ENDOMETRIAL HYPERPLASIA

ABSTRACT

Endometrial hyperplasia affects more than 60.000 women annually in the US.
Thus, appropriate diagnostic algorithm should be performed to conduct the most
proper treatments in order to improve the outcomes of the patient. Risk factors
reported to have the biggest impacts on endometrial hyperplasia are nulliparity
and the increasing BMI. Other risky conditions involve early onset of menarche,
late onset of menopause, diabetes, and chronic anovulation.
The necessity of histological examination is to diagnose the endometrial
hyperplasia. Some sampling methods for endometrial tissue includes pipelle,
dilatation and curettage, and hysteroscopic targeted biopsy. Hysterescopy and
transvaginal ultrasound are also reported to have a role in diagnosing endometrial
hyperplasia.
The three most common options for the management of EH are surveillance,
progestin therapy, and hysterectomy. Other treatment approaches include
pharmacologic treatments other than progestins or conservative surgical treatment.
All management strategies should also be accompanied by removal of the
extrinsic or intrinsic source of unopposed estrogen since excess exposure to
estrogen is a main etiology of endometrial neoplasia.

Keywords: diagnostic, endometrial hyperplasia, management of endometrial

hyperplasia

1
 INTRODUCTION

Endometrial hyperplasia affects approximately 60,000 women per year in the

United States. The mean age of diagnosis is 63 years. It is estimated that
approximately 5% of endometrial cancer cases are diagnosed before the age of 40.
Of the 2 types of endometrial cancer, endometrial adenocarcinoma (or type 1) is
estrogen-dependent and accounts for 85% of all endometrial cancers. This type is
preceded by endometrial intraepithelial neoplasia, which was previously described
as complex estrogen is one of the main risk factors for endometrial hyperplasia
and cancer and can be due to untreated chronic anovulation (as in polycystic ovary
syndrome [PCOS]), conversion of testosterone to estrogen in adipose Other risk
factors include nulliparity, white race, and Lynch syndrome.1

Although endometrial hyperplasia and cancer are rare, the consequences can be
devastating, because the treatment often includes a hysterectomy. An endometrial
cancer diagnosis is made using endometrial sampling, which is recommended in
all women older than age 45 with abnormal uterine bleeding (AUB), and in
younger women with risk factors. Because endometrial sampling is an invasive
and uncomfortable procedure, it is often not performed in young women with
AUB because AUB commonly occurs in adolescents, whereas hyperplasia and
endometrial cancer do not. Little is known about endometrial cancer, its
precursors, or its risk factors in young women. The purpose of this study was to
assess characteristics of women with endometrial hyperplasia or cancer to identify
risk factors and the management.2,3

Case
Ms. M, 47 years old, came with chief complain of vaginal bleeding since 14 days
before admission. The bleeding made the patient change pad for 3 times every
day. Significant weight loss was not complained. Patient denied having nausea
vomiting and abdominal pain. Defecation and urination were normal. Patient also
suffered from hypertension that was daily treated by amlodipine 1x5 mg. She had
menarche at 12 yo, regular menstrual cycle before, without dysmenorrhea. More
detailed menstrual diary can be seen in picture 1.

2
 Picture 1. Menstrual diary
No history of cigarette smoking, no history of Diabetes Mellitus, and no history of
hormonal pills. Patient had already given birth to two kids through normal
spontaneous vaginal delivery method 20 and 17 years ago. On physical
examination, patient’s blood pressure was 170/110 mmHg. No abnormalities in
the general physical examination. On gynecological examination was seen erosion
on the portio at the direction of 11 o’clock and bleeding by palpation. Fluor was
also seen. Rectal vaginal touche examination showed no abnormalities.
Laboratory test showed the Hb level of 5.2 mg/dL. US exam was performed on
the same day when patient came to the ER. It showed an anteflexed uterus with
the size of 87x58x60 mm, endometrium sized 12 mm, a cyst in the uterus sized 36
mm. Follicular retention was seen in the left ovary. The right ovary could not be
observed. Cervical mass was not observed.
Based on all the data that had been achieved, patient was assessed with abnormal
uterine bleeding on P2A0 due to acute cervicitis and anemia due to blood loss.
Blood transfusion with the targeted Hb of 10 mg/dL, primolut 2x5 mg for 10 days,
and clindamycin 2x300 mg were prescribed for the patient.
On October 31st 2019, a fetomaternal US exam was performed. It showed the
irregular stratum basalis of the endometrium with the thickness of 17,8 mm.
Inside of the endometrium, vesicular material was found and that suggested the
description of cystic type of hyperplasia. In the right ovary was found follicular
retention. The FM US exam concluded that that was the thickening endometrium
due to hyperplasia (cystic type). One of the probable causes was the anovulation
cycle (follicular retention in the right ovary).

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 Picture 2. Fetomaternal US exam results on 31/10/2019

On November 1st 2019, curettage was performed. The postsurgical diagnosis was
primary AUB dd/ AUB O due to hyperplasia of the endometrium, ovulatory
dysfunction; acute secondary cervicitis; and secondary anemia.
Pathological anatomical examination was performed on November 4th 2019. It
showed the suggestive result of non-atypical hyperplasia endometrium.

Picture 3. Histopathology result

DISCUSSION

Risk factors and malignancy

On older women, obesity was associated with increased risk of endometrial
hyperplasia. However, as opposed to known risk factors in the older adult
population, PCOS alone was not identified as a risk factor in this small cohort
study. Compared with controls, a higher proportion of women in some studies

4
with endometrial hyperplasia or cancer were obese, with a BMI greated than 30.
Some studies observed a similar trend among patients with a BMI greater than 40.
A recent study on obesity and age at diagnosis of endometrial cancer showed that
unlike non-endometrioid cancers such as papillary serous, clear cell, and poorly
differentiated carcinomas, obesity is associated with endometrioid endometrial
cancer, even after multivariable, because of the increased prevalence of obesity in
children and adolescents in the past an increase in endometrial cancer and its
precursors among younger generations. It is therefore extremely important to be
aware of potential risk factors that might prompt earlier endometrial sampling.1

Because of chronic anovulation and a high prevalence of obesity, PCOS has been
associated with increased rates of increase in the odds of acquiring endometrial
cancer in women younger than 54 years old were included. However, almost all
studies were limited by not taking BMI into ac- count, which might change this
gynecological age of only 9-12 years, PCOS alone was not an independent risk
factor for endometrial hyperplasia or cancer. Interestingly, a study that
investigated women younger than the age of 45 years showed that 25 patients with
PCOS and either complex hyperplasia or endometrial cancer had more advanced
disease or failed to respond to not powered to evaluate this, it indicates that
providers should pay special attention to patients with PCOS, even at younger
ages.1

Although smoking alone was not a risk factor for endometrial hyperplasia or
cancer, a history of PCOS and being a former or current smoker did increase this
risk. Addition- ally, having a BMI greater than 30 and being a former or current
smoker remained statistically significant. This was an unexpected finding, because
the literature shows that to be protective against endometrial disease by causing
oocyte destruction and thereby reducing estrogen simply because of age;
therefore, this phenomenon of women who smoke being less likely to be
diagnosed with endometrial cancer might not occur in this population, because
their larger number of oocytes could outweigh any reduced estrogen effect that
smoking might otherwise have.1

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One case report described performing a curettage of the endometrium along with
administering progestin therapy to two 15-year- old girls with grade 1 disease who
had no evidence of disease at follow-up. One of these women went on to have 2
normal-term pregnancies. Fortunately, women present with lower-grade disease.
This is consistent with another study, in which all patients had intrauterine device
placements continued to be without evidence of disease.1

The list of risk factors associated to endometrial hyperplasia can be seen in the
table 1 below.1

Table 1. Risk factors of endometrial hyperplasia1

The only risk factor of having endometrial hyperplasia in the patient described in
this paper is the age of more than 35 years old.

Diagnosis
To diagnose endometrial hyperplasia, histological examination of endometrial is
needed. The sensitivity for detecting cancer of endometrial samping in

6
postmenopausal and premenopausal women using pipelle was reported to be
99.6% and 91%, respectivelt. The sensitivity was found to be 81% for the atypical
hyperplasia. The hysteroscopy alone accuracy for hyperplasia is only modest
when compared to that of malignancy. Thus, dilatation and curettage or targeted
biopsy are necessary to be performed with hysteroscopy to improve the accuracy.
Radiology is another modality to confirm the diagnosis of endometrial
hyperplasia. While, transvaginal ultrasound probably has an importance in making
the diagnosis of endometrial hyperplasia and both pre and postmenopausal
women. The evidence to evaluate CT and diffusion-MRI or biomarkers is found
to be insufficient hence there are not routinely suggested.4-8

Ultrasound
Imaging the endometrium on days 5-10 of a woman's cycle reduces the variability
in endometrial thickness.5

a) Premenopausal

 Normal endometrial thickness depends on the stage of the menstrual cycle,

but a thickness of >15 mm is considered the upper limit of normal in the
secretory phase.

 Hyperplasia can be reliably excluded in patients only when the

endometrium measures less than 6 mm.

b) Postmenopausal

 A thickness of >5 mm is considered abnormal

The appearance can be non-specific and cannot reliably allow differentiation

between hyperplasia and carcinoma. Usually, there is a homogeneous smooth
increase in endometrial thickness, but endometrial hyperplasia may also cause
asymmetric/focal thickening with surface irregularity, an appearance that is
suspicious for carcinoma. Cystic changes can also be seen in endometrial
hyperplasia.

Ultrasound features that are suggestive of endometrial carcinoma as opposed to

hyperplasia include:

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 Heterogeneous and irregular endometrial thickening

 Polypoid mass lesion

 Intrauterine fluid collection

 Frank myometrial invasion

In this case, endometrial thickness was 17.88 mm in proliferative phase before the
Primolut therapy.

Hysteroscopy
Hysterescopy as one of the diagnostic methods for endometrial malignancy
is based in the scores achieved by doing the hysteroscopy for each of the three
graded indicators. The indicator are necrosis, vessels, and surface. The way it gets
some scores is called by HYCA score. Further scoring system based on HYCA
can be seen below.6
Table 2. HYCA score6

Hysterescopy was not performed in this patient. Thus, hysteroscopy should be

recommended for the patient.

Pathology findings
Endometrial hyperplasia is classified into different groups based upon the type of
cells and stroma (tissue separating the glandular cells) in the sample. Older

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diagnoses used terms such as cystic-glandular hyperplasia and adenomatous
hyperplasia. The WHO in 1994 used categories such as simple and complex
hyperplasia, each of which included forms with and without atypia.  These terms
are defined as follows:9

a) Simple hyperplasia

 The endometrial glands appear dilated and cystic

 There is a lot of stroma with plenty of cells
 The glands are not crowded together
 Nuclei are uniform in shape
 There is no atypia
 The number of mitoses may be normal or increased to varying degrees

b) Complex hyperplasia
 Crowded glands of varying shapes
 Stroma is reduced
 Nuclei are uniform in shape
 The number of mitoses may be normal or increased to varying degrees
c) Atypia

 Nuclei are enlarged and round

 Chromatin shows irregular clumping
 Nuclear membrane may be thicker than usual
 Nucleoli are prominent

d) Endometrial intraepithelial neoplasia (EIN)

All the following criteria must be present for a diagnosis of EIN.

 Gland volume exceeds stromal volume so that the percentage of stroma by

volume (VPS, volume percentage stroma) is less than 55%

 The lesion is more than 1 mm wide

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  The endometrium in the lesion is not secretory or covering an endometrial
polyp; it is not the basal endometrial layer; it is not showing signs of post-
inflammatory repair; all these conditions may mimic EH appearances
 The cells in the lesion are very crowded, the glands are branching or show
budding, and look different from those in the surrounding area
 There are no solid or cribriform areas, or maze-like branching glands
which represent frank cancer rather than EIN

Pathologists found it difficult to make accurate diagnoses based on the

microscopic examination, and the diagnosis often changed when the specimens
were reviewed by other pathologists, because of the overlap between categories
and the lack of clear differentiators. As a result, simpler classifications were
evolved.9

Several systems of classification have been put forward, but those more often
used to report the diagnosis include the revised WHO 2014 classification and a
German system by Mutter and The Endometrial Collaborative Group (2000). The
revised WHO classification in 2014 stressed the presence of atypia rather than
simple or complex architecture. It thus includes hyperplasia without atypia and
hyperplasia with atypia. These correspond roughly to the Mutter categories as
endometrial hyperplasia (EH) and endometrial intraepithelial neoplasia (EIN). A
third system was put forward by a European expert study group (1999) which
names the new histological groups endometrial hyperplasia (EH) and
endometrioid neoplasia (EN).9

Benign hyperplasia or hyperplasia without atypia are lesions which will resolve
with conservative management (i.e. without surgery). There are no genetic
changes characteristic of malignancy. On the other hand, atypical hyperplasia,
EIN, or EN, is associated with existing invasive endometrial carcinoma or a high
risk of such tumors within a few years, and the lesions show the characteristic
mutations in tumor suppressor genes or DNA repair genes, as well as
microsatellite instability. The recommended treatment for EH with atypia is total
hysterectomy.9

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The advantage of these systems is that it is easy to achieve a reproducible
diagnosis based on the microscopic appearance of the endometrial sample. The
categories are differentiated by simple criteria regarding the cellular shape, size,
branching, nuclear size, presence of nucleoli, strongly eosinophilic cytoplasm, and
other morphological aspects. Further confirmation is by assessing the ratio of
stroma to total volume of the tissue. This will help make diagnosis easier, more
accurate, with minimal interobserver variability, and better clinical interpretation.9

In order to standardize classification and treatment of these lesions, it is essential

that a single system be used worldwide to ensure that comparable diagnosis and
treatment standards are available for research.9

In this case, the PA exam showed non-atypical endometrial hyperplasia.

Management

The three most common options for the management of EH are surveillance,
progestin therapy, and hysterectomy. Other treatment approaches include
pharmacologic treatments other than progestins or conservative surgical treatment.
These modalities are not used commonly and have not been well studied.10

11
 Picture 4. Algorithm of endometrial hyperplasia management by RCOG7

All management strategies should also be accompanied by removal of the

extrinsic or intrinsic source of unopposed estrogen since excess exposure to
estrogen is a main etiology of endometrial neoplasia. This may include identifying
and stopping use of nonprescription medications or topical products that contain
estrogen, stopping unopposed estrogen therapy or adding a progestin, correcting
ovulatory dysfunction (eg, PCOS or hyperprolactinemia), losing weight, or,
rarely, removing an estrogen-producing neoplasm. Weight loss, including from

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bariatric surgery, in obese women has multiple health benefits in addition to
reducing high levels of endogenous estrogens due to estradiol and estrone
production by adipocytes. For women with ovulatory dysfunction, the etiology
should be treated (eg, prolactinoma), or if the ovulatory dysfunction is likely to be
chronic (eg, PCOS), women may need maintenance progestin therapy after EH
regression.10 

a) Surveillance 

Surveillance alone may be utilized if the risk of an occult cancer or

progression to cancer is low and the inciting factor that resulted in endometrial
proliferation has been eliminated (eg, patient with anovulation, now corrected,
who had developed simple hyperplasia without atypia).

b) Progestin therapy 

There are no US Food and Drug Administration (FDA)-approved therapies for

the treatment of EH, although various progestins are approved for EH
prevention, and megestrol acetate and depot medroxyprogesterone acetate are
approved for treatment of endometrial carcinoma. Progestins are the most
commonly used therapy, since they oppose the effect of estrogen on the
endometrium. When appropriate and successful, progestin therapy allows for
future attempts at pregnancy. 

c) Hysterectomy 

Total hysterectomy is definitive treatment but is a major surgical procedure

and precludes future fertility. Hysterectomy is usually reserved for
postmenopausal women, women who do not desire future fertility, or those
with pathology suggesting high risk of concomitant endometrial carcinoma.
Risk factors for concomitant endometrial cancer are increased age and
transvaginal ultrasound showing endometrial thickness ≥20 mm.

Treatment with nonprogestin medications or conservative surgery is not standard

clinical practice, but has been described.11
a) Nonprogestin medications 

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  Gonadotropin-releasing hormone (GnRH) agonists were used in
combination with a levonorgestrel (LNg)-releasing intrauterine device
with a release rate of 19.5 mcg/day for five years to successfully treat 24
premenopausal women with either atypical EH or early-stage endometrial
carcinoma. 
 Aromatase inhibitors have been administered to block endogenous
estrogen production in patients with EH. Anastrozole was used
successfully to treat 11 obese postmenopausal women with atypical (n = 2)
and nonatypical EH (n = 9). A small prospective study of 45 patients
showed no simple EH following treatment.
 Ovulation induction (eg, with clomiphene or aromatase inhibitors) in
reproductive-age women will result in formation of a corpus luteum,
exposure to endogenous progesterone, and resolution of EH in some
women. Pregnancy is highly unlikely in the setting of ongoing EH. Careful
surveillance is needed to assure EH regression. This approach is favored
for women with EH without atypia who desire pregnancy.
 Metformin has been shown to both have antiproliferative effects and to
reduce insulin resistance, which may play a role in the development of
endometrial carcinoma in overweight and obese females. A meta-analysis
on the effects of metformin on endometrial cancer observed a reversion to
normal histology in the majority of patients with atypical EH who received
a course of metformin in association with progestin.
 Danazol has been used to successfully treat EH, but is seldom used due to
significant side effects when taken orally. In a series of postmenopausal
women, danazol (400 mg per day for six months) caused
completregression in 83% of patients, with 8% with a relapse within four
months of discontinuing therapy.
b) Alternative surgical treatments
 Hysteroscopic resection of EH was reported to be effective in 68 of 73
treated women, but the long-term consequence of this treatment remains to
be determined. A review of 36 patients treated with hysteroscopic tumor

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 resection combined with hormone therapy reported an 88.9% response
rate, with an 11.1% recurrence rate.
 Bariatric surgery may show promise. There was a significant decreased
rate of all cancers following bariatric surgery compared with obese
controls (3.5 versus 5.8%) in a large retrospective study. The most
frequent cancer in the group who had bariatric surgery was breast (28.3%),
followed by endometrial (17%. In the obese control group, the most
common cancer was endometrial (62.3%).
The patient received Primolut 2x5 mg as the progestin therapy.

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 CONCLUSION

Endometrial hyperplasia is common cause of abnormal uterine bleeding. It

defined as endometrial thickening with a proliferation of irregularly sized and
shaped glands and an increased gland-to-stroma ratio. Most notable among these
are increasing body mass index (BMI) and nulliparity. Histological examination,
transvaginal ultrasound, and hysteroscopic diagnostic approach of endometrial
tissue are necessary to diagnose endometrial hyperplasia. The three most common
options for the management of EH are surveillance, progestin therapy, and
hysterectomy. 

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