Review Article

Diagnosis and Management of Endometrial Hyperplasia

Amy J. Armstrong, MD, William W. Hurd, MD, Sonia Elguero, MD,
Nichole M. Barker, DO, and Kristine M. Zanotti, MD*
From the Departments of Obstetrics and Gynecology (Drs. Armstrong, Elguero, and Barker), Department of Reproductive Endocrinology and Infertility
(Dr. Hurd), and the Department of Gynecologic Oncology (Dr. Zanotti), University Hospitals Case Medical Center, Euclid Ave, Cleveland, OH.
ABSTRACT Endometrial hyperplasia (EH), with or without atypia, is a common gynecologic diagnosis and a known precursor of endo-
metrial carcinoma, the most common gynecologic malignancy. During the reproductive years, the risk of EH is increased by
conditions associated with intermittent or absent ovulation, in particular, polycystic ovary syndrome. After menopause when
ovulation has ceased, EH is more common in women with conditions that increase levels of circulating estrogen such as obe-
sity or estrogen replacement therapy. Women with EH are at increased risk for both concurrent and subsequent endometrial
cancer. The risk of coexisting cancer in women with a diagnosis of EH at endometrial sampling is due to limitations in both
endometrial sampling and the diagnostic reproducibility among pathologists. These diagnostic uncertainties add to the com-
plexity of managing EH. This review offers a rational approach to prevention, diagnosis, and treatment of EH, including hor-
mone therapy and conservative surgical methods. Journal of Minimally Invasive Gynecology (2012) 19, 562571 2012
AAGL. All rights reserved.
Keywords: Endometrial hyperplasia; Progesterone; Infertility; Treatment
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Endometrial hyperplasia (EH) is dened histologically as
abnormal overgrowthof endometrial glands. It is commonlydi-
agnosed in women with uterine bleeding abnormalities. Alone,
EH does not represent a health risk to women. It is signicant
because EHis both a precursor and a marker for concurrent en-
dometrial cancer, in particular in the presence of atypia [1].
Endometrial hyperplasia typically occurs when unop-
posed estrogen (i.e., in the absence of progesterone) stimu-
lates abnormal proliferation of endometrial glands. During
the reproductive years, the risk of EH is increased by condi-
tions associated with intermittent or absent ovulation, in
particular, polycystic ovary syndrome (PCOS). After meno-
pause when ovulation has ceased, EH is more common in
women with conditions that increase levels of circulating es-
trogen such as obesity or estrogen replacement therapy. En-
dometrial hyperplasia can also develop in women with no
apparent risk factors.
The recommended treatment for EHwithout atypia is pri-
marily hormonal, whereas the preferred treatment for EH
with atypia is hysterectomy. This is because EH with atypia
is a signicant risk factor for both concurrent and subsequent
development of endometrial carcinoma. A dilemma results
when EH with atypia is diagnosed in women who wish to re-
tain fertility. In these women, a trial of hormone therapy can
be considered.
The objectives of this review are 3-fold: rst, to review
the epidemiology, risk factors, and typical presentation of
EH; second, to examine the strengths and limitations of con-
temporary approaches for diagnosing and classifying EH;
and third, to reviewmedical and surgical treatment strategies
for managing EH.
Epidemiology
The incidence of EHdiffers greatly depending on age and
symptoms. In asymptomatic premenopausal women, the
The authors have no commercial, proprietary, or nancial interest in the
products or companies described in this article.
Corresponding author: Kristine M. Zanotti, MD, Departments of Obstetrics
and Gynecology, University Hospitals Case Medical Center, 11100 Euclid
Ave, Cleveland, OH 44106.
E-mail: kristine.zanotti@uhhospitals.org
Submitted April 2, 2012. Accepted for publication May 28, 2012.
Available at www.sciencedirect.com and www.jmig.org
1553-4650/$ - see front matter 2012 AAGL. All rights reserved.
http://dx.doi.org/10.1016/j.jmig.2012.05.009
incidence EH without atypia is ,5%, and with atypia is
,1% [2]. In premenopausal women with abnormal uterine
bleeding, the incidence of EH has been reported to be as
high as 10% [3]. In women with PCOS and oligomenorrhea,
the reported incidence of EH is .20% [4]. This is important
to keep in mind because 10% to 20% of endometrial carci-
nomas occur before menopause, primarily in women aged
40 to 50 years.
In postmenopausal women with uterine bleeding, the risk
of EH seems to be lower, whereas the risk of endometrial
carcinoma is much higher. In a recent study, the incidence
of EH without atypia was 4%, and with atypia was 2%,
and the incidence of endometrial carcinoma was 24% [5].
Risk Factors
Risk factors for EH seem to be similar to those for endo-
metrial cancer [6]. Most notable among these are increasing
body mass index (BMI) and nulliparity. Other risk factors for
endometrial carcinoma include chronic anovulation, early
menarche, late onset of menopause, and diabetes [7]. The
theoretical link between most of these conditions is that
they are associated with increased circulating estrogen rela-
tive to progesterone. In support of this is the strong associa-
tion of unopposed estrogen therapy with the development of
EH and endometrial carcinoma [8].
Obesity
Obesity is associated with increased levels of circulating
estrogen relative to progesterone by several mechanisms in-
cluding increased conversion of androstenedione to estrone
within adipose stores, decreased circulating sex hormone
binding globulins, and increased rates of chronic anovula-
tion [9,10]. In a given population, the magnitude of
obesity seems to be proportional to risk for both EH and
endometrial carcinoma. In a case-control study, compared
with nonobese women, obese women (BMI .30 kg/m
2
) ex-
hibited a nearly 4-fold increase in the incidence of EH with
atypia [6]. Women with a BMI R40 kg/m
2
were at a 13-fold
increased risk of EH with atypia and a 23-fold increased risk
of EH without atypia [6].
Chronic Anovulation and PCOS
Women who are anovulatory can be at up to a 3-fold in-
creased risk of endometrial cancer [11]. Although the aver-
age age at diagnosis of EH with atypia is in the 5th decade of
life and beyond, women with chronic amenorrhea are at risk
for this condition in their 20s and 30s [12].
The most common condition associated with chronic an-
ovulation is PCOS, although anovulation can also occur in
perimenopausal women. The syndrome affects approxi-
mately 7% of women of reproductive age, and is the most
common endocrinopathy in that population [13]. Comorbid-
ities commonly associated with PCOS include obesity,
nulliparity, and diabetes, and these conditions are additional
independent risk factors for EH.
Nulliparity and Infertility
In one study, nulliparity and infertility seemed to be inde-
pendent risk factors for EH and endometrial carcinoma, with
odds ratios of 2.8 (95% condence interval [CI], 1.17.2) for
nulliparity and 3.6 for infertility (95% CI, 1.39.9) [14]. In
addition, both of these conditions are associated with other
risk factors for EH including chronic anovulation, obesity,
and PCOS. The reported risk for complex EH with atypia
varies inversely with the number of deliveries [6,15].
Estrogen Therapy
Estrogen-only hormone therapy in postmenopausal
women is strongly associated with EH. In the randomized
placebo-controlled PEPI (Postmenopausal Estrogen/Proges-
tin Interventions) trial, women assigned to receive conju-
gated equine estrogen alone were more likely to develop
simple EH (28% vs 1%), complex EH (23% vs 1%), and
EH with atypia (11.8% vs 0%), whereas combining conju-
gated equine estrogen with cyclic or continuous progestins
protected the endometrium from hyperplastic changes asso-
ciated with estrogen-only therapy [8].
Selective Estrogen-Receptor Modulators
Some selective estrogen receptor modulators (SERMs)
increase the risk of EH. SERMs have mixed estrogen recep-
tor agonist or antagonist activity, depending on the target tis-
sue. Tamoxifen is a SERM that acts as an estrogen receptor
antagonist in breast tissue, and is thus commonly used to pre-
vent and treat breast cancer. However, it is an estrogen recep-
tor agonist in the uterus, and its use is associated with an
increased risk of EH and a 2.5-fold increased risk of endo-
metrial carcinoma [16,17]. Another SERM, raloxifene,
acts as an estrogen receptor antagonist in both breast and
endometrial tissue, and does not increase the risk of
endometrial cancer [18]. In a comparative study, treatment
of postmenopausal women with raloxifene compared with
tamoxifen demonstrated a signicantly lower incidence of
EH (relative risk [RR], 0.19; 95% CI, 0.120.29) and endo-
metrial carcinoma (RR, 0.55; 95% CI, 0.360.83) [17].
Hereditary Nonpolyposis Colorectal Cancer
Hereditary nonpolyposis colorectal cancer (HNPCC),
also known as Lynch syndrome, is an autosomal dominant
genetic condition associated with increased risk of a variety
of cancers related to inherited mutations in select DNA mis-
match repair genes. Women with HNPCC have a 40% to
60% lifetime risk of developing endometrial carcinoma
(RR, 20) compared with noncarriers of mismatch repair
gene mutations [1922]. Although the risk of EH in
HNPCC cohorts is uncertain, this condition is a frequent
Armstrong et al. Endometrial Hyperplasia 563
nding in screening studies in this population [23]. This sug-
gests that endometrial malignancies in these patients are de-
rived from EH.
Diabetes
The association between diabetes and several types of
cancer has been recognized for more than a century [24].
Studies have demonstrated that diabetes increases the risk
of endometrial cancer to approximately twice that in the
nondiabetic population [25]. Although there is likely more
than a single mechanismto explain this association, one pos-
sibility is that the insulin resistance and hyperinsulinemia
associated with type 2 diabetes has a role because insulin
stimulates cell proliferation [24].
Risk Reduction Strategies
Many risk factors associated with EH and endometrial
carcinoma can be treated. The addition of progestins to post-
menopausal estrogen therapy decreases the risk of EH [26].
Studies have demonstrated that progestin treatment for 12 to
14 days per month most effectively reduces the risk of EH
[26,27]. In contrast, there have been few prospective
studies designed to evaluate the effectiveness of treating
other known risk factors.
Treatment of chronic anovulation associated with PCOS
is important [11]. Psrogestin therapy in women with PCOS
and those with chronic amenorrhea is likely to reduce the
risk of developing EH and endometrial carcinoma [28,29].
This therapy can be in the form of progestin-containing
oral contraceptives, cyclic oral progestins, injectable proges-
tins, or a progestin-containing intrauterine system [29].
However, no prospective studies have been performed to
determine which, if any, of these treatment approaches are
effective in preventing EH and endometrial carcinoma in
this group at high risk group.
Obesity and diabetes also must be addressed in these
patients. When obese women are diagnosed with EH, pre-
ventive measures including diet, exercise, and weight loss
are recommended [30]. Diabetes or metabolic syndrome
can be treated with similar lifestyle modications, although
pharmacologic intervention is usually required as well. In
theory, lowering glucose concentrations using insulin-
sensitizing agents such as metformin could decrease the
risk of EH and endometrial cancer associated with type 2
diabetes, and case reports have supported this notion [31].
Prospective studies to determine the effectiveness of metfor-
min in decreasing the risk of EH and endometrial carcinoma
in women with diabetes are ongoing [24,32].
Risk factors for endometrial hyperplasia and carcinoma,
such as obesity and metabolic syndrome, are also risk factors
for a variety of conditions that increase risk of cardiovascu-
lar events and death [33,34]. The risk of death from
cardiovascular events associated with these medical
comorbidities dwarfs the risk observed with endometrial
hyperplasia, and exceeds even that observed with a
diagnosis of endometrial carcinoma in this population
[35]. When modiable risk factors are identied in women
with EH, a focus on preventive measures such as diet, exer-
cise, and weight loss should be considered [30]. Although
there are no studies that quantify the magnitude of therapeu-
tic benet in this regard, lifestyle modications have a far
greater potential for reducing overall morbidity and mortal-
ity than do temporary pharmacologic therapies. Lifestyle
modications should, therefore, be considered an integral
component of a comprehensive management plan.
Diagnosis
Both EH and cancer are most commonly diagnosed
during the investigation of abnormal uterine bleeding.
Abnormal uterine bleeding in the premenopausal population
includes a spectrum of disorders that may include menorrha-
gia, metorrhagia, and oligomenorrhea [36].
In perimenopausal and postmenopausal women with ab-
normal uterine bleeding, endometrial sampling is required
because of the increased risk of endometrial disease. Endo-
metrial biopsy should also be considered in younger women
with prolonged periods of amenorrhea and abnormal uterine
bleeding, in particular if they have other risk factors for EH
as described above.
Another indication for endometrial biopsy is a Papanico-
laou test that reveals atypical glandular cells. This cervical
cytologic nding is associated with a 1.5% risk of EH and
3.0% risk of endometrial carcinoma [37]. Because atypical
glandular cells can originate from the endocervix, endome-
trium, or tubal endothelium, pelvic ultrasonography and col-
poscopy are warranted in addition to endometrial biopsy.
Sampling Method
Detection of endometrial cancer before hysterectomy in
women with abnormal uterine bleeding can decrease the
risk of suboptimal treatment. This can be challenging be-
cause as many as 42% of women found to have EH with aty-
pia at ofce endometrial biopsy will be found to have
concurrent endometrial carcinoma at hysterectomy [38].
Of these cancers, 65% were conned to the endometrium;
however, the remaining cancers were invasive, with 10.6%
involving the outer 50% of the myometrium [38]. Given
these statistics, it may be prudent to consider referral of
patients with atypical EH to a gynecologic oncologist for
surgical management.
The accuracy of both ofce endometrial biopsy and uter-
ine dilation and curettage (D&C) depends on the extent to
which the endometrial disease is global [39]. Studies of hys-
terectomy have demonstrated that ofce endometrial biopsy
samples on average only 4% of the endometrial surface and
that D&C samples less than half [40]. Although the changes
of non-atypical EH are often found diffusely within the en-
dometrium, atypical hyperplasia and endometrial cancer
564 Journal of Minimally Invasive Gynecology, Vol 19, No 5, September/October 2012
are often focal lesions and require more thorough endome-
trial sampling for reliable identication [41].
Because focal lesions often are missed at ofce endome-
trial biopsy, it is recommended that patients at high risk un-
dergo D&C before hysterectomy. This includes women
with EH with atypia, in particular in the postmenopausal
age group [41,42]. However, even with D&C, endometrial
cancer will be missed in as many as 18% of women with
EHwith atypia [41]. It is clear that D&Cdoes not completely
exclude the possibility of concurrent endometrial cancer.
Transvaginal Ultrasound
In women with abnormal uterine bleeding, transvaginal
ultrasound can often guide the diagnostic approach, in par-
ticular after menopause [43]. Postmenopausal women with
an endometrial lining ,4 mm thick have a ,1% risk of ma-
lignancy [44]. Thus, when an endometrial biopsy retrieves
insufcient tissue for diagnosis and the endometrial thick-
ness is ,4 mm, no additional diagnostic tests are required
[45]. Conversely, when the endometrial thickness is .4
mmin these women, D&Cis recommended to obtain a histo-
logic specimen. When ultrasonography reveals a focal endo-
metrial lesion (e.g., a polyp), D&C with hysteroscopy is
indicated regardless of the results of ofce endometrial bi-
opsy because focal lesions often are missed at biopsy alone.
It is important to understand that ultrasonographic mea-
surements of endometrial thickness are less accurate in
many conditions including leiomyomas, adenomyosis, and
obesity. Although some groups have suggested that endome-
trial biopsy is not necessary in postmenopausal women with
abnormal bleeding and endometrial thickness ,4 mm, it
seems prudent to obtain a biopsy specimen regardless of so-
nographic ndings in women at increased risk of EH [44].
Hysteroscopy During D&C
Hysteroscopy provides the advantage of direct visualiza-
tion of the endometrial cavity for directed biopsy of focal
lesions. However, the increased intrauterine pressure that
occurs with introduction of distention media can, in theory,
result in cancer cell dissemination through the fallopian
tubes into the peritoneal cavity. Numerous observational
studies and meta-analyses have found that hysteroscopy is
associated with an increased risk of subsequent positive peri-
toneal cytologic ndings in women with endometrial cancer
[46]. However, it remains unclear whether this association is
correlated with a worse prognosis [47].
Because of this uncertainty, hysteroscopy should be per-
formed in women suspected of having endometrial carci-
noma when the possible benets outweigh the risks. When
clinical symptom assessment, examination, and/or imaging
study ndings suggest the possibility of a large intracavitary
lesion that is likely to be sampled at blind biopsy or curet-
tage, it is reasonable to omit hysteroscopic visual assessment
before endometrial sampling.
Histologic Diagnosis of EH
Histologically, EH manifests as a greater than normal ratio
of gland to stroma. However, the diagnosis of EHseems to rep-
resent 2 different biologic entities. The most common entity,
simple EHwithout atypia, is diffuse endometrial polyclonal en-
dometrial proliferation induced by unopposed estrogen, and is
usually benign. In contrast, EH with atypia is a precancerous
endometrial lesion that can arise from within these benign
changes. This entityis believedtoresult fromclonal outgrowths
of genetically mutated cells that differ both architecturally and
cytologically frombackground cells [48]. Differentiating these
2 entities has remained a diagnostic challenge.
Over the past 50 years, the diagnosis of EH has been
hindered by the use of histologic classication systems
that lacked diagnostic reproducibility and, in some cases,
biologic relevance. Currently, 2 diagnostic classication
systems are used that differ markedly in their origins and de-
velopment: the World Health Organization 1994 (WHO94)
classication system and the Endometrial Intraepithelial
Neoplasia (EIN) classication system [49,50].
WHO94 Classication System
The WHO94 classication system is constructed accord-
ing to histologic ndings, and is based on a large cohort
study [49,51]. The system uses 4 subcategories of EH that
incorporate both architectural and cytologic ndings
prognostic for risk of developing endometrial carcinoma
that ranges from 1% to 29% (Table 1).
Currently, most pathologists use the WHO94 classication
system. Inpractice, the presence of cytologic atypia is the most
important histologic criterion used to stratify risk of progres-
sion to malignancy, and the presence or absence of atypia is
routinely used by gynecologists to determine therapy for EH.
However, there are known problems with the WHO94
classication system. First, it has never been subjected to
rigorous verication. Second, 2 of the 4 subcategories, sim-
ple EH with atypia and complex EH without atypia, are rel-
atively rare ndings in the population. As a result, both are
poorly represented statistically in EH studies and are of
questionable biologic signicance.
The greatest problem with the WHO94 system, however,
is that the histologic criteria used are relatively subjective,
resulting in relatively low interobserver agreement and re-
producibility among pathologists. The magnitude of this
limitation was illustrated in a large prospective multi-
institutional cohort study of complex EH with atypia diag-
nosed by community pathologists [52]. A pathology review
panel of 3 gynecologic pathologists agreed with the initial
diagnosis in only 38% of cases. Furthermore, unanimous
agreement among the panel for any diagnosis was only 40%.
EIN System
The EIN classication system, in contrast to the
WHO94 system, has its origins in molecular studies [50].
Armstrong et al. Endometrial Hyperplasia 565
Monoclonality and mutational analysis of hyperplasia and
subsequent carcinoma were used to dene pre-cancers on
a molecular basis. Computer-assisted analysis of histologic
features observed in biopsy specimens were then used to de-
velop diagnostic criteria for the classication system
(Table 2). Diagnostic criteria include large-scale topo-
graphic features within a specimen, in addition to cytologic
and architectural ndings. These criteria can be applied clin-
ically by the reviewing pathologists or by using formal com-
puted morphometry, referred to as the D score.
Studies suggest that the EIN classication system is more
accurate than the WHO94 classication for predicting dis-
ease progression [1,50]. The EIN system is also better for
identifying women with benign changes that initially seem
to be high risk according to the WHO94 system.
Both the WHO94 and EIN classication systems identify
cellular atypia as the most signicant histologic nding for
predicting risk of endometrial cancer. As a result, most
current therapeutic approaches to EH dichotomize manage-
ment on the basis of presence or absence of cellular atypia
[1,48,53,54]. Management strategies should be further
stratied according to whether a patient wishes to maintain
fertility.
Progestin Therapy
Progestin therapy is the most commonly used approach to
EH without atypia because the risk of concurrent endome-
trial cancer is extremely low [1]. Therapeutic interventions
in these cases should focus on symptom management and
prevention of progression of EH. Medical management
with progestins can also be considered in women with EH
with atypia who wish to retain fertility, but only after thor-
ough evaluation and appropriate counseling, and with
a plan for continued surveillance.
Table 1
World Health Organization 1994 (WHO94) classication system [49]
Class Histologic ndings
Risk of progression
to endometrial
carcinoma [51]
a
Implied treatment option
Simple Proliferation of glandular cells, but glands
relatively unchanged
1% Hormone therapy
Complex Proliferation of glandular cells, and glands
crowded and distorted
3% Hormone therapy or surgery
Simple with atypia Architectural features of simple hyperplasia;
individual cells demonstrating atypia
8% Surgery or hormone therapy for poor surgical
candidates or those who wish to preserve fertility
Complex with atypia Architectural features of complex
hyperplasia; individual cells
demonstrating atypia
29% Surgery or hormone therapy for poor surgical
candidates or those who wish to preserve fertility
a
Data are based on 170 patients with a diagnosis of hyperplasia and followed up for 12 months without hysterectomy [51].
Table 2
Endometrial Intraepithelial Neoplasia classication system
a
Class
Topographic
ndings Diagnostic criteria Category
Risk of
malignancy
Implied treatment
options
Benign endometrial
hyperplasia
Diffuse NA Benign hormone
(estrogen dffect)
0.6% Hormone therapy
or no treatment
Endometrial
intraepithelial
neoplasia
Focal, progressing
to diffuse (clonal)
Area of glands exceeds area
of stroma
Epithelial cells within the crowded
glands are cytologically different
compared with background
Lesion larger than 1 mm
Absence of carcinoma or benign
mimics
Precancerous 19% Hormone therapy
or surgery
Endometrial
adenocarcinoma
Focal, progressing
to diffuse
NA Cancer NA Surgery
NA 5 not available.
a
Data adapted from Baak JP, Mutter GL, Robboy S, et al [50].
566 Journal of Minimally Invasive Gynecology, Vol 19, No 5, September/October 2012
Progestins can be administered by a number of methods.
In women of reproductive age, progestin-containing com-
bined oral contraceptives (COCs) are commonly used to
treat menstrual abnormalities and hirsutism in oligo-
ovulatory women. Current COCs contain ethyl estradiol
plus one of a number of progestins, and are administered
for 21 to 30 days per month. In several studies, use of
COCs has been found to decrease the risk of endometrial
carcinoma by approximately 50%, and this protective effect
seems to persist for decades after their cessation [55]. Al-
though COCs likely prevent or reverse EH in some patients,
few data are available to support this possibility [56].
Progestins alone are used to treat EH in women who are
not candidates for COCs because of medical contraindica-
tions or adverse effects. Progestins can be given orally, by
intramuscular injection, or by insertion of a progestin-
containing uterine device (Table 3). In women of reproduc-
tive age with EH without atypia, progestins can be given for
12 to 14 days per month in an effort to induce predictable
monthly bleeding. For women with persistent EH or EH
with atypia, daily oral progestins or parenteral progestins
are used to provide continuous progestin exposure.
Oral Progestins
Oral progestins have been studied for the treatment of EH
for more than 40 years. Medroxyprogesterone acetate (Prov-
era; Pharmacia & Upjohn Co., Inc., subsidiary of Pzer Inc.,
New York, NY) and megestrol acetate (Megace; Bristol
Myers Pharmaceuticals, New York, NY) were the rst to
be reported for this use by Eichner et al [57] in 1971. Several
other progestins have been used to treat EH, including nor-
ethisterone, levonorgestrel, and lynestrenol [5860].
Reported strategies include daily oral treatment and cyclic
therapy of varying dosages and durations (Table 3).
Progestin-Releasing Intrauterine Device
The progestin-releasing intrauterine device (IUD) (Mir-
ena; Bayer Healthcare Pharmaceuticals, Inc., Montville,
NJ) was originally developed for contraception. This T-
shaped IUD, also referred to as the levonorgestrel intrauter-
ine system (LNG-IUS), has a reservoir that contains 52 mg
levonorgestrel, and is replaced every 5 years.
The progestin-releasing IUD delivers a high dosage of
progestin to the endometrium, with minimal systemic ef-
fects, and is an effective treatment in women with EH who
wish to retain fertility [59]. It achieves a 100-fold higher pro-
gestin concentration in the endometrium compared with oral
administration [61]. This is an ideal option for patients at risk
of deep venous thrombosis (DVT) or when compliance is
a concern. Although menstrual abnormalities are common
with this device, more than 50% of patients will develop
amenorrhea within 6 months of insertion [62].
Progestin-Related Adverse Effects and Risks
Progestins are reasonably well tolerated by patients, even
at high dosages. Adverse effects reported include nausea,
breast tenderness, weight gain, and headache [6365]. The
most consistent laboratory change associated with oral and
injectable progestins is modestly increased high-density
lipoprotein concentrations.
Controversy continues about whether progestin therapy
increases the risk of DVT. It has been well established that
COCs containing both an estrogen and a progestin increase
the risk of DVTin susceptible individuals and that some pro-
gestins used in these formulations are associated with higher
risk than others are [66]. It has been commonly accepted for
years that progestin-only oral contraceptives do not share
this risk [67].
Recent studies have veried that that the progestin-
releasing IUD does not increase risk of DVT [68,69].
However, it seems that injectable depot medroxyprogesterone
increases DVT risk by 3- to 4-fold [69]. Others have shown
that high-dose oral progestin therapy increases DVT risk
[63]. On the basis of these ndings, the progestin-releasing
IUD seems to be the safest progestin treatment option in
women with known clotting disorders or a history of DVT.
Progestin Therapy Effectiveness
Treatment of EH with progestins via any route of admin-
istration is reasonably effective. A systematic review of 45
studies with 391 patients with EH treated with oral or inject-
able progestins demonstrated 66% complete resolution after
39 months [70]. However, 23% of patients with complete
resolution had a recurrence within the study period. Another
systematic review of 24 studies with 1001 patients demon-
strated that progestin-releasing IUD therapy is more likely
than oral progestin therapy to result in regression of complex
EH(regression rates, 92%vs 66%) and EHwith atypia (90%
vs 69%); however, both were equally effective in causing re-
gression of simple EH (96% vs 89%) [71].
On the basis of these limited data, one method of proges-
tin administration cannot be recommended over any other
Table 3
Current progestin therapies for endometrial hyperplasia
Route of
administration Formulation Dose
Oral Medroxyprogesterone 510 mg/d
Megestrol 40320 mg/d
Norethindrone 2.510 mg/d
Intramuscular Medroxyprogesterone 150 mg every 3 mo
Vaginal Progesterone gel 4% or 8%, 4590 mg/d
Progesterone tablet 100200 mg/d
Intrauterine Levonorgestrel
intrauterine device
52 mg; replace
every 5 yr
Armstrong et al. Endometrial Hyperplasia 567
method. Both meta-analyses included studies that were het-
erogeneous insofar as duration of follow-up and method of
endometrial sampling, and the condence intervals were
large. For individual patients, decisions about which method
to use should be made on the basis of symptom and adverse
effect proles, cost, and patient compliance.
Progestin Therapy Duration and Follow-Up
There are no data with which to determine the optimal du-
ration of progestin therapy or follow-up in women with EH,
in particular insofar as frequency or method of endometrial
sampling. These issues are particularly important in women
of reproductive age who desire to maintain fertility. With or
without continued therapy, the risk of recurrence is likely to
increase over time because most patients will continue to
have risk factors such as anovulation or obesity.
Published studies report that in women who desire preg-
nancy, treatment should be with continuous or cyclic oral
progestins for 3 to 6 months or longer or until EH is no lon-
ger found at endometrial biopsy [70,71]. The median time to
resolution was 6 months [70]. If EHdoes not resolve or prog-
resses, progestin therapy is continued or hysterectomy is per-
formed. Decisions about how long to persevere with
persistent disease must be made on an individual basis.
A common interval for repeat endometrial sampling re-
ported in the literature for women with EH treated medically
is every 3 to 6 months [70,71]. There are no data about the
usefulness of symptoms (e.g., bleeding) or other tests (e.g.,
endometrial thickness at ultrasonography) in determining
how often to repeat sampling in individuals during or after
therapy for EH. Of note is that endometrial biopsy can be
performed with the IUD in place [72].
The decision as to whether sampling should be performed
via ofce endometrial biopsy or D&C depends on the dis-
ease category and the patients willingness to undergo re-
peated biopsy procedures in the ofce. It should be
remembered that both diagnostic approaches are relatively
insensitive in focal disease because they sample only a per-
centage of the endometrium.
Subsequent Fertility
In women of reproductive age successfully treated for EH
without atypia, the chance of pregnancy is related to age and
the underlying cause of chronic anovulation. Most of these
women will have PCOS, and in the absence of EH, most
will achieve pregnancy after stepwise treatment with oral
or injectable ovulation induction agents, ovarian surgery,
or in vitro fertilization [73].
There are fewer data on fertility in women with EH with
atypia after progestin treatment. Most series examined
a combination of women with either EH with atypia or stage
Ia endometrial adenocarcinoma [70,74]. In these series,
fewer than half of the women treated for EH and desiring
fertility subsequently delivered a viable infant, most with
the aid of in vitro fertilization. Rates of disease recurrence
or progression while attempting pregnancy are high. The
likelihood of success for these women without the use of
assisted reproductive technologies is uncertain.
Prolonged progestin treatment of EH often uses depot
medroxyprogesterone or a progestin-releasing IUD. It is im-
portant to note that depot medroxyprogesterone is not the
ideal treatment in women who wish to become pregnant in
the near future because the median time for return of fertility
is almost 6 months after the last injection [75]. The
progestin-releasing IUD has less residual effect after re-
moval, and oral progestins seem to have the least.
Non-Progestin Therapy
Insulin sensitizing agents including metformin and rosi-
glitazone have been used to treat simple EH in 2 obese
women with PCOS [76]. The primary mechanism of action
of these agents on the endometrium is likely to be increased
progestin exposure related to increased ovulation. However,
their ability to reduce circulating insulin and insulin-like
growth factor concentrations and to increase progesterone
receptor expression could also have a role [76,77]. The
preventive and therapeutic roles of insulin sensitizing
agents in women with PCOS have yet to be established.
Gonadotropin-releasing hormone agonists and aromatase
inhibitors have also been reported as treatments for EH [78
80]. However, there is not yet enough data to determine the
usefulness of these medical treatments.
Surgical Treatment
When childbearing has been completed, hysterectomy is
the preferred treatment in patients with complex EH with
atypia. However, other treatment options must sometimes
be considered in patients who are poor surgical candidates
because of coexisting medical conditions.
Hysterectomy
Hysterectomy is the most appropriate treatment in most
women with EH with atypia who are no longer interested
in childbearing, because of the high risk of concurrent or
subsequent endometrial carcinoma. Medical management
with progestins can be attempted in motivated women with
EH with atypia who wish to maintain fertility. Hysterectomy
is also indicated in women with EH with or without atypia in
whom medical management has failed.
In the absence of evidence of invasive endometrial carci-
noma, extrafascial hysterectomy via any route is appropriate
for the treatment of EHwith or without atypia. However, one
must consider the risk of nding concurrent malignancy at
hysterectomy, in particular in the presence of EH with aty-
pia. The current recommendations for staging of endome-
trial carcinoma include lymphadenectomy [81]. For this
reason, many clinicians will request intraoperative frozen
section evaluation of the endometrium during hysterectomy
568 Journal of Minimally Invasive Gynecology, Vol 19, No 5, September/October 2012
performed because of EH with atypia. Frozen section analy-
sis will miss approximately one-third of women ultimately
found to have endometrial carcinoma at nal histologic anal-
ysis [8284].
Surgical Approaches Other Than Hysterectomy
In women with EH who have medical contraindications
to major surgery, both endometrial resection and ablation
have been used [85,86]. In theory, removal or destruction
of the endometrium could prevent progression of EH to
endometrial cancer, much in the same way cone biopsy of
the cervix prevents cervical cancer. However, neither of
these methods, developed originally to treat menorrhagia,
destroys all of the endometrium. In addition, both
techniques limit the value of subsequent surveillance using
ultrasonography or endometrial biopsy. Current data are
limited to case reports and small case series, primarily in
women with EH without atypia. Until larger studies with
longer follow-up are reported, endometrial resection or abla-
tion as primary therapy for hyperplasia cannot be recom-
mended.
Conclusion
The appropriate diagnosis and treatment of EHis a critical
aspect of gynecologic care. This precursor to endometrial
carcinoma is often hormone-related, and can be effectively
treated with progestin therapy in many cases. Understanding
risk factors for EH and preventive treatment approaches in
women at risk is an important aspect of health maintenance,
in particular as chronic anovulation becomes more preva-
lent. For EHwithout atypia, progestin therapy is the standard
treatment. However, hysterectomy is sometimes required be-
cause of persistent bleeding abnormalities or disease pro-
gression. In the presence of EH with atypia, hysterectomy
remains the treatment of choice in women who have com-
pleted childbearing. An increasing number of reports indi-
cate that progestin therapy with close follow-up is
a reasonably safe alternative in women with EH with atypia
who desire to maintain fertility. The risk of disease persis-
tence or progression is high in these women, and treatment
must be individualized.
References
1. Salman MC, Usubutun A, Boynukalin K, Yuce K. Comparison of WHO
and endometrial intraepithelial neoplasia classications in predicting
the presence of coexistent malignancy in endometrial hyperplasia.
J Gynecol Oncol. 2010;21:97101.
2. Gol K, Saracoglu F, Ekici A, Sahin I. Endometrial patterns and endocri-
nologic characteristics of asymptomatic menopausal women. Gynecol
Endocrinol. 2001;15:6367.
3. Ash SJ, Farrell SA, Flowerden G. Endometrial biopsy in DUB. J Reprod
Med. 1996;41:892896.
4. Park JC, Lim SY, Jang TK, Bae JG, Kim JI, Rhee JH. Endometrial his-
tology and predictable clinical factors for endometrial disease in
women with polycystic ovary syndrome [published online ahead of
print March 31, 2011]. Clin Exp Reprod Med. 2011;38:4246.
5. Opolskiene G, Sladkevicius P, Valentin L. Prediction of endometrial
malignancy in women with postmenopausal bleeding and sonographic
endometrial thickness R4.5 mm. Ultrasound Obstet Gynecol. 2011;37:
232240.
6. Epplein M, Reed SD, Voigt LF, Newton KW, Holt VL, Weiss NS. En-
dometrial hyperplasia risk in relation to characteristics and exposures
that inuence endogenous hormone levels. Am J Epidemiol. 2008;
168:563570.
7. Elwood JM, Cole P, Rothman KJ, Kaplan SD. Epidemiology of endo-
metrial cancer. J Natl Cancer Inst. 1977;59:10551060.
8. Writing Group for the PEPI Trial. Effects of hormone replacement ther-
apy on endometrial histology in postmenopausal women: the Postmen-
opausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;
275:370375.
9. MacDonald PC, Edman CD, Hemsell DL, Porter JC, Siiteri PK. Effect
of obesity on conversion of plasma androstenedione to estrone in post-
menopausal women with and without endometrial cancer. Am J Obstet
Gynecol. 1978;130:448455.
10. Kaye SA, Folsom AR, Soler JT, Prineas RJ, Potter JD. Association of
body mass and fat distribution with sex hormone concentrations in post-
menopausal women. Int J Epidemiol. 1991;20:151156.
11. Haoula Z, Salman M, Atiomo W. Evaluating the association between
endometrial cancer and polycystic ovary syndrome [published
online ahead of print February 24, 2012]. Hum Reprod. 2012;27:
13271331.
12. Chamlian DL, Taylor HB. Endometrial hyperplasia in young women.
Obstet Gynecol. 1970;36:659666.
13. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO.
The prevalence and features of the polycystic ovary syndrome in an un-
selected population. J Clin Endocrinol Metab. 2004;89:27452749.
14. Farquhar CM, Lethaby A, Sowter M, Verry J, Baranyai J. An evaluation
of risk factors for endometrial hyperplasia in premenopausal women
with abnormal menstrual bleeding. Am J Obstet Gynecol. 1999;181:
525529.
15. Kalandidi A, Tzonou A, Lipworth L, Gamatsi I, Filippa D,
Trichopoulos D. A case-control study of endometrial cancer in relation
to reproductive, somatometric, and life-style variables. Oncology. 1996;
53:354359.
16. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL,
Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer pa-
tients: ndings from the National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-14. J Natl Cancer Inst. 1994;86:527537.
17. Runowicz CD, Costantino JP, Wickerham DL, et al. Gynecologic con-
ditions in participants in the NSABP breast cancer prevention study of
tamoxifen and raloxifene (STAR). Am J Obstet Gynecol. 2011;205:
535.e1535.e5.
18. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on
risk of breast cancer in postmenopausal women: results fromthe MORE
randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA.
1999;281:21892197.
19. Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ.
Life-time risk of different cancers in hereditary non-polyposis colorec-
tal cancer (HNPCC) syndrome. Int J Cancer. 1995;64:430433.
20. Bruun Boilesen AE, Bisgaard ML, Bernstein I. Risk of gynecological
cancers in Danish hereditary non polyposis colorectal cancer families.
Acta Obstet Gynecol Scand. 2008;87:11291135.
21. Stoffel E, Mukherjee B, Raymond VM, et al. Calculation of risk of co-
lorectal and endometrial cancer among patients with Lynch syndrome.
Gastroenterology. 2009;137:16211627.
22. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks
for carriers and noncarriers from families with a DNA mismatch repair
gene mutation: a prospective cohort study [published online ahead of
print February 13, 2012]. J Clin Oncol. 2012;30:958964.
23. Auranen A, Joutsiniemi T. Asystematic reviewof gynecological cancer
surveillance in women belonging to hereditary nonpolyposis colorectal
cancer (Lynch syndrome) families. Acta Obstet Gynecol Scand. 2011;
90:437444.
Armstrong et al. Endometrial Hyperplasia 569
24. Gallagher EJ, LeRoith D. Diabetes, cancer, and metformin: connections
of metabolism and cell proliferation. Ann N Y Acad Sci. 2011;1243:
5468.
25. Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk
of endometrial cancer: a metaanalysis. Diabetologia. 2007;50:
13651374.
26. Whitehead MI. Prevention of endometrial abnormalities. Acta Obstet
Gynecol Scand Suppl. 1986;134:8191.
27. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial
cancer in relation to use of oestrogen combined with cyclic progestagen
therapy in postmenopausal women. Lancet. 1997;349:458461.
28. Balen A. Polycystic ovary syndrome and cancer. Hum Reprod Update.
2001;7:522525.
29. American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 108. Polycystic ovary syndrome. Obstet Gynecol. 2009;
114:936949.
30. Linkov F, Edwards R, Balk J, et al. Endometrial hyperplasia, endome-
trial cancer and prevention: gaps in existing research of modiable risk
factors. Eur J Cancer. 2008;44:16321644.
31. Session DR, Kalli KR, Tummon IS, Damario MA, Dumesic DA. Treat-
ment of atypical endometrial hyperplasia with an insulin-sensitizing
agent. Gynecol Endocrinol. 2003;17:405407.
32. Atiomo W, Read A, Golding M, et al. Local recruitment experience in
a study comparing the effectiveness of a low glycaemic index diet with
a low calorie healthy eating approach at achieving weight loss and re-
ducing the risk of endometrial cancer in women with polycystic ovary
syndrome (PCOS). Contemp Clin Trials. 2009;30:451456.
33. Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of car-
diovascular risk and prevention of cardiovascular disease in women
with the polycystic ovary syndrome: a consensus statement by the An-
drogen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J
Clin Endocrinol Metab. 2010;95:20382049.
34. de Groot PC, Dekkers OM, Romijn JA, Dieben SW, Helmerhorst FM.
PCOS, coronary heart disease, stroke and the inuence of obesity: a sys-
tematic review and meta-analysis. Hum Reprod Update. 2011;17:
495500.
35. von Gruenigen VE, Tian C, Frasure H, Waggoner S, Keys H,
Barakat RR. Treatment effects, disease recurrence, and survival in
obese women with early endometrial carcinoma: a Gynecologic Oncol-
ogy Group study. Cancer. 2006;107:27862791.
36. Fraser IS, Critchley HO, Munro MG, Broder M. Writing Group for this
Menstrual Agreement Process. A process designed to lead to interna-
tional agreement on terminologies and denitions used to describe ab-
normalities of menstrual bleeding. Fertil Steril. 2007;87:466476.
37. Schnatz PF, Guile M, OSullivan DM, Sorosky JI. Clinical signicance
of atypical glandular cells on cervical cytology. Obstet Gynecol. 2006;
107:701708.
38. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial
carcinoma in women with a biopsy diagnosis of atypical endometrial
hyperplasia: a Gynecologic Oncology Group study. Cancer. 2006;
106:812819.
39. Goldstein SR. Modern evaluation of the endometrium. Obstet Gynecol.
2010;116:168176.
40. Rodriguez MH, Platt LD, Medearis AL, Lacarra M, Lobo RA. The use
of transvaginal sonography for evaluation of postmenopausal size and
morphology. Am J Obstet Gynecol. 1988;159:810814.
41. Suh-Bergmann E, Hung YY, Armstrong MA. Complex atypical hyper-
plasia: the risk of unrecognized adenocarcinoma and value of preoper-
ative dilation and curettage. Obstet Gynecol. 2009;114:523529.
42. McKenney JK, Longacre TA. Low-grade endometrial adenocarcinoma:
a diagnostic algorithm for distinguishing atypical endometrial hyper-
plasia and other benign (and malignant) mimics. Adv Anat Pathol.
2009;16:122.
43. Goldstein RB, Bree RL, Benson CB, et al. Evaluation of the
woman with postmenopausal bleeding. J Ultrasound Med. 2001;20:
10251036.
44. American College of Obstetricians and Gynecologists. ACOGCommit-
tee Opinion No. 440. The role of transvaginal ultrasonography in the
evaluation of postmenopausal bleeding. Obstet Gynecol. 2009;114:
409411.
45. Jacobs I, Gentry-Maharaj A, Burnell M, et al. Sensitivity of transvaginal
ultrasound screening for endometrial cancer in postmenopausal
women: a case-control study within the UKCTOCS cohort. Lancet On-
col. 2011;12:3848.
46. Takac I, Zegura B. Ofce hysteroscopy and the risk of microscopic ex-
trauterine spread in endometrial cancer. Gynecol Oncol. 2007;107:
9498.
47. Polyzos NP, Mauri D, Tsioras S, Messini CI, Valachis A, Messinis IE.
Intraperitoneal dissemination of endometrial cancer cells after hystero-
scopy: a systematic review and meta-analysis. Int J Gynecol Cancer.
2010;20:261267.
48. Mutter GL, Endometrial Collaborative Group. Endometrial intraepithe-
lial neoplasia (EIN): will it bring order to chaos? Gynecol Oncol. 2000;
76:287290.
49. Scully RE, Bonglio TA, Kurman RJ, Silverberg SG, Wilkinson EJ. In-
ternational Histological Classication and Typing of Female Genital
Tract Tumours. 2nd ed. New York, NY: Springer-Verlag; 1994:1189.
50. Baak JP, Mutter GL, Robboy S, et al. The molecular genetics and
morphometry-based endometrial intraepithelial neoplasia classication
system predicts disease progression in endometrial hyperplasia more
accurately than the 1994 World Health Organization classication sys-
tem. Cancer. 2005;103:23042312.
51. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hy-
perplasia: a long-term study of untreated hyperplasia in 170 patients.
Cancer. 1985;56:403412.
52. Zaino RJ, Kauderer J, Trimble CL, et al. Reproducibility of the diagno-
sis of atypical endometrial hyperplasia: a Gynecologic Oncology Group
study. Cancer. 2006;106:804811.
53. Bergeron C, Nogales FF, Masseroli M, et al. A multicentric European
study testing the reproducibility of the WHO classication of endome-
trial hyperplasia with a proposal of a simplied working classication
for biopsy and curettage specimens. Am J Surg Pathol. 1999;23:
11021108.
54. Lacey JV Jr, Mutter GL, Nucci MR, et al. Risk of subsequent endome-
trial carcinoma associated with endometrial intraepithelial neoplasia
classication of endometrial biopsies. Cancer. 2008;113:20732081.
55. Mueck AO, Seeger H, Rabe T. Hormonal contraception and risk of en-
dometrial cancer: a systematic review. Endocr Relat Cancer. 2010;17:
R263R271.
56. Muneyyirci-Delale O, Gupta A, Abraham C, Chandrareddy A,
Bowers CH Jr, Cutler JB. Management of dysfunctional uterine bleed-
ing based on endometrial thickness. Int J Womens Health. 2010;2:
297302.
57. Eichner E, Abellera M. Endometrial hyperplasia treated by progestins.
Obstet Gynecol. 1971;38:739742.
58. Bese T, Vural A, Ozturk M, et al. The effect of long-term use of proges-
terone therapy on proliferation and apoptosis in simple endometrial hy-
perplasia without atypia. Int J Gynecol Cancer. 2006;16:809813.
59. Buttini MJ, Jordan SJ, Webb PM. The effect of the levonorgestrel re-
leasing intrauterine system on endometrial hyperplasia: an Australian
study and systematic review. Aust N Z J Obstet Gynaecol. 2009;49:
316322.
60. Ozdegirmenci O, Kayikcioglu F, Bozkurt U, Akgul MA, Haberal A.
Comparison of the efcacy of three progestins in the treatment of sim-
ple endometrial hyperplasia without atypia [published online ahead of
print January 25, 2011]. Gynecol Obstet Invest. 2011;72:1014.
61. Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concen-
trations of levonorgestrel in women using a levonorgestrel-releasing
IUD. Clin Endocrinol (Oxf). 1982;17:529536.
62. Suhonen SP, Allonen HO, Lahteenmaki P. Sustained-release estradiol
implants and a levonorgestrel-releasing intrauterine device in hormone
replacement therapy. Am J Obstet Gynecol. 1995;172:562567.
570 Journal of Minimally Invasive Gynecology, Vol 19, No 5, September/October 2012
63. Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic ve-
nous thromboembolism in users of progestogens alone. Lancet. 1999;
354:16101611.
64. Heinemann LA, Assmann A, DoMinh T, Garbe E. Oral progestogen-
only contraceptives and cardiovascular risk: results from the Transna-
tional Study on Oral Contraceptives and the Health of Young Women.
Eur J Contracept Reprod Health Care. 1999;4:6773.
65. World Health Organization. Cardiovascular disease and use of oral and
injectable progestogen-only contraceptives and combined injectable
contraceptives: results of an international, multicenter, case-control
study. Contraception. 1998;57:315324.
66. Lidegaard Nielsen LH, Skovlund CW, Skjeldestad FE,
Lkkegaard E. Risk of venous thromboembolism from use of oral con-
traceptives containing different progestogens and oestrogen doses:
Danish cohort study 2001-9. BMJ. 2011;343:d6423.
67. Bergendal A, Odlind V, Persson I, Kieler H. Limited knowledge on
progestogen-only contraception and risk of venous thromboembolism.
Acta Obstet Gynecol Scand. 2009;88:261266.
68. Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM,
Bailey KR. Is progestin an independent risk factor for incident venous
thromboembolism? a population-based case-control study. Thromb Res.
2010;126:373378.
69. van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. The risk
of deep venous thrombosis associated with injectable depot-
medroxyprogesterone acetate contraceptives or a levonorgestrel
intrauterine device. Arterioscler Thromb Vasc Biol. 2010;30:
22972300.
70. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and re-
productive outcomes with progestin therapy in women with endome-
trial hyperplasia and grade 1 adenocarcinoma: a systematic review.
Gynecol Oncol. 2012;125:S149S150.
71. Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK,
Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-
releasing intrauterine system for endometrial hyperplasia: a system-
atic review and metaanalysis. Am J Obstet Gynecol. 2010;203:
547.e1547.e10.
72. Laurelli G, Di Vagno G, Scaffa C, Losito S, Del Giudice M, Greggi S.
Conservative treatment of early endometrial cancer: preliminary results
of a pilot study. Gynecol Oncol. 2011;120:4346.
73. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Group [published correction appears in Hum Reprod. 2008;23:1474].
Consensus on infertility treatment related to polycystic ovary syn-
drome. Hum Repod. 2008;23:462477.
74. Shirali E, Yarandi F, Eftekhar Z, Shojael H, Khazaeipour Z. Pregnancy
outcome in patients with stage 1a endometrial adenocarcinoma, conser-
vatively treated with megestrol acetate. Arch Gynecol Obstet. 2012;285:
791795.
75. Pardthaisong T. Return of fertility after use of the injectable contracep-
tive Depo Provera: up-dated data analysis. J Biosoc Sci. 1984;16:2334.
76. Legro RS, Zaino RJ, Demers LM, et al. The effects of metformin and
rosiglitazone, alone and in combination, on the ovary and endometrium
in polycystic ovary syndrome. Am J Obstet Gynecol. 2007;196:
402.e1402.e11.
77. Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS. Met-
formin treatment exerts anti-invasive and antimetastatic effects in hu-
man endometrial carcinoma cells. J Clin Endocrinol Metab. 2011;96:
808816.
78. Li HZ, Chen XN, Qiao J. Letrozole as primary therapy for endometrial
hyperplasia in young women. Int J Gynaecol Obstet. 2008;100:1012.
79. Agorastos T, Bontis J, Vakiani A, Vavilis D, Constantinidis T.
Treatment of endometrial hyperplasias with gonadotropin-releasing
hormone agonists: pathological, clinical, morphometric, and DNA-
cytometric data. Gynecol Oncol. 1997;65:102114.
80. Agorastos T, Vaitsi V, Pantazis K, Efstathiadis E, Vavilis D, Bontis JN.
Aromatase inhibitor anastrozole for treating endometrial hyperplasia in
obese postmenopausal women. Eur J Obstet Gynecol Reprod Biol.
2005;118:239240.
81. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix,
and endometrium. Int J Gynaecol Obstet. 2009;105:103104.
82. Salman MC, Usubutun A, Dogan NU, Yuce K. The accuracy of frozen
section analysis at hysterectomy in patients with atypical endometrial
hyperplasia. Clin Exp Obstet Gynecol. 2009;36:3134.
83. Attard Montalto S, Coutts M, Devaja O, Summers J, Jyothirmayi R,
Papadopoulos A. Accuracy of frozen section diagnosis at surgery in
pre-malignant and malignant lesions of the endometrium. Eur J Gynae-
col Oncol. 2008;29:435440.
84. Indermaur MD, Shoup B, Tebes S, Lancaster JM. The accuracy of fro-
zen pathology at time of hysterectomy in patients with complex atypical
hyperplasia on preoperative biopsy. Am J Obstet Gynecol. 2007;196:
e40e42.
85. Vilos GA, Harding PG, Ettler HC. Resectoscopic surgery in women
with abnormal uterine bleeding and nonatypical endometrial hyperpla-
sia. J Am Assoc Gynecol Laparosc. 2002;9:131137.
86. Jarvela IY, Santala M. Treatment of non-atypical endometrial hyperpla-
sia using thermal balloon endometrial ablation therapy. Gynecol Obstet
Invest. 2005;59:202206.
Armstrong et al. Endometrial Hyperplasia 571