5-Fluorouracil disrupts ovarian preantral follicles in young C57BL6J mice

Almeida, Juliana Zani de; Lima, Laritza Ferreira de; Vieira, Luis Alberto; Maside, Carolina; Ferreira, Anna Clara Accioly; Araújo, Valdevane Rocha; Duarte, A.B.G.; Raposo, Ramon da Silva; Báo, Sônia Nair; Campello, C.C.; Oliveira, Luiz F. S.; Costa, Thayse P. da; Abreu, José G.; Figueiredo, J.R.; Oriá, Reinaldo B.

doi:10.1007/s00280-020-04217-7

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…78,83 However, Almeida et al (2021) observed a significant depletion (p < .05) in the amount of morphologically regular primordial, transition and primary follicles in 5FU-treated ovaries in comparison with the control group. 85 Since there is a scientific gap between the aforementioned studies, it is recommended that further research be focused on evaluating the effect of 5FU on primordial and primary follicles. 26 Decrease testosterone level and reduction of stimulation of Sertoli cells 26,32 LH level and GnRh elevation 3,26 Sertoli cells abnormality 26 Decrease inhibin hormone, ABP and transferrin proteins level 4,5 FSH level and GnRh elevation 6,7,32 Female Elevated atresia in the growing follicles (secondary and antral) 8,9 Decrease estrogen level and aberrations of ovulation 10 FSH level and GnRh elevation with negative/positive effect on LH 10,26 ABP, Androgen-binding protein; FSH, Follicle-stimulating hormone; GnRh, Gonadotropin hormone-releasing hormone; HPG, Hypothalamic-pituitarygonadal; LH, Luteinizing hormone.…”

Section: Effect Of 5fu On Ovarian Function and Secondary Folliclesmentioning

confidence: 99%

5-Fluorouracil-induced toxicity in both male and female reproductive systems: A narrative review

Pirzaman,

Ebrahimi,

Doostmohamadian

et al. 2023

Hum Exp Toxicol

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The chemotherapeutic drug 5-fluorouracil (5FU) is frequently used to treat a wide range of solid malignant tumors, such as colorectal, pancreatic, gastric, breast, and head and neck cancers. Its antitumoral effects are achieved by interfering with the synthesis of RNA and DNA and by inhibiting thymidylate synthase in both malignant and non-malignant cells. Therefore, it can be responsible for severe toxicities in crucial body organs, including heart, liver, kidney, and reproductive system. Given the fact that 5FU-induced reproductive toxicity may limit the clinical application of this drug, in this study, we aimed to discuss the main locations and mechanisms of the 5FU-induced reproductive toxicity. Initially, we discussed the impact of 5FU on the male reproductive system, which leads to damage of the seminiferous epithelial cells and the development of vacuoles in Sertoli cells. Although no noticeable changes occur at the histopathological level, there is a decrease in the weight of the prostate. Additionally, 5FU causes significant abnormalities in spermatogenesis, including germ cell shedding, spermatid halo formation, polynucleated giant cells, and decreased sperm count. Finally, in females, 5FU-induced reproductive toxicity is characterized by the presence of atretic secondary and antral follicles with reduced numbers of growing follicles, ovarian weight, and maturity impairment.

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Section: Effect Of 5fu On Ovarian Function and Secondary Folliclesmentioning

confidence: 99%

5-Fluorouracil-induced toxicity in both male and female reproductive systems: A narrative review

Pirzaman,

Ebrahimi,

Doostmohamadian

et al. 2023

Hum Exp Toxicol

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“…In parallel with our results, it has been shown in previous studies that 5-FU application decreases the number of primordial and primary follicles and increases the number of atretic follicles. [6,45] Treatments with SLB reversed 5-FU-induced ovarian injury and follicular reserve parameters. Similar to our findings, Yildirim et al reported that SLY protects ovarian tissue against streptozotocin-induced injury by decreasing the levels of stromal degeneration, follicular degeneration and stromal fibrosis.…”

Section: Discussionmentioning

confidence: 94%

The therapeutic effect of silibinin against 5‐fluorouracil‐induced ovarian toxicity in rats

Demir

Menteşe

Kucuk

et al. 2023

J Biochem & Molecular Tox

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Abstract5‐Fluorouracil (5‐FU) is a fluoropyrimidine group antineoplastic drug with antimetabolite properties and ovotoxicity is one of the most important side effects. Silibinin (SLB) is a natural compound that is used worldwide and stands out with its antioxidant and anti‐inflammatory properties. The aim of this study was to evaluate the therapeutic effect of SLB in 5‐FU‐induced ovototoxicity using biochemical and histological analysis. This study was carried out in five main groups containing six rats in each group: control, SLB (5 mg/kg), 5‐FU (100 mg/kg), 5‐FU + SLB (2.5 mg/kg), and 5‐FU + SLB (5 mg/kg). The levels of ovarian malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), superoxide dismutase (SOD), catalase (CAT), 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), tumor necrosis factor‐alpha (TNF‐α), myeloperoxidase (MPO), and caspase‐3 were determined using spectrophotometric methods. Hematoxylin and eosin staining method was employed for histopathological examination. MDA, TOS, 8‐OHdG, TNF‐α, MPO, and caspase‐3 levels in 5‐FU group were significantly increased compared with the control group, while the levels of TAS, SOD, and CAT were decreased (p < 0.05). SLB treatments statistically significantly restored this damage in a dose‐dependent manner (p < 0.05). Although vascular congestion, edema, hemorrhage, follicular degeneration, and leukocyte infiltration were significantly higher in the 5‐FU group compared with the control group, SLB treatments also statistically significantly restored these damages (p < 0.05). In conclusion, SLB has a therapeutic effect on the ovarian damage induced by 5‐FU via decreasing the levels of oxidative stress, inflammation, and apoptosis. It may be helpful to consider the usefulness of SLB as an adjuvant therapy to counteract the side effects of chemotherapy.

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“…When young C57BL/6J female mice were injected with 5-FU, secondary follicles were lost totally (Ref. 47 ). Furthermore, genes involved in apoptosis and Wnt signalling pathways were significantly up-regulated when ovaries from young mice were cultured in vitro with 5-FU (Ref.…”

Section: Adverse Effects Of 5-fu On Female Reproductionmentioning

confidence: 99%

“…Furthermore, genes involved in apoptosis and Wnt signalling pathways were significantly up-regulated when ovaries from young mice were cultured in vitro with 5-FU (Ref. 47 ). In adult mice, administration of 5-FU-induced atresia of secondary and antral follicles, and profoundly reduced corpus luteum counts, leading to a decreased ovarian volume (Refs 48 , 49 ).…”

Section: Adverse Effects Of 5-fu On Female Reproductionmentioning

confidence: 99%

Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans

Naren

Guo

Bai

et al. 2022

Expert Rev. Mol. Med.

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Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and clinicians. 5-Fluorouracil (5-FU) has been widely used as a chemotherapeutic agent in the clinical treatment of various cancers, but several studies showed its adverse effects on reproduction. Reproductive toxicity of 5-FU often associates with developmental block, malformation and ovarian damage in the females. In males, 5-FU administration alters the morphology of sexual organs, the levels of reproductive endocrine hormones and the progression of spermatogenesis, ultimately reducing sperm numbers. Mechanistically, 5-FU exerts its effect through incorporating the active metabolites into nucleic acids directly, or inhibiting thymidylate synthase to disrupt the function of DNA and RNA, leading to profound effects on cellular metabolism and viability. However, some studies suggested that the toxicity of 5-FU on reproduction is reversible and certain drugs used in combination with 5-FU during chemotherapy could protect reproductive systems from 5-FU damage both in females and males. Herein, we summarise the recent findings and discuss underlying mechanisms of the 5-FU-induced reproductive toxicity, providing a reference for future research and clinical treatments.

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5-Fluorouracil disrupts ovarian preantral follicles in young C57BL6J mice

Cited by 12 publications

References 37 publications

5-Fluorouracil-induced toxicity in both male and female reproductive systems: A narrative review

5-Fluorouracil-induced toxicity in both male and female reproductive systems: A narrative review

The therapeutic effect of silibinin against 5‐fluorouracil‐induced ovarian toxicity in rats

Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans

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