ASSOCIATION OF RISK FACTOR WITH ENDOMETRIAL HYPERPLASIA

HISTOPATHOLOGIC DIAGNOSIS IN ANATOMIC PATOLOGY OF

RSUP.MOHAMMAD HOESIN PALEMBANG FOR
JANUARY 1ST 2014 - JULY 31ST 2018

Rifqoh Trikurnia1, Wresnindyatsih2, Msy Rulan Adnindya2

1
Program Studi Pendidikan Dokter, Fakultas Kedokteran, Universitas Sriwijaya
2
Bagian Patologi Anatomi, Fakultas Kedokteran, Universitas Sriwijaya
3
Bagian Anatomi, Fakultas Kedokteran, Universitas Sriwijaya
Jl. Dr. Mohammad Ali Komplek RSMH Palembang Km. 3,5 Palembang, 30126, Indonesia
Email: rifqoh3kurnia@gmail.com

Abstrak

Kasus hiperplasia endometriummasih menjadi masalah umum ginekologi yang harus diperhatikan karena menimbulkan
gejala berupa perdarahan yang abnormal yang dapat menyebabkan keresahan pada wanita. Faktor risikohiperplasia
endometrium antara lain usia 46- 55 tahun, nullipara, obesitas, dan diabetes melitus. Tujuan penelitian ini untuk
mengetahui hubungan antara faktor risiko hiperplasia endometrum dengan diagnosis histopatologi hiperplasia
endometrium. penelitian analitik observasional dengan desain cross sectional. Penelitian dilakukan di RSUP dr.
Mohammad Hoesin Palembang selama dua bulan. Pengambilan Data dilakukan dengan menggunakan data sekunder yang
merupakan data pasien hiperplasia endometrium. Pasien hiperplasia endometrium paling banyak ditemukan pada usia 46
-55 tahun sebanyak 41,4%, pada pasien multipara sebesar 44,5%, pasien yang tidak mengalami obesitas sebanyak 71,9 %,
dan pada pasien yang tidak mengalami diabetes melitus sebanyak92,9%. Tipe hiperplasia non atipikal merupakan tipe
hiperplasia endometrium yang paling banyak ditemukan yaitu sebesar 67,2. Terdapat hubungan yang bermakna antara
usia dengan diagnosis histopatologi hiperplasia endometrium karena didapatkan nilai p value (p=0,000) dari (α=0,5)
Sedangkan, pada variabel yang lainnya tidak ditemukan hubungan yang bermakna antara paritas, obesitas, dan diabetes
melitus dengan diagnosis hiperplasia endometrium. Terdapat hubungan yang bermakna antara usia dengan diagnosis
histopatologi hiperplasia endometrium. Sedangkan , variabel yang lainnya tidak dietmukan hubungan yang bermakna
dengan diagnosis hiperplasia endometrium.

Kata Kunci : Faktor Risiko, Usia, DObesitas diagnosis Hiperplasia Endometrium.

Abstract

The case of endometrial hyperplasia is still a common gynecological problem that must be considered because it causes
symptoms of abnormal bleeding that can cause anxiety in women. Risk factors for endometrial hyperplasia include age
46-55 years, nullipara, obesity, and diabetes mellitus. The purpose of this study was to determine the relationship
between risk factors for endometrial hyperplasia and histopathological diagnosis of endometrial hyperplasia.
Observational analytic study with cross sectional design. The study was conducted at RSUP Dr. Mohammad Hoesin
Palembang for two months. Data retrieval is done using secondary data which is a data of patients with endometrial
hyperplasia. Most patients with endometrial hyperplasia were found at the age of 46-55 years as much as 41.4%, in
multiparous patients by 44.5%, patients who were not obese as much as 71.9%, and in patients who did not have
diabetes mellitus as much as 92 , 9%. The type of non-atypical hyperplasia is the most common type of endometrial
hyperplasia which is equal to 67.2. There is a significant relationship between age and histopathological diagnosis of
endometrial hyperplasia because the value of p value is obtained (p = 0,000) from (α = 0.5) Whereas, in the other
variables there is no significant relationship between parity, obesity, and diabetes mellitus with a diagnosis endometrial
hyperplasia. There is a significant relationship between age and histopathological diagnosis of endometrial hyperplasia.
Whereas, the other variables did not include significant relationships with the diagnosis of endometrial hyperplasia.

Keywords: Risk factors, age, obesity, diagnosis of endometrial hyperplasia

 1. Introduction
Endometrial hyperplasia is a gynecological
case that often occurs 120,000 new cases each
year in the European Union (BAAK, Mutter,
2000).The incidence of endometrial hyperplasia
has declined sharply from 1980 to 1999 and has
increased in 2003 in the United States (Lacey Jr
et al., 2012). The decrease in the incidence of
endometrial hyperplasia in the United States
occurs because of the effect of stopping
estrogen use as hormone therapy. Increased
incidence of endometrial hyperplasia occurs
due to an increase in obese women in the
United States (Lacey Jr et al., 2012)
Basically older age especially those
who have experienced postmenopause, women
with PCOS, nullipara women and infertility
women are at risk of developing endometrial
hyperplasia because ovulation does not occur
so there is no increase in LH (Luteinizing
Hormone) to produce a corpus luteum which
causes progesterone not to be produced so the
balance of the endometrial wall is disrupted and
increases endometrial proliferation. Late early
menarche and perimenopause cause a lot of
estrogen exposure in the body so that it can
cause cell proliferation to become endometrial
hyperplasia. Women who are obese and
diabetes mellitus experiences resistance and
hyperinsulinemia causes deposits in fat tissue
resulting in expression of aromatization which
inhibits apoptosis and triggers cell proliferation.
Risk factors that cause endometrial hyperplasia
are older age, postmenstruation, early menarche,
slow perimenopause, obesity, diabetes mellitus,
nullipara, and Polycystic ovarian syndrome
(Sanderson, et all., 2017).
The classification of endometrial
hyperplasia consists of atypical and
non-atypical hyperplasia (WHO, 2014). In this
study, the latest classification of endometrial
hyperplasia will be used using medical record
data from 2014 to 2018. Until now, the
incidence of endometrial hyperplasia is still
found, information on prevalence and the
relationship between risk factors and diagnosis
of endometrial hyperplasia is needed as an
overview regarding risk factors with
histopathological diagnosis of endometrial
hyperplasia. Therefore this study was
conducted to determine the incidence of
endometrial hyperplasia and its risk factors, and
data to compare with other studies.
2. Methods
This study was an analytical study with a cross
sectional design in the Anatomy Pathology
Section of Dr. RSUP Mohammad Hoesin
Palembang. This research was conducted from
July to December 2018. The population of this
study was all medical record data of patients
with endometrial hyperplasia who were
examined at the Anatomical Pathology
Laboratory of RSUP Dr. Mohammad Hoesin
Palembang period January 1, 2014 - July 31,
2018. The inclusion criteria in this study were
the diagnosis of histopathological work of
endometrial hyperplasia including atypical
hyperplasia and non atypical hyperplasia. The
exclusion criteria in this study are incomplete
patient data on medical records. The research
mop was all medical record data of patients
diagnosed with endometrial hyperplasia in the
PA section of the RSMH Palembang period 1
January 2014 - 31 July 2018. Samples were
taken using a total sampling technique with a
minimum of 110 samples. Variables in this
study include independent variables (age, parity
number, obesity, diabetes mellitus and
dependent variables which include
histopathological diagnosis of endometrial
hyperplasia including atypical hyperplasia and
non atypical hyperplasia.
Data used in this study uses secondary data
obtained from the medical record data of
patients with endometrial hyperplasia in the
Obstetrics Section of Gynecology and
Pathology Anatomy Dr. RSUP Mohammad
Hoesin Palembang during the period of January
2014 - July 2018. The data obtained from
medical records were then collected according
to age groups, parity, obesity, diabetes mellitus,
and histopathological features of endometrium.
and then processed and analyzed by univariate
and bivariate analysis. Univariate analysis was
used to determine the incidence of endometrial
hyperplasia. and then the next frequency
distribution will be obtained which is presented
in the form of tables or graphs and explained in
narrative form. And bivariate analysis was used
to determine the relationship between
dependent variables with the type of
histopathology of endometrial hyperplasia
using the Chi-Square or Fischer Exact method.
group over 65 years. Atypical endometrial
hyperplasia is more common in the age group
46-55 years (19 cases). While atypical
endometrial hyperplasia is not found in the age
group less than 25 years.

3. Results Table 3. Distribution of Endometrial

Hyperplasia According to the Parity Group (n = 128)
Univariate Analysis
Parity n
Table 1. Distribution of Endometrial Hyperplasia by %
Age Group (n = 128) 0 (Nullipara) 43 33.6
Age n % 1(Primipara) 18 14.1
<25 1 8 2- 4 (multipara) 57 44.5
26 – 35 16 12.5 >4 (Grandemultipara) 10 .8
36 – 45 47 36.7 Total 128 100
46 – 55 53 41.4
56 – 65 10 7.8 Based on the results of the study, it
was found that patients who had only a small
> 65 1 8
number of endometrial hyperplasia were 10
Based on the results of the study, it patients (7.8%). While the most group
was found that the age group with fewer experienced endometrial hyperplasia were 57
endometrial hyperplasia was less than 25 years multiparous patients (44.5%) and 43 nulliparas
of age and more than 65 years of age each of or (33.6%).
8%. Whereas the most age group with
endometrial hyperplasia was the age group Table 4. Distribution of Histopathological
46-55 years as much as 41.4%. Types of Endometrial Hyperplasia According to the
Parity Group (n = 128)
Table 2. Distribution of Histopathological Hiperplasia Hiperplasia non
Types of Endometrial Hyperplasia by Age Group (n = atipikal atipikal
Paritas
128) n
n
Hiperplasia Hiperplasia Nullipara 12 31
Age Primipara 4 14
atipikal non atipikal
n n Multipara 19 38
Grande 7 3
< 25 0 1
Multipara
26 – 35 5 11
36 – 45 8 39 Total 42 86
46 – 55 19 34
56 – 65 9 1
> 65 1 0 Based on the results of the study, it
Total 42 86 was found that the group of patients who
experienced non-atypical endometrial
Based on the results of the study, hyperplasia were as many as 38 people.
there were more cases of non-atypical Meanwhile, the group of patients who had only
endometrial hyperplasia found in the age group a little atypical hyperplasia were a three-person
36-45 years (39 cases) and the age group 46-55 grandemultural group. The group with more
years (34 cases). While non-atypical atypical endometrial hyperplasia was a
endometrial hyperplasia is not found in the age multiparous group of 19 people. While the
group of patients who had only atypical n n
endometrial hyperplasia were four primiparous Ada 4 6
groups. Tidak 38 80
Table 5. Distribution of Endometrial Ada
Hyperplasia According to Obesity (n = 128)
Obesitas N % Total 42 86

Obesitas 36 28.1
Based on the results of the study it
Tidak Obesitas 92 71.9 was found that patients who had more atypical
Total 128 100 and atypical hyperplasia were 80 patients and
Based on the results of the study, it 38 people who did not have diabetes mellitus.
was found that patients who had more While patients who only had a little atypical
endometrial hyperplasia were 92 non-obese and atypical hyperplasia were patients with
patients (71.9%) compared to 36 obese patients diabetes mellitus of four and six respectively.
Table 9. Distribution of Endometrial
(28.1%). Histopathology Diagnosis (N = 128)
Table 6. Distribution of Histopathological
Types of Endometrial Hyperplasia According to
Obesity (n = 128)
Endometrial Hyerplasia n %
Hiperplasia Hiperplasia non atipikal Diagnosis
Obesitas atipikal Non Atipikal 86 67,2
n n Atipikal 42 32,8
Obesitas 16 20 Total 128 100
Tidak 26 66 128
Obesitas Based on the results of the study, the
Total 42 86 highest type of endometrial hyperplasia was
Based on the results of the study it non-atypical at 86 people (67.2%). While the
was found that patients who had more atypical only small type was atypical hyperplasia of 42
and atypical hyperplasia were 66 patients and people (32.8%).
26 people who were not obese. Whereas
patients who only had a little atypical and Bivariate Analysis
atypical hyperplasia were obese patients each at Table 10. Relationship between Age and
16 and 20 people. Histopathology of Endometrial Hyperplasia
Table 7. Distribution of Endometrial
Hyperplasia According to Diabetes Mellitus (n = 128)
Diabetes Melitus N % Hiperplas Hiperplasia OR
P
Age ia atipikal non atipikal (CL
Ada 18 7,8 95%)
Tidak Ada 110 92,9 n n
Total 128 100 ≤ 52 Tahun 22 83 4,14
Based on the results of the study, it >52 tahun 20 3 (0,161
was found that patients who had more 0,000 –
endometrial hyperplasia were 110 patients who 0,361)
did not have diabetes mellitus (92.9%) Total 42 42
compared with 18 patients with diabetes
mellitus (7.8%).
Table 8. Distribution of Histopathological Based on the chi-square statistical test
Types of Endometrial Hyperplasia According to with a 2x2 table, the P value is 0.000 (p <0.05).
Diabetes Mellitus (n = 128) This means that it can be concluded that there
Diabetes Hiperplasia Hiperplasia non atipikal is a significant relationship between age and
Melitus atipikal histopathological diagnosis of endometrial
hyperplasia. OR value of 4.14, which means Hiperplasia Hiperplasia non
that the age of ≤ 52 years is 4.14 times more atipikal atipikal
risk for atypical hyperplasia. n n
Ada 4 6
Table 11. Relationship between Parity and Tidak Ada 38 80
Histopathological Diagnosis of Endometrial 0,87
Hyperplasia Total 42 86

Hiperplasia Hiperplasia P
Parity Based on fisher exact statistics with
atipikal non atipikal
n n 2x2 tables, the P value is 0.87 (p> 0.05). This
Tidak 19 34 means that it can be concluded that there is no
Punya Anak significant relationship between diabetes
Punya Anak 23 52 0,67 mellitus and the histopathological diagnosis of
endometrial hyperplasia.
Total 42 86
4. DISCUSSION
Based on the chi-square statistical test
The highest age group with
with a 2x2 table, the P value is 0.67 (p> 0.05).
endometrial hyperplasia is the age group 46-55
This means that it can be concluded that there
years. While the age group with the least
is no significant relationship between the
endometrial hyperplasia is a group of less than
amount of parity and the histopathological
25 years and more than 65 years. The most
diagnosis of endometrial hyperplasia.
common atypical and atypical endometrial
Table 12. Relation of Obesity to the
hyperplasia cases were found in the 36–55 year
Diagnosis of Histopathology of Endometrial age group of 73 cases. Whereas atypical and
Hyperplasia atypical cases of endometrial hyperplasia are
not found at ages more than 65 years and less
than 25 years. There is a significant
Hiperplasia Hiperplasia P relationship between age and the diagnosis of
Obesitas
atipikal non atipikal endometrial hyperplasia. This is in accordance
n n with previous studies that stated endometrial
Obesitas 16 20 hyperplasia most commonly occurs in the
Tidak 26 66 fourth and fifth decades (46-50 years). This is
Obesitas 0,09 because at that age is a transition period or
Total 42 86 perimenopause period. "The average age of
menopause for Indonesian women is 45.2
Based on the chi-square statistical test years." "While in the United States the average
with a 2x2 table, the P value is 0.09 (p> 0.05). age of menopausal women is 51.3 years old"
This means that it can be concluded that there (Safitri, 2009), (Sur and Chakravorty, 2016),
is no significant relationship between obesity (Reed et al., 2010), (Gargi, 2010), (Indahwati,
and the histopathological diagnosis of 2007), (Budiman, 2014), (Shrestha, 2018).
endometrial hyperplasia. The most parity groups with
endometrial hyperplasia were multiparas and
Table 13. Relationship between Diabetes nulliparas. Most atypical and atypical
Mellitus and Histopathological Diagnosis of
endometrial hyperplasia is found in multiparous
Endometrial Hyperplasia
and primiparous groups of 57 and 43
Diabetes P respectively. While the group of patients who
had the least non-atypical hyperplasia were
patients with a grandemultar of three people.
The patients who had the least atypical
endometrial hyperplasia were four primiparous
groups. In this study there was no significant
relationship between parity and
histopathological diagnosis of endometrial
hyperplasia. Endometrial hyperplasia is found
in nullipara and multipara parity status
(Indahwati, 2007), (Wachidah, 2011),
(Budiman, 2014), (Hasan, 2015). The
nulliparous group is most at risk of developing
endometrial hyperplasia because it relates to
anovulatory cycles characterized by long-term
estrogen exposure because of the higher
number of menstrual cycles throughout life
(Flake, 2003), (William, 2007) (Hasan, 2015).
The results of this study found that
patients who had the most atypical and
non-atypical endomerium hyperplasia were
patients who were not obese and did not suffer
from diabetes mellitus. Statistically there is no
significant relationship between obesity and
diabetes mellitus to the histopathological
diagnosis of endometrial hyperplasia. This is in
accordance with previous studies which stated
that there was no significant relationship
between obesity and diabetes mellitus with a
histopathological diagnosis of endometrial
hyperplasia (Wise, 2016). However, many
studies suggest that there is a significant
relationship between obesity and diabetes
mellitus with a diagnosis of endometrial
hyperplasia (Friberg, 2014). This can be
explained because obesity patients and diabetes
mellitus experience insulin resistance and
hyperinsulinemia which can stimulate ovarian
and endometrial cell proliferation. Insulin
resistance will cause hyperinsulinemia as a
reaction to compensate for insulin insensitivity.
Hyperinsulinemia can stimulate the growth of
endometrial stromal cells by binding to
receptors on endometrial cells.
Hyperinsulinemia can bind and activate IGF-I
receptors through decreasing levels of
insulin-like growth factor (IGF) -binding
protein-1 and pro-binding IGFtein-3 increases
circulation IGF-I freely activates IGF-I
receptors in endometrium stimulates cell
proliferation (Kazer, 1995) (Nestler, 1991)
(Irwin, 1993).
The most competitive type found is
the non-atypical type compared to atypical ie
86 people (67.2%) and 42 people (32.8%)
respectively. This is in accordance with
previous studies of obtaining patients with the
most type of endometrial hyperplasia,
non-atypical type of endometrial hyperplasia
(Re et al., 2015), (Gargi, 2010), (Budiman,
2014). The underlying difference between
non-atypical and atypical endometrial
hyperplasia is a visible histological picture.
Non-atypical endometrial hyperplasia is a
milder type compared to the atypical type.
About 1.6% of patients diagnosed with
non-atypical endometrial hyperplasia can
develop endometrial carcinoma (Alianto, 2018).
The type of non-atypical endometrial
hyperplasia can turn into atypical hyperplasia if
there is more cell mutation and cell
proliferation. As many as 22% of atypical
endometrial hyperplasia patients can turn into
endometrial carcinoma (Alianto, 2018). The
most common atypical endometrial hyperplasia
is found. This is possible due to the large
number of patients who are aware early on to
check themselves early so often the
non-atypical type or the initial type of
endometrial hyperplasia is found. This is very
good for the future so that it can be diagnosed
and managed early so that it can be prevented
and does not occur to worse conditions.
5. CONCLUSION
Based on the results of the study
found a significant relationship between age
and histopathological diagnosis of endometrial
hyperplasia. The highest age for endometrial
hyperplasia is the age group 46-55 years.
Daftar Acuan
1. Abbot SD dkk. 1986. Dissociation
Between Pituitay GnRH binding Sites and
LH Respones to GnRH in vitro. Mollecular
and Cellular Endocrinology 48 1919 – 197.
Doi: 10.1016/0303-7207(86)90041-9
2. Alianto Ricky.2018. Perbedaan Nilai
Rerata AgNOR antara Lesi Hiperplasia
Endometrium Non Atipik, Endometrioid
Intrapithelial Neoplasia, dan Karsinoma
Endometrioid Endometrium. Program
Pendidikan Magister Kedokteran Klinik
Departemen Patologi Anatomik Fakultas
Kedokteran Universitas Sumatera Utara
Medan.
3. Anwar H Nassar. 2005.Gynecologists
Attitude Towards Hormone Therapy in
The Post Women’s Health Initiative Study
Era.52(1),18-25
4. Flake, Gordon P, Janet Andersen, Darlene
Dixon., 2003, Etiology And Pathogenesis
Of Uterine Leiomiomas: A Review,
Enviromental Health Perspective,
111(8):p;1037-1054.
5. Friberg Emilie, Christos S. Mantzoros and
Alicja Wolk. Cancer Epidemiology,
Biomarkers and Prevention Diabetes and
Risk Of Endometrial Cancer A 12. Jose E Sanchez, dkk. 2012. Estrogen
Population-Based Prospective Cohort
Study. Cancer Epideiol Biomarkers Prev
2007;16:267-280.
6. Gargi Bandhyopadhaya.2010. Examination
of the Regulation Galectin-3 Expresssion
in Cancer. 355-369.
7. Garrido, Gracia JC dkk. 2007.The
Integrated Action of Oestrogen Receptor
Isoforms and Sites with Progesterone
Receptor in Gonadotrope ModulatesLH
Secretion: Evidence From Tamoxifen-
Treated Ovariectomizedrats.Journal of
Endrocrinology 193 107 -119. doi:
10.1677/JOE-06-021.
8. Garrido, Gracia JC, Gordon A, Aguilar R,
Monterde.2008. Morphological Effects of
Oestradiol- 17β, and Selective Oestrogen
Receptor α and β Agonist on Luteinising
Hormone-Secreting Cells in
Tamoxifen-Treated Ovariectomised Rats.
Histology 23 1453- 14639.
9. Jose E Sanchez, dkk. 2012. Estrogen
Receptor (ESR) 2 Partially offsets the
absence of ESR1 in Gonadotropes of
Pituitary- Spesific Esr1 Knokcout Female
Mice. Reproduction: 143(4),549-558,2012.
10. Irwin JC, Fuentes, Duspin BA.1999.
Guidence LC.Insulin-Like Growth Factor
Regulation of Human Endometrial Stromal
Cell Function: Coordinate Effects on
Insulin-like growth factor binding
protein-1, cell proliferation, and prolactin
Secretion. Regul: 48 165-177.
11. Indahwati, D., Suryawan, A. and
Sastrawinata, U.2010. Hubungan
Kerapatan Reseptor Hormon Estrogen
pada Wanita Perimenopause terhadap
Kejadian Tipe Hiperplasia Endometrium.
Jurnal Kedokteran Maranatha, 6 (2), p.
pp-1.
Receptor (ESR) 2 Partially offsets the
absence of ESR1 in Gonadotropes of
Pituitary- Spesific Esr1 Knokcout Female
Mice. Reproduction: 143(4),549-558,2012.
13. Khaled M Zeitoun dan Serdar E
Bulun.1999. Aromatase: A Key Molecule
in The Pathophysiology of Endometriosis
And Therapeutic Target.
72(6),961-969,1999.
14. Kazer RR. 1995. Insulin Resistance,
Insulin- like growth factor I, and Breast
Cancer: Hypothesis. Int J Cancer:
62:403.
15. Nestler JE, Powers LP, Matt DW, et al. A
Direct Effect of Hyperinsulinemia on
Serum Sex Hormone-Binding Globulin
Levels in Obese Women With The
Polycystic Ovary Syndrome. J Clin
Endocrinol Metab; 72:83-9.
16. POGI (Perkumpulan Obstetri dan
Ginekologi Indonesia) dan HIFERI
Himpunan Endokrinologi Reproduksi dan
Fertilitas Indonesia. Konsensus
Tatalaksana Perdarahan Uterus Abnormal
17. Prawirohardjo.2005.IlmuKandungan.
Jakarta: Yayasan Bina Pustaka.
18. Ramenzalani, Fariba, dkk. Relationships
Between Serum Luteinizing Hormon Level,
Endometrial Thickness and Body Mas
Index in Polycistic Ovary Syndrome
Patiens with and Without Endometrial
Hyperplasia.
19. Shresta Pravin. 2018. Endometrial Study
by Ultrasonografi and Its Correlation with
Histopathology in Abnormal Uterine
Bleeding. Asian Journal of Medical
Sciences:9 (2), 31-35.
20. Sietse Mosselman dkk. ERB:
Identification and Characterization of A
Novel Human Estrogen Receptor. FEBS
Letters 392 (1), 49 -53.
21. Sur D dan Chakravorty R. 2016.
Correlation of Endometrial Thickness and
Histopathology in Woman with Abnormal
Uterine Bleeding. Reproductive System
and Sexual Disorder. 124 (3):404-411