Nakamura Akiko, Tanaka Yuji, Amano Tsukuru, Takebayashi Akie, Takahashi Akimasa, Hanada Tetsuro, Tsuji Shunichiro, Murakami Takashi
Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Mol Hum Reprod. 2024 Dec 11;30(12). doi: 10.1093/molehr/gaae041.
Mammalian target of rapamycin (mTOR) inhibitors have been used clinically as anticancer and immunosuppressive agents for over 20 years, demonstrating their safety after long-term administration. These inhibitors exhibit various effects, including inhibition of cell proliferation, interaction with the oestrogen and progesterone pathways, immunosuppression, regulation of angiogenesis, and control of autophagy. We evaluated the potential of mTOR inhibitors as therapeutic agents for endometriosis, examined the secondary benefits related to reproductive function, and assessed how their side effects can be managed. We conducted a thorough review of publications on the role of the mTOR pathway and the effectiveness of mTOR inhibitors in endometriosis patients. These results indicate that the mTOR pathway is activated in endometriosis. Additionally, mTOR inhibitors have shown efficacy as monotherapies for endometriosis. They may alleviate resistance to hormonal therapy in endometriosis, suggesting a potential synergistic effect when used in combination with hormonal therapy. The potential reproductive benefits of mTOR inhibitors include decreased miscarriage rates, improved implantation, and prevention of age-related follicular loss and ovarian hyperstimulation syndrome. Activation of the mTOR pathway has also been implicated in the malignant transformation of endometriosis. Preclinical studies suggest that the dosage of mTOR inhibitors needed for treating endometriosis may be lower than that required for anticancer or immunosuppressive therapy, potentially reducing dosage-dependent side effects. In conclusion, while mTOR inhibitors, which allow for pregnancy during oral administration, show potential for clinical use in all stages of endometriosis, current evidence is limited to preclinical studies, and further research is needed to confirm clinical effectiveness.
雷帕霉素哺乳动物靶点（mTOR）抑制剂作为抗癌和免疫抑制剂已临床应用20多年，长期给药后证明了其安全性。这些抑制剂具有多种作用，包括抑制细胞增殖、与雌激素和孕激素途径相互作用、免疫抑制、调节血管生成以及控制自噬。我们评估了mTOR抑制剂作为子宫内膜异位症治疗药物的潜力，研究了与生殖功能相关的次要益处，并评估了如何管理其副作用。我们对关于mTOR途径的作用以及mTOR抑制剂在子宫内膜异位症患者中的有效性的出版物进行了全面综述。这些结果表明mTOR途径在子宫内膜异位症中被激活。此外，mTOR抑制剂已显示出作为子宫内膜异位症单一疗法的疗效。它们可能减轻子宫内膜异位症对激素治疗的耐药性，提示与激素治疗联合使用时可能存在协同效应。mTOR抑制剂潜在的生殖益处包括降低流产率、改善着床以及预防与年龄相关的卵泡丢失和卵巢过度刺激综合征。mTOR途径的激活也与子宫内膜异位症的恶性转化有关。临床前研究表明，治疗子宫内膜异位症所需的mTOR抑制剂剂量可能低于抗癌或免疫抑制治疗所需的剂量，有可能减少剂量依赖性副作用。总之，虽然口服给药期间允许怀孕的mTOR抑制剂在子宫内膜异位症的所有阶段都显示出临床应用潜力，但目前的证据仅限于临床前研究，需要进一步研究以确认临床有效性。
