https://scholars.lib.ntu.edu.tw/handle/123456789/579833
標題: | Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy | 作者: | CHU-CHUN HUANG Chou, Chia-Hung YU-SHIH YANG HONG-NERNG HO CHIA-TUNG SHUN Wen, Wen-Fen SHEE-UAN CHEN MEI-JOU CHEN |
關鍵字: | AMP-activated protein kinases; anti-Mullerian hormone; apoptosis; cyclophosphamide; fertility preservation; mTOR protein; metformin; p21; p53 | 公開日期: | 2021 | 卷: | 27 | 期: | 1 | 來源出版物: | Molecular human reproduction | 摘要: | Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/579833 | ISSN: | 1460-2407 | DOI: | 10.1093/molehr/gaaa084 | SDG/關鍵字: | cyclophosphamide; everolimus; mammalian target of rapamycin; metformin; Muellerian inhibiting factor; protein p21; protein p53; rapamycin; alkylating agent; antidiabetic agent; cyclophosphamide; everolimus; hydroxymethylglutaryl coenzyme A reductase kinase; metformin; mTOR protein, mouse; protective agent; protein p53; rapamycin; target of rapamycin kinase; Trp53 protein, mouse; animal cell; animal experiment; animal tissue; antiapoptotic activity; Article; C57BL 6 mouse; controlled study; female; female fertility; fertility preservation; granulosa cell; histopathology; immunohistochemistry; in vitro study; mouse; nonhuman; ovarian reserve; ovary function; protein expression; protein function; randomized controlled trial; treatment duration; animal; apoptosis; C57BL mouse; cell culture; drug effect; fertility; metabolism; ovary follicle; AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cells, Cultured; Cyclophosphamide; Everolimus; Female; Fertility; Hypoglycemic Agents; Metformin; Mice; Mice, Inbred C57BL; Ovarian Follicle; Protective Agents; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53 |
顯示於: | 醫學系 |
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