Risk factors for endometrial polyps’ development in reproductive-age women

Introduction

Endometrial polyps are hyperplastic growths of the stromal and glandular compartments of the endometrium [1]. The prevalence of endometrial polyps in women is approximately 7.8% [2]. At the same time, according to Chernukha et al. [3], in women of reproductive age, their frequency varies from 21.7% to 27.3%. Similar data are presented by Capmas et al. [4]. Thus, with 2402 outpatient hysteroscopies performed on women with an average age of 39.4 years for several indications, the prevalence of endometrial polyps was 27.2% [4]. In general, it has been observed that the prevalence of endometrial polyps is higher in women over 30 years of age [5].

Endometrial polyps are the most frequently observed pathological finding in the uterine cavity and usually represent benign formations, but rarely can lead to endometrial adenocarcinoma (2–13%) [6].

Polyps in the uterine cavity can be single or multiple and of different sizes. Their sizes range from 5 mm to the size of the uterine cavity [7]. Although endometrial polyps are usually asymptomatic, they can lead to uterine bleeding, infertility, and pelvic pain.

It is important to note that the etiology of endometrial polyps is still unknown. Moreover, to date, there are few publications concerning the factors of the development of endometrial polyps in women of reproductive age. This fact determined the direction of this particular research.

The purpose of this review is to summarize the available scientific data on the factors of the development of endometrial polyps in women of reproductive age.

Therefore, a search by keywords (polyps, endometrium, developmental factors, reproductive age) was conducted among scientific papers in the databases such as Science Direct, Cochrane Library, and PubMed for 2000–2022.

Main points

Etiopathogenesis and risk factors for endometrial polyps are not very clear, but there are several theories. Thus, it is believed that polyps are associated with estrogen stimulation, which may be the result of an increased number of estrogen receptors (ERs), mainly alpha ERs, in the glandular cells of the polyp compared to normal endometrium and a decrease in the expression of progesterone receptors (PRs) A and B in polyps compared to normal endometrium. It is known that endometrial polyps contain both ERs and PRs, and it was found that the expression of these receptors was significantly higher in the glandular epithelium of endometrial polyps compared to normal epithelium [8]. In addition, there was a decrease in the expression of ERs and PRs in the stromal cells of endometrial polyps [9], which can prevent decidual changes in the polyp stroma and menstrual discharge, which is observed in the intact part of the endometrium.

According to Chan et al. [10] and Nijkang et al. [11], the use of tamoxifen (an estrogen agonist used to treat breast cancer) is associated with a higher risk of endometrial polyps. However, the polyps associated with taking tamoxifen are histologically different from the polyps in people who did not take tamoxifen. Thus, McGurgan et al. [12] noticed that the use of tamoxifen reduced the level of estrogen receptors and increased the level of PRs in these polyps, as well as reduced the level of apoptotic cells. These results confirmed their hypothesis that tamoxifen promotes the growth of polyps by inhibiting apoptosis. Gokmen Karasu et al. [13] reported the possibility of a direct effect of tamoxifen on apoptosis or indirect effects through a progesterone-related mechanism. Academic specialists [13] also observed that low expression of the anti-apoptotic marker persisted in polyps exposed to tamoxifen. A number of other authors [14] also described the relationship of tamoxifen intake with polyps.

However, the formation of endometrial polyps seems to be related to the type and dosage of estrogens and progestogen during hormone replacement or menopausal therapy; in particular, a progestogen with high antiestrogenic activity may play an important role in preventing the development of endometrial polyps [15].

It is important to note that obesity is associated with increased production of endogenous estrogen due to an increase in the level of aromatase enzymes that convert from androgens in adipose tissue into estrogen. However, according to Hassa et al. [16], the relationship of endometrial polyps with obesity and diabetes mellitus as independent risk factors is insignificant.

Also, Hassa et al. [16] established that arterial hypertension was a significant risk factor for the development of endometrial polyps. Despite the unknown etiology of this relationship, it is noteworthy that the prevalence of hypertension is higher in patients with endometrial polyps and endometrial cancer. Extensive studies on this issue have not been conducted, but a significant relationship between endometrial polyps and diabetes mellitus, hypertension, and obesity has been found [17].

The authors of this particular study believe that hypertension is not a risk factor, since most patients with high blood pressure have an increased body mass index. That is, hypertension and endometrial polyps are correlated rather than causal. So Gregoriou et al. [18] found no association between the size of polyps, hypertension, abnormal uterine bleeding, and malignant transformation.

Bagdasaryan et al. [19] identified extragenital diseases (in the form of diseases of the gastrointestinal tract, endocrinopathies, diseases of the cardiovascular system, and obesity as well) as risk factors for the development of endometrial polyps in women of reproductive age. Also, the authors [19] noted that in patients with endometrial polyps, the lack of contraception, especially hormonal, was a risk factor, as well as the presence of infertility, and a large number of artificial abortions.

Tabrizi [20] believes that age is the most important predisposing factor, which cannot be disagreed with, given the prevalence of endometrial polyps in different age groups. Thus, endometrial polyps are rare in women under the age of 20. The incidence increases steadily with age, reaches a peak in the fifth decade of life, and gradually decreases after menopause [21].

The study by Nappi et al. also seems to be interesting for this particular review [17], as the authors conducted an analysis of independent variables in endometrial polyps. Their analysis showed that only an increase in the age of patients was a significant risk factor and that it acted as a distorting factor for all postulated risk factors.

However, the balance between mitotic activity and apoptosis probably also plays a role in regulating the development of a normal endometrium during the menstrual cycle. The role of Bcl-2, which is an inhibitor of apoptosis, and the Ki-67 protein, which is a cellular marker of cell proliferation and mitotic activity, has been reported [22]. Taylor et al. [22] marked an increase in Bcl-2 expression in the polyps of the proliferative phase in both the glandular epithelium and stroma compared with the proliferative endometrium, but this increase was not observed in any of the polyps in the secretory phase. A local increase in Bcl-2 expression in endometrial polyps may explain the inability of polyps to undergo normal cyclic apoptosis and, therefore, not disappear during the menstrual cycle. In the studies by Mourits et al. [23], Altaner et al. [24], and Antunes Jr et al. [25], there was also a decrease in apoptosis in the endometrial polyp tissue.

In addition, the role in the development of endometrial polyps is assigned to the Bax gene, which causes apoptosis. The analysis of endometrial polyps showed an increased Bcl-2/Bax ratio, which may ultimately be a mechanism contributing to the growth of endometrial polyps [26].

According to Banas et al. [27], glandular, menopause-independent DNA-fragmentation factor of AB 40 (DFF40), 45 (DFF45) and Bcl-2 overexpression may play an important role in the pathogenesis of this pathology. Miranda et al. [28] also reported that Ki-67 expression was significantly higher in polyp samples in women treated with tamoxifen compared to samples in women who did not take hormones.

The formation of endometrial polyps may also be the result of chronic inflammation in the endometrium. Mast cells are known to initiate and control inflammation through the secretion of cytokines and growth factors. Cyclooxygenase-2 (COX-2), a key enzyme involved in prostaglandin production in mast cells, is significantly higher in polyps compared to normal endometrium [11]. Therefore, inflammation leads to the formation of new blood vessels and tissue growth.

It was found that the number of mast cells in endometrial polyps was seven times higher compared to normal endometrium [29], while most of these mast cells were activated [30]. Secreting mast cells are able to induce or enhance angiogenesis [31], and, as a consequence, an increase in the density of blood vessels can be expected.

According to Belov and Ponomareva [32], endometrial polyps are more often combined with chronic endometritis and proliferative endometrial processes in women of reproductive age. In addition, the authors noted that in all the age groups, endometrial polyps were more likely to develop in nulliparous women who had a history of curettage of the uterine cavity during spontaneous abortion or therapeutic and diagnostic curettage, as well as chronic endometritis.

According to Nijkang et al. [11], the biology of polyps is the same throughout the human body, regardless of the specific type (for example, endometrial, nasal, and colorectal). Therefore, data on risk factors can be extrapolated from studies of polyps of other localizations. Thus, increased expression of vascular endothelial growth factor (VEGF) is observed in nasal polyps with increased vascular density. Angiogenic factors such as VEGF and basic fibroblast growth factor (bFGF), in turn, stimulate the migration of mast cells.

VEGF and TGF-β1 levels were found to be significantly higher in endometrial polyps compared to normal endometrium. VEGF is an angiogenic factor, while TGF-β1 is associated with the formation of fibrous tissue, both of which are characteristic of endometrial polyps. This is confirmed by a higher concentration of Ki67 (tissue proliferative factor) in endometrial polyps compared to normal endometrium [28].

A number of other authors [33][26] also associate the increased activity of endometrial aromatase, TGF-β, VEGF, Bcl-2, and genetic factors with the development of endometrial polyps.

It is necessary to note that the difference in the expression of growth factors may be important for the existence of two different types of endometrial polyps, one of which is hormone-dependent, and the other has an inflammatory nature.

In some studies, the level of endometrial glycodelin protein in plasma was higher in patients with endometrial polyp compared to the control group. It has been argued that the angiogenic factor glycodelin may play a role in the formation of endometrial polyps [34][35].

Cytogenetic studies have also shown that chromosomal abnormalities may play a role in the development of this pathology. Endometrial polyps arise as a result of chromosomal rearrangements (translocations) in stromal cells. Dal Cin et al. [36] identified three main cytogenetically abnormal subgroups, including sites 6p21-22, 12q13-15, and 7q22.

The expression of p63, aromatase P450 (aroma P450), and steroidogenic factor-1 (SF-1) may also play a role in the formation of endometrial polyps [37]. Stewart et al. [38] concluded that the immunoreactivity of stromal p16 was characteristic of polyps.

Conclusion

As a result of the analysis of the scientific literature, the following conclusions were made:

1. The prevalence of endometrial polyps depends on the studied population, while the actual frequency is difficult to determine, since polyps can be asymptomatic and regress over time.
2. The realization of endometrial polyps, apparently, depends not on one, but on many factors of development (genetic, hormonal, metabolic, and medicinal).
3. An increase in the amount of endogenous estrogen, the introduction of exogenous estrogen, and age are the most important predisposing risk factors for the development of endometrial polyps.