Endometrial carcinoma has the highest incidence among gynecological cancers in developed countries, with rising trends and a last decade increase in the incidence of 1% in the white race and 2–3% in women of other races [1]. Given its high incidence and the increasing number of cancer survivors, there is considerable interest in science and research for improving the quality of life of patients and achieving optimal health care outcomes.

Currently, there is significant interest in second- and third-line treatments, as well as therapies for advanced or relapsing disease. Through 2024, a plethora of international randomized clinical trials have been conducted, with many more ongoing [2, 3]. Although the treatment of aggressive disease is of high importance, attention should also be aimed at the effort aimed to study the pathology and pathophysiology of this disease. In order to improve the prognosis, early diagnosis and timely treatment, it is crucial to understand the mechanisms underlying the pathogenesis of this disease.

It is known that a high percentage of endometrial tumors express estrogen receptors and it is therefore reasonable to assume that exogenous substances that alter the hormonal order of the woman can affect the tumor genesis, favoring transformation and progression of the malignancy [4, 5]. It has been shown that estrogens can stimulate cells that express their receptors to proliferate and that chronic exposure induces mitosis with potential genomic instability and thus consequently is related to hyperplasia and malignant transformation [6].

In 2002 the World Health Organisation (WHO) published the following definition: “An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations”.

Endocrine disrupting chemicals (EDCs) are exogenous substances or mixtures found in the environment, food or in drinking water and dust that disrupt endocrine system function by mimicking the action of steroid hormones and interfer with the synthesis, secretion, transport, metabolism, binding action, or elimination of natural hormones in the blood [7]. The exposure of women to these substances could predispose them to the development of endometrial pathology, representing an important health risk. The most popular EDCs are polychlorinated biphenyls (PCBs), bisphenol A (BPA), alkylphenol, dioxins, cadmium, arsenic, lead, and mercury. Most of the available data comes from in vitro studies or from casecontrol studies conducted on a small number of patients [4, 8].

The data available in the literature supporting a cause-effect relationship between exposure to EDC and endometrial cancer development are insufficient, given the low tissue concentrations and the confounding factors and biases that may influence the reliability of the research [9]. Although prolonged and/or high-dose exposure of EDC appears to have been established in several animal studies, conclusive human data are still missing [10].

In animal models, the real ability of these disruptors to predispose to the development of uterine pathology has been assessed and there is a high potential for intrauterine or neonatal exposure while exposure of adults at high concentrations did not affect this trend [11].

Recently, a Spanish study analyzed data from women exposed to pesticides with endocrine disrupting (ED) activity and demonstrated that occupational contact with these substances exposed women to a significantly higher risk of developing endometrial cancer compared to none exposed patients (odds ratio (OR) = 2.08; 95% confidence interval (95% CI) = 1.13–3.88). Additionally, prolonged exposure was connected to an additional risk, although even less exposure predisposed to the development of malignancy [12].

Increasing industrialization and the resulting increased residential exposure are also a major public health concern. In urban areas, the increase of 5 parts per billion nitrogen dioxide (NO${}_2$), a traffic-related air pollutant, is associated with an increased number of endometrial cancers recorded in the resident population in the analyzed area of 23% (hazard ratio = 1.23, 95% CI = 1.04–1.46) [13].

Wen et al. [14] conducted a case-control study of 397 women analyzing and comparing the lifestyle and occupational exposure of 101 healthy women and 296 patients with uterine pathology (49 with endometrial carcinoma and 247 with uterine leiomyomatosis). Urinary concentrations of nonylphenol (NP) and oxylphenol (OP) were measured in a urine sampls and patients with a history of endometrial carcinoma had significantly higher concentrations of both substances as compared to healthy controls. In addition, patients with urinary concentrations of NP $>$3.35 mg/g creatinine had a significantly higher risk of developing malignant endometrial pathology (OR = 4.47, 95% CI = 1.69–11.84, p 0.01) [14].

A 2024 study by Costas et al. [15] revealed that the serum total xenoestrogen burden correlates with endometrial cancer risk with an inverted-U dose-response pattern. Positive associations were observed for the intermediate exposure category compared to the lowest category [OR = 2.11 (95% CI: 1.13, 3.94) for organohalogenated compounds and OR = 3.32 (95% CI: 1.62, 6.81) for endogenous hormones and more polar xenoestrogens]. No significant associations were found between the third and first exposure categories OR = 1.22 (95% CI: 0.64, 2.31) for organohalogenated compounds, and OR = 1.58 (95% CI: 0.75, 3.33) for endogenous hormones and polar xenoestrogens [15].

In conclusion, the carcinogenic effect of endocrine disruptors is plausible, although broad studies are required to elucidate their mechanisms and entities. It is essential to implement necessary measures to limit exposure to these substances, particularly during life stages most vulnerable to oncogenic environmental influences, such as the embryonic period and puberty.

Large-scale epidemiological studies are necessary to minimize confounding variables and identify risk factors for endometrial cancer development. Ideally, a comprehensive analysis of patient habits and domestic and occupational exposures within such studies would allow for the stratification of individuals based on their susceptibility to the disease.

A further issue could be to establish a possible correlation between specific EDC and endometrial cancer in the light of its recent molecular classification in to 4 groups: polymerase epsilon (POLE) ultramutated, microsatellite instability (MSI) hypermutated, copy-number (CN) low and CN high in order to maximize the personalization of the therapeutic path of patients with endometrial cancer and identify patients most at risk of developing the primary disease along with recurrences.