REVIEW
Endometrial hyperplasia
Elizabeth Moore
Mahmood Shafi
Abstract
Endometrial hyperplasia is an abnormal glandular proliferation of the
endometrium resulting from exposure to unopposed oestrogens of
endogenous and exogenous sources. Endometrial hyperplasia is rare in
women under the age of 30 with an increasing incidence with age and
an overall peak incidence in women aged 50e54 years. Most women
diagnosed with endometrial hyperplasia present with abnormal uterine
bleeding including menorrhagia, inter menstrual bleeding or postmeno-
pausal bleeding. The classification of endometrial hyperplasia is currently
debated but the most widely used classification system (WHO 1994)
defines endometrial hyperplasia as simple or complex with or without aty-
pia. Treatment of endometrial hyperplasia can be medical or surgical and
is dependent on cause, malignant potential, fertility requirements and
medical co-morbidities as well as patient preference.
Keywords abnormal uterine bleeding; endometrial carcinoma; endo-
metrial hyperplasia
Introduction
Endometrial hyperplasia is defined by the National Cancer
Institute as an abnormal overgrowth of the endometrium. It is
stated that there are four types of endometrial hyperplasia:
simple endometrial hyperplasia, complex endometrial hyper-
plasia, simple endometrial hyperplasia with atypia, and complex
endometrial hyperplasia with atypia and that these differ in
terms of how abnormal the cells are and how likely it is that the
condition will become cancer.
This is a simplified definition of a complicated condition,
which is thought to be a histological precursor of type I endo-
metrial cancer. Historically there are inconsistencies in the defi-
nition and terminology of the disease with a poorly understood
natural history and rate of progression to cancer.
Classification
All forms of endometrial hyperplasia share certain morphological
features (Box 1). Hyperplasia is generally a diffuse abnormality
involving much of the endometrium but may be localized.
Elizabeth Moore MRCOG is an ST3 in Obstetrics and Gynaecology at
Watford General Hospital, Watford, UK. Conflicts of interest: none
declared.
Mahmood Shafi MB BCh MD DA FRCOG is a Consultant Gynaecological
Surgeon and Oncologist at Cambridge University Hospitals NHS Foun-
dation Trust, Addenbrookes Hospital, Cambridge, UK. Conflicts of
interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 23:3
Features of endometrial hyperplasia
C Increased gland:stroma ratio
C Irregularities in gland shape
C Cystic dilation
C Budding and branching
C Villous and villoglandular growths
C Cribriform structures
C Evidence of mitotic activity but level variable
C Uterus often enlarged
C Tissues obtained at curettage may be considerable
Box 1
Prior to 1994 there was no standardized terminology or clas-
sification system for endometrial hyperplasia. Lesions tended to
be described as mild, moderate or severe hyperplasia based on
subjective histological assessment.
In 1994 the World Health Organisation (WHO) developed
a classification system for endometrial hyperplasia with an
attempt to correlate morphological features with clinical
outcome. Endometrial hyperplasia was differentiated histologi-
cally with respect to architectural complexities and cytologically
with respect to atypia and defined as simple with or without
atypia or complex with or without atypia. Simple and complex
forms are distinguished by architectural alterations characterized
by glandular complexity, glandular crowding and the amount of
stroma separating glands. The risk of progression to endometrial
carcinoma is closely related to the presence of architectural
crowding and cytological atypia (Table 1).
There is much debate in the literature regarding the WHO
1994 classification for endometrial hyperplasia as it is felt that it
does not meet the required criteria for a classification scheme.
Morphological classification schemes should define criteria that
are easy to assess, are reproducible and are of clinical relevance.
The histological features of the WHO 1994 classification system
are felt to be subject to observer interpretation making them
qualitative rather than absolute. In particular there is no
consensus regarding the cytological features of atypical hyper-
plasia. There also appears to be no consecutive progression
between the classes of endometrial hyperplasia. Inter- and intra-
observer variation of the WHO 1994 classification has been
found to be high with poor reproducibility among pathologists. It
is also felt that the WHO 1994 classification system does not
clearly direct management and that concomitant cancer lesions
may be missed.
An alternative classification system based on molecular
genetics and morphometric features has subsequently been
proposed. This classifies lesions as endometrial hyperplasia
(EH), endometrial intraepithelial neoplasia (EIN) or cancer. It is
argued that this classification system has a stronger biological
underpinning, is more reproducible and highly predictive of
clinical outcome.
The EIN classification system was developed by incorporating
morphometric criteria derived from computer image analysis of
histological sections of atypical endometrial hyperplasia and
88 2013 Published by Elsevier Ltd.
 REVIEW

WHO 1994 classification

Definition Histology Cytology Rate of progression
to cancer

Simple hyperplasia C Endometrial glands predominately C Resembles normal proliferative 0.7e1.5%

without atypia simple (tubular or cystic) structures endometrium but cells larger
C Minimal glandular crowding C Columnar cells
C Low gland:stroma ratio C Amphophilic cytoplasm
C Abundant intervening stroma C Pseudostratified smooth oval nuclei
between glands C Nuclei maintain orientation to
C Varying degrees of irregular underlying basement membrane
branching with infoldings and C Evenly dispersed chromatin
outpouchings C Small nucleoli
C Cells of columnar epithelium C Variable number of mitoses
maintain orientation to underlying
basement membrane
Simple hyperplasia C Nuclei 3e8%
with atypia  Stratification with loss of polarity
 Enlarged, rounded with
irregular shapes
 Coarsening of chromatin
creating a vesicular appearance
 Prominent nucleoli
 Mitotic activity, variable amount
C Cytoplasm
 Eosinophilia, diffuse or focal
C Glands
 Often markedly increased
gland-stroma ratio
Complex hyperplasia C Gland crowding with back to  Identical to simple hyperplasia 3e9%
without atypia back position but with without atypia
Complex hyperplasia intervening stroma present  Identical to simple hyperplasia 20e30%
with atypia C Gland:stroma ratio 2:1 with atypia
C Structural complexity of glands
including outpouchings, infoldings
and budding

Table 1

clinical outcomes. Practically this means that initially the patholo-
gist needs to exclude a mimic of endometrial hyperplasia. These
include disordered proliferation, secretory endometrium and
benign polyps. Invasive carcinoma should be excluded and it
should be confirmed that the sample could be EIN or EH. The
maximum diameter of the lesion then needs to be defined. If <1 mm
it can be classified as hyperplasia with low cancer progression risk.
If >1 mm the area should be demarcated and a morphological D
score measurement is performed in the selected area. The D score is
based on architectural and cytological features including volume
percentage stroma, outer surface area and standard deviation of the
short nuclear axis to give a value of
4 to 4. A D score <0 is
associated with a high risk of progression to cancer (19e38%) and
the lesion is defined as EIN. A D score >1 corresponds to lesion with
low risk of progression to cancer (0e0.6%) and is termed benign. A
score of 0e1 is uncertain and has approximately a 5% risk of
progression to cancer.
Studies have found the EIN classification system to be more
reproducible amongst pathologists in comparison to WHO 1994
classification system, with high correlation with clinical
outcome. Sensitivity, specificity, negative predictive value
(NPV) and positive predictive values (PPV) are all higher for
EIN compared to WHO 1994 (Table 2). However, it is worth
noting that the D score is not applicable to everyday clinical
practice.
There are two further classification systems documented in
the literature; the European classification system and the modi-
fied WHO classification system however these appear to be less
widely discussed. Table 3 illustrates a comparison of the four
major classification systems.
As a result of the difficulties associated with histological
diagnosis of endometrial hyperplasia a competent pathologist as
part of the multi disciplinary management of patients with
possible endometrial hyperplasia is of utmost importance.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 23:3 89 2013 Published by Elsevier Ltd.
 REVIEW

correlate with a similar age of peak incidence in endometrial

Comparison of EIN and WHO 1994 classification
systems
Sensitivity Specificity PPV
EIN 100% 82% 38%
WHO 1994 91% 58% 15%
Table 2
Epidemiology
There is well-documented data on the incidence of endometrial
cancer with 7835 new cases diagnosed in the UK in 2009 and an
estimated lifetime risk of developing endometrial cancer of 1 in
46. There is less robust data regarding the incidence of endo-
metrial hyperplasia.
The overall incidence of endometrial hyperplasia in women
aged between 18 and 90 has been estimated at 133/100,000
women with rates of simple hyperplasia, complex hyperplasia
and atypical hyperplasia estimated at 58/100,000 women, 63/
100,000 women and 17/100,000 women respectively.
It is possible that the rates of endometrial hyperplasia have
been underestimated as the majority of studies looking at the
incidence of endometrial hyperplasia have only looked at
symptomatic women, there have been few studies looking at the
incidence of endometrial hyperplasia via endometrial sampling
in asymptomatic women.
Endometrial hyperplasia is rare in women under the age of 30
with an increasing incidence with age and an overall peak inci-
dence of 386/100,000 women in women aged 50e54 years. The
incidence then appears to decrease, with endometrial hyperplasia
being found to be more common in early postmenopausal
women (within 5 years of menopause) compared to late post-
menopausal women (over 5 years from menopause).
The incidence of simple hyperplasia is highest in women aged
50e54 years with a rate of 142/100,00 women. Similarly the
incidence of complex hyperplasia is highest in this age group
with rates of 212/100,000 women. Rates of atypical hyperplasia
are highest in a slightly older population with a peak incidence of
54/100,000 women in women aged 60e64 years. This appears to
cancer.
Clinical presentation
NPV
Most women diagnosed with endometrial hyperplasia present
100% with abnormal uterine bleeding including menorrhagia, inter
99% menstrual bleeding or postmenopausal bleeding. However, only
a minority of women who present with abnormal uterine
bleeding are subsequently diagnosed with endometrial hyper-
plasia. The incidence of endometrial hyperplasia in women
presenting with abnormal uterine bleeding has been estimated to
be approximately 15%.
It is also worth noting that a small number of women with
endometrial hyperplasia can be asymptomatic. However, it is
possible that these are women with early stage disease and that
symptoms may develop with disease progression leading to
further investigation.
Risk factors
The risk factors for endometrial hyperplasia are the same as
those for endometrial carcinoma, the majority of which are the
result of exposure of the endometrium to oestrogen unopposed
by a progestin. Unopposed oestrogen can be of an endogenous or
exogenous source. It is thought that unopposed oestrogen has
a carcino-mutagenic effect on stromal and glandular cells of the
endometrium leading to hyperplastic lesions. Table 4 outlines
endogenous and exogenous sources of oestrogen exposure.
There should be a high suspicion of endometrial hyperplasia
in any woman with risk factors presenting with abnormal uterine
bleeding.
Hormone replacement therapy
Modern hormone replacement therapy regimes contain oes-
trogen and/or progestogen given in a continuous or cyclical
manner. Women who have not undergone a hysterectomy and
are therefore at risk of developing endometrial cancer are given
a preparation containing both oestrogen and progestogen. The
use of progestogen with oestrogen in a cyclical preparation has
been shown to reduce but not eliminate the risk of endometrial
hyperplasia and endometrial cancer. It has been shown that
5.3% of women taking cyclical oestrogen and progestogen
developed endometrial hyperplasia with 0.7% developing atyp-
ical hyperplasia. There has been no association identified

Classification systems for endometrial hyperplasia

WHO1994 EIN European WHO (modified)

Simple hyperplasia Hyperplasia Hyperplasia Hyperplasia Endogenous and exogenous causes of oestrogen
without atypia without atypia exposure
Complex hyperplasia Endogenous Exogenous
without atypia
Simple hyperplasia EIN Endometrial Hyperplasia Chronic anovulation Oestrogen replacement therapy
with atypia neoplasia with atypia Obesity Tamoxifen
Complex hyperplasia Borderline Diabetes
with atypia Polycystic ovarian syndrome
Carcinoma Carcinoma Carcinoma Hormone secreting tumours

Table 3 Table 4

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 REVIEW
between the use of continuous oestrogen and progestogen
therapy and the development of endometrial hyperplasia.
Tamoxifen
Tamoxifen is a selective oestrogen receptor modulator (SERM)
widely used as adjunctive treatment in postmenopausal women
with oestrogen receptor positive breast cancer. The primary
therapeutic effect of Tamoxifen is its anti-oestrogenic effects on
the breast however, it has pro-oestrogenic effects on the uterus
and bone. The risk of developing endometrial cancer in post-
menopausal women taking Tamoxifen is thought to be 2e3 times
higher than the general population risk. This risk is dependent on
both the dosage and length of Tamoxifen treatment. Currently
the use of Tamoxifen is limited to 5 years as it is thought that the
risks begin to outweigh the benefits at this time point.
The risk of endometrial hyperplasia in women taking
Tamoxifen has been estimated to range from 4 to 30%. Routine
endometrial surveillance for endometrial hyperplasia/carcinoma
in women taking Tamoxifen is not currently recommended
however, women should be closely monitored and investigated
with endometrial sampling should symptoms develop.
If women develop endometrial hyperplasia during Tamoxifen
use the use of Tamoxifen should be reassessed. If Tamoxifen is to be
continued a hysterectomy should be considered for these women.
There is some evidence to suggest that women taking
Tamoxifen can be divided into low and high-risk groups for the
development of endometrial hyperplasia/carcinoma depending
on the pretreatment presence or absence of benign endometrial
polyps. There is therefore a potential role for pretreatment
screening in terms of investigation with ultrasound with or
without hysteroscopy to determine this risk.
Risk of cancer
It is widely accepted that the presence of endometrial hyperplasia
is a risk factor for progression to endometrial carcinoma. Some
argue that endometrial hyperplasia is a precursor lesion in the
natural history of endometrial carcinoma. Estimated rates of
cancer progression for simple endometrial hyperplasia with and
without atypia are low at 0.7e1.5% and 3e8% respectively.
Complex endometrial hyperplasia without atypia has an esti-
mated risk of cancer progression of 3e9%. Complex endometrial
hyperplasia with atypia has the highest rate of progression to
cancer with an estimated risk of 20e30% (Table 1).
More controversially it has been suggested that endometrial
carcinoma may already be present in a significant number of
women with a tissue diagnosis of endometrial hyperplasia.
Studies have found rates of concurrent carcinoma in women
undergoing hysterectomy for endometrial hyperplasia to range
from 17e52%. It is possible that this is due to sampling errors
with endometrial biopsies not accurately assessing the whole of
the endometrium and therefore missing adjacent areas of endo-
metrial carcinoma. This is important when considering treatment
for these women as in women diagnosed with endometrial
hyperplasia a hysterectomy may be undertaken which may be
insufficient treatment for a confirmed diagnosis of endometrial
carcinoma.
It is thought that rates of myometrial invasion may be as high
as 39% in women with concurrent endometrial carcinoma
diagnosed on hysterectomy undertaken for endometrial
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 23:3
hyperplasia. This highlights the potential role of imaging in the
pre-operative assessment of these women in which an MRI scan
may be of benefit. This is however, not currently recommended
in the management of women with endometrial hyperplasia.
Genetics
The understanding of the pathogenesis of endometrial hyper-
plasia and endometrial carcinoma is still incomplete however,
a number of genetic alterations have been identified (Table 5).
Figure 1 illustrates a proposed schema for the development of
endometrial carcinoma from normal endometrial glands.
Endometrial carcinoma is monoclonal in comparison to the
normal endometrium, which is polyclonal. Benign endometrial
polyps as well as endometrial hyperplasia have also been found
to be monoclonal. Clones of atypical hyperplasia have an altered
genotype that is conserved in subsequent carcinoma.
Mutations in PTEN, K-ras and B-catenin genes lead to alter-
ations in signal transduction pathways. Type I endometrial
cancer is molecularly characterized by microsatellite instability
and reduced expression of PTEN, B-catenin and K-ras.
Investigation
There is currently no routine screening test for endometrial
cancer or its precursor lesions.
Currently there is limited guidance for the investigation and
management of postmenopausal bleeding. However, it is advised
that women with postmenopausal bleeding are referred to
a gynaecology cancer unit/center for further investigation as a 2-
week wait referral. Further investigation is likely to include
transvaginal ultrasound scan (USS) and endometrial sampling.
There is less clear guidance about the investigation of abnormal
uterine bleeding in pre-menopausal women.
Thickening of the endometrium on TVUS in postmenopausal
women may indicate the presence of pathology. Currently in the
UK an endometrial thickness over 5 mm requires further inves-
tigation by hysteroscopy and endometrial biopsy due to the risk
of endometrial carcinoma.
Ultrasound has also been used to try and distinguish normal
endometrium from endometrial hyperplasia and endometrial
carcinoma. Endometrial thickness appears to correlate with the
severity of the lesion with an average thickness of 3 mm in
atrophy, 10e12 mm in hyperplasia and 18 mm in carcinoma. By
using a cut-off of 5 mm it is thought that the majority of cases of
Prevalence of molecular alterations in endometrial
hyperplasia and endometrial carcinoma
Atypical Endometrial
hyperplasia carcinoma
PTEN mutation 16.7e36% 26e83%
K-ras mutation 13e22% 15e35%
Microsatellite instability 4.2e50% 28e44%
Beta-catenin mutation 13e35% 23e80%
Table 5
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 REVIEW

Schematic representation progression of normal endometrial glands to endometrial carcinoma

Normal Endometrial Simple/Complex Endometrioid Endometrioid

Glands Hyperplasia Adenocarcinoma G1-2 Adenocarcinoma G3

Hyperoestrogenism MIN Loss of p16

Mutation K-ras HER-2/neu amplification
Mutation PTEN Mutation p53

Figure 1

both endometrial carcinoma and endometrial hyperplasia should
be identified and investigated further.
The initial investigation of women with postmenopausal
bleeding is likely to also include endometrial sampling for example
Pipelle biopsy. Endometrial sampling is undertaken to obtain
a representative tissue sample to enable histological diagnosis.
However, it is widely accepted that endometrial sampling may not
give a representative picture of the entire endometrial cavity.
The gold standard for diagnosis of endometrial hyperplasia is
therefore endometrial biopsy. Most commonly this is undertaken
during hysteroscopy to visualize the endometrial cavity. This can
be performed as an outpatient procedure or under general
anaesthetic. Despite endometrial biopsy being the current gold
standard for the diagnosis of endometrial hyperplasia there are
currently a number of difficulties with the histological diagnosis
and differentiation of the different categories of endometrial
hyperplasia as outlined previously.
Treatment
Treatment of endometrial hyperplasia is yet to be standardized
and there is no randomized control trial evidence to direct
treatment. Treatment is dependent on cause, malignant potential,
fertility requirements and medical co-morbidities as well as
patient preference. Treatment can be medical or surgical but due
to the malignant potential of endometrial hyperplasia all women
with endometrial hyperplasia should be managed by a gynaeco-
logical oncology team. The general principles of treatment are
outlined in Figure 2.
The general principle governing medical management is that
progesterone has an antimitotic effect on endometrial cells by
modulation of the growth stimulatory effects of oestrogen.
Progesterone reduces oestrogen secretion by acting on the
hypothalamicepituitary axis. Progesterone reduces the avail-
ability of oestrogen receptors and induces an increase in oestra-
diol metabolism to a less active form thereby reducing oestrogen
levels. Overall this leads to a reduction in the effects of oestrogen,
which, as outlined above is thought to play a major role in the
pathogenesis of endometrial hyperplasia.
Medical management of endometrial hyperplasia is recom-
mended for those women who are not fit for surgery, for women
who wish to preserve fertility and for women with simple
hyperplasia without atypia. However, there is very little data on
which type of progestin is most effective and there is no guidance
as to what dose over what period of time should be used. There is
little data to support the use of either low or high dose proges-
togens or whether cyclic or continuous treatment is better. Box 2
highlights the variety of options available for the medical
management of endometrial hyperplasia.

Principles of treatment of endometrial hyperplasia

Endometrial
Hyperplasia

Simple Complex Atypical

Hyperplasia Hyperplasia Hyperplasia

Wait and see/ Premenopausal Postmenopausal Premenopausal Postmenopausal

progestogens

Progestogens Progestogens Progestogens Hysterectomy

Hysterectomy Hysterectomy +/ BSO
+/ BSO +/ BSO

Figure 2

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Options for medical management of endometrial
hyperplasia
C Progestins
 Low dose (12e14 days per month)
e Medroxyprogesterone acetate
10e20 mg/day
e Norethindron acetate 5 mg/day
e Micronized progesterone 200 mg
e Megestrole acetate 20e40 mg/day
 High dose (21 days per month)
e Medroxyprogesterone acetate
40e100 mg/day
e Micronized progesterone
300e400 mg/day
e Megestrol acetate 80e160 mg/day
C Oral contraceptives
C Ovulation induction
C Intrauterine devices releasing levonorgesterel
C Danazol
C GnRH analogues
C Aromatase inhibitors
C Intrauterine devices releasing danazol
C Mifepristone
Box 2
It is accepted that a repeat endometrial biopsy is required
every 3e6 months in women undergoing all modes of medical
management to identify any disease progression.
Response rates in women with endometrial hyperplasia
without atypia are encouraging. In women undergoing low dose
progestagen treatment response rates have been estimated at
around 80%, persistence rates 6%, recurrence rates 14% and
cancer progression rates 0%.
In women with endometrial hyperplasia with atypia response
rates to high dose progestagens are variable with an overall
response rate of 87e100% but with significant differences with
respect to type of progestagens used.
Definitive treatment should be sought if carcinoma is found
during follow-up sampling or if hyperplasia persists after 12
months.
Options for surgical management are also varied and include
dilatation and curettage, endometrial ablation or resection and
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 23:3
hysterectomy with or without bilateral salpingo-oophorectomy.
There is current discussion in the literature as to the benefit of
frozen section.
The most widely utilized method of surgical management is
hysterectomy. Ablative techniques are not usually recommended
as this does not enable a definitive histological diagnosis.
Endometrial resection would provide a histological diagnosis but
further treatment may be required if concurrent endometrial
carcinoma with myometrial invasion is identified. Hysterectomy
may also be insufficient treatment if women are found to have
concurrent endometrial carcinoma on definitive histology.
Therefore, consideration is always given to bilateral salpingo-
oophorectomy at the same procedure. Following hysterectomy,
no routine follow-up is necessary.
Conclusion
Endometrial hyperplasia should be considered in the differential
diagnosis in any women presenting with abnormal uterine
bleeding particularly in postmenopausal women who have been
exposed to unopposed oestrogen either from an endogenous or
exogenous source.
A robust classification system for endometrial hyperplasia
based on biological and genetic features is currently required to
give an accurate assessment of the disease burden within the
population, to determine the risk of progression to cancer and to
guide management for patients with this disease. A
FURTHER READING
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2 Baak JPA, Mutter GL. EIN and WHO94. J Clin Pathol 2005; 58:
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3 Gultekin M, Diribas K, Durson P, Ayhan A. Current management of
endometrial hyperplasia and endometrial intraepithelial neoplasia
(EIN). Eur J Gynaecol Oncol 2009; 4: 396e401.
4 Horn LC, Meinel A, Handzel R, Einenkel J. Histopathology of endo-
metrial hyperplasia and endometrial carcinoma. An update. Ann Diagn
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5 Mutter GL. Diagnosis of premalignant endometrial disease. J Clin
Pathol 2002; 55: 326e31.
6 Mills AM, Longacre TA. Endometrial hyperplasia. Semin Diagn Pathol
2010; 27: 199e214.
7 Mazur MT. Endometrial hyperplasia/adenocarcinoma. A conventional
approach. Ann Diagn Pathol 2005; 9: 174e81.
93 2013 Published by Elsevier Ltd.