{"paper_id":"4b89594c-8044-4944-b650-e24f9d444041","body_text":"Endometriosis is a gynecological disease associated with chronic pelvic pain and infertility. This disease is diagnosed in 5–10% of women of reproductive age [ 1 ]. For a woman, the disease is associated with malaise, undergoing therapy, and performing costly operations. Women often have to give up their daily duties because of the bothersome symptoms of the disease. Endometriosis is characterized by the presence of uterine endometrial tissue outside of its normal location. Pathological endometrial tissue occurs on the peritoneum of the pelvis, ovaries, and rectovaginal septum, as well as even in the pericardium, pleura, and brain. The disease causes extensive adhesions and distortions in the pelvis [ 2 ]. Endometriosis is diagnosed surgically using the technique of laparoscopy or laparotomy [ 3 ]. Another method of endometriosis diagnosis is vaginal ultrasound (TVUS) or magnetic resonance imaging (MRI) [ 4 , 5 ]. The American Society for Reproductive Medicine (ASRM) guidelines are used to assess the severity of the disease. There are four degrees of endometriosis: minimal, mild, moderate, and severe [ 6 ]. In addition, there are three types of endometriosis: peritoneal, ovarian, and rectovaginal. The clinical picture differs depending on the patient, and the treatment procedures depend on the symptoms and fertility status [ 7 ]. Endometriosis is idiopathic in origin, but there are several theories that could explain its origin. It is assumed that the following factors may be responsible for the development of endometriosis: immune dysfunction, genetic aspects, lifestyle, and environmental pollution [ 8 , 9 , 10 ]. As the etiology of endometriosis is not well understood and estrogen is central to disease pathogenesis, regulating the key pathological processes in endometriosis including immunological, inflammatory, angiogenic, antiapoptotic, cellular, and molecular mechanisms, the potential contribution of exposure to endocrine-disrupting chemicals (EDCs) has been hypothesized in endometriosis. EDCs are of particular interest as potential contributors to endometriosis because they can alter steroidogenesis and immunologic function, in addition to being the epigenetic causal factors involved in disease progression [ 11 ]. According to WHO’s definition, an endocrine disruptor is an exogenous substance or mixture that alters the function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or its subpopulations (WHO 1996). EDCs are compounds that have the ability to interact with the endocrine system interfering with its normal functioning. They are widespread in the environment; thus, exposure occurs through contact with these compounds through food, water, air, plastics, or cosmetics. EDCs can be categorized as persistent or non-persistent. Persistent chemicals are those chemicals that tend to endure in the environment for years after their release, whereas, nonpersistent chemicals are exogenous chemicals or mixtures of industrial agents that can interfere with the normal action of hormones with a shorter half-life and lower liposolubility [ 11 ].\nNumerous studies have been conducted on the influence of exposure to persistent endocrine-disrupting factors (e.g., dioxins, polychlorinated biphenyls, organochlorine pesticides, and some metals) on endometriosis. The obtained results did not confirm the validity of the statement concerning the influence of exposure to dioxins on the risk of developing endometriosis [ 12 , 13 ]. Similarly, numerous studies have been carried out on the influence of polychlorinated biphenyls on the occurrence of endometriosis, and most of them failed to confirm the existence of associations between these chemicals and the occurrence of endometriosis [ 12 , 14 , 15 , 16 ]. In addition, studies on persistent pesticide exposure and endometriosis have been conducted, but the results did not provide a clear indication of a link between pesticide exposure and the occurrence of endometriosis [ 17 , 18 , 19 ].\nNon-persistent compounds are chemicals widely found in the environment. in many everyday products, e.g., plastics, lubricants, solvents, plasticizers, and pesticides. Low levels of exposure may cause endocrine or reproductive disorders [ 20 ]. These are substances that may disrupt the functioning of the endocrine system and, consequently, affect the fertility of men and women [ 21 , 22 , 23 , 24 , 25 , 26 ]. Compared to studies evaluating the link between persistent endocrine-disrupting chemical exposure and endometriosis studies on the effects of exposure to nonpersistent chemicals are rare. As the exposure to non-persistent chemicals is widespread and associated with reproductive and gynecological disorders, as well as poor fertility, this review aims to answer the question regarding the effect of exposure to widespread nonpersistent endocrine-disrupting chemicals on endometriosis, taking into account the limitations and strength of the presented studies.\n\nThe PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was employed in this review.\nA systematic search of the literature was carried out to identify relevant studies published in English from 2003 to February 2021. Relevant studies were also identified through a review of the references cited in all the published studies. The following databases were used: PubMed, Scopus, Elsevier, Web of Science, Springer, and EBSCO. The keywords for our search included a combination of terms referring to exposure to non-persistent chemicals and outcome, i.e., exposure to bisphenols, benzophenones, phthalates, parabens, organophosphate pesticides, synthetic pyrethroids, and endometriosis.\nThe most recent human studies published in English in peer-reviewed journals since 2003 were included in this review.\nThe period was chosen to reflect findings over the past 19 years. During that time, animal and in vitro studies provided evidence on the toxicity of several non-persistent environmental EDCs, especially in the case of endometriosis risk.\nIn total, 482 articles were found as a result of the search, and they were all checked for eligibility. The reference lists of the selected articles were subject to a manual search to identify additional articles.\nA total of 22 publications on exposure to non-persistent endocrine-disrupting chemicals and endometriosis were selected by two reviewers, with an excellent agreement (k = 0.80). This review included original peer-reviewed studies that looked at exposure to non-persistent endocrine-disrupting chemicals and endometriosis in humans. The majority of the articles (80%) did not meet the inclusion criteria for our study, as they did not address the endometriosis risk. Publications containing duplicate data or published before 2003 were excluded. We also excluded studies that analyzed the impact of environmental EDCs on different endocrinological disorders (uterine leiomyoma, polycystic ovary syndrome, and recurrent miscarriages), as well as occupational exposure studies. Articles focused on animal research, in vitro studies, and review papers as well as articles published in a language other than English were excluded.\nTwo researchers identified relevant articles and independently assessed those to be included in this review; incongruences were resolved by discussion and the intervention of a third independent author. Articles were displayed by title and abstract. Duplicate and irrelevant items were excluded. The remaining articles were subjected to a full-text review. All full-text articles were thoroughly examined to identify the aims of the studies, statistical methods, and accurate results. The following information was taken into account when selecting the studies: authors and years of publication; the main purpose of the study; results; type of study; accuracy of the results. For the purpose of this review, the following information was abstracted from each study: study population; type of exposure and methods used for its assessment (including biomarkers); type of study, level of exposure to selected endocrine-disrupting factor; results. All articles cited were summarized and discussed.\n\nPhthalates are synthetic chemicals with a wide range of applications. They are used in the production of plastics, e.g., paints, adhesives, floors, rubber materials, medicines, and even packages intended for contact with food [ 27 , 28 , 29 , 30 ]. Due to their wide application, they are present in the environment. Exposure to phthalates occurs through food, skin, and air [ 31 , 32 ]. Some phthalates can cause allergies and may disrupt the functioning of the human endocrine system [ 33 , 34 , 35 ]. Moreover, it has been found that exposure to phthalates during fetal life may affect the DNA methylation of genes responsible for the androgenic, estrogenic, and spermatogenetic responses [ 36 ]. Research has been conducted on the effects of phthalates on children’s health, reproductive disorders, and premature puberty among girls [ 37 ]. The studies showed an adverse effect of phthalates on the level of reproductive hormones such as luteinizing hormone, free testosterone, and sex hormone-binding globulin, as well as thyroid function [ 38 , 39 ].\nIn the human body, phthalates have a short half-life of about 12 h [ 40 ]. Phthalates can be divided into short branched and long-branched phthalates. Short-branched phthalates are hydrolyzed to monoester phthalates and then excreted in the urine. In contrast, long-branched phthalates undergo several biotransformations and are then excreted in the urine or feces.\nThe association between environmental exposure and the occurrence of endometriosis was investigated in 12 studies [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ] ( Table 1 ), including 9 case-control studies [ 41 , 42 , 43 , 44 , 45 , 47 , 49 , 50 , 51 ], 2 cross-sectional studies [ 46 , 52 ], and 1 cohort study [ 48 ]. The studies were performed in the United States, Brazil, India, Italy, Taiwan, Pakistan, Japan, Korea, and China. Women in most of the studies were recruited from fertility and gynecology centers [ 43 , 45 , 49 , 50 , 51 ], three studies were conducted in hospitals or universities [ 42 , 47 , 48 ], two were based on the National Health and Nutrition Examination Survey (NHANES) [ 46 , 52 ], and one was based on US health system research in the Pacific Northwest [ 41 ]. The concentrations of phthalates were mostly determined in urine samples [ 41 , 42 , 45 , 46 , 48 , 49 , 50 , 52 ], followed by serum samples [ 43 , 44 , 47 , 51 ] and peritoneal fluid [ 44 ]. The age of women participating in the studies ranged from 18 to 54 years. In studies performed by Upson et al. (2013) [ 41 ], Fernandez et al. (2019) [ 42 ], Reddy et al. (2006) [ 43 ], Weuve et al. (2010) [ 46 ], Louis et al. (2013) [ 48 ], Itoh et al. (2009) [ 49 ], Kim et al. (2015) [ 50 ], Kim et al. (2011) [ 51 ], and Zhang et al. (2021) [ 52 ], a questionnaire about women’s lifestyle factors (e.g., smoking, sporting activity, and birth control), was used, whereas in studies by Cobellis et al. (2003) [ 44 ], Huang et al. (2010) [ 45 ], and Nazir et al. (2018) [ 47 ], lifestyle factors were not assessed. Endometriosis in most studies was diagnosed by surgery or magnetic resonance imaging [ 41 , 42 , 43 , 44 , 45 , 47 , 48 , 49 , 50 , 51 ]. Endometriosis diagnosis was based on a questionnaire in two studies [ 46 , 52 ].\nIn the study by Upson et al. (2013) [ 41 ], there was a strong inverse relationship between urinary MEHP (mono-(2-ethyl)-hexyl phthalate) content and endometriosis (OR: 0.3, 95% CI: 0.1–0.7). In the study by Huang et al. (2010) [ 45 ], an increased concentration of a phthalate metabolite, MnBP (mono-benzyl phthalate) was observed in cases versus controls (OR: 3.46, 95% CI: 1.16–10.3). The study by Nair et al. (2018) [ 47 ] showed that exposure to DEHP (diethylhexyl phthalate) was only related to advanced stages of endometriosis (stage III and IV). Similar conclusions regarding the advanced stages of endometriosis and exposure to MEHP were obtained by Kim et al. (2011) [ 51 ]. Another study performed by Kim et al. (2015) [ 51 ] showed a statistically significant association between the concentration of three phthalate metabolites, MEHHP (mono-(2-ethyl-5-hydroxyhexyl) phthalate) (OR:2.52, 95% CI: 1.03–6.14), MEOHP (-mono-(2-ethyl-5- oxohexyl) phthalate) (OR:2.89, 95% CI: 1.04–8.04), and MECPP (mono-(2-ethyl-5-carboxypentyl) phthalate) (OR:2.57, 95% CI: 0.92–7.13) and endometriosis. Louis et al. (2013) [ 48 ] showed a significant relationship between the occurrence of endometriosis and exposure to phthalates (MBP, MCMHP, MECPP, MEHP, MEHHP, MEOHP, and MOP) in the population cohort group. In the study conducted by Reddy et al. (2006) [ 43 ], phthalates (DnBP, BBP, DnOP, and DEHP) were observed in all samples of women with endometriosis; moreover, the results for all samples were statistically significant at  p  < 0.05 compared to control women. Kim et al. (2015) [ 50 ] found that the urinary concentrations of MEHHP, MEOHP, and MECPP were significantly higher in women with endometriosis compared to controls.\nIn five studies, no association was found between the concentration of phthalates and the risk of endometriosis [ 42 , 44 , 46 , 49 , 52 ].\nIn conclusion, seven of the presented studies found an association between the concentration of at least one phthalate metabolite and endometriosis. In five studies, no association was noted between phthalate concentration and endometriosis.\nBisphenol A (BPA) is a monomer found in many plastics and epoxy resins. Bisphenol A is a common chemical in everyday items. Approximately eight billion pounds of BPA are produced annually, of which up to over 200 thousand pounds per year may be released into the environment [ 53 ]. BPA is used in the production of toys, containers for drinks and food, sports equipment, medical equipment, and cables. Human exposure occurs through the diet, through inhalation of house dust, and through the skin [ 54 ]. Bisphenol A has been shown to disrupt hormonal balance. This compound shows estrogenic activity because it binds to estrogen receptors [ 55 ]. Moreover, it has been shown that BPA can bind to androgens, blocking their endogenous action, and may it act on the secretion of thyroid hormones [ 56 ]. Exposure of the fetus and newborn to bisphenol A may have negative developmental effects such as reduced maturation cycle, prostate changes, altered development of mammary glands, changes in body weight, and changes in the brain. On the other hand, exposure to bisphenol A in adulthood may lead to sperm damage, a decrease in estradiol, miscarriage or premature birth, development of diabetes mellitus [ 57 ], and reproductive system impairment in both women and men [ 58 ]. Low doses of BPA may also affect the functioning of the human endocrine system [ 59 ].\nThe relationship between exposure to bisphenol A and the development of endometriosis was investigated in nine studies [ 42 , 48 , 49 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ] ( Table 2 ). Seven of them were performed using a case-control study design [ 42 , 60 , 61 , 62 , 63 , 64 , 65 ], while one was conducted as a cross-sectional study [ 66 ], and one was conducted as a cohort study [ 48 ]. The studies were performed in Brazil, Japan, the United States, Spain, Iran, Italy, and China. The majority of women in the studies were recruited from gynecological hospitals or fertility treatment centers [ 61 , 63 , 64 , 65 , 66 ], while the remainder were involved in studies conducted by hospitals or universities [ 42 , 48 , 62 ]. One study was conducted within the U.S. health system in the Pacific Northwest [ 60 ]. BPA concentrations were mostly analyzed mostly in urine (eight studies) [ 42 , 48 , 60 , 61 , 62 , 63 , 65 ], while only study evaluated serum concentrations [ 64 ]. Women aged 18 to 54 years were recruited for the studies [ 42 , 48 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ], and they were diagnosed by surgery laparoscopy, laparotomy, or magnetic resonance imaging. In eight studies all women completed a questionnaire about lifestyle [ 42 , 48 , 60 , 61 , 62 , 63 , 65 , 66 ], while one study did not implement a questionnaire [ 64 ].\nUpson et al. (2014) [ 60 ] found a significant association of exposure to BPA with the occurrence of non-ovarian pelvic endometriosis (OR:3.0; CI: 1.2, 7.3), but not with the occurrence of ovarian endometriosis. Peinado et al. (2020) [ 61 ] observed a relationship between BPA concentration and the occurrence of endometriosis (OR: 1.5, 95%; CI: 1.0–2.3). Rashidi et al. (2017) [ 62 ] revealed the relationship between BPA concentration in urine and the occurrence of endometriosis (OR: 1.75, 95%; CI: 1.41–2.17). An Italian study by Simonelli et al. (2017) [ 63 ] also established a relationship between the occurrence of endometriosis and exposure to BPA. Cobellis et al. (2009) [ 64 ] observed a detectable level of BPA in every woman with endometriosis but no detectable level in the control group.\nIn three studies, no relationship was found between BPA exposure and endometriosis [ 42 , 48 , 66 ].\nIn conclusion, the majority of the studies showed an association between BPA exposure and endometriosis, with only three studies observing no association.\nParabens are commonly used as preservatives in food, cosmetic, and pharmaceutical products. These compounds are easily absorbed by the human body. Industrially, parabens are produced by esterification of PHBA (4-hydoxybenzoic acid) with appropriate alcohol in the presence of a catalyst. High efficiency and ease of reaction have contributed to the popularity of using parabens as a preservative [ 67 ]. Parabens may disrupt the hormonal balance by acting on enzymes responsible for the synthesis of estrogens or by modifying them to a free, unconjugated form [ 68 ]. In addition, parabens can also lead to hormonal disruptions in men. Exposure to parabens can result in androgen antagonistic activity, inhibition of sulfotransferase enzymes, and genotoxic activity [ 69 ]. Parabens are associated with increased levels of estradiol in healthy premenopausal women which can lead to irregular menstrual cycles. However, no relationship was observed between the concentration of paraben metabolites and the occurrence of polycystic ovary syndrome (PCOS) [ 70 ]. Parabens are components of feminine hygiene products, which may additionally result in increased exposure to this group of chemical compounds [ 71 ].\nOnly one study investigated the relationship between the development of endometriosis and exposure to parabens [ 72 ] ( Table 3 ). Peinado et al. (2021) conducted a case-control study among women aged 20 to 54 years from the EndEA (Endometriosis y Exposicion Ambiental) study, involving two hospitals in Spain. A concentration of parabens was detected in urine samples. The women completed a questionnaire about lifestyle and the cosmetic products used. Endometriosis was confirmed by laparoscopy. A significant relationship was identified between the occurrence of endometriosis and the concentration of MeP (methylparaben) (OR: 5.63,  p  < 0.001). For the remaining examined parabens—EtP (ethylparaben), PrP (propylparaben), and BuP (buthylparaben)—no association was found.\nAs this was the first study to examine the relationship between exposure to parabens and endometriosis, it is difficult to draw conclusions. More studies should be performed in this direction to establish recommendations.\nBenzophenones (BP) are filters for ultraviolet light. BP absorbs mainly UV-B light. Due to their properties, they are used in the production of creams and products to protect human skin against the harmful effects of ultraviolet radiation [ 73 ]. As benzophenones are frequently used, many studies examined the relationship between exposure to benzophenones and reproductive and gynecological disorders. Studies found a correlation between exposure to benzophenones and fetal growth [ 74 ]. Fetal exposure to benzophenones may cause delayed growth, and the effects of exposure are more pronounced in female fetuses [ 74 ]. It was found that BP may affect reproductive function by interfering with estrogen receptors [ 75 ].\nIn two studies, the link between exposure to benzophenones and the occurrence of endometriosis was analyzed [ 72 , 76 ] ( Table 4 ). In a case-control study performed by Peinado et al. (2021) [ 72 ] among women aged 20 to 54 years from the EndEA (Endometriosis y Exposicion Ambiental) study involving two hospitals in Spain, the concentrations of benzophenone-1 (BP-1), benzo-phenone-3(BP-3), and 4-hydroxibenzophenone (4-OH-BP) were determined in urine samples. There was a significant correlation between BP-1 (OR:5.12,  p  = 0.011) and BP-3 (OR: 4.98,  p  = 0.008) and the occurrence of endometriosis. A matched cohort study by Kunisue et al. (2012) [ 76 ] was performed among women aged 18–54 years participating in the ENDO project (Endometriosis, Natural History, Diagnosis, and Outcomes). The women were divided into two groups; women who had undergone laparoscopy or laparotomy (operative cohort), and women who were diagnosed with magnetic resonance imaging (population cohort). The research showed no relationship between the concentrations of 2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH-BP), and 4-hydroxybenzophenone (4OH-BP) and the occurrence of endometriosis. As only two studies were performed on the effect of exposure to benzophenones on endometriosis, it is difficult to provide a conclusion.\nOrganophosphorus (OP) and pyrethroid (PYR) pesticides are non-persistent endocrine disruptors [ 77 , 78 ]. OP is widely used in agriculture and horticulture to control plant pests. Organophosphorus pesticides exhibit toxicological effects by inhibiting the enzyme acetylcholinesterase [ 79 ]; moreover, OP can cause chronic neuropsychiatric disorders [ 80 ]. The relationship between exposure to pesticides and fetal death due to congenital abnormalities was investigated, revealing that exposure to pesticides between 3 and 8 weeks of pregnancy could lead to the assumed hypothesis [ 81 ]. It has been shown that the use of sprayers with OP as a component may have a negative impact on the quality of sperm in men [ 82 ]. Furthermore, organophosphorus pesticides could impair the functioning of the sexual endocrine system [ 83 ]. Pyrethroid pesticides are also used in agriculture and horticulture as insecticides. It is suspected that some may be carcinogenic, and it is also assumed that they may have a negative effect on the endocrine system [ 84 ]. A study was conducted showing that PYR exposure may have an effect on birth weight [ 85 ]. The effect of pyrethroids on the estrogenic and anti-progestogenic pathways was investigated, concluding that some pyrethroids may contribute to reproductive dysfunction [ 86 ].\nOnly one study examined the effect of non-persistent pesticides (organophosphate and synthetic pyrethroids) on the risk of developing endometriosis [ 87 ] ( Table 5 ). The study by Li et al. (2020) [ 87 ] was carried out using a matched cohort study design among women aged 18–54 years participating in the ENDO project (Endometriosis, Natural History, Diagnosis, and Outcomes). The metabolites of the non-persistent pesticides were determined in urine samples (IMPY- 2-isopropyl-4-methyl-6-hydroxypyrimidine, MDA- malathion dicarboxylic acid, PNP- para -nitrophenol, TCPY-3,5,6-trichloro-2-pyridinol, 2,4-D—2,4-dichlorophenoxyacetic acid, 2,4,5-T—2,4,5-trichlorophenoxyacetic acid, 3-PBA—3-phenoxybenzoic acid, 4F-3PBA- 4-fluoro-3-phenoxybenzoic acid,  trans/cis -DCCA- trans/cis -3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid,  cis -DBCA- cis -3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid). The women were divided into two groups, women who had undergone laparoscopy or laparotomy (operative cohort), and women who were diagnosed by magnetic resonance imaging (population cohort). The study found a significant association between endometriosis and urinary concentration of diazinon (the parent compound of IMPY) OR and chlorpyrifos and chlorpyrifos-methyl (parent compounds of TCPY) IMPY, (OR: 1.89; 95%, CI: 1.12–3.20) and TCPY, (OR: 1.65; 95% CI: 1.02–2.69).\nExposure to phthalate and endometriosis.\nAbbreviations: LOQ—limit of quantitation, IQR—interquartile range, OR—odds ratio, SD—standard deviation, SE—standard error, MEHP—mono-(2-ethyl)-hexyl phthalate, MEHHP—mono-(2-ethyl-5-hydroxyhexyl) phthalate, MEOHP—mono-(2-ethyl-5-oxohexyl) phthalate, MECPP—mono-(2-ethyl-5-carboxypentyl) phthalate, MBzP—mono-benzyl phthalate, MEP—monoethyl phthalate, MiBP—mono-iso-butyl phthalate, MnBP—mono-benzyl phthalate, MMP—mono-methyl phthalate, MBP—mono-butyl phthalate, MCHP—mono-cyclohexyl phthalate, MiNP—mono-isononyl phthalate, DnBP—di-n-butyl phthalate, BBP—butyl benzyl phthalate, DnOP—di-n-octyl phthalate, DEHP—diethylhexyl phthalate, 5oxo-MEHP—mono-(2-ethyl-5-oxo-hexyl) phthalate, 5OH-MEHP- mono-(2-ethyl 5-hydroxyhexyl) phthalate, MCPP—mono (3-carboxypropyl) phthalate, MCMHP—mono-[(2-carboxymethyl) hexyl] phthalate, MNP—mono-isononyl phthalate, MOP—mono-octyl phthalate, MNM—mono-n-methyl phthalate, MIBP—mono-isobutyl phthalate.\nExposure to Bisphenol-A and endometriosis.\nAbbreviations: BPA—bisphenol A, OR—odds ratio, SD—standard deviation.\nExposure to parabens and endometriosis.\nAbbreviations: OR—odds ratio, SD—standard deviation, MeP—methylparaben, EtP—ethylparaben, PrP—propylparaben, BuP—buthylparaben.\nExposure to benzophenones and endometriosis.\nAbbreviations: OR—odds ratio, SD—standard deviation, BP-1—benzophenone-1, BP-3—benzo-phenone-3, 4-OH-BP-4-hydroxibenzophenone, 2OH-4MeO-BP—2-hydroxy-4-methoxybenzophenone, 2,4OH-BP—2,4-dihydroxybenzophenone, 4OH-BP—4-hydroxybenzophenone.\nExposure to nonpersistent pesticides and endometriosis.\nAbbreviations: OR—odds ratio, IMPY—2-Isopropyl-4-methyl-6-hydroxypyrimidine, MDA—malathion dicarboxylic acid, PNP—3,5,6-trichloro-2-pyridinol, TCPY—3,5,6-trichloro-2-pyridinol, 4F-3PBA—4-fluoro-3-phenoxybenzoic acid, 3-PBA—3-phenoxybenzoic acid, 2,4-D—2,4-dichlorophenoxyacetic acid, 2,4,5-T—2,4,5-trichlorophenoxyacetic acid, trans/cis-DCCA—trans/cis-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid, cis-DBCA—cis-3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid.\n\nMost of the studies reviewed in this paper showed an association between exposure biomarkers and non-persistent EDCs, with endometriosis, involving at least one metabolite of these compounds ( Table 6 ). Five of the reviewed studies showed an association between the concentration of BPA and endometriosis, while four observed no association.\nIn the case of phthalates exposure, the seven reviewed studies found an association between the concentration of at least one phthalate metabolite and endometriosis whereas most studies on single compounds indicated no significant association. Additionally, several studies included up to 10 metabolites, increasing the risk of random associations. Five studies found no association between phthalate concentration and endometriosis. Only one study was performed to assess the link between exposure to parabens and endometriosis, finding a significant relationship between the concentration of MeP and endometriosis. For the remaining examined parabens—EtP, PrP, and BuP—no association was found. Additionally, only one study assessed the effect of exposure to non-persistent pesticide exposure on endometriosis, observing a significant association between endometriosis and the urinary concentration of diazinon (the parent compound of IMPY) as well as chlorpyrifos and chlorpyrifos-methyl (parent compounds of TCPY).\nOnly two studies were performed on the effect of exposure to benzophenones on endometriosis. Their results were inconclusive, making it difficult to provide a conclusion on this effect. A comparison of the reviewed studies is presented in  Table 6 .\nThe inconsistencies in the results may have been due to many limitations of the presented studies, such as differences in the confounding factors used in the statistical models, study design, study population, biomarkers of exposure, biological fluids used for assessment, creatinine or specific gravity adjustment, time of exposure, and outcome assessment (diagnosis  versus  questionnaire data).\nIn most of the presented studies, a case-control study design was used, which is often used to identify factors that may contribute to a medical condition by comparing subjects who have that condition/disease (cases) with those who do not but are otherwise similar (controls). On the other hand, case-control studies also have some limitations, whereby associations measured may or may not represent causal relationships. It can be hard to establish if there is true temporality (i.e., if the exposure preceded the outcome; or vice versa). Furthermore, cases and controls may have different recollections of exposure, leading to a unique source of bias. The study populations were mostly recruited mostly from fertility and gynecology centers. Non-persistent endocrine-disrupting chemicals were analyzed in urine in most of the reviewed studies. Additionally, the authors did not state the number of analyzed urine samples collected from each patient. As non-persistent endocrine disruptors are metabolized in 24–48 h, a single urine sample may not reliably define exposure and its association with endometriosis. However, as people do not change their lifestyle very often, exposure is typically habitual. Thus, as reported by Meeker et al. (2005) [ 88 ], a single sample can adequately predict longer-term average exposure. The outcomes (endometriosis) in most presented studies were assessed by surgery or magnetic resonance imaging. However, in two studies, the diagnosis was based on questionnaire data. In most studies, similar confounding factors were used in the statistical models, e.g., age, smoking status, body mass, age at menarche, education level, and pregnancy status.\nIn the case of studies investigating phthalate exposure, the divergence of the results may have arisen from the various confounding factors identified in the studies, such as differences in creatinine adjustment, sample size, study design, phthalate metabolites assessed, and biological fluids in which the concentrations of phthalates were measured. In studies of the effect of BPA exposure on endometriosis, the inconsistent results may have been due to the differences in the selection of study groups. In benzophenone studies, the use of diverse biomarkers (different benzophenones) and various confounding factors may have affected the results.\n\nIn conclusion, despite the numerous limitations of the results, the reviewed studies suggest that exposure to non-persistent endocrine disruptors, especially in the case of bisphenol A and phthalates is associated with endometriosis. The results of the studies on parabens, benzophenones, and non-persistent insecticides were inconclusive.\nThe studies were mostly well-designed epidemiological studies, using biomarkers of exposure, where the outcome (endometriosis) was based on a confirmed diagnosis. Additionally, the statistical models were adjusted for potential confounding factors.\nDue to the insufficient evidence, further epidemiological studies are needed to confirm these findings.","source_license":"CC-BY-4.0","license_restricted":false}