recommended for treatment failures.

Once endometrial sampling has demonstrated successful regression with no evidence of hyperplasia, we suggest that the patient actively pursue fertility options. If childbearing is delayed, we suggest continuing progestin therapy. Options include megestrol acetate, MPA, oral contraceptive pills, depot medroxyprogesterone acetate, or a progestin releasing intrauterine contraception [50-52,54,55] . Repeating an endometrial biopsy every 6 to 12 months should be considered initially. After a normal biopsy on a maintenance regimen and resumption of normal cyclic menses, less frequent endometrial sampling is reasonable.

Hysterectomy is considered the treatment of choice for women who are not planning future pregnancy or who are unwilling or unable to comply with medical therapy and follow-up endometrial sampling.

Postmenopausal women No atypia — If ovarian/adrenal tumors and use of exogenous hormone therapy have been excluded (see "Diagnostic evaluation" above), we suggest treatment with continuous medroxyprogesterone acetate (MPA) 10 mg daily for three months. A follow-up endometrial biopsy should be performed immediately after cessation of drug therapy. In one study including 65 patients, this regimen resulted in regression of simple and/or complex endometrial hyperplasia to normal endometrium after three months of therapy in 86 percent of patients, with a relapse rate of 6 percent after discontinuing therapy [48] . No patient developed endometrial cancer.

If follow-up endometrial biopsy shows persistent endometrial hyperplasia without atypia and the patient continues to have bleeding, a hysterectomy should be offered or consideration can be given to continued treatment with follow up biopsies every 6 to 12 months. If endometrial hyperplasia has regressed, then treatment is discontinued with repeat diagnostic evaluation if postmenopausal bleeding recurs.

If the woman is taking hormone replacement therapy at diagnosis of endometrial hyperplasia, the hormones should be discontinued and MPA initiated as described above. If MPA treatment is successful, and resumption of hormone replacement therapy is desired, then concurrent progestin

treatment at higher doses and for longer intervals is advised with a repeat endometrial biopsy in three to six months. (See "Preparations for postmenopausal hormone therapy" and see "Treatment of menopausal symptoms with hormone therapy").

Postmenopausal women with endometrial hyperplasia unrelated to exogenous estrogen or an ovarian neoplasm are often obese. (See "Etiology" above, section on endogenous estrogen). We encourage these patients to lose weight and treat them with MPA as described above. With atypia — Endometrial hyperplasia with atypia is considered a premalignant condition, preferably treated with hysterectomy. At the time of surgery, the hysterectomy specimen should be assessed by the pathologist for endometrial cancer and staging should be performed if endometrial cancer is identified. If hysterectomy is not felt to be an option, continuous oral megestrol acetate at doses of 40 mg two to four times per day (or MPA 10 mg/day) can be administered after coexistent endometrial cancer has been excluded by hysteroscopy with directed biopsies. An endometrial biopsy should be performed after three months of therapy. Continuous maintenance megestrol acetate (or MPA) is an option if there is regression; however, follow-up endometrial biopsies should be performed every 6 to 12 months, indefinitely. Hysterectomy is advisable if atypia persists since there is a high risk of a subsequent diagnosis of endometrial cancer either because of progression or incomplete sampling.

Other therapies — Several other approaches are under investigation: Gonadotropin-releasing hormone (GnRH) analogs can be given to produce a pseudomenopausal state [62-64] . In one report, approximately 86 percent of women (mean age 46 years) had regression of hyperplasia without atypia to normal endometrium after six months of GnRH agonist treatment; however, this regimen was not effective in the three women with atypia [62] . Hysteroscopic resection of endometrial hyperplasia was reported to be effective in 68 of 73 treated women, but the long term consequence of this treatment remains to be determined [65] . Danazol has also been used successfully, but has significant side effects [66-70] . In a series of postmenopausal women, danazol (400 mg per day for six months) caused complete regression in only 83 percent of patients, with 8 percent relapse within four months of discontinuing therapy [66] .

PREVENTION

Endogenous estrogen source — A medical disease or tumor resulting in chronically unopposed endogenous estrogen secretion should be treated as appropriate for the underlying etiology (eg, thyroid hormone replacement in hypothyroid women). If treatment of the underlying etiology does not restore normal ovulatory cycles (eg, cirrhosis), then we suggest use of one of the regimens described below to prevent development of endometrial hyperplasia.

The increased risk of endometrial hyperplasia in women with chronic anovulation, such as with polycystic ovary syndrome, is best treated by combined estrogen-progestin therapy, such as oral contraceptive pills (OCs). This provides daily exposure to a progestin, which antagonizes the endometrial proliferative effect of estrogen. It also inhibits ovarian androgen production by inhibiting gonadotropin secretion and raises sex hormone-binding globulin production, so that the free testosterone concentration falls more than total testosterone concentration. (See "Diagnosis of polycystic ovary syndrome in adults" and see "Treatment of polycystic ovary syndrome in adults").

Alternative treatments for primary endometrial protection in women who cannot or prefer not to take OCs include intermittent or continuous progestins. Intermittent therapy should be continued as long as chronic anovulation is present: Medroxyprogesterone acetate (5 to 10 mg) daily for 12 to 14 days per month Norethindrone acetate (5 to 15 mg) daily for 12 to 14 days per month Micronized progesterone in a vaginal cream (200 mg) daily for 12 to 14 days per month Depot medroxyprogesterone acetate (150 mg intramuscularly) every three months Levonorgestrel intrauterine contraception (Mirena®), which releases 15 to 20 mcg of levonorgestrel daily. (See "Approach to intrauterine contraception", section on Levonorgestrel IUC).

There are no strong data supporting the use of one of these regimens over another. Choice of regimen therefore depends upon issues such as cost, convenience, and side effects.

Women who experience significant side effects (eg, irritability, depression, headaches) from progestin therapy may require an adjustment in dose, type of progestin, or interval of progestin administration. As an example, a woman who does not tolerate MPA 5 to 10 mg given cyclically may be able to tolerate 2.5 mg given continuously.

Obese women should be encouraged to lose weight, which has multiple health benefits in addition to reduction of estradiol and estrone production by adipocytes. (See "Health hazards associated with obesity in adults" and see "Overview of therapy for obesity in adults").

Exogenous estrogen source — Among women treated with estrogen replacement therapy, the excess risk of endometrial hyperplasia and carcinoma can be largely abolished by concurrent therapy with a progestin. As an example, the PEPI trial showed that, compared to unopposed estrogen therapy, combined estrogen-progestin therapy or placebo led to marked reductions in

the incidence of simple (0.8 versus 27.7 percent), complex (0.8 versus 22.7 percent), and atypical hyperplastic (zero versus 11.8 percent) endometrial lesions [16] . In the PEPI trial and in a review from the Cochrane Database, at least 12 days of progestin therapy per month was as effective as continuous low-dose progestin [16,71] . There are data suggesting that shorter duration progestin therapy is not as protective [19,71-73] . This issue is discussed in detail elsewhere. (See "Postmenopausal hormone therapy: Benefits and risks", section on Protective effect of progestins).

SUMMARY AND RECOMMENDATIONS Endometrial hyperplasia is classified as simple or complex and with or without atypia. Complex endometrial hyperplasia with atypia can be difficult to distinguish from endometrial cancer. (See "Classification" above). Simple hyperplasia without atypia is unlikely to progress to malignancy, while approximately 30 percent of women with untreated complex hyperplasia with atypia will develop a malignancy. (See "Classification" above). Endometrial hyperplasia almost always results from unopposed estrogen stimulation. Causes of unopposed estrogen are anovulation, obesity, exogenous hormone treatment without a progestin, and estrogen producing ovarian tumors (rare). (See "Etiology" above). Endometrial biopsy should be performed in women with abnormal uterine bleeding or with abnormal cells on cervical cytology in whom endometrial hyperplasia or carcinoma is a possibility (show table 2). Further diagnostic testing is indicated in some patients. (See "Diagnostic evaluation" above). We suggest progestins rather than surgery or no intervention for treatment of endometrial hyperplasia without atypia (Grade 2B). Medical treatment prevents abnormal uterine bleeding, preserves fertility in premenopausal women, and reverses endometrial hyperplasia. (See "Treatment" above). We recommend hysterectomy for women with endometrial hyperplasia with atypia, given its premalignant potential and the risk of undiagnosed coexisting endometrial cancer (Grade 1B). Women who have not completed childbearing or are poor surgical candidates can be managed with a progestin and serial endometrial biopsies to monitor the endometrium. (See "Treatment" above). We suggest that anovulatory or oligo-ovulatory reproductive-aged women and women receiving estrogen replacement therapy receive progestins for prevention of endometrial hyperplasia (Grade 2B). There is no standard type, dose, or duration of progestin therapy. Options depend upon the specific needs of the individual (show table 3). (See "Prevention" above).

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

Kurman, RJ, Norris, HJ. Endometrial hyperplasia and related cellular changes. In: Blaustein's Pathology of the Female Genital Tract, 4th ed, Kurman, RJ (Ed), New York: Springer-Verlag, 1994. p. 441. Kurman, RJ, Kaminski, PF, Norris, HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985; 56:403. Zaino, R, Kauderer, J, Trimble, CL, et al. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a

gynecologic oncology group study. Cancer 2006; 106:804. Trimble, CL, Kauderer, J, Zaino, R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006; 106:812. Wentz, WB. Progestin therapy in endometrial hyperplasia. Gynecol Oncol 1974; 2:362. Kendall, BS, Ronnett, BM, Isacson, C, et al. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am J Surg Pathol 1998; 22:1012. Bergeron, C, Nogales, FF, Masseroli, M, et al. A multicentric European study testing the reproducibility of the WHO classification of endometrial hyperplasia with a proposal of a simplified working classification for biopsy and curettage specimens. Am J Surg Pathol 1999; 23:1102. Skov, BG, Broholm, H, Engel, U, et al. Comparison of the reproducibility of the WHO classifications of 1975 and 1994 of endometrial hyperplasia. Int J Gynecol Pathol 1997; 16:33. Fox, H, Buckley, CH. The endometrial hyperplasias and their relationship to endometrial neoplasia. Histopathology 1982; 6:493. Mutter, GL. Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The Endometrial Collaborative Group. Gynecol Oncol 2000; 76:287. Dietel, M. The histological diagnosis of endometrial hyperplasia. Is there a need to simplify?. Virchows Arch 2001; 439:604. Baak, JP, Orbo, A, van Diest, PJ, et al. Prospective multicenter evaluation of the morphometric D-score for prediction of the outcome of endometrial hyperplasias. Am J Surg Pathol 2001; 25:930. Baak, JP, Mutter, GL, Robboy, S, et al. The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer 2005; 103:2304. Epplein, M, Reed, SD, Voigt, LF, et al. Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history. Am J Epidemiol 2008; 168:563. Potischman, N, Swanson, CA, Siiteri, PK, Hoover, RN. Reversal of relation between body mass and endogenous estrogen concentrations with menopausal status. J Natl Cancer Inst 1996; 88:756. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996; 275:370. Genant, HK, Lucas, J, Weiss, S, et al. Low-dose esterified estrogen therapy. Arch Intern Med 1997; 157:2609. Cushing, KL, Weiss, NS, Voigt, LF, et al. Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol 1998; 91:35. Weiderpass, E, Adami, HO, Baron, JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91:1131. Schiff, I, Sela, HK, Cramer, D, et al. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril 1982; 37:79. Kohler, MF, Nishii, H, Humphrey, PA, et al. Mutation of the p53 tumor-suppressor gene is not a feature of endometrial hyperplasias. Am J Obstet Gynecol 1993; 169:690. Tashiro, H, Isacson, C, Levine, R, et al. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 1997; 150:177. Sherman, ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol 2000; 13:295. Ali, IU. Gatekeeper for endometrium: the PTEN tumor suppressor gene. J Natl Cancer Inst 2000; 92:861. Mutter, GL, Lin, McFitzgerald, JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924. Boland, CR, Thibodeau, SN, Hamilton, SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria

for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58:5248. Lerner, J, Timor-Tritsch, I, Monteagudo, A. Use of transvaginal sonography in the evaluation of endometrial hyperplasia and carcinoma. Obstet Gynecol Surv 1996; 51:718. Fleischer, AC, Wheeler, JE, Lindsay I, I, et al. An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 2001; 184:70. Archer, DF, McIntyre-Seltman, K, Wilborn, WW Jr, et al. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol 1991; 165:317. Cohen, I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 2004; 94:256. Fisher, B, Costantino, JP, Wickerham, DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371. Cheng, WF, Lin, HH, Torng, PL, Huang, SC. Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients. Gynecol Oncol 1997; 66:233. ACOG Committee Opinion No. 336: Tamoxifen and Uterine Cancer. Obstet Gynecol 2006; 107:1475. Bornstein, J, Auslender, R, Pascal, B, et al. Diagnostic pitfalls of ultrasonographic uterine screening in women treated with tamoxifen. J Reprod Med 1994; 39:674. Lahti, E, Blanco, G, Kauppila, A, et al. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 1993; 81:660. Berliere, M, Charles, A, Galant, C, Donnez, J. Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol 1998; 91:40. Garuti, G, Cellani, F, Centinaio, G, et al. Histopathologic behavior of endometrial hyperplasia during tamoxifen therapy for breast cancer. Gynecol Oncol 2006; 101:269. Lipscomb, GH, Lopatine, SM, Stovall, TG, Ling, FW. A randomized comparison of the Pipelle, Accurette, and Explora endometrial sampling devices. Am J Obstet Gynecol 1994; 170:591. Silver, MM, Miles, P, Rosa, C. Comparison of Novak and Pipelle endometrial biopsy instruments. Obstet Gynecol 1991; 78:828. Stovall, TG, Solomon, SK, Ling, FW. Endometrial sampling prior to hysterectomy. Obstet Gynecol 1989; 73:405. Karlsson, B, Gransberg, S, Wikland, M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding - A nordic multicenter study. Am J Obstet Gynecol 1995; 172:1488. Van den, Bosch T, Vandendael, A, Van Schoubroeck, D, et al. Combining vaginal ultrasonography and office endometrial sampling in the diagnosis of endometrial disease in postmenopausal women. Obstet Gynecol 1995; 85:349. Clark, TJ, Mann, CH, Shah, N, et al. Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial hyperplasia. Acta Obstet Gynecol Scand 2001; 80:784. Clark, TJ, Neelakantan, D, Gupta, JK. The management of endometrial hyperplasia: an evaluation of current practice. Eur J Obstet Gynecol Reprod Biol 2006; 125:259. Eichner, E, Abellera, M. Endometrial hyperplasia treated by progestins. Obstet Gynecol 1971; 38:739. Gal, D, Edman, CD, Vellios, F, Forney, JP. Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia. Am J Obstet Gynecol 1983; 146:316. Gambrell, RD Jr. Progestogens in estrogen-replacement therapy. Clin Obstet Gynecol 1995; 38:890. Ferenczy, A, Gelfand, M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol 1989; 160:126. Affinito, P, Di Carlo, C, Di Mauro, P, et al. Endometrial hyperplasia: efficacy of a new treatment with a vaginal cream containing natural micronized progesterone. Maturitas 1994; 20:191. Perino, A, Quartararo, P, Catinella, E, et al. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil 1987; 18:137.

Wildemeersch, D, Dhont, M. Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Am J Obstet Gynecol 2003; 188:1297. Vereide, AB, Arnes, M, Straume, B, et al. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol 2003; 91:526. Randall, TC, Kurman, RJ. Progestin treatment of atypical hyperplasia and well- differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997; 90:434. Dhar, KK, Needhirajan, T, Koslowski, M;, Woolas, RP. Is levonorgestrel intrauterine system effective for treatment of early endometrial cancer? Report of four cases and review of the literature. Gynecol Oncol 2005; 97:924. Montz, FJ, Bristow, RE, Bovicelli, A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002; 186:651. Lindahl, B, Willen, R. Endometrial hyperplasia. Clinico-pathological considerations of a prospective randomised study after abrasio only or high-dose gestagen treatment. Results of 2 years follow-up of 292 patients. Anticancer Res 1991; 11:403. Casper, RF. Regulation of estrogen/progestogen receptors in the endometrium. Int J Fertil Menopausal Stud 1996; 41:16. Lindahl, B, Willen, R. Spontaneous endometrial hyperplasia. A prospective, 5 year follow-up of 246 patients after abrasio only, including 380 patients followed-up for 2 years. Anticancer Res 1994; 14:2141. Wheeler, DT, Bristow, RE, Kurman, RJ. Histologic alterations in endometrial hyperplasia and well-differentiated carcinoma treated with progestins. Am J Surg Pathol 2007; 31:988. Wildemeersch, D, Janssens, D, Pylyser, K, et al. Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up. Maturitas 2007; 57:210. Ushijima, K, Yahata, H, Yoshikawa, H, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007; 25:2798. Grimbizis, G, Tsalikis, T, Tzioufa, V, et al. Regression of endometrial hyperplasia after treatment with the gonadotrophin-releasing hormone analogue triptorelin: a prospective study. Hum Reprod 1999; 14:479. Colacurci, N, De Placido, G, Galasso, M, et al. The use of GnRH agonists depot for the treatment of dysfunctional uterine bleeding. Acta Eur Fertil 1991; 22:229. Pace, S, Figliolini, M, Grassi, A, et al. Low-risk endometrial hyperplasia: hysteroscopy and histologic evaluation after treatment with LH-RH analogue. Clin Exp Obstet Gynecol 1994; 21:79. Cianferoni, L, Giannini, A, Franchini, M. Hysteroscopic resection of endometrial hyperplasia. J Am Assoc Gynecol Laparosc 1999; 6:151. Mariani, L, Sedati, A, Giovinazzi, R, et al. Postmenopausal endometrial hyperplasia: role of danazol therapy. Int J Gynaecol Obstet 1994; 44:155. Bulletti, C, Jasonni, VM, Tabanelli, S, et al. Danazol reverses endometrial hyperplasia to normal endometrium. Acta Eur Fertil 1987; 18:185. Soh, E, Sato, K. Clinical effects of danazol on endometrial hyperplasia in menopausal and postmenopausal women. Cancer 1990; 66:983. Sedati, A, Mariani, L, Giovinazzi, R, et al. The effectiveness of danazol therapy in postmenopausal women affected by endometrial hyperplasia. Clin Exp Obstet Gynecol 1992; 19:161. Grio, R, Piacentino, R, Marchino, GL, et al. Danazol in the treatment of endometrial hyperplasia. Panminerva Med 1993; 35:231. Lethaby, A, Farquhar, C, Sarkis, A, et al. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2000; :CD000402. Whitehead, MI, Fraser, D. The effects of estrogens and progestogens on the endometrium. Modern approach to treatment. Obstet Gynecol Clin

North Am 1987; 14:299. Cerin, A, Heldaas, K, Moeller, B. Adverse endometrial effects of long-cycle estrogen and progestogen replacement therapy. The Scandinavian LongCycle Study Group. N Engl J Med 1996; 334:668.