*2.2. Risk Factors of Endometriosis*

A number of modifiable and non-modifiable risk factors have been reported to be both positively and negatively associated with the development of endometriosis (Figure 1) [27,28,43,44]. Non-modifiable risk factors known to be associated with endometriosis are the following: genetic, endocrine, immunological, and ethnicity [21,45]. There are also modifiable factors, the effect of which could be decreased substantially by lifestyle changes. Those factors are microbiotic, environmental factors (exposure to endocrine-disrupting chemicals), alcohol/caffeine intake, smoking, and physical activity [27]. Those factors may influence estrogen levels and contribute to the development of endometriosis [27].

**Figure 1.** Risk factors for endometriosis and endometrial cancer. Created at BioRender.com (accessed on 15 July 2021).

The risk of endometriosis has been strongly linked to ethnicity. Many researchers have reported a nine-fold increase in risk of endometriosis development among women of Asian ethnicity if compared with the European-American Caucasian female population [27,43,46]. Among other factors, prolonged estrogen exposure (e.g., early age at menarche, shorter menstrual cycles, nulliparity) [47], low body mass index, and uterine outlet obstruction [48] have been suggested as predisposing to endometriosis.

It is well known that endometriosis has a strong genetic predisposition [25,43]. The evidence for an association between genetic polymorphisms and risk of endometriosis is robust [43]. Together with the strong link to hereditary factors, development of endometriosis is also affected by environmental exposures [26]. Environmental factors such as elevated levels of phthalate esters, persistent organochlorine pollutants, perfluorochemicals, and exposure to cigarette smoke can increase risk of developing endometriosis by inducing

oxidative stress, altering hormonal homeostasis, or by changing immune responses [43]. Maternal exposure to diethylstilbestrol (DES) has been associated with a greater risk of endometriosis in female offspring [28].

Modifiable risk factors such as caffeine intake have been hypothesized to be influential in the pathology of gynecological disease due to its ability to influence estradiol levels [27,49]. Much like caffeine, alcohol intake and tobacco smoking are hypothesized to alter reproductive hormones due to the activation of aromatases leading to increased conversion of testosterone to estrogens [27]. Moreover, tobacco smoking may also increase the inflammatory response. Physical activity has been shown to reduce the risk of developing many gynecological diseases [27,50]. Other risk factors, such as the presence of lower genital tract infections, have also been proposed as risk factors. [43,51].

Some genetic factors have been found to serve as risk factors for endometriosis. Genome-wide association studies have, to date, identified 19 independent single-nucleotide polymorphisms (SNPs) as being significantly associated with endometriosis [52]. Moreover, the authors found a significant genetic overlap between endometriosis and EC in a genetic correlation analysis, which found 13 SNPs that appeared to be involved in development of both conditions [52].
