Green-top Guideline No. 67
RCOG/BSGE Joint Guideline | February 2016
Endometrial hyperplasia is defined as irregular proliferation of the endometrial glands with an increase
in the gland to stroma ratio when compared with proliferative endometrium.
The incidence of endometrial hyperplasia is estimated to be at least three times
higher than endometrial cancer and if left untreated it can progress to cancer.
The most common presentation of endometrial hyperplasia is abnormal uterine bleeding.
This includes heavy menstrual bleeding, intermenstrual bleeding, irregular bleeding, unscheduled bleeding on hormone replacement therapy (HRT) and postmenopausal bleeding.
What are the risk factors for endometrial hyperplasia?
increased body mass index (BMI) with excessive peripheral conversion of androgens in adipose tissue to
estrogen
anovulation associated with the perimenopause or polycystic ovary syndrome
(PCOS)
estrogen-secreting ovarian tumours, e.g. granulosa cell tumours (with up to 40%
prevalence of endometrial hyperplasia)
and drug-induced endometrial stimulation, e.g. the use of systemic estrogen replacement therapy or long-term tamoxifen.
elements such as immunosuppression and infection may also be involved.
two-fold increased incidence of endometrial hyperplasia (69% versus 33%) compared with nontransplanted controls.
How should endometrial hyperplasia be classified?
The revised 2014 World Health Organization (WHO) classification is recommended. This separates
endometrial hyperplasia into two groups based upon the presence of cytological atypia
(i) hyperplasia without atypia and (ii) atypical hyperplasia.
it was developed based upon histological characteristics and oncogenic potential.
What diagnostic and surveillance methods are available for endometrial hyperplasia?
Diagnosis requires histological examination of the endometrial tissue.
Endometrial surveillance should include endometrial sampling by outpatient endometrial biopsy.
Diagnostic hysteroscopy should be considered to facilitate or obtain an endometrial sample, especially
where outpatient sampling fails or is nondiagnostic.
TVS may have a role in diagnosing endometrial hyperplasia in pre- and
postmenopausal women.
Direct visualisation and biopsy of the uterine cavity using hysteroscopy should be undertaken where
endometrial hyperplasia has been diagnosed within a polyp or other discrete focal lesion.
There is insufficient evidence evaluating computerised tomography (CT), diffusion-weighted magnetic
resonance imaging (MRI) or biomarkers as aids in the management of endometrial hyperplasia and
their use is not routinely recommended.
Outpatient endometrial biopsy is convenient and has high overall accuracy for diagnosing
endometrial cancer.
Despite a negative biopsy result, 2% of women will still have endometrial hyperplasia.
Systematic reviews have suggested a cut-off of 3 mm or 4 mm for ruling out endometrial cancer and
have shown that the probability of cancer is reduced to less than 1% when the endometrial
thickness is less than the cut-off.
For women with PCOS and absent withdrawal bleeds or abnormal uterine bleeding, a TVS should be considered.
A prospective study of 56 women with PCOS found that no woman with
an endometrial thickness of less than 7 mm had endometrial hyperplasia.
Hysteroscopy with additional endometrial assessment may be necessary if abnormal
bleeding persists or if intrauterine structural abnormalities such as polyps are suspected on
TVS or endometrial biopsy.
A small cohort study has shown that up to 10% of endometrial pathology can be missed even with inpatient endometrial sampling.
hysteroscopy is more accurate in detecting than excluding endometrial disease and
has a higher accuracy for endometrial cancer than endometrial hyperplasia.
How should endometrial hyperplasia without atypia be managed?
The risk of endometrial hyperplasia without atypia progressing to
endometrial cancer is less than 5% over 20 years.
Majority of cases of endometrial hyperplasia without atypia will regress spontaneously during follow-up.
Reversible risk factors are obesity and the use of HRT .
The indication and type of combined HRT regimen should be reviewed.
Ongoing tamoxifen treatment should be reviewed in conjunction with the woman’s oncologist.
Progestogen treatment is indicated in women who fail to regress following observation alone and in
symptomatic women with abnormal uterine bleeding.
Progestogen treatment appears to have higher regression rates (89–96%)46 compared with
observation only (74.2–81%).
Spontaneous regression often occurs in women with hyperplasia without atypia.
What should the first-line medical treatment of hyperplasia without atypia be?
Both continuous oral and local intrauterine (levonorgestrel-releasing intrauterine system [LNG-IUS]
progestogens are effective in achieving regression of endometrial hyperplasia without atypia.
LNG-IUS should be the first-line medical treatment because
compared with oral progestogens it
has a higher disease regression rate with a more favourable bleeding profile and
it is associated with fewer adverse effects.
Continuous progestogens should be used (medroxyprogesterone 10–20 mg/day or norethisterone
10–15 mg/day) for women who decline the LNG-IUS.
Cyclical progestogens should not be used because they are less effective in inducing regression of
endometrial hyperplasia without atypia compared with continuous oral progestogens or the LNG-IUS.
Oral progestogens can have significant adverse effects and norethisterone at a high dose
has similar contraindications to combined contraceptive pills.
The LNG-IUS achieves a higher
concentration of levonorgestrel at the level of the endometrium compared with oral
progestogens.
In women of reproductive age the LNG-IUS can also provide effective contraception and it
is recommended as first-line treatment for heavy menstrual bleeding.
What should the duration of treatment and follow-up of hyperplasia without atypia be?
Treatment with oral progestogens or the LNG-IUS should be for a minimum of 6 months in order to
induce histological regression of endometrial hyperplasia without atypia.
If adverse effects are tolerable and fertility is not desired, women should be encouraged to retain the
LNG-IUS for up to 5 years as this reduces the risk ofrelapse, especially if it alleviates abnormal uterine
bleeding symptoms.
Endometrial surveillance should be arranged at a minimum of 6-monthly intervals, although review
schedules should be individualised and responsive to changes in a woman’s clinical condition.
At least two consecutive 6-monthly negative biopsies should be obtained prior to discharge.
Women should be advised to seek a further referral if abnormal vaginal bleeding recurs after
completion of treatment because this may indicate disease relapse.
In women at higher risk of relapse, such as women with a BMI of 35 or greater orthose treated with oral
progestogens, 6-monthly endometrial biopsies are recommended.
Once two consecutive negative endometrial biopsies have been obtained then long-term follow-up should be considered with annual endometrial biopsies.
Between 3 and 6 months the regression rates improved for the LNG-IUS from 84% to 100% and for oral
medroxyprogesterone from 50% to 64%.
When is surgical management appropriate for women with endometrial hyperplasia
without atypia?
Hysterectomy should not be considered as a first-line treatment for hyperplasia without atypia because
progestogen therapy induces histological and symptomatic remission in the majority of women
and
avoids the morbidity associated with major surgery.
Hysterectomy is indicated in women not wanting to preserve their fertility when
(i) progression to atypical hyperplasia occurs during follow-up, or
(ii) there is no histological regression of hyperplasia despite 12 months of treatment, or
(iii) there is relapse of endometrial hyperplasia after completing progestogen treatment, or
(iv) there is persistence of bleeding symptoms, or
(v) the woman declines to undergo endometrial surveillance or comply with medical treatment
Postmenopausal women requiring surgical management for endometrial hyperplasia without atypia
should be offered a bilateral salpingo-oophorectomy together with the total hysterectomy.
Endometrial ablation is not recommended for the treatment of endometrial hyperplasia because
complete and persistent endometrial destruction cannot be ensured and intrauterine adhesion
formation may preclude future endometrial histological surveillance.
How should atypical hyperplasia be managed?
should undergo a total hysterectomy because of the risk of
underlying malignancy or progression to cancer.
risk of cancer in 4 years was 8% (95% CI 1.31–14.6), which increased to 12.4%
(95% CI 3.0–20.8) after 9 years and to 27.5% (95% CI 8.6–42.5) after 19 years.
Atypical hyperplasia has also been associated with a rate of concomitant carcinoma of up to 43% in
women undergoing hysterectomy.
Lymphadenectomy should not be routinely performed in atypical hyperplasia because this
would result in unnecessary surgical risk for the majority of women.
Although endometrial
cancer has been reported in 43% of cases during hysterectomy, the cancer was usually early
stage with low risk of lymphovascular disease.
How should women with atypical hyperplasia who wish to preserve their fertility or who
are not suitable for surgery be managed?
Histology, imaging and tumour marker results should be reviewed in a multidisciplinary meeting and
a plan for management and ongoing endometrial surveillance formulated.
First-line treatment with the LNG-IUS should be recommended, with oral progestogens as a
second-best alternative.
Once fertility is no longer required, hysterectomy should be offered in view of the high risk of disease
relapse.
observational studies of women with atypical
hyperplasia, the risk of co-existing ovarian cancer was up to 4%, the risk of progression to
higher than stage I endometrial cancer was about 2% and the risk of metastatic disease and
death was about 0.5%.
investigations prior to fertility-sparing
treatment should be undertaken and these include tumour markers such as CA125 and imaging with
TVS and/or MRI scan to rule out co-existing ovarian cancer and invasive endometrial cancer.
fertility-sparing management of atypical hyperplasia is possible, with one-quarter of
women achieving a live birth.
How should women with atypical hyperplasia not undergoing hysterectomy be followed up?
Routine endometrial surveillance should include endometrial biopsy.
Review intervals should
be every 3 months until two consecutive negative biopsies are obtained.
In asymptomatic women with a uterus and evidence of histological disease regression, based upon a
minimum of two consecutive negative endometrial biopsies, long-term follow-up with endometrial
biopsy every 6–12 months is recommended until a hysterectomy is performed.
Failure of atypical endometrial hyperplasia to regress is a worrying sign for underlying
endometrial cancer.
If fertility-sparing therapy fails to induce regression of atypical
hyperplasia by 12 months or there is evidence of progression to cancer, women should be
strongly recommended to undergo hysterectomy.
The risk of relapse is especially high in the first 2 years from diagnosis. If relapse occurs during follow-up, women should also be advised to undergo hysterectomy as it is often associated with endometrial cancer at the final hysterectomy specimen.
How should endometrial hyperplasia be managed in women wishing to conceive?
Disease regression should be achieved on at least one endometrial sample before women attempt to
conceive.
Women with endometrial hyperplasia who wish to conceive should be referred to a fertility specialist
to discuss the options for attempting conception, further assessment and appropriate treatment.
Assisted reproduction may be considered as the live birth rate is higher and it may prevent relapse
compared with women who attempt natural conception.
Prior to assisted reproduction, regression of endometrial hyperplasia should be achieved as this is
associated with higher implantation and clinical pregnancy rates.
Women with endometrial hyperplasia who wish to conceive should be followed up to
ensure disease regression.
Once regression of the endometrial hyperplasia is achieved,
women can be advised to attempt natural conception.
However, as a hyperplastic
endometrium may predispose women to infertility, an early referral for fertility specialist
consultation can be offered as per national recommendations.
Obese women should aim for a BMI of less than 30.
A hysterectomy should be recommended to women with atypical endometrial hyperplasia
once fertility is no longer required because of the high relapse rate of disease and the
potential for disease progression.
HRT and endometrial hyperplasia
Systemic estrogen-only HRT should not be used in women with a uterus.
All women taking HRT should be encouraged to report any unscheduled vaginal bleeding promptly.
All women taking HRT should report any unscheduled vaginal bleeding promptly and be referred for
further investigation.
Stopping sequential combined HRT may be sufficient to induce regression of endometrial hyperplasia.
How should endometrial hyperplasia be managed in women on adjuvant treatment for
breast cancer?
What is the risk of developing endometrial hyperplasia on adjuvant treatment for breast
cancer?
Women taking tamoxifen should be informed about the increased risks of developing endometrial
hyperplasia and cancer.
They should be encouraged to report any abnormal vaginal bleeding or
discharge promptly.
Women taking aromatase inhibitors (such as anastrozole, exemestane and letrozole) should be
informed that these medications are not known to increase the risk of endometrial hyperplasia and
cancer.
Should women on tamoxifen be treated with prophylactic progestogen therapy?
There is evidence that the LNG-IUS prevents polyp formation and that it reduces the incidence of
endometrial hyperplasia in women on tamoxifen.
The effect of the LNG-IUS on breast cancer recurrence
risk remains uncertain so its routine use cannot be recommended.
How should women who develop endometrial hyperplasia while on tamoxifen treatment
for breast cancer be managed?
The need for tamoxifen should be reassessed and management should be according to the histological
classification of endometrial hyperplasia and in conjunction with the woman’s oncologist.
The use of tamoxifen should be reassessed in conjunction
with the woman’s oncologist and an alternative treatment sought if appropriate.
How should endometrial hyperplasia confined to an endometrial polyp be managed?
Complete removal of the uterine polyp(s) is recommended and an endometrial biopsy should be
obtained to sample the background endometrium.
Subsequent management should be according to the histological classification of endometrial
hyperplasia.
Women with atypical hyperplasia in a polyp were slightly more
likely to have hyperplasia in the surrounding endometrium than those with hyperplasia
without atypia.
About the Author
