良性攝護腺腫大 (Benign prostatic enlargement, BPE)、良性攝護腺增生 (Benign prostatic hyperplasia, BPH) 及攝護腺癌 (Prostate cancer, PCa)是近年來老年男性最常見的疾病,並逐漸受到重視。過去研究指出影響攝護腺疾病的因子眾多,其中荷爾蒙失調 及發炎所導致的氧化壓力上升為較明確之危險因子,但荷爾蒙及氧化壓力的調控容易受到環境因子的干擾。鄰苯二甲酸酯 (Phthalates, PAEs) 為目前討論較為廣泛之環境因子, 常添加於塑膠材料中作為增塑劑、油漆塗料的溶劑或個人衛生用品的定香劑等。因製程 中多屬混合物狀態,故 PAEs 極易於製造及使用過程中釋放至環境及食物鏈,人體可經由食入、吸入以及皮膚接觸暴露到 PAEs。文獻顯示 PAEs 因具有弱雌激素及抑制雄激 素的特性,可影響雄性生殖及造成內分泌系統失衡。此外,動物研究指出在暴露 PAEs 後, 個體之抗氧化能力顯著低於對照組;流行病學研究亦觀察到氧化壓力與 PAEs 之暴露可能呈現正相關。由以上結果可知,暴露 PAEs 可同時影響個體生殖荷爾蒙及氧化壓力之平衡,是否因此造成攝護腺細胞異常增生,最終導致攝護腺肥大亟需研究之。
本研究自成大醫院泌尿科門診招募 246 位經醫師診斷為攝護腺疾病患者,於初步訪視時排除其他環境因子之職業暴露、基因遺傳疾病及受荷爾蒙藥物治療之患者,簽署人體試驗同意書後,進行問卷調查、尿液及血液樣本採集,尿液樣本量測 11 種 PAEs 代 謝物 (MMP、MEP、MiBP、MnBP、MBzP、MEHP、MEHHP、MEOPP、MECPP、MiNP 及 MiDP)與 8-OHdG 濃度;血液樣本則檢測血清中生殖荷爾蒙(LH、FSH、Inhibin B、 SHBG、E1、E2、TT、FT、DHT、DHEA、DHEA-S及AD)、氧化壓力指標 (MDA及iNOS) 及 PSA 濃度。此外,亦收集受試者臨床診斷及檢查結果,包括攝護腺特異性抗原 (PSA)、尿流速檢測 (Voided volume、Maximum flow、Mean flow)、直腸超音波檢查 (TRUS)、直腸觸診 (DRE)、國際攝護腺症狀評分 (IPSS)等。進一步排除攝護腺癌及資料缺漏的 個案後,共納入 202 位 BPH 及 BPE 患者進行後續統計分析。將 BPH 及 BPE 患者 依攝護腺體積以三分位分成輕、中、重度攝護腺肥大患者三組。生殖荷爾蒙濃度分析結果指出,E2、the E2: E1 ratio 及 the E2: TT ratio 於三組間具統計上顯著差異 (P-value < 0.05);FSH、E2、the E2: E1 ratio 及 the E2: TT ratio 於三組間具統計上顯著趨勢性 (P-trend < 0.05)。三組間氧化壓力指標分析結果指出,經 creatinine 校正後 8-OHdG 及 MDA 於三組間具統計上顯著差異 (P-value < 0.05);MDA 及 iNOS 於三組間具統計上顯著趨勢性增加(P-trend < 0.05)。而 PAEs 代謝物濃度於三組間,經 creatinine 校正後之 MEHP、MECPP 及 ∑DEHP 於三組間具統計上顯著差異 (P-value < 0.05);MiBP、 MnBP、MEHP、MEHHP、MEOHP、MECPP、∑DEHP、∑DBP 及 MEHP% 於三組間具統計上顯著趨勢性增加 (P-trend < 0.05)。經校正影響因子 (年齡、BMI、抽菸、喝酒、 採血時間、採血季節)後之複迴歸結果發現血清中 E2、the E2: E1 ratio、the E2: TT ratio 與攝護腺體積呈顯著正相關 (P-value < 0.05);MDA及 iNOS 與攝護腺體積亦呈顯著正相關 (P-value < 0.05);尿液中 MiBP、MnBP、MEHP、MEHHP、MEOPP、MECPP、MEHP % 均與 8-OHdG 呈顯著正相關 (P-value < 0.05)。校正干擾因子 (年齡、BMI、抽菸、喝酒、高血壓)後 E1、E2、DHT 及 the E2: TT ratio 與 PSA 及攝護腺體積具顯著正相關 (P-value < 0.05);尿液中 8-OHdG 與 PSA 及攝護腺體積具顯著正相關 (P-value < 0.01),DEHP 代謝物皆與血中 E2、DHT、the E2: TT ratio 及尿中 8-OHdG 皆呈顯著正相關 (P-value < 0.05);MBzP、MEOPP、MECPP、MiNP、MiDP 及 ΣDEHP 與血中 iNOS 呈顯著正相關 (P-value < 0.05);而因 DEHP 及 DBP 代謝物與 PSA 及攝護腺體積成 顯著正相關 (P-value < 0.05),因此推測 PAEs 可能促使細胞中雌激素受體α (ERα) 的活性增加,導致攝護腺產生異常增殖等現象。進一步評估本研究族群其 PAEs 暴露與雌激素受體及雄激素受體之結合及拮抗效應指標,結果指出重度攝護腺肥大患者 ERα binding effect 及 AR antiandrogenic effect 有顯著較高的趨勢 (P-value < 0.05),且經校正年齡及 BMI 後之單變量分析結果指出,ERα binding effect 及 AR antiandrogenic effect 大於 75 百分位數時,攝護腺體積有顯著增加之趨勢 (P-value < 0.01),顯示與攝護腺增生的誘發具有相關性。由以上的結果可進一步推測 PAEs 暴露在攝護腺疾病發展上所扮演之角色可能為促進攝護腺疾病之危險因子包括荷爾蒙失衡及氧化壓力上升等效應,因而增加攝護腺肥大之罹病風險,其詳細機制尚需深入之研究探討。

The objectives of present study are to asses the relationships among oxidative stress, steroid hormones and prostatic disease, then to explore the active mechanism among phthalate exposure, steroid hormone and prostatic disease in adult man. 202 men with prostate disease were recruited from urology clinics in south Taiwan, and all were categorized based on the urologist’s diagnoses. Clinical examination, oxidative stress level, steroid hormones and urinary phthalate metabolites were measured. All subjects were divided into three subgroups according to prostate volume. The subjects with large-sized prostate group had a significant higher PSA levels and intravesical protruding ratio (P-value < 0.001). The concentration of serum E2, the E2: E1 ratio and the E2: TT ratio as well as the level of urinary 8-OHdG and serum MDA showed significant higher in the large-sized prostate group (P-value < 0.05). Urinary MiBP, MnBP, the DEHP metabolites and MEHP% were also significant higher in the large-sized prostate group. In multiple regression models controlled for potential confounders, serum E1, E2, DHT and the E2: TT ratio were significantly postively associated with PSA and prostate volume (P-value < 0.05). Urinary 8-OHdG was positively associated with PSA and prostate volume (P-value < 0.01). Urinary DEHP metabolites were positively associated with serum E2, DHT, the E2: TT ratio and urinary 8-OHdG (P-value < 0.05). Urinary MBzP, MEOPP, MECPP, MiNP and MiDP were positively associated with serum iNOS (P-value < 0.05). Urinary DEHP and DiBP metabolites were positively associated with serum PSA and prostate volume (P-value < 0.05). The subjects with large-sized prostate volume had higher estrogen receptor binding effect and androgen receptor antagonistic effect than the other two groups (P-value < 0.05). Our results suggested that phthalate exposure might affect prostate size, imbalance of antioxidant capacity and estrogen level in eldly men with BPH and BPE, which might be an important hyperplasia-promoting role in prostatic disease progress.

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