Examining the Impact of Environmental Non-Persistent Compounds: Phthalates, BPA, and Benzophenone on Endometriosis

This review considered English-language articles published between 2003 and 2023. Six databases were searched: Web of Science, Elsevier, PubMed, Springer, and EBSCO. Search terms included, non-persistent chemicals, exposure to phthalates, bisphenols, benzophenones, UV filters, and the outcome of endometriosis. This resulted in 108 publications. From those records, we excluded studies in animals or cell lines or other experimental settings (n=13). We did not include review articles (n=72). Therefore, 18 studies focusing on the relationship between phthalates, bisphenols, or benzophenones and endometriosis risk were selected for inclusion in this review.

The specific properties of phthalates vary depending on their chemical structure 37 , 38 . Common sources of exposure include consumer products like nail polish, body lotions, hair care products, and paints. Additionally, certain medications, including didanosine, omeprazole, and theophylline, contain phthalates, leading to potential exposure through ingestion 37 . Once ingested or absorbed, phthalates are metabolized in the body. Mono-butyl phthalate (MBP), mono-iso-butyl phthalate (MiBP), di(2-ethylhexyl) phthalate (DEHP), and their metabolites like mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) are the most detected phthalate metabolites in human specimens 39 . A concern regarding phthalates is their potential to act as endocrine-disrupting chemicals (EDCs). Phthalate metabolites can mimic estrogen by interacting with estrogen receptors 40 . This endocrine-disrupting property has been linked to menstrual cycle irregularities and polycystic ovary syndrome (PCOS) 41 . We identified ten studies (one cross-sectional 42 , one cohort 2 , and eight case-control 42 - 49 ) on phthalates and endometriosis ( Table 1 ). The age of the women ranged from 18 to 54 years old (reproductive age). In multiple studies, a questionnaire about women's lifestyle factors (birth control, physical activity, smoking, alcohol consumption) was used 2 , 42 - 46 whereas some studies, such as Cobellis et al. (2003), did not assess lifestyle factors 43 . Endometriosis diagnosis was based on surgery or magnetic resonance imaging in most studies 2 , 43 - 48 , while in Weuve et al. (2010), it was based on a self-report questionnaire 42 . The relationship between phthalate exposure and endometriosis remains complex and inconsistent. While some research has found no association between these factors 42 , 43 , 48 , other studies suggest a potential link. For instance, Upson et al. (2003) reported an inverse association among women with higher urinary levels of mono(2-ethylhexyl) phthalate (MEHP) [OR=0.3, 95% CI: 0.1-0.7] 46 . In contrast, several studies have identified elevated levels of specific phthalates, including mono(2-ethylhexyl) phthalate (MEHHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), in women with endometriosis compared to healthy controls 2 , 44 . Kim et al. (2015) reported particularly high urinary concentrations of three phthalate metabolites: mono(2-ethylhexyl) phthalate (MEHHP) (OR=2.52, 95% CI: 1.03-6.14), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEOHP) (OR=2.89, 95% CI 1.04-8.04), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) (OR=2.57, 95% CI: 0.92-7.13) in women with endometriosis 44 . Louis et al. (2013), the population cohort group, found a significant relationship between the presence of endometriosis and exposure to phthalates (mono(3-carboxypropyl) phthalate (MCMHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MOP)) 2 . Reddy et al. (2006) found statistically significant (p < 0.05) phthalate concentrations (di-n-octyl phthalate (DnOP), butyl benzyl phthalate (BBP), di-n-butyl phthalate (DnBP), and di(2-ethylhexyl) phthalate (DEHP)) in samples of women with endometriosis compared to the control women 49 . Bisphenol A (BPA), a widely used chemical in polycarbonate plastics, epoxy resin coatings, and other consumer products 2 . Humans are exposed to BPA through ingestion and dermal contact 50 , 51 . BPA, like phthalates, mimics estrogen, influencing hormone levels and production 52 . BPA is absorbed by the gastrointestinal tract, rapidly metabolized in the liver, and excreted in urine 53 . We identified seven studies (two cross sectional 29 , 48 , one cohort 2 , and four case control 54 - 57 ). Women aged 18 to 54 years were recruited for the studies. Six of the studies ascertained endometriosis diagnosis by laparoscopy, laparotomy, or magnetic resonance imagine 2 , 48 , 54 - 57 . Lee & Eata (2022) relied on self-report of endometriosis. In six studies all women completed lifestyle questionnaires 2 , 29 , 48 , 54 - 56 while one study did not 57 . The association between BPA and endometriosis remains inconsistent. One study found no association 2 . However, a smaller study by Cobellis et al. (2009) detected BPA in all women with endometriosis but not in controls 57 . Several studies have reported a positive association between BPA and endometriosis. One study specifically linked BPA to non-ovarian pelvic endometriosis (OR=3.0, 95% CI: 1.2-7.3) 29 , 55 . Rashidi et al. (2017) also found an association (OR=1.75, 95% CI: 1.41-2.17) 54 , and Peinado et al. (2020) observed a similar relationship (OR=1.5, 95% CI: 1.0-2.3) 56 . Lee & Eata (2022) reported a positive association (OR=1.47, 95% CI: 1.00-2.14), with women in the highest BPA quartile being more than three times as likely to report endometriosis compared to those in the lowest quartile (OR=3.58, 95% CI: 1.00-12.89) 29 . One concern is the potential endocrine-disrupting activity of BP-3 and its metabolites. While BP-3 itself exhibits weak estrogenic properties, its breakdown product, benzophenone-1 (BP-1), has been found to be more potent in terms of estrogenic activity 17 , 58 . Like phthalates and BPA, endocrine disruptors can interfere with the body's hormonal system, potentially leading to reproductive issues, developmental abnormalities, and other health problems. Several BP-type UV filters have been quantified, such as, 2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP, also known as BP-3), 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2'-dihydroxy-4-methoxybenzophenone (2,2'OH-4MeO-BP), 2,2',4,4'-tetrahydroxybenzophenone (2,2',4,4'OH-BP), and 4-hydroxybenzophenone (4OH-BP). Two articles were identified on the relationship between benzophenones and endometriosis 56 , 59 . In a case-control study of 124 women with laparoscopically confirmed endometriosis, BP-1 and BP-3 were associated with endometriosis, while 4-hydroxibenzophenone (4-OH-BP) was not 76 . In a matched exposure cohort study (n=695), among the operative cohort (n=473), 2,4OH-BP was associated with an increased odds of endometriosis 59 . Other BP-like UV filters were not associated with endometriosis in the operative or population cohorts. In the operative cohort endometriosis was confirmed by surgical visualization and the study was able to adjust for important confounding factors like Kunisue et al. (2012) found no association between several BPs and endometriosis 59 .

In conclusion, the reviewed studies suggest a potential association between exposure to non-persistent endocrine disrupting chemicals, especially phthalates and bisphenol A, and endometriosis. While evidence associating benzophenones to endometriosis is limited and inconclusive, further epidemiological research using multivariable models is necessary to strengthen these results.

The inconsistencies in findings may be attributed to several methodological limitations across the reviewed studies. Key issues include confounding variables in statistical models, diverse study designs, varying biomarker measurement methods, different biospecimens used, and inconsistencies in exposure assessment, temporality, and outcome definition (self-reported versus laparoscopic-confirmed endometriosis). Case-control studies were the main study design in this review, which limits the ability to establish causality due to the inability to determine temporality. In case control studies, recall bias, where cases may overreport exposure compared to controls, is a potential concern. Additionally, selection bias may have influenced results, as most study populations were recruited from specialized fertility or gynecology clinics. The primary biomarker, urinary endocrine disruptors, presents challenges due to their non-persistent nature and metabolism within 24-48 hours. A single urine sample may not accurately reflect long-term exposure. While most studies controlled for age, smoking status, BMI, age at menarche, education, and pregnancy status, residual confounding remains a possibility. A challenge in researching the link between phthalates, BPA, and BP UV filters and endometriosis lies in the chemicals' short half-lives within the human body. These compounds are rapidly metabolized and excreted, making their detection in biological samples at the time of endometriosis onset or progression difficult to obtain. Consequently, studies often rely on measuring metabolites around the time of endometriosis diagnosis in cohort studies, or after endometriosis diagnosis as in case-control or cross-sectional studies, which can complicate data interpretation. The average delay of about 9 years until diagnosis of endometriosis further complicates answering this question, as even incident diagnosis of endometriosis in a cohort study likely occurred several years after actual disease development 60 . Moving forward, it would be important to identify available cohorts that had stored biospecimens at young adulthood from which to measure chemical exposures and are followed forward in time for reporting of endometriosis. This would enable a measurement of chemical exposure closer in time to development of endometriosis. Additionally, it can be challenging to compare across studies due to differences among comparison group selection, which includes some who were free of endometriosis on laparoscopy and others by self-report, while other studies had additional criteria for controls, such as not being diagnosed with infertility. Itoh and colleagues included controls who had ASRM stage I endometriosis as controls, which may help explain their null findings in contrast to several others who found that phthalates were associated with an increased odds of endometriosis.

Endometriosis is defined as the presence of endometrial-like tissue that normally lines the uterus, found outside the uterus 1 . This misplaced tissue responds like the uterine lining, building vascular tissue during the follicular phase and then undergoing inflammation, breakdown, and bleeding along with the intrauterine lining during each menstrual cycle 1 . A complex disease characterized by chronic inflammation and dependence on estrogen, endometriosis affects an estimated 6-11% of the United States female population of reproductive age 2 . Endometriosis manifests in various forms of ectopic tissue. These commonly include superficial peritoneal lesions, where endometrial tissue attaches to the peritoneum, the lining of the abdominal cavity 3 . Deep-infiltrating endometriosis describes lesions that burrow deeper than 5mm beneath the peritoneum 3 . Ovarian endometriotic cysts, also known as endometriomas, are dark fluid-filled cysts of varying sizes found within the pelvis or abdomen 3 . These lesions can appear in numerous locations: ovaries, peritoneum, uterosacral ligaments, posterior cul-de-sac, vagina, gastrointestinal tract, urinary bladder, and ureters 4 . For many women, the presence of this tissue triggers chronic inflammation and pain 1 . This inflammation, along with oxidative damage and potential exposure to endocrine-disrupting chemicals (EDCs), can lead to a range of symptoms that significantly impact quality of life: pelvic pain, painful periods (dysmenorrhea), pain during sex (dyspareunia), and infertility 4 . Beyond the physical burden, endometriosis can negatively affect mental health and overall well-being 5 . The economic impact is also substantial, with low quality of life translating to financial strain for diagnosed individuals (lost opportunities in education and careers, impact on productivity, taking time off work, opting for part-time employment) 6 , 7 . Notably, endometriosis is present in 50-80% of women experiencing pelvic pain and up to 50% of women struggling with infertility 8 . In the United States alone, it's the third leading cause of gynecological hospitalization after childbirth complications and abnormal uterine bleeding 9 . The annual economic burden of endometriosis in the US is estimated to exceed $22 billion annually 3 . While factors such as age, body mass index (BMI), race, parity, smoking, alcohol consumption, age at menarche, and genetics are recognized as potential risk factors for endometriosis, the precise pathogenesis remains elusive. Three primary hypotheses—retrograde menstruation, metaplasia, and genetics/epigenetics—have been proposed to explain the presence of endometrial-like tissue outside the uterus 10 . However, the picture is becoming increasingly complex. Emerging evidence suggests that environmental factors, particularly EDCs prevalent in our environment and food, may also play a significant role. These chemicals can disrupt the hormonal system, potentially contributing to the development and progression of endometriosis. Non-persistent compounds like phthalates, bisphenol A (BPA), and benzophenone (BP) ultraviolet (UV) filters are chemicals widely found in consumer products that may cause endocrine or reproductive disorders even with low exposure 11 . Phthalates are a group of chemicals that are commonly used in plastics to enhance flexibility and are found in products like food packaging, personal care items, and children's toys 9 . Primary exposure occurs through ingestion of contaminated food or beverages. Phthalates have endocrine-disrupting properties, mimicking and blocking estrogen and potentially stimulating the growth of endometrial tissue and disrupting hormonal balance 12 , 13 . BPA is a chemical compound used in producing polycarbonate plastics found in products like water bottles and food containers 14 Human exposure primarily occurs through diet 15 . These chemicals mimic the behavior of natural hormones in the body, specifically estrogen. By mimicking estrogen function, BPA can disrupt the hormonal balance in cellular processes 16 . BP UV filters are chemicals in sunscreens that absorb or reflect UV light. They have shown multiple endocrine-disrupting effects 17 . First proposed in the 1920s by John Sampson 18 , the retrograde menstruation hypothesis suggests that menstrual blood, containing endometrial cells, might travel backward through the fallopian tubes into the abdominal cavity. These displaced cells could then implant and grow outside the uterus, leading to endometriosis. However, this theory has limitations. Many women experience retrograde menstruation, yet not all develop endometriosis 19 . This suggests there may be additional factors at play that allow these cells to establish themselves and thrive outside their intended location. The metaplastic hypothesis proposes a different origin for the misplaced tissue. It suggests that cells lining the abdominal cavity (coelomic epithelium) might transform into endometrial-like tissue under certain unknown conditions 20 . This theory could explain why some endometriotic lesions appear solely on the peritoneum, the lining of the abdominal cavity 21 . Further research is needed to understand the potential triggers for this cellular transformation and its role in endometriosis development. The most recent hypothesis delves into the potential role of genetics and epigenetics. This theory suggests that specific genetic or epigenetic changes in cells like those in the endometrium, bone marrow, or even stem cells, might contribute to the development of endometriosis 20 . The idea is that most women might develop tiny lesions, but depending on these genetic and epigenetic factors, the lesions may either regress or progress into larger, more troublesome ones. This hypothesis requires further investigation to identify the specific genetic or epigenetic alterations involved. Estrogen plays a crucial role in endometriosis. This hormone fuels the growth and persistence of tissue and the associated inflammation and pain 22 . Understanding these hypotheses and the role of estrogen is vital for developing better treatments, prevention of endometriosis, and understanding potential risk factors. Endometriosis is closely linked to inflammation, the body's natural defense mechanism triggered by injury 23 . Endometriotic lesions can produce inflammatory mediators and pain-inducing substances, altering the healthy environment within the peritoneal cavity (lining of the abdomen) and pelvic region 23 - 25 . This altered environment, including inflammatory cells 26 , fuels the growth, implantation, infiltration, and migration of endometriotic lesions, but also stimulates angiogenesis, the formation of new blood vessels, which is crucial for supplying oxygen and nutrients to the growing tissue. These lesions can further stimulate the production of inflammatory cells and substances, creating a vicious cycle that perpetuates endometriosis-associated inflammation. Macrophages, immune cells involved in both inflammation and tissue repair, are found in high numbers within endometriosis lesions. Research suggests that different macrophage subtypes (M1 and M2) may play opposing roles in endometriosis – M1 inhibits cell proliferations and M2 promotes cell proliferation 27 . Endometriotic lesions also produce inflammatory mediators like cytokines and chemokines, creating an environment that promotes the growth and spread of endometrial tissue 28 . Adding to the complexity, exposure to endocrine disrupting chemicals (EDCs) like phthalates, BPA, and UV filters may disrupt hormonal balance and contribute to the inflammatory processes observed in endometriosis. These chemicals can alter cellular signaling pathways, leading to increased production of inflammatory mediators and a pro-inflammatory microenvironment. Endometriosis impacts overall health beyond dysmenorrhea, affecting multiple organ systems 7 . Infertility rates are doubled in women with endometriosis compared to those without, affecting up to 50% of cases 8 , 29 Potential links to ovarian cancer 30 , autoimmune diseases 31 , and cardiovascular disease (including hypertension, high cholesterol 32 - 35 , and subclinical atherosclerosis 36 ) exist, but require further study. The goal of this review was to summarize novel published research on exposures to environmental contaminants like phthalates, BPA, and BP UV filters and endometriosis.