Estetrol與Ethinylestradiol 對精神健康及外表特徵影響的比較研究：基於美國 TriNetX 資料庫的真實世界數據分析

研究背景：含炔雌醇（Ethinyl estradiol, EE）的複合型口服避孕藥（COCs）已廣泛應用數十年，但其精神和身體副作用（特別是情緒障礙和痤瘡）仍受關注。雌四醇（Estetrol, E4）作為2021年核准的新型雌激素成分，具有獨特的藥理特性，並可能帶來更佳的安全性和耐受性。然而，關於E4與EE為基礎的COCs在精神和皮膚方面真實世界對比資料有限。研究方法：本回顧性佇列研究利用TriNetX醫療健康研究網路，納入2021年4月至2024年12月期間服用E4或EE為基礎COCs的女性。使用傾向性評分匹配人口學、臨床及用藥變數，評估精神健康（情緒障礙、抑鬱發作、焦慮障礙、精神病性障礙、物質濫用、失眠）及身體外觀的影響（痤瘡、水腫），最長追蹤三年。並進行年齡與肥胖狀態分層分析及多種敏感性分析以驗證結果穩健性。研究結果：匹配後各納入1,073例E4和EE使用者。E4組抑鬱發作（風險比HR: 0.624，95%CI: 0.396–0.981）、焦慮障礙（HR: 0.712，95%CI: 0.519–0.978）及痤瘡（HR: 0.505，95%CI: 0.275–0.927）風險顯著低於EE組。精神病性障礙、失眠及水腫兩組無顯著差異。E4對精神結局的優勢在16–35歲及非肥胖女性中更為明顯。敏感性分析顯示結果未見明顯變化，與主要分析結果相符。結論：真實世界數據中，E4較EE顯著降低抑鬱發作、焦慮障礙及痤瘡風險，尤其適用於年輕及非肥胖女性。本研究結果支持以雌四醇（E4）為基礎的複方口服避孕藥（COCs）可作為關注精神副作用或有情緒／焦慮障礙病史女性的較安全選擇然而，仍需進行更長期的追蹤研究，以進一步驗證其相關性並釐清潛在機制。

Background: Ethinyl estradiol (EE)-containing combined oral contraceptives have been in widespread use for several decades, but concerns remain regarding their psychiatric and physical side effects, particularly mood disturbances and acne. Estetrol (E4), a novel estrogenic component approved in 2021, offers a distinct pharmacological profile with potentially improved safety and tolerability. However, real-world comparative data on the psychiatric and dermatological effects of E4- versus EE-based COCs are limited.Methods: This retrospective cohort study leveraged the TriNetX healthcare research network to compare women prescribed E4-based versus EE-based COCs between April 2021 and December 2024. After propensity score matching for demographic, clinical, and medication variables, psychiatric outcomes (mood disorders, depressive episodes, anxiety disorders, psychotic disorders, substance misuse, insomnia) and physical outcomes (acne, edema) were assessed over up to three years of follow-up. Subgroup analyses were performed by age and obesity status; sensitivity analyses tested robustness across matching variables, follow-up durations, and global datasets.Results: After matching, 1,073 users each of E4 and EE were included. E4 users showed a significantly lower risk of depressive episodes (HR: 0.624, 95% CI: 0.396–0.981), anxiety disorders (HR: 0.712, 95% CI: 0.519–0.978), and acne (HR: 0.505, 95% CI: 0.275–0.927) compared to EE users. No significant differences were observed for psychotic disorders, insomnia, or edema. The psychiatric benefit of E4 was most pronounced in women aged 16–35 years and those without obesity. Sensitivity analyses confirmed the consistency of results.Conclusion: The use of E4-based COCs is correlated with a lower risk of depressive episodes, anxiety disorders, and acne compared to EE-based COCs in real-world practice, especially among younger and non-obese women. These findings support considering E4-based COCs as a safer alternative for women concerned about psychiatric side effects or with a history of mood or anxiety disorders. Further longer-term studies will be essential to elucidate these relationships and clarify the underlying mechanisms.