Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage
Any abnormal activation of primordial follicles and subsequent depletion can irreversibly diminish the ovarian reserve, which is one of the major chemotherapy-induced adverse effects in young patients with cancer. Herein, we investigated the effects of rapamycin on the activation and development of...
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| Format: | Article |
| Language: | English |
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The Society for Reproduction and Development
2022-06-01
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| Series: | The Journal of Reproduction and Development |
| Subjects: | |
| Online Access: | https://www.jstage.jst.go.jp/article/jrd/68/4/68_2022-001/_pdf/-char/en |
| _version_ | 1797633918883594240 |
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| author | Xiuying CHEN Zhijing TANG Haiyun GUAN Hexia XIA Chao GU Yan XU Bin LI Wei ZHANG |
| author_facet | Xiuying CHEN Zhijing TANG Haiyun GUAN Hexia XIA Chao GU Yan XU Bin LI Wei ZHANG |
| author_sort | Xiuying CHEN |
| collection | DOAJ |
| description | Any abnormal activation of primordial follicles and subsequent depletion can irreversibly diminish the ovarian reserve, which is one of the major chemotherapy-induced adverse effects in young patients with cancer. Herein, we investigated the effects of rapamycin on the activation and development of ovarian follicles to evaluate its fertility-sparing therapeutic value in a cyclophosphamide (CTX)-treated mouse model. Based on ovarian histomorphological changes and follicle counting in 50 SPF female C57BL/6 mice, daily administration of 5 mg/kg rapamycin for 30 days was deemed an ideal dosage and duration for administration in subsequent experiments. Compared with the control group, rapamycin treatment inhibited the activation of quiescent primordial follicles, with no obvious side effects observed. Finally, 48 mice were randomly divided into four groups: control, rapamycin-treated, cyclophosphamide-treated, and rapamycin intervention. Body weight, ovarian histomorphological changes, number of primordial follicles, DDX4/MVH expression, apoptosis of follicular cells, and expression of apoptosis protease-activating factor (APAF)-1, cleaved caspase 3, and caspase 3 were monitored. Co-administration of rapamycin reduced primordial follicle loss and the development of follicular cell apoptosis, thereby rescuing the ovarian reserve after CTX treatment. On analyzing the mTOR signaling pathway, we observed that rapamycin significantly decreased CTX-mediated overactivation of mTOR and its downstream molecules. These findings suggest that rapamycin exhibits potential as an ovarian-protective agent that could maintain the ovarian primordial follicle pool and preserve fertility in young female patients with cancer undergoing chemotherapy. |
| first_indexed | 2024-03-11T12:01:23Z |
| format | Article |
| id | doaj.art-1c6a6181f86f4f5c8d37b4375e116dbe |
| institution | Directory Open Access Journal |
| issn | 0916-8818 1348-4400 |
| language | English |
| last_indexed | 2024-03-11T12:01:23Z |
| publishDate | 2022-06-01 |
| publisher | The Society for Reproduction and Development |
| record_format | Article |
| series | The Journal of Reproduction and Development |
| spelling | doaj.art-1c6a6181f86f4f5c8d37b4375e116dbe2023-11-08T05:05:55ZengThe Society for Reproduction and DevelopmentThe Journal of Reproduction and Development0916-88181348-44002022-06-0168428729410.1262/jrd.2022-001jrdRapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damageXiuying CHEN0Zhijing TANG1Haiyun GUAN2Hexia XIA3Chao GU4Yan XU5Bin LI6Wei ZHANG7Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaObstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, ChinaAny abnormal activation of primordial follicles and subsequent depletion can irreversibly diminish the ovarian reserve, which is one of the major chemotherapy-induced adverse effects in young patients with cancer. Herein, we investigated the effects of rapamycin on the activation and development of ovarian follicles to evaluate its fertility-sparing therapeutic value in a cyclophosphamide (CTX)-treated mouse model. Based on ovarian histomorphological changes and follicle counting in 50 SPF female C57BL/6 mice, daily administration of 5 mg/kg rapamycin for 30 days was deemed an ideal dosage and duration for administration in subsequent experiments. Compared with the control group, rapamycin treatment inhibited the activation of quiescent primordial follicles, with no obvious side effects observed. Finally, 48 mice were randomly divided into four groups: control, rapamycin-treated, cyclophosphamide-treated, and rapamycin intervention. Body weight, ovarian histomorphological changes, number of primordial follicles, DDX4/MVH expression, apoptosis of follicular cells, and expression of apoptosis protease-activating factor (APAF)-1, cleaved caspase 3, and caspase 3 were monitored. Co-administration of rapamycin reduced primordial follicle loss and the development of follicular cell apoptosis, thereby rescuing the ovarian reserve after CTX treatment. On analyzing the mTOR signaling pathway, we observed that rapamycin significantly decreased CTX-mediated overactivation of mTOR and its downstream molecules. These findings suggest that rapamycin exhibits potential as an ovarian-protective agent that could maintain the ovarian primordial follicle pool and preserve fertility in young female patients with cancer undergoing chemotherapy.https://www.jstage.jst.go.jp/article/jrd/68/4/68_2022-001/_pdf/-char/encyclophosphamideovarian reserveprimordial folliclerapamycin |
| spellingShingle | Xiuying CHEN Zhijing TANG Haiyun GUAN Hexia XIA Chao GU Yan XU Bin LI Wei ZHANG Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage The Journal of Reproduction and Development cyclophosphamide ovarian reserve primordial follicle rapamycin |
| title | Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage |
| title_full | Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage |
| title_fullStr | Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage |
| title_full_unstemmed | Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage |
| title_short | Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage |
| title_sort | rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide induced damage |
| topic | cyclophosphamide ovarian reserve primordial follicle rapamycin |
| url | https://www.jstage.jst.go.jp/article/jrd/68/4/68_2022-001/_pdf/-char/en |
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