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FACTORS LEADING TO THE DEVELOPMENT OF ENDOMETRIAL
HYPERPLASIA IN WOMEN OF REPRODUCTIVE AGE (A REVIEW)
Dustova Nigora Kakhramonovna
Kurbonova Gulnora Radzhabovna
Bukhara, Uzbekistan, postal code 200100
Bukhara State Medical Institute named after Abu Ali ibn Sina, Uzbekistan,
Bukhara, A.Gijduvan str.1 Tel: +998(65) 223-00-50 e-mail: info@bsmi.uz,
https://orcid.org/0000-0003-0707-5673
https://doi.org/10.5281/zenodo.14500989
Abstract.
Despite the progress made in the study of etiopathogenesis, new
methods for diagnosing and treating endometrial hyperplasia, the problem of
treating patients with this pathology still remains far from being solved. All this
dictates the need to optimize the tactics of managing patients with endometrial
hyperplasia in reproductive age, which should be aimed not only at creating
adequate comprehensive approaches to predicting the development and
recurrence of endometrial hyperplasia, but also at developing uniform protocols
for managing patients with this pathology. Key words: Endometrial hyperplasia,
abnormal uterine bleeding, hyperestrogenism, proliferation, apoptosis.
INTRODUCTION
Endometrial hyperplasia (EH) is a benign pathological process of the
uterine mucosa, characterized by proliferation (growth) of the glands and an
increase in the glandular-stromal ratio (the ratio of glandular and stromal cells).
The main characteristic feature of the disease is the growth of the inner layer of
the uterus - the endometrium, leading to a thickening and increase in its volume.
Hyperplastic processes of the endometrium are still of great scientific,
medical and social significance in terms of the frequency of occurrence,
disorders of the reproductive system and the lack of adequate methods of
treatment [1,2,3]. Abnormal uterine bleeding, which is the most common clinical
manifestation of endometrial hyperplasia, is the most common reason for
visiting a gynecologist and ranks second among gynecological problems
associated with referring a woman to hospitalization [4,5]. The issues of
treatment of patients with endometrial hyperplasia cover a wide range of
conservative and surgical methods. However, young women who want to
preserve their reproductive function (in the absence of cellular atypia),
conservative therapy is relevant, among which hormonal therapy takes the
leading place. Due to this, hormonal effect on hyperplastic endometrium has not
lost its clinical significance. Endometrial hyperplasia is known to be a
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consequence of absolute or relative hyperestrogenism and progesterone
deficiency, which leads to excessive (uncontrolled) cell division and reduced
apoptosis [6,7].
The classic therapy for endometrial hyperplasia (EH) is the administration
of progestins to counteract estrogenic influence. Progesterone has an
antiproliferative effect on the mitotic activity of endometrial cells. Progestins
reduce the number of estrogen receptors and accelerate their catabolism by
stimulating 17-beta-hydroxysteroid dehydrogenase and sulfotransferase, and
thus reduce estrogen dominance in the hormonal background, leading to
endometrial hyperplasia [8]. However, recent reports of clinical studies have
shown side effects of these drugs with long-term use, which is associated with
their androgenic activity: an increase in plasma insulin concentration, a decrease
in serum HDL levels, an increase in LDL, vasoconstriction, blocking the action of
NO synthetase, etc. [9].
At present, based on the analysis of the work of gynecological hospitals, it is
important to develop the basis for determining a medical strategy in the
treatment of GE in relation to the choice of a conservative method of treating
women of reproductive age. In this direction, it seems promising to take into
account psychosomatic disorders, the frequency of which ranges from 30% to
57% of the total number of women applying to antenatal clinics [10,11].
Hyperplastic processes in the endometrium are a large group of histological
changes in the glands and stroma of the endometrium, which are the basis for
the formation of neoplastic processes in the uterus. One of the most significant
factors with which the risk of developing this pathology is directly associated is
the perimenopausal period, when the frequency of hormone-dependent
pathology increases. Hyperplastic processes in the endometrium are one of the
most common causes of uterine bleeding and hospitalization. The question of
the risk of developing malignant transformation of HE remains open [1,2].
According to domestic and foreign studies, the degree of risk of malignancy of
various HPE variants is determined by the morphological state of the
endometrium and depends primarily on the severity of cellular atypism and, to a
lesser extent, on age, ovarian condition, concomitant endocrine diseases, and
other factors [4]. It has been proven that histopathological and molecular
changes reflect the possible risk of transition of HE to EC. The degree of risk of
malignancy of various HPE variants is determined by the morphological state of
the endometrium and depends primarily on the severity of cellular atypism and,
to a lesser extent, on age, the state of the ovaries, concomitant endocrine
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diseases, and other factors [4]. It has been proven that histopathological and
molecular changes reflect the possible risk of transition of HE to EC. The degree
of risk of malignancy of various HPE variants is determined by the
morphological state of the endometrium and depends primarily on the severity
of cellular atypism and, to a lesser extent, on age, the state of the ovaries,
concomitant endocrine diseases, and other factors [4]. It has been proven that
histopathological and molecular changes reflect the possible risk of transition of
HE to EC.
The complexity of the etiopathogenesis of HPE creates significant
difficulties in the choice of treatment methods. This can explain the lack of
uniform recommendations on the choice of a drug, the dose and the optimal
duration of its use, which is often inadequate, and therefore, one has to deal with
relapses of HE [5]. Recurrent uterine bleeding, oncological alertness in long-
term proliferative processes against the background of concomitant pathology,
dictate the need for more active management of this group of patients [6]. Thus,
despite the progress made in the study of etiopathogenesis, new methods for
diagnosing and treating HPE, the problem of treating patients with this
pathology still remains far from being solved.
THE PURPOSE OF OUR RESEARCH
The aim of this study was to study the causes of recurrent endometrial
hyperplastic processes in women of reproductive age.
RESULTS AND DISCUSSIONS.
The problem of endometrial hyperplastic processes (HPE) in women of
reproductive age is one of the urgent problems of gynecology due to the high
prevalence of this pathology in women of this age [11,12]. The unrelenting
interest in it is determined by the tendency of HPE to a long, recurrent course,
the absence of specific, pathognomonic symptoms, the complexity of differential
diagnosis and the choice of treatment methods [13,14]. The endometrium, the
inner glandular layer of the uterus, is a dynamic tissue that undergoes a series of
changes during the menstrual cycle during a woman's reproductive years [1].
The delicate balance between endometrial proliferation and apoptosis is
maintained by a complex process involving a number of factors: hormonal
balance, molecular mechanisms, environment, age, and so on.
One of these gynecological diseases is endometrial hyperplasia (EH), which
is characterized by non-physiological proliferation of endometrial glands with
various changes in the phenotypic properties of cells and an increase in the
glandular-stromal ratio of more than [3].
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The prevalence of endometrial hyperplastic processes among
gynecological diseases ranges from 10 to 50%, which is constantly growing [4].
According to the literature data, in Western Europe there are about 200,000
new cases of endometrial hyperplasia per year [5]. The need for hospitalization
for surgical treatment and a decrease in the quality of life retain the significance
of the problem of HE [6]. About 40% of young women with endometrial
hyperplasia undergo intrauterine interventions, which may be the cause of
infertility in women of the reproductive period [7].
Proliferative diseases of the endometrium, according to modern concepts,
are defined as a complex of morphological lesions from benign to malignant,
mediated by a transitional preinvasive stage [8]. In fact, they form a
heterogeneous group of pathological processes: from normal polyclonal
endometrium, which responds to abnormal hormonal influences, to proliferative
monoclonal lesions that occur focally and are accompanied by a high risk of
endometrial cancer (EC) [9]. In this connection, it is important to focus on
precancerous lesions of the endometrium, which are a characteristic sequence of
pathomorphological processes [16].
According to official data for 2019 in Russia, the prevalence of endometrial
cancer (EC) is 27,151 cases, which is about 8% of the total incidence of
malignant neoplasms in the female population [10]. In 2021, Western colleagues
registered more than 66,570 newly diagnosed cases of EC in women and more
than 12,940 deaths from this disease, which ranks 4th among all cancers in
women. It was also noted that every year the incidence of endometrial cancer
increases by 1%, and mortality by 2%. According to the American Cancer
Society, an estimated 70% of uterine cancers are associated with overweight
and lack of physical activity and, therefore, are potentially preventable [11].
According to RCTs, approximately 6.5% of patients who were diagnosed
with HE were aged 20 to 44 years, and 70-88% did not give birth [12]. However,
it has been noted that the incidence of endometrial hyperplasia is three times
higher than the incidence of endometrial cancer [13]. From the modern point of
view, HE is considered as a polyetiological pathological process, the
development and progression of which can be facilitated by many different
reasons [17]. The pathogenesis of HPE is characterized by a complex interaction
of systemic processes (neuroendocrine, metabolic and immune) and local
changes (receptor status and genetic apparatus of endometrial cells), as well as
the participation of biologically active substances, growth factors, markers of
proliferation and apoptosis, etc. Having an unequal degree of development, HPE
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often become a favorable background for the occurrence of precancer, and then
endometrial cancer (EC) [18]. The question of the risk of developing malignant
transformation of HE remains open [19]. According to domestic and foreign
studies, the degree of risk of malignancy of various HPE variants is determined
by the morphological state of the endometrium and depends primarily on the
severity of cellular atypism and, to a lesser extent, on age, the state of the
ovaries, concomitant endocrine diseases, and other factors [20]. It has been
proven that histopathological and molecular changes reflect the possible risk of
transition of HE to EC. Despite the fact that HE is considered as a risk factor or
precursor of uterine cancer, which is given rather modest attention to this
problem, as evidenced by the lack of serious monographs, modern randomized
placebo-controlled studies, relatively few original articles. At the same time,
many unresolved issues have accumulated that require scientific coverage and
further development.Approximately one third of women of reproductive age
seek medical attention for abnormal uterine bleeding associated with GE.
The problem of recurrence of endometrial hyperplasia is acute in modern
medicine and requires more detailed study. According to the literature, a
significant percentage of patients do not respond to conservative treatment or
show relapse after remission with the risk of developing EC [18]. For this reason,
in recent years there has been a growing interest in the study of clinical,
imaging, histological and molecular factors that may affect the outcome of
therapy [19-21]. Immunohistochemistry is the most commonly used tool in the
evaluation of tissue markers for the diagnosis, prognosis and treatment of a
large number of diseases and has played an important role in this field [22].
Estrogen receptors a and b (ERa and ERb) Estrogens bind to one of two
nuclear receptors (EIa and EK|3), which are both encoded by independent
genes. The receptors act as ligand-dependent transcription factors with
subsequent modulation of gene expression. Studies have proven the importance
of estrogens in the regulation of endometrial cell proliferation, angiogenesis, and
inflammation [20]. The relationship between excess estrogen exposure and GE
has been unequivocally established [21]. There are conflicting literature data
regarding EI expression levels between normal and hyperplastic endometrium.
All this is due to the fact that there are complex interactions between the cyclic
endometrium and steroid hormones [21]. Some studies describe increased
expression of ERa in HE without atypia compared to normal secretory
endometrium [20]. On the contrary, -found no relationship between ERa or ERp
expression and HE without atypia.
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Progesterone receptors (PR) Progesterone counteracts the proliferative
effects of estrogen by inducing secretory differentiation of the glandular and
stromal endometrium and suppresses ERa expression. Progesterone exerts its
action through progesterone receptors (PR), which also act through a ligand-
activated transcription factor as do estrogen receptors [22]. Extensive studies
using in vitro cell systems as well as genomic analyzes have identified PR as a
gene regulated by estrogen [20]. PR isoforms: PR-A and PR-B are spatially and
temporally controlled in endometrial compartments during the menstrual cycle.
A significant association was found between HE recurrence without atypia, low
stromal PRA, and high expression of glandular PRB.
CONCLUSIONS
The relevance of the problem of endometrial hyperplastic processes does not
lose its significance both from the standpoint of endometrial cancer prevention
and from the standpoint of restoring and maintaining reproductive function.
Thus, endometrial hyperplastic processes are a multifactorial disease, the
formation of which involves the processes of hormone-dependent, hormone-
independent endometrial cell proliferation, chronic inflammation, as well as
genetic and epigenetic mechanisms. There is very little research data on the
influence of genetic factors in the development of endometrial hyperplasia. Early
diagnosis, prognosis of recurrence and response to conservative treatment is an
opportunity not to be missed. Therefore, further research is needed in this area.
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