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 10fold 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 nonEIN 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 [3840] . 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).

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