mTOR inhibitors as potential therapeutics for endometriosis: a narrative review

Abstract

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.

Keywords: adenomyosis; endometriosis; everolimus; fertility preservation; hormonal resistance; mTOR inhibitor; rapamycin; sirolimus.

Graphical Abstract

Potential role of mTOR inhibitors in endometriosis and fertility. mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; OHSS, ovarian hyperstimulation syndrome.

Figure 1.

The mTOR signalling pathway and the role of mTOR inhibitors in endometriosis. PTEN, phosphatase and tensin homologue; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTORC1, mammalian target of rapamycin Complex 1; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; P70S6K, 70-kDa ribosomal protein S6 kinase.

Figure 2.

Various effects of mTOR inhibitors on patients with endometriosis. mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; OHSS, ovarian hyperstimulation syndrome.

Figure 3.

Involvement of the mTOR pathway and gonadotropins in follicular development. Follicular development can be divided into gonadotropin-independent and -dependent phases. The early stages, which are critical for preserving primordial follicles, occur during the gonadotropin-independent phase, which is primarily regulated by the mTOR pathway and not by hormones. mTOR, mammalian target of rapamycin; LEP, low-dose oestrogen–progestin combinations.