*3.2. Risk and Protective Factors of Endometrial Cancer*

Multiple genetic (non-modifiable) and non-genetic (modifiable) risk factors have been associated with the development of EC (Figure 1) [78,88,89]. Genome-wide association studies have found nine independent SNPs being significantly associated with EC [52].

Race is a non-modifiable, genetic factor that plays an important role in the development of EC, as rates are highest in North America and northern Europe, lower in eastern Europe and Latin America, and the lowest in Asia and Africa [79,84,90]. Age is another non-modifiable risk factor. It is well-documented that EC primarily affects postmenopausal women, with the average age of 60 at the time of diagnosis [90]. The peak age-specific incidence is from 75 to 79 years, with 85% of cases occurring after the age of 50 and only 5% before the age of 40 [90]. Young, premenopausal women diagnosed with EC usually have other factors, contributing to the risk of the disease.

Several non-genetic risk factors are linked with an increased risk of EC, particularly for the most prevalent histological subtype of endometrioid EC [78]. These include obesity, physical inactivity, excess of endogenous estrogens, insulin resistance, and polycystic ovary syndrome [3,78,79,84,88]. In addition, conditions involving excess of exogenous estrogens due to hormone replacement with unopposed estrogen (i.e., estrogen therapy without progesterone) predispose women to endometrial cancer [88,90].

Tamoxifen (selective estrogen receptor modulator (SERM)) used for breast cancer treatment approximately doubles the risk of both endometrioid and non-endometrioid types of EC if administered for 5 years and longer [78,88]. The mechanism behind is antiestrogenic effects in the breast and proestrogenic effects in the uterus [88,91].

The recent systematic review studying risk factors of EC concluded the presence of strong evidence associating increased body mass index (BMI) and obesity with the risk of EC development [78,85,90,92]. According to the US statistics, 57% of all ECs are attributable to obesity [76,80,86]. In the United Kingdom (UK) almost half of all ECs are attributed to overweight (BMI <sup>≥</sup> 25 kg/m<sup>2</sup> ) and obesity (BMI <sup>≥</sup> 30 kg/m<sup>2</sup> ) [93]. If compared with all other cancers, EC has the strongest association with obesity [78,88,93]. Women with a normal BMI have a much lower lifetime risk of EC (up to 3%), but for every 5-unit increase in BMI, the risk of EC increases by more than 50% [88,93,94]. Although the average age at diagnosis is 63 years, EC incidence is increasing among young obese women [88]. Specific lipid metabolites, including phospholipids and sphingolipids (sphingomyelins), demonstrated good accuracy for the detection of EC [93]. The underling mechanisms of the association of obesity with EC are not fully understood; however, they likely include higher estrogen levels in postmenopausal women due to aromatase activity and adipose tissue conversion of androgens into estrogens, hyperinsulinemia, and chronic inflammation [78,95,96].

As a condition closely associated with insulin resistance and obesity, highly suggestive evidence that diabetes mellitus increases the risk of EC was reported in recent systematic reviews [78,97]. Hyperinsulinemia, which is a common phenomenon prior to diabetes onset, likely has a causal association with EC through direct mitogenic effects or by increasing the levels of bioavailable estrogen through a reduction in sex hormone binding globulin levels [78,98].

However, there are some factors that have protective effect against EC [3,78,88]. Those factors include parity (with an inverse association between parity and the risk of endometrial cancer) and oral contraceptive pills [88]. The recent systematic review studying risk factors of EC found strong evidence for a 40% reduction in endometrial cancer incidence among parous compared to nulliparous women [78]. Hormonal changes during pregnancy

may explain this association, usually featured by increased progesterone production with protective effects on the endometrium [78].

Oral contraceptive use reduces the risk of endometrial cancer up to 40%. Moreover, the longer the administration, the stronger the protective effect, which can persist even decades after cessation [88,99]. Additionally, coffee consumption has been shown to be inversely associated with EC [78,100,101].

Some researchers reported evidence that smoking reduced the risk of EC in cohort studies, although the evidence became strong when case–control studies were included [78,101]. The majority of the published cohort studies showed a reduction in risk of endometrial cancer among current or former smokers compared to never smokers [78,92,102,103]. A mechanism behind the link between decreased incidence of EC and smoking is the possible anti-estrogenic effect of nicotine; however, it has limited direct evidence and requires further investigations [78].
