近年來不孕症(infertility)盛行率有逐年增加的現象，其中可歸因於女性之因素約佔30%。研究指出女性不孕症之影響因素眾多且複雜，包含生理因素(年齡、基因、BMI等)、心理因素(壓力、情緒等)、疾病(荷爾蒙分泌異常、排卵異常、骨盆腔感染、子宮內膜異位症、子宮肌瘤、多囊性卵巢症候群等)、生活習慣(抽菸、飲酒或藥癮等)及環境毒物如內分泌干擾物暴露等。環境中的鄰苯二甲酸酯類(phthalate esters, PAEs)為已知的內分泌干擾物質，具高延展性及可塑性，常用於塑膠製品製造；或添加於化粧品及個人衛生用品作為溶劑及定香劑使用。文獻指出PAEs具生長發育及生殖毒性，動物實驗結果顯示PAEs暴露可能抑制人體芳香轉化酶(aromatase)活性，導致雌二醇(estradiol, E2)及孕酮(progesterone, P4)濃度降低，使發情週期延長和停止排卵。人類流行病學研究結果顯示PAEs暴露與女童性早熟、流產、子宮內膜異位及子宮肌瘤等生殖相關疾病具顯著相關性，導致不孕症的罹患機率增加。然而目前尚未有研究探討PAEs暴露與女性生殖荷爾蒙濃度變化的相關性，以及是否因體內PAEs濃度而影響體內生殖荷爾蒙濃度之平衡，進而增加女性成人罹患不孕症之機率？目前其機制尚不明確。因此，本研究擬探討女性不孕成人尿液中PAEs代謝物濃度對血清中生殖荷爾蒙濃度之影響。本研究自國立成功大學附設醫院不孕症門診中心招募79位女性成人作為研究對象，經簽署同意書後，收取其尿液、血液檢體及PAEs暴露評估問卷，並分析血清中生殖荷爾蒙濃度、尿液中PAEs代謝物濃度及進行PAEs暴露評估問卷解析，整合所有數據後探討女性成人日常生活中PAEs暴露來源、內在暴露劑量及其對生殖荷爾蒙濃度之影響，進而評估PAEs生殖荷爾蒙之可能影響機轉。研究結果顯示受試者尿液中PAEs代謝物之幾何平均濃度(範圍)依序為MEP：17.38 (1.51-740.49) µg/g-cre, MnBP：11.62 (1.84-145.83) µg/g-cre, MECPP：10.48 (1.85-293.99) µg/g-cre, MiBP：7.60 (1.39-102.86) µg/g-cre, MEOHP：7.44 (1.08-128.60) µg/g-cre, MEHHP：5.79 (0.28-211.35) µg/g-cre, MEHP：4.33 (1.08-54.68) µg/g-cre, MMP：3.31 (0.34-14.04) µg/g-cre, MBzP：1.23 (0.21-23.01) µg/g-cre, MIDP：0.42 (0.08-1.26) µg/g-cre及MINP：0.27 (0.04-1.26) µg/g-cre，並以MEP幾何平均濃度為最高。研究顯示MEHP具較高動物毒性，因此本研究以尿液中MEHP濃度之高低將受試者分成高、低濃度組並比較其尿液中PAEs代謝物濃度之差異，結果顯示高濃度組尿液中MEHP、MEOHP、MBzP、MINP、MIDP、∑DEHP及MEHP%皆顯著高於低濃度組。比較高低濃度組血清中生殖荷爾蒙濃度之差異，亦發現高濃度組體內游離睪固酮(free testosterone, fT)濃度顯著低於低濃度組。進一步探討PAEs與生殖荷爾蒙濃度之關係，結果顯示血清中抑制素B(inhinbin B)與MEOHP、MBzP及MEHP%呈顯著正相關性； P4濃度與MEHP%呈顯著負相關性；與MEHHP及MECPP則呈顯著正相關；泌乳激素(prolactin, PRL)與MEOHP、MECPP與∑DEHP呈顯著正相關；硫酸脫氫表雄酮 (dehydroepiandrosterone sulfate, DHEA-S)與MEHP%呈顯著負相關性；性腺荷爾蒙結合蛋白(sex hormone-binding globulin, SHBG)與MEP呈顯著正相關；fT則與MEHHP及MECPP呈統計上顯著正相關，但與MBzP及MEHP%呈顯著負相關性；而E2與睪固酮(testosterone, TT)之比值(E2/TT)則發現與MiBP呈顯著正相關； E2與雌酮(estrone, E1)之比值(E2/E1)與MEHHP及MECPP呈顯著正相關，但與MEHP%呈顯著負相關性。而在游離雌性素指標(free estrogen index, FEI)則發現與MBzP及MEHP%呈顯著負相關性。經校正年齡、BMI及抽血時間等因子後，以複迴歸分析後發現多數PAEs代謝物濃度與E2/TT之比值呈負相關性，雖未達統計上顯著意義，但仍可發現暴露於PAEs可能會降低Arom之活性，進而使體內E2濃度將低，進而干擾女性體內生殖荷爾蒙濃度之平衡。由於各種PAEs對雌激素受體結合效應皆不相同，進一步估算其對雌激素受體(ER-α)影響之總和效應濃度。結果顯示高濃度組之ER-α結合效應劑量顯著高於低濃度組(1.22±0.93 vs. 0.63±0.63, p<0.001)。而比較其PAEs日暴露劑量及健康危害指標亦發現，高濃度組於日暴露劑量及健康危害指標上皆顯著高於低濃度組(p<0.05)，表示高濃度組受PAEs暴露情形較高，且可能比低濃度組產生較高之健康風險。綜合上述結果，本研究發現PAEs暴露與女性體內生殖荷爾蒙濃度之干擾具相關性，並可能影響其生殖功能及生理週期之表現，但由於其影響機制尚不明確，因此未來仍需進行研究以釐清PAEs暴露對女性生殖荷爾蒙調控之影響機制。

The prevalence of infertility was increased in recent years, and the female infertility accounted for 30%. The risk factors of female infertility were numerous and complex, including physical (age, genes, BMI etc.), psychological (stress, emotion etc.), disease (hormonal imbalance, ovulated disorder, inflammatory disease, adenomyosis, endometriosis, polycystic ovarian syndrome etc.), life style (smoking, drugs, alcohol etc.) and environmental pollutants or endocrine disruptors. Phthalate esters (PAEs) were known endocrine disrupting compounds (EDCs), and were widely used in PVC products, plastic food containers, personal care products, cosmetics and commercial products. Numerous evidences indicated that phthalates exposures cause adverse reproductive effects including increased serum estradiol, reduced progesterone levels and aromatase activity, prolonged estrous cycles, no ovulations, and some reproductive disease, and then increased the probability of infertility. However, little is known about the active mechanism and impact of PAEs on female infertility. The aim of this study was to investigate the relationship between the urinary PAE metabolites and serum reproductive hormone levels in women who seeking treatment from infertile clinics. 79 participants were recruited from Obstetrics and Gynecology clinics, National Cheng Kung University Hospital. After signing the informed consent and obstetrician diagnosis, urine and blood samples were collected and stored with phthalate free containers. Questionnaire interview were conducted for demographic characteristics and exposure profile of phthalates. Levels of PAE metabolites in urine were analyzed by HPLC/MS/MS and serum reproductive hormones were measured for all participants. All the data were integrated to explore the phthalate exposure profile, PAE metabolites, reproductive hormone levels and active mechanism of PAEs to disrupt reproductive hormones in women. The average (range) of urinary PAE metabolite levels were MEP：17.38 (1.51-740.49) µg/g-cre, MnBP：11.62 (1.84-145.83) µg/g-cre, MECPP：10.48 (1.85-293.99) µg/g-cre, MiBP：7.60 (1.39-102.86) µg/g-cre, MEOHP：7.44 (1.08-128.60) µg/g-cre, MEHHP：5.79 (0.28-211.35) µg/g-cre, MEHP：4.33 (1.08-54.68) µg/g-cre, MMP：3.31 (0.34-14.04) µg/g-cre, MBzP：1.23 (0.21-23.01) µg/g-cre, MIDP：0.42 (0.08-1.26) µg/g-cre and MINP：0.27 (0.04-1.26) µg/g-cre. MEP is the highest of the eleven measured PAEs metabolites. All subjects were classified to high and low concentration group according to the urinary MEHP concentration. The levels of MEHP, MEOHP, MBzP, MINP, MIDP, ∑DEHP and MEHP% in high concentration group were significantly higher than low concentration group. The serum free testosterone (fT) in high concentration group was significantly lower than low concentration group. The significantly positive correlation were found between inhibin B with MEOHP, MBzP, MEHP%; P4 with MEHHP, MECPP; SHBG with MEP; PRL with MECPP, ∑DEHP; fT with MEHHP, MECPP; E2/TT with MiBP; E2/E1 with MEHHP, MECPP. In addition, the significantly negative correlation were found between inhibin B with MnBP, MEHHP, MBzP; P4 with MEHP%; DHEA-S with MEHP%; fT with MBzP, MEHP%; E2/E1 with MEHP% in present study. After adjusting for age, BMI and phlebotomized day, the negative trend between PAE metabolites and some reproductive hormones were found with no significance. The internal estrogenic activities of PAEs in high concentration group were significantly higher than the low concentration group. Finally, the daily intake of PAEs and the hazard index of PAEs were assessed. The daily intake and hazard index of PAEs in high concentration group were significantly higher than those of low concentration group. In conclusions, we found that exposure to PAEs may disrupt the balance of reproductive hormone levels in women, and then affect the reproductive function and menes. However, the actives mechanism of the PAEs exposure on reproductive hormone levels is still unclear in present study. Further researches are needed to collect more data to confirm our findings.

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