Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms
Abstract
:Simple Summary
Abstract
1. Introduction
2. Gynotoxic Properties of Anticancer Drugs
2.1. Alkylating Drugs
2.1.1. Non-Human Studies
2.1.2. Human Tissue Studies
2.1.3. Effects on Cancer Patients
2.2. Antimetabolites
2.2.1. Non-Human Studies
2.2.2. Human Tissue Studies
2.2.3. Effects on Cancer Patients
2.3. Topoisomerase Inhibitors
2.3.1. Non-Human Studies
2.3.2. Human Tissue Studies
2.3.3. Effects on Cancer Patients
2.4. Mitosis Inhibitors
2.4.1. Non-Human Studies
2.4.2. Effects on Cancer Patients
3. Potential Ovarian-Protective Mechanisms
3.1. Hormones
3.1.1. Anti-Müllerian Hormone
3.1.2. Ghrelin
3.1.3. Luteinizing Hormone (Lutropin)
3.1.4. Melatonin
3.2. Modulating Factors
3.2.1. Sphingolipids
3.2.2. MicroRNA
3.3. Natural Compounds
3.3.1. Quercetin
3.3.2. Rapamycin
3.3.3. Resveratrol
3.4. Synthetic Compounds
3.4.1. Bortezomib
3.4.2. Dexrazoxane
3.4.3. Gonadoliberin Analogs
3.4.4. Imatinib
3.4.5. Metformin
3.4.6. Tamoxifen
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Model | Dose | Treatment Duration | Gynotoxic Effects | Ref. |
---|---|---|---|---|---|
Cyclophosphamide | 3-week-old ICR mice | 100 mg/kg (i.p.) | Single dose | Decrease in the number of follicles, impaired hemostasis of oocyte quality, reduced ability to develop an embryo | [35] |
3-week-old B6C3F1 mice | 120 mg/kg (i.p.) | Single dose | Deterioration of oocytes, reduction and fibrosis of the ovaries | [36] | |
Sprague–Dawley rats | 20 mg/kg (i.p.) | Once per day for 10 days | Apoptosis of ovarian cells (apoptosis index [AI] = 13.6%) | [37] | |
Pregnant Charles Foster rats (average age: 120 days) | 2 mg/kg (i.p.) | Single dose | Prevention of folliculogenesis in offspring resulting in anovulation and infertility | [38] | |
Pregnant 129 or L1 mice | 7.5 mg/kg (i.p.) | 10.5 and 11.5 days of pregnancy | Loss of PMFs and increased follicle growth activation in offspring | [39] | |
Swiss albino mice | 200 mg/kg (i.p.) | Single dose on the 14th, 21st, or 28th day after birth | Long-term effects on oocyte developmental competence in early but not adult life | [40] | |
4–8-week-old CD-1 mice | 100 mg/kg (i.p.) | Single dose | Possible negative effects on the fertility of subsequent generations | [41] | |
6–8-week-old C57BL/6 mice | 70 mg/kg (i.p.) | Single dose | POF induction | [42] | |
C57BL/6 mice | 300 mg/kg (i.p.) | Single dose | PMF depletion | [43] | |
8-week-old C57BL/6 mice | 100 mg/kg (i.p.) | 6 doses over 2 weeks | Loss of follicles, irreversible deterioration of oocytes | [44] | |
Experimental xenografts of human ovaries | 75 mg/kg (i.v.) | Single dose | Apoptotic follicle death | [45] | |
Experimental xenografts of human ovaries | 200 mg/kg (i.p.) | Single dose | Reduction in PMFs | [46] | |
Cisplatin | 6-week-old CD-1 mice | 2 mg/kg (i.p.) | Once per day for 15 days | Reduction in the total number of follicles in the ovaries, especially PMFs | [47] |
8-week-old C57BL/6 mice | 2.5 mg/kg (i.p.) | Once per day for 5 days → one week break → once per day for 5 days | Increased number of atretic follicles, decreased number of antral follicles | [48] | |
PN10 and PN50 of C57BL/6J mice | 2 or 4 mg/kg (i.p.) | Single dose | Mitochondrial dysfunction in oocytes | [49] | |
C57BL/6 mice | 5 mg/kg (i.p.) | Single dose | PMF depletion | [43] | |
Mature Sprague-Dawley mice | 0.5, 1, 1.5, 2, 3 or 4 mg/kg (i.p.) | Once a day for 10 days | Disorders of the estrous cycle, lack of mature follicles | [50] | |
5–6-week-old rats | 5 mg/kg (i.p.) | Single dose | Reduction in PMFs | [51] | |
5-Fluorouracil | 6–8-week-old C57BL/6 mice | 150 mg/kg (i.p.) | Single dose | Mild ovotoxic effects | [52] |
26–30-day-old C57BL/6J mice | 450 mg/kg (i.p.) | Single dose | Decreased survival of preantral follicles | [53] | |
8–9-week-old C57BL/6J mice | 125 mg/kg (i.p.) | 3-fold injection | Progressive atresia of growing follicles, reduction in ovarian volume, no change in number of PMFs | [54] | |
8-week-old ICR mice | 50 mg/kg (i.p.) | Once per day for 4 days | Inhibition of oocyte maturation and early embryonic development | [55] | |
Doxorubicin | 5-day, 21-day or 8-week CD-1 mice | 10 mg/kg (i.p.) | Single dose | Ovarian reserve depletion, PMFs atresia, excessive PMF activation | [56] |
7–8-week-old ICR mice | 10 mg/kg (i.v.) | Single dose | Effects on oocytes | [57] | |
4-week-old or 7–8-week-old ICR mice | 7.5 or 10 mg/kg (i.p.) | Single dose | Reduction in the size and weight of the ovary, reduction in ovulation, reduction in the population of PMFs and secondary follicles | [58] | |
6-week-old or 10–22-week-old C57BL/6 or 129/Sv mice | 10 mg/kg (i.p.) | Single dose | Impaired expression of collagen IV, less differentiated luteal cells (smaller cytoplasm, reduced expression of StAR) | [59] | |
Sprague-Dawley rats | 15 mg/kg (cumulative dose; i.p.) | 7 injections | Decrease in the number of follicles, decrease in the volume of the ovaries and the uterus | [60] | |
Irinotecan | 2-month-old ICR mice | 100 mg/kg (i.p.) | Single dose | Mild toxicity to the ovaries | [61] |
8-week-old MCH mice | 20, 100 or 500 µg/mouse (i.p.) | Single dose | Increased apoptotic processes in ovarian follicles | [62] | |
Paclitaxel | 6–8-week-old Wistar rats | 5 mg/kg (i.p.) | 5 doses at 3-day intervals | Reduction in the number of antral follicles | [63] |
7-week-old ICR mice | 30 mg/kg (i.p.) | Single dose | Destruction of antral follicles on day 1 after chemotherapy | [64] | |
2-month-old Wistar rats | 4.6 mg/kg (MTD, i.v.) | Single dose | Destruction of PMFs and follicles bilaterally and multilaterally, decreased ovarian reserve, increased fetal mortality | [65] | |
5–6-week-old rats | 7.5 mg/kg (i.p.) | Single dose | Reduction in the number of PMFs | [51] | |
Docetaxel | 8-week-old CD-1 mice | 5 or 10 mg/kg (i.p.) | 2 doses (1st and 14th day) | Reduction in ovarian weight, number of secondary follicles, and total number of follicles | [66] |
6–8 week B6 mice | 30 mg/kg (i.p.) | Single dose | Reduction in total number of follicles, destruction of ovarian structure | [67] |
Drug | Model | Dose | Treatment Duration | Gynotoxic Effects | Ref. |
---|---|---|---|---|---|
Cyclophosphamide | Metaphase II mouse oocytes | 10.25 µM | 45-min incubation | Mitochondrial membrane damage in oocytes | [68] |
Human ovary cortex sections taken from premenopausal cancer patients | 0.5–500 µg/mL | 2–48-h incubation | Damage to granular cell nuclei, changes in basement membrane (depending on cyclophosphamide concentration) | [34] | |
Cisplatin | Follicles from ovaries of 13-day-old C57BL/6 mice | 10−2, 10−3, or 10−4 µM | 13-day incubation | Decrease in survival and growth of follicles | [69] |
Ovaries of newborn mice | 0.1, 0.5, 1, or 5 µg/mL | 24-h incubation | Ovarian damage, loss of follicles | [70] | |
Ovaries of young CD-1 mice | 0.5, 1, or 5 μg/mL | 24-h incubation | Reduction in number and condition of follicles, damage to PMFs and granulosa cells | [71] | |
Human granulosa cells (COV434, HGrC1, HLGC) | 20, 40, or 100 µg/mL | 140-h incubation | Induction of apoptosis in mitotic non-luteinized and non-mitotic luteinized granulosa cells | [72] | |
Biopsies of human ovaries | 5 or 10 μg/mL | 6-day incubation | Deterioration of follicle health, increased cell apoptosis, reduced proliferation | [73] | |
5-Fluorouracil | Isolated preantral mouse ovarian follicles | 0.3, 1, 3, 10, or 30 mM | Maximum 12-day incubation | Negative effects on follicle growth, estradiol production, and oocyte maturation | [74] |
Doxorubicin | Granulosa cells from ovaries of 21–23-day-old ICR mice | 0.4, 0.8, or 1.6 μg/mL | 24-h incubation | Induced cell apoptosis, increase in ROS levels, decrease in mitochondrial membrane potential | [75] |
Follicles from ovaries of 7–8-week-old ICR mice | 10 µM | 2-h incubation | Effects on oocytes | [57] | |
Multilayered secondary ovarian follicles of CD-1 mice | 2, 20, 100, or 200 nM | 24-h incubation | Dose-dependent toxicity for follicle growth and survival, as well as 17β-estradiol secretion | [76] | |
Multilayered secondary ovarian follicles of rats | 200 nM | Single dose | Ca2+ release from the endoplasmic reticulum through activation of Src kinase | [77] | |
Human primary granulosa cells | 0.01, 0.05, 0.1, 0.2, or 0.5 μg/mL | 48-h incubation | Induction of cytotoxicity and miR-132 expression in granulosa cells | [11] | |
Biopsies of human ovaries | 1 or 2 μg/mL | 6-day incubation | Deterioration of follicle health, increased cell apoptosis, reduced proliferation | [73] | |
Paclitaxel | Early secondary follicles taken from BDF1 mice | 2.5 × 10−4, 2.5 × 10−3, or 2.5 × 10−2 µM | 12-day incubation | Reduced growth of preantral or more mature follicles (depending on paclitaxel concentration) | [78] |
Follicles from ovaries of 13-day-old C57BL/6 mice | 10−8–10−10 M | 13-day incubation | Reduced survival and growth of ovarian follicles | [69] | |
Docetaxel | Neonatal ovaries taken from C57Bl/6J mice | 0.1, 1, or 10 µM | 24-h incubation | Negative effects on early growing follicles, reduction of PMFs, induction of somatic cell apoptosis | [79] |
Protective Factor | Drug | Model | Protective Mechanisms | Ref. |
---|---|---|---|---|
Anti-Müllerian hormone | Cyclophosphamide | 6-week-old Swiss mice | Protection against loss of PMFs | [168] |
Cyclophosphamide | 6-week-old mice | Reducing follicle activation, protecting follicle reserve, improving long-term fertility and reproductive outcomes | [169] | |
Cyclophosphamide | 8-week-old C57/B6 mice | Protection of ovarian reserve | [170] | |
Cyclophosphamide, carboplatin, doxorubicin | 6–7-week-old nu/nu mice | Protection of ovarian reserve by blocking activation of PMFs | [6] | |
Cyclophosphamide | Heterotransplantation of human ovarian tissue from a 12-year-old female donor | Protection of ovarian reserve | [170] | |
Ghrelin | Cisplatin | Wistar rats | Preservation of the number of PMFs and primary follicles | [171] |
Cisplatin | 5-week-old ICR mice | Synergistic protective effects of ghrelin and melatonin against follicular damage and ovarian failure | [172] | |
Luteinizing hormone (lutropin) | Cisplatin | 4- or 5-week-old mice | Protecting PMFs reserve, preserving fertility at reproductive age | [173] |
Melatonin | Cisplatin | 7-week-old C57BL/6J mice | Mitigating ovarian damage | [174] |
Cisplatin | 8-week-old C57BL/6 mice | Reducing toxicity to ovaries, preserving long-term fertility | [175] | |
Cisplatin | 3-month-old Wistar rats | Modulating ovarian dysfunction, preserving fertility | [176] | |
Cyclophosphamide | 3- or 6-week-old ICR mice | Prevention of ovarian granulosa cell loss | [177] | |
Cyclophosphamide | 8-week-old Swiss mice | Prevention of PMFs loss, reduction of cell apoptosis and oxidative damage in the ovary | [178] | |
Cyclophosphamide | Sprague-Dawley rats | Protecting ovaries from damage by activating the Hippo pathway | [179] | |
Sphingolipids (C1P, S1P) | Cyclophosphamide | 6–8-week-old mice | Reduction of ovarian damage | [102] |
Busulfan | 8-week-old FVB/NJNarl mice | Protection of PMFs, partial preservation of ovarian function | [180] | |
Dacarbazine | 6–8-week-old BALB/c mice | Preserving the number of PMFs | [181] | |
Cyclophosphamide, doxorubicin | Heterotransplantation of human ovarian tissue fragments | Protection of follicles from chemotherapeutic-induced apoptosis | [45] | |
Cyclophosphamide | Human fetal ovarian xenografts | Prevention of follicle apoptosis, maintenance of the PMF population in transplants | [122] | |
MicroRNA | Cyclophosphamide, busulfan | 6-week-old ICR mice | Prevention of follicular atresia | [182] |
Quercetin | Cyclophosphamide | 5–6-week-old C57BL/6 mice | Reducing follicle loss and apoptosis of growing follicles | [183] |
Cyclophosphamide | 6–8-week-old C57BL/6 mice | Protection of ovarian reserve by reversing dysfunction and activating mitochondrial biogenesis, regulating pyroptosis | [184] | |
Cyclophosphamide | 12-week-old Sprague-Dawley rats | Restoring ovarian function, inhibiting oxidative stress | [185] | |
Cyclophosphamide | 10–12-week-old Wistar rats | Protection of early-stage and total follicles | [186] | |
Cisplatin | Wistar rats | Ovarian protection through antioxidant, anti-inflammatory, and anti-apoptotic activities | [187] | |
Rapamycin (sirolimus) | Cyclophosphamide | 8-week-old BALB/c mice | Prevention of follicle activation | [109] |
Cyclophosphamide | 5-week-old C57BL/6 mice | Protection of PMFs, reduction of follicular cell apoptosis | [188] | |
Cisplatin | 4-week-old BALB/c mice | Protection of PMFs | [189] | |
Resveratrol | Cyclophosphamide, busulfan | 6-week-old C57BL/6 mice | Prevention of oogonial stem cell loss, reduction of ovarian cell apoptosis | [190] |
Cyclophosphamide | 7-week-old Sprague-Dawley rats | Prevention of PMF activation, reduction of chemotherapeutic-induced cell apoptosis | [191] | |
Doxorubicin | 6–8-week-old C57BL/6 mice | Increase in number of primary and antral follicles, decrease in number of atretic follicles, preservation of number of PMFs | [192] | |
Cisplatin | Sprague-Dawley rats | Protection of ovarian follicles, increasing levels of progesterone, folliculotropic hormone, and LH | [193] | |
Cisplatin | 3-week-old Sprague-Dawley rats | Mitigation of follicle loss and AMH lowering, inhibition of inflammatory mediator elevation | [194] | |
Cisplatin | 12–14-week-old Wistar rats | Mitigation of oxidative stress, inflammation, and cell apoptosis | [195] | |
Cisplatin | Wistar rats | Maintaining the number of PMFs and primary follicles | [196] | |
Bortezomib | Doxorubicin | 4-week-old CD-1 mice | Preventing accumulation of chemotherapeutics in ovaries, reducing DNA damage, prolonging fertility time | [197] |
Dexrazoxane | Doxorubicin | 4-week-old CD-1 mice | Protection of ovaries, improvement of reproductive health | [198] |
Goserelin | Cisplatin | 6-week-old BALB/c nu/nu mice | Shortening of estrous cycles, prolongation of estrous duration, protection of PMF and preantral follicles | [199] |
Triptorelin | Cyclophosphamide | 10-week-old mice | Increase in the number of PMFs, primary, secondary and antral follicles | [200] |
5-Fluorouracil | 50-day-old Sprague-Dawley rats | Protection against ovarian damage by modulating hormones, Bax, Bcl-2, and NF-κB | [201] | |
Imatinib | Cisplatin | 5-day CD1 mice | Oocyte protection | [119] |
Metformin | Cyclophosphamide | 6–8-week-old C57BL/6 mice | Preservation of ovarian function and fertility in mice | [202] |
Cyclophosphamide | 6–8-week-old C57BL/6 mice | Increase in number of antral follicles, AMH levels, and litter size | [203] | |
Cyclophosphamide together with busulfan | 6-week-old mice | Protection against ovarian damage, reducing oxidative damage and inflammation | [204] | |
Carboplatin | 3-month-old Wistar rats | Increased AMH levels and number of PMFs | [205] | |
Tamoxifen | Cyclophosphamide, doxorubicin | 4–6-week-old Sprague-Dawley rats | Reduction in follicle loss, improvement in reproductive function | [206] |
Protective Factor | Drug | Model | Protective Mechanisms | Ref. |
---|---|---|---|---|
Anti-Müllerian hormone | Cyclophosphamide | Human ovarian cortex biopsies | Reduction in follicle damage (by about half) and PI3K activation | [207] |
MicroRNA | Cyclophosphamide (active metabolite) | Mouse ovaries | Reduction of ovarian cell apoptosis | [208] |
Rapamycin (sirolimus) | Cisplatin | Rat ovaries | Inhibition of activation and protection of PMFs | [189] |
Resveratrol | Cyclophosphamide (active metabolite) | Primary cultures of rat granulosa cells | Reduction of oxidative stress levels | [209] |
Dexrazoxane | Doxorubicin | Mouse cell line KK-15 | Protection against DNA damage, increase in cell viability | [210] |
Doxorubicin | Marmoset ovarian tissue | Protection from DSBs, increase in number of granulosa cells in antral follicles | [211] | |
Imatinib | Cisplatin | Ovaries of newborn mice | Protection of ovarian follicles | [70] |
Cisplatin | In vitro culture and subrenal grafting of mouse ovaries | Oocyte protection | [212] | |
Cyclophosphamide | Preantral mouse follicles | Protection of AMH production, no effect on metaphase II oocyte retrieval | [213] | |
Tamoxifen | Cyclophosphamide | Ovaries of newborn rats | Counteracting follicle loss | [214] |
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Markowska, A.; Antoszczak, M.; Markowska, J.; Huczyński, A. Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms. Cancers 2024, 16, 2288. https://doi.org/10.3390/cancers16122288
Markowska A, Antoszczak M, Markowska J, Huczyński A. Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms. Cancers. 2024; 16(12):2288. https://doi.org/10.3390/cancers16122288
Chicago/Turabian StyleMarkowska, Anna, Michał Antoszczak, Janina Markowska, and Adam Huczyński. 2024. "Gynotoxic Effects of Chemotherapy and Potential Protective Mechanisms" Cancers 16, no. 12: 2288. https://doi.org/10.3390/cancers16122288