Table 1.
Exposure to phthalate and endometriosis.
| Study | Study Design | Samples Measured | Concentration of Endocrine Disrupting Chemicals (EDC) | Study Population | RESULTS | |
|---|---|---|---|---|---|---|
| Upson et al. (2013) [41] United States, Seattle, research was conducted among of a large healthcare system in the U.S. Pacific Northwest |
population-based case-control | urinary concentration of MEHP, MEHHP, MEOHP, MECPP, MBzP, MEP, MiBP, MnBP LOQ = 0,2 ng/mL | Median (IQR): Cases: MEHP = 2.2 ng/mL (0.6–4.6) MEHHP = 14.8 ng/mL (5.3–31.0) MEOHP = 8.1 ng/mL (3.5–18.0) MECPP = 14.4 ng/mL (5.9–32.5) MBzP = 4.5 ng/mL (2.2–9.9) MEP = 61.9 ng/mL (23.5–155.9) MiBP = 1.3 ng/mL (0.6–2.7) MnBP = 9.8 ng/mL (5.0–20.9) |
Median (IQR): Controls: MEHP = 3.4 ng/mL (1.0–11.1) MEHHP = 18.8 ng/mL (6.3–56.5) MEOHP = 10.8 ng/mL (3.5–29.1) MECPP = 18.0 ng/mL (5.8–51.9) MBzP = 5.0 ng/mL (2.0–11.5) MEP = 43.9 ng/mL (16.8–144.4) MiBP = 1.5 ng/mL (0.7–3.1) MnBP = 10.0 ng/mL (4.9–23.5) |
287 reproductive-age women 92- cases 195- controls Women with endometriosis age range 18–49 years Women were recruited by in-person interviews covering a range of topics, including reproductive history and contraceptive use as well as medical and family history and lifestyle behaviors. The case group was surgically-confirmed cases and population-based controls. (1996–2001) |
A strong inverse association between urinary MEHP concentration and endometriosis, when comparing the fourth and first MEHP quartiles (OR 0.3, 95% CI: 0.1–0.7). No statistically significant association between urinary concentrations of other DEHP metabolites MEHHP, MEOHP, and ∑DEHP and endometriosis, increased not statistically significant of endometriosis and urinary concentrations of MBzP and MEP was found. |
| Fernandez et al. (2019) [42] Brazil, Diagnosis of endometriosis was performed at the Endometriosis Center of Hospital School of the Federal University of Minas Gerais. |
case-control study | urinary concentration of MMP, MiBP, MBP, MCHP, MiNP, MOP, MBzP, MEHP |
Median: Cases: MMP = 57.6 µg/g MiBP = 129.8 µg/g MBP = 64.2 µg/g MCHP = 7.0 µg/g MEHP = 22.4 µg/g MiNP = 21.8 µg/g MOP = 670 µg/g MBzP = 23.8 µg/g |
Median: Controls: MMP = 45.3 µg/g MiBP = 181.8 µg/g MBP = 72.4 µg/g MCHP = 4.6 µg/g MEHP = 21.2 µg/g MiNP = 14.7 µg/g MOP <LOQ MBzP < LOQ |
52 women 30—cases 22- controls Women with endometriosis age range 18–45 years Participants signed a free informed consent form and filled out a questionnaire, with questions related to food habits, gynecological history, medicine intake as well as personal information. Criteria were confirmation of endometriosis by video laparoscopy surgery with histological diagnosis and the absence of the disease, respectively. |
The phthalate metabolites that had the highest concentrations, were MOP and MiBP, in which the values of 670 µg/g and 560 µg/g, respectively. The relationship between endometriosis and all grouped metabolites was not statistically significant with p = 0.225. |
| Reddy et al. [43] (2006) India, The women were recruited at two centers: Bhagwan Mahavir Medical Hospital and Research Centre and Maternal Health and Reproductive Institute of Reproductive Medicine, Hyderabad, which receives cases from all over the region of Andhra Pradesh |
case-control study | Serum cocncentration of DnBP, BBP, DnOP, DEHP | Arithmetic mean: Cases: DnBP = 0.44 µg/mL BBP = 0.66 µg/mL DnOP = 3.32 µg/mL DEHP = 2.44 µg/ml |
Arithmetic mean: Controls I: DnBP = 0.08 µg/mL BBP = 0.12 µg/mL DnOP = 0 µg/mL DEHP = 0.5 µg/mL Controls II DnBP = 0.15 µg/mL BBP = 0.11 µg/mL DnOP = 0 µg/mL DEHP = 0.45 µg/mL |
108 reproductive-age women. 49—cases 38—controls I 21—controls II Average age was 26.6 years in endometriosis cases, 27.4 years in control group I 27.1 years in control group II. Women completed a questionnaire to obtain information on the general obstetric and gynecological details including age at menarche, length of the menstrual cycle, associated symptoms, duration and amount of blood loss, duration of infertility, and socio-demographic details like age, body mass index (BMI) and limited information on diet were used for this study. The case group included 49 women who were diagnosed with endometriosis by laparoscopy. Group I comprised 38 women who attended the same hospital for other gynecological pathology (e.g., fibroids, tubal defects, polycystic ovaries, idiopathic infertility, and pelvic inflammatory disease) but were laparoscopically without endometriosis. Control group II comprised 21 women who attended the same hospital for laparoscopic tubal sterilization, with proven fertility and no evidence of endometriosis or other gynecological disorders. |
The phthalate esters were observed in all samples for women with endometriosis. Besides correlation PEs with endometriosis was strong and statistically significant at p < 0.05 for all compounds DnBP: p < 0.0001; BBP: p < 0.0001; DnOP: p < 0.0001 DEHP: p < 0.0014 |
| Cobellis et al. (2003) [44] Italy No information about the centers of treatment. |
case-control study | Serum concentrations or peritoneal fluid of DEHP and MEHP | Serum concentrations Cases: Median DEHP = 0.57 µg/mL MEHP = 0.38 µg/mL Peritoneal fluid Cases: Median DEHP = 0.46 µg/mL MEHP = 0.37 µg/mL |
Controls: Median DEHP = 0.18 µg/mL MEHP = 0.58 µg/mL |
79 women 55—cases 24—controls Women with endometriosis age range 22–45 years. Women aged range 18–48 years without known infertility or reproductive diseases served in the controls. Diagnosis was confirmed by histological examination of the endometriotic lesions. Exclusion criteria were medical treatment for endometriosis or ovarian cyst before the surgery, and any surgical procedure in the previous 12 months. |
Endometriotic women showed significantly higher plasma DEHP concentrations than controls. No significant differences in either the DEHP/MEHP plasma concentrations (p > 0.31) or DEHP/MEHP peritoneal fluid concentrations (p > 0.66) were observed in the endometriotic patients as a function of the disease stage at the time of diagnosis. |
| Huang et al. (2010) [45] Taiwan Women with endometriosis came from the Department of Obstetrics and Gynecology at a medical center in Taiwan. |
Case-control study | Urinary concentration of MMP, MEP, MnBP, MBzP, 5oxo-MEHP, 5OH-MEHP, MEHP, ΣMEHP | Median Cases: MMP = 37.8 ng/mL/52.4 µg/g creatinine MEP = 31.6 ng/mL/58.0 µg/g creatinine MnBP = 60.2 ng/mL/94.1 µg/g creatinine MBzP = 5.6 ng/mL/12.2 µg/g creatinine 5oxo-MEHP = 12.1 ng/mL/19.0 µg/g creatinine 5OH-MEHP = 13.6 ng/mL/16.7 µg/g creatinine MEHP = 2.7 ng/mL 4.2 µg/g creatinine ΣMEHP = 28.7 ng/mL/42.4 µg/g creatinine |
Median Controls: MMP = 28.1 ng/mL/32.1 µg/g creatinine MEP = 37.2 ng/mL/71.4 µg/g creatinine MnBP = 35.4 ng/mL/58.0 µg/g creatinine MBzP = 5.9 ng/mL/8.9 µg/g creatinine 5oxo-MEHP = 9.2 ng/mL/7.8 µg/g creatinine 5OH-MEHP = 5.7 ng/mL/9.9 µg/g creatinine MEHP = 0.8 ng/mL/3.4 µg/g creatinine ΣMEHP = 28.5 ng/mL/18.9 µg/g creatinine |
57 women 28 with endometriosis 29—control group Women with endometriosis were recruited who underwent laparotomy and had pathologic confirmation of endometriosis. Controls were patients without any gynecologic conditions. (2005–2007) |
In cases versus controls, an increased level of urinary mono-n-butyl phthalate (94.1 versus 58.0 µg/g creatinine, OR 3.46, Cl: 1.16–10.3, p < 0.05) was observed |
| Weuve et al. (2010) [46] United States Massachusetts The women were recruited from National Health and Nutrition Examination Survey (NHANES) |
cross-sectional study | Urinary concentration of MEHP, MBP, MEP, MBzP, MEHHP, MEOHP | Geoetric mean (SD) Cases: MBP = 28.9 (4.1) ng/mg MEP = 207.0 (27.5) ng/mg MEHP = 2.5 (0.4) ng/mg MBzP = 14.4 (2.5) ng/mg MEHHP = 16.5 (2.8) ng/mg MEOHP = 11.5 (1.9) ng/mg |
Geoetric mean (SD) Controls: MBP = 25.5 (1.0) ng/mg MEP = 219.9 (14.1) ng/mg MEHP = 3.4 (0.1) ng/mg MBzP = 14.1 (0.6) ng/mg MEHHP = 19.7 (1.4) ng/mg MEOHP = 13.5 (1.0) ng/mg |
1227 women 87 with endometriosis 1020 control group Women was recruited 20–54 years of age. Sociodemographic information and medical histories of the survey participants and their families were collected during the household interviews Women were classified based on the history of endometriosis according to their response to the question “Has a doctor or other health professional ever told you that you had endometriosis?” (1999–2004) |
No statistically significant association between assessed metabolites and endometriosis was found. |
| Nair et al. (2018) [47] Pakistan/ Australia This study was financially supported by the University of Health Sciences, Lahore, Pakistan. |
case-control study | Serum concentration of DEHP | Arithmetic mean: Cases: DEHP = 65.29 (ng/mL) Arithmetic mean in all the four stages of endometriosis: DEHP stage I = 60.4 ng/mL DEHP stage II = 58.68 ng/mL DEHP stage III = 66.25 ng/mL DEHP stage IV = 68.11 ng/mL |
Arithmetic mean: Controls: Not detected |
100 women 50 with endometriosis 50 without endometriosis Women with endometriosis age range 20–40 years. Only cases were included who were infertile and had been declared positive for endometriosis after laparoscopy by expert surgeons, according to the criteria set by the American Society for Reproductive Medicine (ASRM, 2012). ASRM guidelines classify endometriosis into four stages: I—minimal, II—mild, III—moderate, and IV—severe. For controls, due to ethical considerations, laparoscopy was not done. |
DEHP exposure was associated with advanced stages III and IV of endometriosis. |
| Louis et al. (2013) [48] United States, Utah The women were recruited in 14 participating clinical centers in the Salt Lake City, Utah, and San Francisco, California geographic areas. |
matched cohort design | Urinary concentration of phthalate metabolites: MMP, MEP, MCPP, MBP, MiBP, MECPP, MCMHP, MEHHP, MEOHP, MCHP, MBzP, MEHP | Geometric mean Operative Cohort: Endometriosis: MMP = 2.12 ng/mL MEP = 107.2 ng/mL MCPP = 2.71 ng/mL MBP = 12.07 ng/mL MiBP = 7.28 ng/mL MECPP = 24.68 ng/mL MCMHP = 29.34 ng/mL MEHHP = 16.34 ng/mL MEOHP = 10.98 ng/mL MCHP = 0.03 ng/mL MBzP = 6.96 ng/mL MEHP = 4.75 ng/mL MOP = 0.06 ng/mL MNP = 0.16 ng/mL Without endometriosis: MMP = 2.35 ng/mL MEP = 109.6 ng/mL MCPP = 3.41 ng/mL MBP = 11.01 ng/mL MiBP = 6.82 ng/mL MECPP = 24.98 ng/mL MCMHP = 29.19 ng/mL MEHHP = 14.40 ng/mL MEOHP = 10.12 ng/mL MCHP = 0.04 ng/mL MBzP = 7.82 ng/mL MEHP = 4.12 ng/mL MOP = 0.06 ng/mL MNP = 0.16 ng/mL |
Geometric mean Population Cohort Endometriosis: MMP = 3.67 ng/mL MEP = 152.0 ng/mL MCPP = 5.75 ng/mL MBP = 19.13 ng/mL MiBP = 13.32 ng/mL MECPP = 54.15 ng/mL MCMHP = 53.54 ng/mL MEHHP = 32.37 ng/mL MEOHP = 23.03 ng/mL MCHP = 0.04 ng/mL MBzP = 9.85 ng/mL MEHP = 8.32 ng/mL MOP = 0.06 ng/mL MNP = 0.22 ng/mL Without endometriosis: MMP = 2.71 ng/mL MEP = 138.2 ng/mL MCPP = 4.06 ng/mL MBP = 11.24 ng/mL MiBP = 7.59 ng/mL MECPP = 20.27 ng/mL MCMHP = 22.51 ng/mL MEHHP = 11.86 ng/mL MEOHP = 8.29 ng/mL MCHP = 0.03 ng/mL MBzP = 6.46 ng/mL MEHP = 3.07 ng/mL MOP = 0.05 ng/mL MNP = 0.16 ng/mL |
626 women 495 operative cohort 131 population cohort Women was recruited 18–44 years of age. In-person standardized interviews were conducted with women prior to surgery or MRI followed by an anthropometric assessment Operative cohort was undergoing laparoscopy/laparotomy. Endometriosis was confirmed in 190 women, and 283 were without endometriosis. The population cohort received standardized pelvic magnetic resonance imaging (MRI) for the assessment of endometriosis. 127 women were confirmed with endometriosis in the population cohort. (2007–2009) |
A significant association was observed between MBP, MCMHP, MECPP, MEHP, MEHHP, and MEOHP and endometriosis in the population cohort. No significant association between urinary concentration phthalates occurrence and endometriosis in the operative cohort. |
| Itoh et al. (2009) [49] Japan The women were recruited from the Department of Obstetrics and Gynecology of the Jikei University School of Medicine for the treatment of infertility. |
case-control study | Urinary concentration of MEP, MnBP, MBzP, MEHP, MEHHP, MEOHP | Cases (II-IV stages): Median unadjusted for creatinine (creatinine-adjusted) MEP = 39.6 µg/L (18.9 µg/g creatinine) MnBP = 87.2 µg/L (47.6 µg/g creatinine) MBzP = 3.9 µg/L (2.1 µg/g creatinine) MEHP = 10.2 µg/L (4.9 µg/g creatinine) MEHHP = 39.6 µg/L (19.2 µg/g creatinine) MEOHP = 39.5 µg/L (19.1 µg/g creatinine) |
Controls (0–1 stages): Median unadjusted for creatinine (creatinine-adjusted) MEP = 21.4 µg/L (11.2 µg/g creatinine) MnBP = 84.3 µg/L (43.3 µg/g creatinine) MBzP = 3.2 µg/L (1.8 µg/g creatinine) MEHP = 8.3 µg/L (4.2 µg/g creatinine) MEHHP = 32.2 µg/L (17.3 µg/g creatinine) MEOHP = 32.1 µg/L (16.3 µg/g creatinine) |
137 women Women were recruited 20–45 years of age. Participants were interviewed before laparoscopic examination by a single trained interviewer using a structured questionnaire to collect information on demographic factors, age, height, weight, personal and family medical, reproductive and menstrual history, oral contraceptive use, food, and alcohol consumption, and smoking history. The severity of endometriosis was diagnosed using laparoscopy. Cases of endometriosis have been classified into five stages based on the American Fertility Society classification and then categorized into: 80 controls (stage 0 or I) 57 cases (stages II-IV). (I-minimal, II-mild, III-moderate, and IV-severe) |
No significant association between endometriosis and urinary concentration of phthalate. |
| Kim et al. (2015) [50] Korea The women were recruited from the department of Obstetrics & Gynecology in Asan Medical Center, Seoul, Korea. |
case-control study | Urinary concentration of: MEHHP, MEOHP, MnBP, MECPP | Arithmetic mean ± SE Cases: MEHHP = 18.2 ± 1.7 µg/g creatinine MEOHP = 13.4 ± 1.1 µg/g creatinine MnBP = 41.7 ± 6.2 µg/g creatinine MBzP = 5.8 ± 1.0 µg/g creatinine MECPP = 23.8 ± 1.9 µg/g creatinine |
Arithmetic mean ± SE Controls: MEHHP = 12.9 ± 1.4 µg/g creatinine MEOHP = 10.3 ± 0.9 µg/g creatinine MnBP = 32.4 ± 3.1 µg/g creatinine MBzP = 7.3 ± 1.9 µg/g creatinine MECPP = 19.0 ± 1.7 µg/g creatinine |
88 women 55—cases 33—controls The mean age in the endometriosis group was 29.9 years and in the control group was 32.6 years. Any women with a history of occupational exposure to reproductive toxicants, smoking, alcohol, and other addictions were excluded from this study. Th endometriosis group had undergone pelviscopic surgery, exploratory laparotomy, or transabdominal hysterectomy. (2012–2013) |
Significant association between urinary concentrations of phthalates and endometriosis: MEHHP OR = 2.52; p = 0.041 MEOHP OR = 2.89; p = 0.043 MECPP OR = 2.57; p = 0.071 |
| Kim et al. (2011) [51] Korea The women were recruited from the department of Obstetrics and Gynecology in Asan Medical Center, Seoul, Korea |
case-control study | Serum concentration of MEHP, DEHP | Arithmetic mean ± SE Cases: MEHP = 17.4 ± 1.5 ng/mL DEHP = 179.7 ± 32.5 ng/mL |
Arithmetic mean ± SE Controls: MEHP = 12.4 ± 1.1 ng/mL DEHP = 92.5 ± 31.1 ng/mL |
266 women 97—cases 169—controls All of the subjects recruited in this study were from urban areas, without a history of occupational exposure to reproductive toxicants, smoking, alcohol, and other addictions. This study comprised a total of 266 patients who had undergone pelviscopic surgery, exploratory laparotomy, myomectomy, or transabdominal hysterectomy. The endometriosis group had surgical and histologic evidence of advanced-stage endometriosis. (January 2009 and September 2009. |
Plasma levels of MEHP were significantly higher in those with advanced-stage of endometriosis (levels of phthalate esters might be quite different between the patients with stage I–II and III–IV endometriosis). MEHP OR = 1.020(1.003–1.038)/p = 0.020 No significant association between DEHP and endometriosis. DEHP OR= 1.001 (1.000–1.002)/p = 0.161 |
| Zhang et al. (2021) [52] China The women were recruited from the National Health and Nutrition Examination Survey (NHANES) |
cross-sectional study | Urinary concentration of: MBP, MCHP, MEP, MEHP, MNP, MOP, MBzP, MNM, MCPP, MEHHP, MEOHP, MIBP | Geometric mean for the whole population: MBP = 20.89 ng/mL MCHP = 0.45 ng/mL MEP = 160.27 ng/mL MEHP = 3.55 ng/mL MNP = 1.19 ng/mL MOP = 1.32 ng/mL MBzP = 8.80 ng/mL MNM = 1.65 ng/mL MCPP = 2.16 ng/mL MEHHP = 20.06 ng/mL MEOHP = 14.03 ng/mL MIBP = 4.13 ng/mL |
1204 women 77—cases 1127—controls Women were recruited from 20–54 years of age, information about endometriosis was based on a questionnaire. (2001–2006) |
No association between examined phthalates metabolites and endometriosis. | |
Abbreviations: 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.